Nephrology

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

rpizzi@frontlinemedcom.com

On Twitter @richpizzi

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

rpizzi@frontlinemedcom.com

On Twitter @richpizzi

All kidney transplant recipients with abnormal liver function test results should be tested for hepatitis E virus RNA, according to a recent finding by French investigators.

Hepatitis E virus (HEV) is most often transmitted through the fecal-oral route in contaminated drinking water or food, but it also can be transmitted by blood and blood products. A research letter from Dr. Vincent Mallett of the Université Paris Descartes Sorbonne Paris Cité and colleagues published in Annals of Internal Medicine reported a case of HEV transmission to a kidney transplant recipient through plasma exchange.

CDC/Wikimedia Commons/Public Domain

Nineteen months after a 48-year-old patient received a kidney transplant, Dr. Mallett and his colleagues detected HEV RNA genotype 3f in the patient’s blood based on sequencing, and the patient tested positive for anti-HEV IgG and negative for anti-HEV IgM. The physicians confirmed that the patient had been infected for more than 1 year by finding HEV RNA in a frozen plasma sample drawn 5 months after transplantation. The kidney donor had tested negative for HEV RNA, and the patient’s stored blood samples tested negative for HEV markers before transplantation.

The investigators said that the method of HEV transmission remained undetermined until the investigators tested for HEV RNA in stored samples of all 18 blood products used during the peritransplantation period. From a single sample of fresh frozen plasma from a donor who had tested negative on multiple occasions for hepatitis C virus, HIV-1 and -2, and hepatitis B virus before the plasma was used, the researchers recovered a strain of HEV identical to the one infecting the patient. This plasma had been used during a plasma exchange for treating acute humoral rejection.

Plasma exchange typically involves the removal of 2-5 L of plasma several times a week, Dr. Mallett and associates said, which often is replaced with donor plasma. If replacement involves 2.5 L (10 bags) of donor plasma, which is a typical amount, then the risk for HEV is 10 times greater than the risk involving a single bag.

“In some circumstances, replacement procedures use plasma that has been pooled from many donors and then treated with solvents and detergents to inactivate infectious agents,” they wrote. “However, HEV is not affected by this treatment, so pooling multiplies the risk for infection.”

On the basis of these findings, the coauthors said that “all kidney transplant recipients with abnormal liver function test results, especially those treated with plasma exchange, should be tested for HEV RNA.”

Read the letter in Annals of Internal Medicine (2016 Mar 1. doi: 10.7326/L15-0502).

rpizzi@frontlinemedcom.com

On Twitter @richpizzi

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, prin0088@umn.edu.

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, prin0088@umn.edu.

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, prin0088@umn.edu.

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.¹ Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.² Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).²

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.³ In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.⁴

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.⁵ For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.⁶

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.³ It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
3. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care. 2004;27(1):66-69.
4. American Diabetes Association. Standards of medical care in diabetes­­—2015: summary of revisions. Diabetes Care. 2015;38(suppl):S4.
5. Park YW, Allison DB, Heymsfield SB, Gallagher D. Larger amounts of visceral adipose tissue in Asian Americans. Obes Res. 2001;9(7):381-387.
6. Rao G, Powell-Wiley TM, Ancheta I, et al; American Heart Association Obesity Committee of the Council on Lifestyle and Cardiometabolic Health. Identification of obesity and cardiovascular risk in ethnically and racially diverse populations: a scientific statement from the American Heart Association. Circulation. 2015;132(5):457-472.

Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.¹ Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.² Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).²

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.³ In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.⁴

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.⁵ For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.⁶

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.³ It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
3. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care. 2004;27(1):66-69.
4. American Diabetes Association. Standards of medical care in diabetes­­—2015: summary of revisions. Diabetes Care. 2015;38(suppl):S4.
5. Park YW, Allison DB, Heymsfield SB, Gallagher D. Larger amounts of visceral adipose tissue in Asian Americans. Obes Res. 2001;9(7):381-387.
6. Rao G, Powell-Wiley TM, Ancheta I, et al; American Heart Association Obesity Committee of the Council on Lifestyle and Cardiometabolic Health. Identification of obesity and cardiovascular risk in ethnically and racially diverse populations: a scientific statement from the American Heart Association. Circulation. 2015;132(5):457-472.

Q) Recently, I have seen four or five Asian-American patients with really bad kidney function. All of them were thin but had diabetes, hypertension, and a serum creatinine > 2 mg/dL. The kidney disease was a shock to them (and me). Am I missing something here?

Diabetes and hypertension are the most common causes of chronic kidney disease (CKD), with diabetes slightly edging out hypertension for the number 1 slot.¹ Although Asian Americans have a tendency toward a lower body mass index (BMI) than the general population, this does not exclude them from developing diabetes or hypertension.

About 20% (1 in 5) of Asian-American adults have both diabetes and hypertension. In fact, Asian Americans with a BMI ≤ 25 often develop type 2 diabetes (T2DM), which is a direct contrast to other racial and ethnic groups in whom T2DM is more prevalent at higher BMIs. The current thinking is that Asian Americans have a higher percentage of body fat at lower BMIs.² Among racial and ethnic subgroups, Asian Americans have the highest prevalence of undiagnosed diabetes (close to 50%).²

In 2004, after adjusting for lower BMI, McNeely and Boyko found that the incidence of diabetes in Asian Americans was 60% higher than in the Hispanic population.³ In 2015, this influenced the American Diabetes Association (ADA) to change its recommendation for diabetes screening in Asian Americans, lowering the threshold to a BMI of 23.⁴

Since abdominal or visceral fat is a risk factor for heart disease, hypertension, and diabetes, and it appears that the Asian-American population carries excess fat centrally, this population is also at risk for cardiac disease.⁵ For that reason, in this population, the American Heart Association recommends measuring waist circumference to screen for hidden abdominal adiposity.⁶

Thus, the trend you are seeing in your patient population is really only the tip of the iceberg. The Asian-American population is the fastest-growing ethnic group in the United States.³ It’s time to update your diabetes screening protocols. —SWM

Shushanne Wynter-Minott, DNP, FNP-BC
Memorial Healthcare System, Hollywood, Florida

References
1. CDC. National Chronic Kidney Disease Fact Sheet, 2014. www.cdc.gov/diabetes/pubs/pdf/kidney_Factsheet.pdf. Accessed February 3, 2016.
2. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
3. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care. 2004;27(1):66-69.
4. American Diabetes Association. Standards of medical care in diabetes­­—2015: summary of revisions. Diabetes Care. 2015;38(suppl):S4.
5. Park YW, Allison DB, Heymsfield SB, Gallagher D. Larger amounts of visceral adipose tissue in Asian Americans. Obes Res. 2001;9(7):381-387.
6. Rao G, Powell-Wiley TM, Ancheta I, et al; American Heart Association Obesity Committee of the Council on Lifestyle and Cardiometabolic Health. Identification of obesity and cardiovascular risk in ethnically and racially diverse populations: a scientific statement from the American Heart Association. Circulation. 2015;132(5):457-472.

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

Q) We were operating on a 58-year-old woman for a subcapital fracture of her right hip. The orthopedist mentioned that the patient had kidney disease and that it probably caused her hip fracture. I didn’t know kidney disease causes hip fractures. Is this true?

Evolving evidence suggests an association between diminishing renal function and increased risk for fracture. Here’s a look at the available data:

Atherosclerosis Risk in Communities (ARIC) Study. During a median 13 years’ follow-up of 10,955 community-based older adults, investigators identified higher albuminuria level and decreased creatinine-based estimated glomerular filtration rate (eGFR) as significant risk factors for fracture. Other risk factors included older age, race (Caucasians had the highest incidence), and sex (women were more likely than men to sustain a fracture). A nonlinear relationship was observed between eGFR and fracture diagnosis, with a graded association between fracture and albuminuria level.⁷

Cardiovascular Health Study. In this study of 4,699 older community-based adults, kidney function was assessed by measurement of serum cystatin C. During a mean follow-up of 7.1 years, higher cystatin C levels correlated to a higher risk for hip fracture in both sexes. In women, there was a significant association between diminishing renal function and hip fracture status: Those with lower eGFRs had a higher incidence of fractures. There was a similar magnitude of association among men, but it was not ­significant.⁸

Health, Aging and Body Composite Study. In 2,754 older adults, an association was noted between decreased femoral neck bone mineral density (BMD) and increased risk for fracture in those with and without CKD stage 3 to 5. With a concurrent diagnosis of osteoporosis, there was a 110% increased risk for nonspinal fracture in those with CKD and a 63% increased risk for those without CKD.⁹ In a study of 485 adult hemodialysis patients, decreased total hip and femoral neck BMD was associated with an increased risk for fractures in women with parathyroid hormone levels on the lower range of acceptable in this population (intact parathyroid hormone level [IPTH] < 204 pg/mL) and for spinal fractures in both genders.¹⁰

Bone changes associated with deterioration of renal function are complex and multifactorial. Human bone is a composite of protein fused to mineral crystals, primarily calcium and phosphate. Bone is dynamic, being broken down and rebuilt throughout adulthood, with the skeleton almost completely rebuilt every 10 years.¹¹

CKD–mineral and bone disorder (CKD–MBD) is a systemic disorder seen in those with kidney disease that affects bone and mineral metabolism. Its manifestations include abnormalities in the bone, calcifications of vascular and/or soft tissues, abnormal vitamin D metabolism, and disruptions in the phosphorus, calcium, and parathyroid hormone levels. These components, and the severity of the condition, vary by stage of CKD. One component of CKD–MBD, renal osteodystrophy, is associated with changes in bone morphology and is definitively diagnosed by bone biopsy.¹²

Care of these patients is complex and can be compounded by osteoporosis and/or loss of bone strength. Osteoporosis, like CKD, increases in incidence with age and is associated with fracture risk.¹¹

While useful for diagnosing osteoporosis and predicting fracture risk in the general population, dual-energy X-ray densitometry (DXA) has not been recommended in those with CKD due to the type of bone changes that occur with diminished renal function.¹² However, evolving evidence regarding use of DXA in these patients prompted a Kidney Disease: Improving Global Outcomes (KDIGO) “controversies” conference to recommend reexamination of the evidence regarding this recommendation.¹³ KDIGO’s 2009 clinical practice guideline on CKD–MBD (http://kdigo.org/home/mineral-bone-disorder/) can be of benefit in the assessment and care of affected patients. —CS

Cindy Smith, DNP, APRN, CNN-NP, FNP-BC
Renal Consultants, PLLC, South Charleston, West Virgina

References
7. Daya NR, Voskertchian A, Schneider ALC, et al. Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2016;67(2):218-226.
8. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18:282-286.
9. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136.
10. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients­­—a single-center cohort study. Nephrol Dial Transplant. 2012;27:345-351.
11. Office of the Surgeon General (US). Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
13. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87(3):502-528.

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LOS ANGELES – The equipoise between carotid stenting and endarterectomy received a further boost in 10-year results from the landmark Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) that compared the two options head-to-head.

Reported the day after results from another big trial that pitted carotid stenting against surgery, the Asymptomatic Carotid Trial (ACT I), the new long-term results from the CREST study mean that deciding among the options relies largely on patient preference although individual clinical characteristics might favor one approach or the other, experts said.

Mitchel L. Zoler/Frontline Medical News

The big remaining unknown and wild card is whether doing no procedural intervention at all and relying entirely on optimal, contemporary medical treatment works just as well as endarterectomy or carotid stenting. The role for stand-alone medical therapy against carotid surgery or stenting (on top of medical therapy) is currently undergoing a formal, direct comparison in the randomized Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2).

Taking the 5-year outcome results from ACT I and the 10-year outcome results from CREST both into account, “we now have a lot of evidence that both carotid stenting and surgery are safe and durable. The results support both options” for either patients with symptomatic carotid artery stenosis or asymptomatic patients with carotid stenosis as extensive as in the patients enrolled in these trials, said Dr. Thomas G. Brott at the International Stroke Conference.

“In routine practice, we lay out the options of endarterectomy, carotid stenting, or no intervention with just medical treatment to patients and let them decide,” noted Dr. Brott, professor of neurology and director of research at the Mayo Clinic in Jacksonville, Fla.

CREST randomized 2,502 symptomatic or asymptomatic patients with significant carotid stenosis during 2000-2008 at 117 U.S. and Canadian centers. From this group, 1,607 consented and were available for long-term follow-up, done at a median of 7.4 years and as long as 10 years after follow-up.

The study’s primary, long-term endpoint was stroke, MI, or death during the periprocedural period (30 days after treatment or 36 days after enrollment depending on when the procedural intervention occurred) plus the rate of ipsilateral stroke during up to 10 years of follow-up. This combined endpoint occurred in 10% of the patients who underwent endarterectomy and in 12% of those who had stenting, a difference that was not statistically significant, Dr. Brott reported. Concurrent with his presentation at the meeting, sponsored by the American Heart Association, the results also were published online (N Engl J Med. 2016 Feb 18. doi: 10.1056/NEJMoa1505215).

The results included a secondary endpoint that showed a significant benefit for endarterectomy. The tally of periprocedural strokes or deaths plus ipsilateral strokes during 10-year follow-up was 8% for the surgical group and 11% for those who received a stent, a 37% excess hazard with stenting.

Dr. Brott attributed this secondary difference between the two arms of the study to a statistically significant excess of stroke or death during the periprocedural period in the patients treated by stenting, and more specifically an excess of strokes. The rate of total periprocedural strokes was 4% with stenting and 2% with endarterectomy, a statistically significant difference. Although an embolic protection device was used “when feasible” during stenting, this protection can be fallible, Dr. Brott noted. In contrast, the results from the ACT I trial showed no statistically significant difference in the rate of periprocedural total strokes between the stented and endarterectomy patients.

Dr. Brott had no relevant disclosures. The CREST trial received partial funding from Abbott Vascular.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

CHICAGO – Surgeons can expect to see more abdominal organ transplant recipients presenting with aortic aneurysms, as transplant survival rates increase along with the age of organ donors and recipients.

“The consensus is that abdominal aortic aneurysms (AAAs) have a more aggressive course post-transplant and within that context, probably need to be managed more aggressively,” Dr. Michael J. Englesbe of the University of Michigan, Ann Arbor said at the annual Northwestern Vascular Symposium.

Some 270,000 Americans are living with a functioning liver or kidney graft, and their average age has risen from 47 years to 57 years over the last decade.

Though the data isn’t great, it’s hypothesized that the immunosuppression prerequisite for successful organ transplantation promotes the progression of atherosclerosis and aneurysm growth in transplant patients, he said.

New-onset diabetes, hyperlipidemia, and hypertension are all common post-transplant due to immunosuppression therapy. Aortic aneurysms are also reported to rupture at smaller sizes in transplant recipients.

Intriguingly, the opposite effect has been observed in experimental animal models, where immunosuppression with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors has been shown to stabilize atherosclerotic lesions and inhibit aneurysm expansion.

The reason for this disparity is unclear, but immunosuppressants likely augment other cardiovascular comorbidities such as hypertension and atherosclerosis and this may trump their anti-inflammatory effects and lead to worse aneurysm disease and faster expansion in humans, Dr. Englesbe speculated in an interview.

As for when aneurysms should be fixed, kidney transplant candidates should undergo AAA repair prior to transplantation since the risk of renal complications after aneurysm repair puts the allograft at risk, Dr. Englesbe advised. Either an open or endovascular approach can be used.

In liver transplant candidates, elective AAA repair should be avoided if possible and is contraindicated if any signs of hepatic decompensation are present such as muscle wasting, ascites, platelet count less than 50 x 10⁹/L, or encephalopathy. For well-compensated cirrhotic patients, endovascular repair is best.

One of the most important considerations for any solid-organ transplant patient undergoing aneurysm repair is perioperative management of immunosuppression, Dr. Englesbe stressed.

Transplant patients are maintained on oral calcineurin inhibitors such as cyclosporine and tacrolimus (Prograf) throughout the perioperative period to prevent organ rejection, but these drugs have nephrotoxic effects. About 10% of recipients, typically the sicker patients, will be switched to mTOR inhibitors such as everolimus (Afinitor) and sirolumus (Rapamune) as a kidney-sparing alternative.

“Part of the mechanism of these [mTOR] drugs is that they really affect fibroblast functioning, so patients that are on these medications, their wound will fall apart and they will invariably get a hernia,” Dr. Englesbe said. “You have to stop them upwards of about 6 weeks before surgical intervention, and I think this is also true for many endografts.”

He highlighted a case in which an mTOR inhibitor was started three months after liver transplant due to renal dysfunction in a patient who was fully healed, but within three weeks, “her wound fell apart, completely fell apart.” She developed several seromas underneath her incision, one of which became infected and took months to close.

“The transplant professionals – your nephrologists, your cardiologists – aren’t going to know this fact, but as a transplant surgeon it’s usually the first question we’re going to ask with respect to any post-transplant patient we’re going to operate on, so it’s something to keep in mind,” Dr. Englesbe said.

Another take-home message was the importance of maintaining kidney function in kidney recipients presenting with aortic aneurysm, as mortality in these patients is about 10-fold higher once the kidney fails, he said. A recent study reported that AAAs are significantly more common in kidney than liver transplant recipients (29.6% vs. 11.4%; P = .02), despite a similar prevalence for any aneurysm (4%) in both groups (J Vasc Surg. 2014 Mar;59;594-8).

When kidney recipients present, preoperative imaging of the aorta from the aneurysm to the kidney allograft is mandatory, he said. Endovascular repair is preferred, whenever possible.

The renal graft is typically sewn to the external iliac artery 3 cm to 10 cm from the bifurcation of the external and internal iliac arteries. Because of this, repair is challenging when aneurysmal disease involves the iliac artery, Dr. Englesbe observed. Aneurysmal dilation is less common in the external iliac, but stenting an iliac aneurysm can still compromise inflow to the transplanted kidney.

Several surgical techniques including axillofemoral bypass, aortofemoral shunt, or extracorporeal circuit have been reported to preserve renal function during open AAA repair in renal transplant recipients. These techniques are not without their own risk of complications and should be avoided in patients with low creatinine, but are appropriate in patients with marginal or impaired renal function, according to Dr. Englesbe, who reported having no relevant disclosures.

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

pwendling@frontlinemedcom.com

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

pwendling@frontlinemedcom.com

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

pwendling@frontlinemedcom.com

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. A computed tomography scan of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine outpatient care includes oral hydration, antiemetics, and pain medications. Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple randomized controlled trials (RCTs) suggest that an alpha-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk of bias.

Treatment with tamsulosin or nifedipine provided no benefits in terms of rate of kidney stone passage, time to passage, analgesic use, or pain.

STUDY SUMMARY: MET doesn’t increase the rate of stone passage

The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 years with a single ureteric stone measuring ≤10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones >10 mm typically require surgery or lithotripsy.)

In this RCT, 1167 adults were randomized to take tamsulosin 0.4 mg/d, nifedipine 30 mg/d, or placebo for 4 weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At 4 weeks, 1136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤5 mm vs >5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21%) of participants. The mean days to stone passage was 15.9 (n=84) for placebo, 16.5 (n=79) for tamsulosin and 16.2 (n=74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, -2.9 to 3.9; P=.78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first 4 weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, -1.6 to 2.8; P=.45).

There was no difference between groups in the VAS pain score at 4 weeks. The MET vs placebo difference was 0.0 (95% CI, -0.4 to 0.4; P=.96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT'S NEW: This large RCT contradicts results from previous meta-analyses

The SUSPEND study is the first large, multi­center RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, multicenter, well-designed RCT.⁹

CAVEATS: This trial included fewer women than previous studies

The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

lfranki@frontlinemedcom.com

Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

lfranki@frontlinemedcom.com

Incidence of newly acquired hepatitis C virus has increased recently in patients undergoing hemodialysis, according to a health advisory from the Centers for Disease Control and Prevention.

In 2014 and 2015, 36 cases of HCV infection were reported to the CDC from 19 clinics in eight states. While investigation is ongoing, HCV transmission between patients has been confirmed in at least nine facilities, and in several facilities, lapses in infection control were also identified. Better screening and awareness of HCV infection potential may also play a role in the increased disease incidence.

The CDC recommends that dialysis facilities assess current infection control practices, environmental cleaning, and disinfection practices to evaluate adherence to standards, address any gaps, screen patients for HCV, and to report all HCV infections to the CDC promptly.

“Dialysis facilities should actively assess and continuously improve their infection control, environmental cleaning and disinfection, and HCV screening practices, whether or not they are aware of infections in their clinic. Any case of new HCV infection in a patient undergoing hemodialysis is likely to be a health care–associated infection and should be reported to public health authorities in a timely manner,” the CDC said

Find the full health advisory on the CDC website.

lfranki@frontlinemedcom.com