Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient.

INTRODUCTION: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. METHODS: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. RESULTS: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. DISCUSSION/CONCLUSION: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA - resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Prevalence, incidence, and risk factors for hepatitis C virus infection in hemodialysis patients.

Hepatitis C virus (HCV) infection is common in dialysis patients and is associated with increased morbidity and mortality. We used the Dialysis Outcomes and Practice Patterns Study (DOPPS, 1996-2015) to assess trends in the prevalence, incidence, and risk factors for HCV infection as defined by a documented diagnosis or antibody positivity. Among prevalent hemodialysis patients, HCV prevalence was nearly 10% in 2012-2015. Prevalence ranged from 4% in Belgium to as high as 20% in the Middle East, with intermediate prevalence in China, Japan, Italy, Spain, and Russia. HCV prevalence decreased over time in most countries participating in more than one phase of DOPPS, and prevalence was around 5% among patients who had recently (<4 months) initiated dialysis. The incidence of HCV infection decreased from 2.9 to 1.2 per 100 patient-years in countries participating in the initial phase of DOPPS. Although most units reported no seroconversions, 10% of units experienced 3 or more cases over a median of 1.1 years. High HCV prevalence in the hemodialysis unit was a powerful facility-level risk factor for seroconversion, but the use of isolation stations for HCV-positive patients was not associated with significantly lower seroconversion rates. Overall, despite a trend toward lower HCV prevalence among hemodialysis patients, the prevalence of HCV infection remains higher than in the general population. Combined with a high prevalence of HCV infection among patients with Stage 5 CKD, high rates of HCV seroconversion in a subset of hemodialysis units may contribute to this disparity.

Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality.

Intravenous (IV) iron is required for optimal management of anemia in the majority of hemodialysis (HD) patients. While IV iron prescription has increased over time, the best dosing strategy is unknown and any effect of IV iron on survival is unclear. Here we used adjusted Cox regression to analyze associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the Dialysis Outcomes and Practice Patterns Study. The primary exposure was total prescribed IV iron dose over the first 4 months in the study, expressed as an average dose/month. Compared with 100-199 mg/month (the most common dose range), case-mix-adjusted mortality was similar for the 0, 1-99, and 200-299 mg/month categories but significantly higher for the 300-399 mg/month (HR of 1.13, 95% CI of 1.00-1.27) and 400 mg/month or more (HR of 1.18, 95% CI of 1.07-1.30) groups. Convergent validity was proved by an instrumental variable analysis, using HD facility as the instrument, and by an analysis expressing IV iron dose/kg body weight. Associations with cause-specific mortality (cardiovascular, infectious, and other) were generally similar to those for all-cause mortality. The hospitalization risk was elevated among patients receiving 300 mg/month or more compared with 100-199 mg/month (HR of 1.12, 95% CI of 1.07-1.18). In light of these associations, a well-powered clinical trial to evaluate the safety of different IV iron-dosing strategies in HD patients is urgently needed.

Potassium-binding resins: Associations with serum chemistries and interdialytic weight gain in hemodialysis patients.

BACKGROUND: Although potassium-binding sodium-based resins (K resins) have been prescribed to treat hyperkalemia for 50 years, there have been no large studies of their effects among hemodialysis (HD) patients. METHODS: Data from 11,409 patients in the Dialysis Outcomes and Practice Patterns Study in Belgium, Canada, France, Italy, and Sweden (nations where ≥5% of patients were prescribed a sodium- based K resin; seven other countries had <5% use) between 2002 and 2011 were analyzed. Linear mixed models examined associations between K resin use and interdialytic weight gain (IDWG) and serum electrolyte concentrations. Mortality was analyzed using Cox regression. An instrumental variable approach was used to partially account for unmeasured confounders. RESULTS: The K resin prescription rate was 20% overall. As hypothesized, patients prescribed a K resin had greater IDWG and higher serum bicarbonate, phosphorus, and sodium (but not calcium) concentrations. Patients prescribed a K resin had higher serum K levels, but serum K levels were lower in an instrumental variable analysis limiting treatment by indication bias. K resin use was not associated with mortality risk. CONCLUSION: We report the first large study of K resin use and associated laboratory and clinical outcomes in HD patients. The prescription rate of K resins varied dramatically by country and dialysis center. The results suggest that K resin use may effectively lower serum K, although at the expense of somewhat higher phosphatemia and greater IDWG, and had no clear association with mortality. Further study is warranted to elucidate the optimal role for K resins in modern dialysis care.

Hepatitis C infection is very rarely treated among hemodialysis patients.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with increased mortality among hemodialysis (HD) patients. Guidelines from Kidney Disease: Improving Global Outcomes recommend that infected HD patients awaiting renal transplantation be treated for HCV and that clinicians decide whether to treat other infected patients on a case-by-case basis. We evaluated the extent and outcome of HCV therapy among HD patients. METHODS: The Dialysis Outcomes and Practice Patterns Study is an observational study; 49,762 HD patients in 12 nations enrolled between 1996 and 2011. We reviewed HCV status, use of interferon or ribavirin, and survival over a median 1.4 years per study phase. RESULTS: 4,735 patients (9.5%) were HCV+. Only 48 (1.0%) of the 4,589 HCV+ patients with prescription data were receiving antiviral medication. Among the subset of 617 HCV+ patients also known to be on a waiting list for renal transplantation, only 3.7% were receiving treatment. After restricting to HCV+ patients with overlapping propensity for antiviral treatment, 4 (9.5%) of 42 treated patients and 638 (21.0%) of 3,037 untreated patients died. The hazard ratio for adjusted mortality comparing treated patients with untreated patients was 0.47 (95% CI, 0.17-1.26). CONCLUSIONS: HD patients with hepatitis C infection very rarely receive antiviral therapy. Increased intervention might prolong survival for some patients and in particular might improve the prospects for those awaiting renal transplantation.

Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. METHODS: Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. RESULTS: IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥ 800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. CONCLUSIONS: IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.

High-dose intravenous epoetin does not increase blood pressure in critically ill patients with acute kidney injury.

AIMS: Treatment of renal anemia with erythropoietic stimulating agents sometimes increases blood pressure. It is uncertain whether this is due to direct vasoconstriction and/or increased red blood cell mass. MATERIALS AND METHODS: We conducted a post-hoc analysis of 160 critically ill patients in the EARLYARF trial with elevated urinary γ-glutamyltranspeptidase and alkaline phosphatase, indicating acute kidney injury. Patients received 2 doses of intravenous (i.v.) epoetin (500 U/kg), 24 hours apart, or placebo, in a randomized, double-blind study design. Hourly intra-arterial mean arterial pressure (MAP), and norepinephrine equivalent dose (NED: determined using equipotency conversion factors for doses of epinephrine, vasopressin, phenlyephrine, or dopamine) were extracted from clinical records. The differences between baseline and maximum MAP and NED (ΔMAP and ΔNED) over 4, 24, 72-hour, and 30-day periods following study drug administration were compared between groups. RESULTS: At baseline, MAP was 78 ± 14 mmHg in the epoetin group and 81 ± 15 mmHg in the placebo group (p = 0.22). There were no differences between groups in ΔMAP (6 ± 14 versus 7 ± 14 mmHg; p = 0.53), in ΔNED, or in ΔMAP adjusted for ΔNED at 4 hours, or at any time points. A subgroup analysis of only those patients not requiring vasopressor support (n = 71) also showed no differences between epoetin and placebo for all outcomes. CONCLUSION: We concluded that intravenous high dose epoetin does not acutely increase blood pressure, suggesting no acute vasoconstrictor effect in this setting.

Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.

KDOQI practice guidelines recommend predialysis blood pressure <140/90 mm Hg; however, most prior studies had found elevated mortality with low, not high, systolic blood pressure. This is possibly due to unmeasured confounders affecting systolic blood pressure and mortality. To lessen this bias, we analyzed 24,525 patients by Cox regression models adjusted for patient and facility characteristics. Compared with predialysis systolic blood pressure of 130-159 mm Hg, mortality was 13% higher in facilities with 20% more patients at systolic blood pressure of 110-129 mm Hg and 16% higher in facilities with 20% more patients at systolic blood pressure of ≥160 mm Hg. For patient-level systolic blood pressure, mortality was elevated at low (<130 mm Hg), not high (≥180 mm Hg), systolic blood pressure. For predialysis diastolic blood pressure, mortality was lowest at 60-99 mm Hg, a wide range implying less chance to improve outcomes. Higher mortality at systolic blood pressure of <130 mm Hg is consistent with prior studies and may be due to excessive blood pressure lowering during dialysis. The lowest risk facility systolic blood pressure of 130-159 mm Hg indicates this range may be optimal, but may have been influenced by unmeasured facility practices. While additional study is needed, our findings contrast with KDOQI blood pressure targets, and provide guidance on optimal blood pressure range in the absence of definitive clinical trial data.

Naturally occurring higher hemoglobin concentration does not increase mortality among hemodialysis patients.

A small percentage of hemodialysis patients maintain higher hemoglobin concentrations without transfusion or erythropoietic therapy. Because uncertainty exists regarding the effects of higher hemoglobin concentration on mortality and quality of life among hemodialysis patients, studying this group of patients with sufficient endogenous erythropoietin may provide additional insights. The prospective, observational Dialysis Outcomes and Practice Patterns Study provides an opportunity to investigate this group. Among 29,796 patients in 12 nations, 545 (1.8%) maintained hemoglobin concentrations >12 g/dl for 4 months without erythropoietic support. This subset tended to be male, to have a longer duration of end-stage renal disease, and to not dialyze via a catheter. Cystic disease as the underlying cause of renal failure was over-represented in this group but was present in only 25%. Lung disease, smoking, and cardiovascular disease were associated with increased likelihood of naturally higher hemoglobin concentration. Quality-of-life scores were not higher among this subset compared with the other patients. Unadjusted mortality risk for patients with hemoglobin >12 g/dl and no erythropoietic therapy was lower than for the other patients, but after thorough adjustment for case mix, there was no difference between groups (relative risk, 0.98; 95% CI 0.80 to 1.19). These data show that naturally occurring hemoglobin concentration >12 g/dl does not associate with increased mortality among hemodialysis patients.

Massive adrenocortical carcinoma presenting as peripheral edema: a case report.

BACKGROUND: Adrenocortical carcinoma is a rare, but potentially lethal, malignancy that is usually detected as an incidental finding on abdominal imaging studies or owing to hormonal complications. This report recounts an unusual presentation with leg edema due to compression of the inferior vena cava. The dearth of proven effective treatment is also addressed. CASE PRESENTATION: A 65-year-old White male physician presented with severe, bilateral pitting edema that extended from the toes to the thighs. It progressed over several months. He also experienced paroxysmal dyspnea. Evaluation of cardiac, hepatic, and renal function failed to determine a cause. Computed tomography revealed a tumor above the right kidney, with compression of the intrahepatic inferior vena cava and upstream distension. Serum cortisol and dehydroepiandrosterone sulfate concentrations were elevated, 24-hour urinary cortisol level was elevated, and serum adrenocorticotropic hormone and testosterone concentrations were suppressed. A 27-cm tumor, the right lobe of the liver, the right kidney, and 26 lymph nodes were resected. Histological study confirmed the diagnosis of adrenocortical carcinoma. Ki67 proliferation index was 26.7% (worse prognosis associated with index > 10%). Lymph nodes were negative for malignancy, but a separate 2.7-cm tumor was found near the renal hilum. Adjuvant mitotane chemotherapy was prescribed. Serum testosterone concentration returned to normal. High-dose hydrocortisone administration was needed because of adrenal suppression and CYP 3A4 induction by mitotane. CONCLUSION: Imaging of the abdomen and pelvis should be conducted in cases of unexplained leg edema. In this case, a large adrenal cancer compressed the vena cava. Iron deficiency followed resection of the large tumor. Advanced stages of adrenocortical carcinoma are associated with poor prognosis. Mitotane chemotherapy is a standard but unproven adjuvant treatment that is associated with many complications, and its induction of hepatic CYP 3A4 enzymes necessitates adjustment of other medications.

Hemodialysis vascular access training and practices are key to improved access outcomes.

Recognizing that autologous arteriovenous fistula use was associated with improved outcomes in hemodialysis patients, the 1997 Dialysis Outcomes Quality Initiative (DOQI) vascular access practice guidelines from the National Kidney Foundation stressed fistulas as the optimal means of dialysis vascular access. In the United States, this emphasis has continued with the Fistula First Breakthrough Initiative. Much of the data supporting fistulas for dialysis access are derived from longitudinal cohorts, including the Dialysis Outcomes and Practice Patterns Study (DOPPS), dialysis provider databases, and other sources. This article reviews major findings from these data sources, focusing on specific practices and characteristics associated with greater arteriovenous fistula use in dialysis facilities worldwide. Important and often overlooked characteristics that are discussed in detail include specific preferences of dialysis staff regarding access type and the emphasis placed on fistula primacy and the number of fistulas created during surgical training. For example, in the DOPPS, the risk of initial fistula failure was 34% lower when fistulas were placed by surgeons who had created at least 25 fistulas during training (P = 0.002). It is imperative that dialysis clinicians advocate actively for specific dialysis access types on behalf of individual patients. Vascular surgery teaching programs must supervise adequate numbers of fistula procedures for every trainee.

Independent and joint associations of nutritional status indicators with mortality risk among chronic hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

OBJECTIVE: To consider the Kidney Disease Outcomes Quality Initiative recommendation of using multiple nutritional measurements for patients on maintenance dialysis, we explored data for independent and joint associations of nutritional indicators with mortality risk among maintenance hemodialysis patients treated in 12 countries. SETTING: Dialysis units in seven European countries, the United States, Canada, Australia, New Zealand, and Japan. MAIN OUTCOME: Mortality risk. METHODS: We conducted a prospective cohort study of 40,950 patients from phases I to III of the Dialysis Outcomes and Practice Patterns Study (1996-2008). Independent and joint effects (interactions) of nutritional indicators (serum creatinine, serum albumin, normalized protein catabolic rate, body mass index [BMI]) on mortality risk were assessed by Cox regression with adjustments for demographics, years on dialysis, and comorbidities. RESULTS: Important variations in nutritional indicators were seen by country and patient characteristics. Poorer nutritional status assessed by each indicator was independently associated with higher mortality risk across regions. Significant multiplicative interactions (each p < or = 0.01) between indicators were also observed. For example, by using patients with serum creatinine 7.5-10.5 mg/dL and BMI 21-25 kg/m(2) as referent, BMI <21 kg/m(2) was associated with lower mortality risk among patients with creatinine >10.5 mg/dL (relative risk = 0.68) but with higher mortality risk among those with creatinine <7.5 mg/dL (relative risk = 1.38). The association of lower albumin concentration with higher mortality risk was stronger for patients with lower BMI or lower creatinine. CONCLUSION: The joint effects of nutritional indicators on mortality indicate the need to use multiple measurements when assessing the nutritional status of hemodialysis patients.

Rosiglitazone is associated with mortality in chronic hemodialysis patients.

Recent studies have associated rosiglitazone, a thiazolidinedione drug, with adverse cardiovascular outcomes in the general population with diabetes. Using data from the Dialysis Outcomes and Practice Patterns Study in the United States, we examined cardiovascular hospitalization and mortality associated with prescription of rosiglitazone, compared with other oral hypoglycemic agents, among 2393 long-term hemodialysis patients who were followed for a median of 1.1 yr. We assessed mortality risk using Cox models in patient-level and dialysis facility-level analyses that used the facility proportion of patients on rosiglitazone as the predictor (instrumental variable approach) and adjusted the models for demographics, comorbid conditions, laboratory values, and achieved dialysis dosage. Compared with patients prescribed other oral hypoglycemic agents, patients prescribed rosiglitazone had significantly higher all-cause (hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.05 to 1.82) and cardiovascular (HR 1.59; 95% CI 1.14 to 2.22) mortality, and their adjusted HR for hospitalization with myocardial infarction was 3.5-fold higher (P = 0.02). We did not observe similar associations in a secondary analysis evaluating pioglitazone. By the instrumental variable approach, facilities with more than the median adjusted percentage (6.2%) of patients who had diabetes and were prescribed rosiglitazone had significantly higher all-cause mortality (HR 1.36; 95% CI 1.15 to 1.62) and cardiovascular mortality (HR 1.42; 95% CI 1.07 to 1.88) than facilities with less than the median expected percentage prescribed rosiglitazone. Our practice-based findings suggest significant associations of rosiglitazone use with higher cardiovascular and all-cause mortality among hemodialysis patients with diabetes.

The burden of amputation among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Hemodialysis patients are at increased risk of amputation, particularly those with diabetes. Limited data exist about the prevalence, incidence, risk factors for, and sequelae of amputation in hemodialysis patients. STUDY DESIGN: A prospective observational study of hemodialysis practices and outcomes. SETTING & PARTICIPANTS: Data from 29,838 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from 1996 to 2004 were analyzed. PREDICTOR/FACTOR: Demographic factors, comorbid conditions, laboratory values, years since end-stage renal disease onset, and currently prescribed medications at study enrollment. OUTCOME: Prior amputation at study enrollment by using logistic regression and amputation during follow-up by using Cox models. Amputation was ascertained from medical record review. RESULTS: There was a high prevalence (6%) and incidence (2.0 events/100 patient-years at risk) of amputation in hemodialysis patients; patients with diabetes had a more than 9 times greater incidence of new amputation. Wide variations among countries were observed in risk of amputation, with the lowest prevalence in Japan and the highest in Belgium, France, and Germany. Traditional cardiovascular risk factors, such as age, peripheral vascular disease, and smoking were predictive of amputation, as were such risk factors related to hemodialysis as altered mineral metabolism and years of hemodialysis therapy. In patients with diabetes, greater relative risks of amputation were observed in men, smokers, and those with other diabetic complications, anemia, and malnutrition. The relative risk of mortality after amputation was 1.54 (95% confidence interval, 1.41 to 1.68; P < 0.001) with a mean survival of 2.0 versus 3.8 years. LIMITATIONS: The database does not differentiate between types of amputations; some amputations may have concerned the upper limbs and could have been linked to ischemia related to vascular access. CONCLUSIONS: Amputation in hemodialysis patients is a very frequent event, particularly in patients with diabetes, and is associated with both traditional cardiovascular risk factors and factors linked to kidney failure treated by hemodialysis. Interventional trials are needed to reduce the burden of amputation.

The normal hematocrit cardiac trial revisited.

The Normal Hematocrit Cardiac Trial (NHCT) was the first large, randomized study of patients receiving hemodialysis to examine the outcomes of treating anemia to a target hematocrit range of 42 +/- 3% versus maintaining partial correction in a range of 30 +/- 3%. The results of the NHCT and a meta-analysis adding eight subsequent trials of normalization of hematocrit/hemoglobin in chronic kidney disease (CKD) have demonstrated increased thrombovascular events and mortality associated with the higher targets. This article expands and clarifies the results of the NHCT, including data that were edited from the original publication, and highlights findings from more recent studies in the field. Paradoxically, none of the randomized trials has reported an association between higher attained hemoglobin concentration and mortality within randomized groups. Mean platelet count did not increase among the patients in the normal-hematocrit group in the NHCT or in two other large trials, CREATE and CHOIR. Exposure to high doses of erythropoietic stimulating agents and/or intravenous iron could be mediating complications in the CKD anemia-normalization studies, but post-hoc analyses to probe such potential associations have yielded conflicting results and are clearly hindered by the risk of confounding by indication. The mechanisms underlying the deleterious outcomes associated with efforts to correct renal anemia fully remain unproven.