Dialysis-dependent Chronic Kidney Disease Research Articles

Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions

In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n= 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n= 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P= 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P= 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P= 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P= 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P= 0.87). Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.

Cognition in People With End-Stage Kidney Disease Treated WithHemodialysis: A Systematic Review and Meta-analysis.

Cognitive impairment is associated with poorer quality of life, risk for hospitalization, and mortality. Cognitive impairment is common in people with end-stage kidney disease treated with hemodialysis, yet the severity and specific cognitive deficits are uncertain. Systematic review and meta-analysis. Adults receiving hemodialysis compared with the general population, people with non-dialysis-dependent chronic kidney disease (NDD-CKD), people receiving peritoneal dialysis, or people with nondialyzed chronic kidney failure. Randomized controlled trials, cohort or cross-sectional studies without language restriction. Validated neuropsychological tests of cognition. Cognitive test scores, aggregated by cognitive domain: orientation and attention, perception, memory, language, construction and motor performance, concept formation and reasoning, and executive functions. 42 studies of 3,522 participants. Studies were of high or uncertain risk of bias, assessed by the Newcastle-Ottawa Scale. People treated with hemodialysis had worse cognition than the general population, particularly in attention (n=22; standardized mean difference [SMD],-0.93; 95% CI,-1.18 to-0.68). Hemodialysis patients performed better than nondialyzed patients with chronic kidney failure in attention (n=6; SMD, 0.70; 95% CI, 0.45 to 0.96) and memory (n=6; SMD, 0.36; 95% CI, 0.08 to 0.63), but had poorer memory than the general population (n=16; SMD,-0.41; 95% CI,-0.91 to 0.09) and people with NDD-CKD (n=5; SMD,-0.40; 95% CI,-0.60 to-0.21). There were insufficient data to show other differences among people receiving hemodialysis and those receiving peritoneal dialysis or with NDD-CKD. Potentially biased studies, not wholly adjusted for education. High heterogeneity, mainly due to the large variety of tests used to assess cognition. People treated with hemodialysis have impaired cognitive function compared to the general population, particularly in the domains of orientation and attention and executive function. Cognitive deficits in specific domains should be further explored in this population and should be considered when approaching education and chronic disease management.

Reolysin Combined with Carfilzomib for Treatment of Relapsed Multiple Myeloma Patients

Introduction. The viral oncolytic agent, Reolysin (RV), is a promising novel therapeutic that selectively proliferates in myeloma cells. Our group conducted a phase 1 clinical trial of single agent RV in patients with relapsed and refractory multiple myeloma (MM), and reported that treatment was well tolerated and associated with prolonged disease stability in 25% of patients. Objective responses were not evident, likely because the viral RNA present in the myeloma cells was not producing infectious viral particles. Proteasome inhibitors can lead to myeloma cell death due to increased endoplasmic reticulum (ER) stress and induction of ER-stress related apoptosis (Kelly, Oncogene, 2012). We confirmed this effect preclinically with Carfilzomib (CFZ), and hypothesized that the addition of CFZ to RV would increase viral proliferation and MM cell death sufficiently to obtain objective response in patients with relapsed MM.Methods. For this pilot trial, patients were required to have relapsed myeloma with IMWG-defined measurable disease, ANC ≥ 1,000/uL, platelet count ≥ 50,000/uL, with no creatinine requirements. Cohorts of 6 patients each were planned. Cohort 1 included patients who were CFZ na•ve or had not progressed on a CFZ containing regimen. Intravenous CFZ (20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 thereafter), Reolysin (3 x 1010 TCID50/day), and dexamethasone (20 mg) were administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (Table 1). In situ based methodologies were used to examine the distribution of CD138, CD8, NK cells (CD117 and IL-22), CD 68, PD L1, reoviral capsid protein, and reoviral RNA in bone marrow biopsies performed prior to treatment on days 1 and 9 of cycle 1.Results. Seven patients have been enrolled, four are male, and all are Caucasian. Patients have a median age of 64, and have received on average 2.4 prior lines of therapy and 4.4 prior treatments. All patients were previously exposed to Revlimid and Velcade, and 4 patients were Velcade refractory. One patient was previously treated with CFZ but was deemed to be CFZ sensitive, one patient has dialysis-dependent CKD, and all but one patient had evidence of high-risk cytogenetics on CD138-selected FISH at the time of enrollment. 6/7 patients suffered myalgias and fever after the first two doses of Reolysin, but these symptoms did not recur in any subsequent doses. Treatment has been well tolerated in 5 patients, but 2 patients were removed from study after 2 doses of combination therapy, one for congestive heart failure, and the other for gastrointestinal bleed in the setting of grade 4 thrombocytopenia and an arteriovenous malformation. Due to these 2 DLTs, patient 7 was enrolled at dose level -1 (Carfilzomib 20 mg/m2 and Reolysin 3 x 109 TCID50/day on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle). Within the first 14 days following the initiation of treatment, the mean decrease in platelets for the 7 evaluable patients was 79 (50 - 139), and this included grade 4 (N = 1), and asymptomatic grade 2 (N = 3), and grade 1 (N = 3) events. All patients have had a reduction of the monoclonal protein, 5 patients remain on study, and the longest duration of response is currently 8 cycles. Responses are VGPR (N = 2), PR (N = 3), MR (N = 1), and SD (N = 1) (Figure 1). Intracellular viral replication will be reported at the meeting.Conclusion. This 3-drug regimen is relatively well tolerated in heavily treated patients with relapsed MM. Most patients experience low grade fever and myalgias after the first two doses, and patients have evidence of thrombocytopenia in cycle 1. Combination treatment is associated with reduction of the monoclonal protein in all patients, and 86% (6/7) CFZ-sensitive patients have evidence of objective response.Table 1Combination treatment dose levelsDose levelDexamethasone (IVP)Carfilzomib (IVPB)Reolysin (IVPB)-120 mg/day20 mg/m2 /day3 x 109 TCID50/day1 (starting dose)20 mg/dayC1 Day 1 & 2 - 20 mg/m2 /dayC1 Day 8 & onward - 27 mg/m2 /day3 x 1010 TCID50/day [Display omitted] DisclosuresOff Label Use: Reolysin - oncolytic viral, anti-cancer agent.

Cause-Specific Deaths in Non-Dialysis-Dependent CKD.

CKD is associated with higher risk of death, but details regarding differences in cause-specific death in CKD are unclear. We examined the leading causes of death among a non-dialysis-dependent CKD population using an electronic medical record-based CKD registry in a large healthcare system and the Ohio Department of Health mortality files. We included 33,478 white and 5042 black patients with CKD who resided in Ohio between January 2005 and September 2009 and had two measurements of eGFR<60 ml/min per 1.73 m(2) obtained 90 days apart. Causes of death (before ESRD) were classified into cardiovascular, malignancy, and non-cardiovascular/non-malignancy diseases and non-disease-related causes. During a median follow-up of 2.3 years, 6661 of 38,520 patients (17%) with CKD died. Cardiovascular diseases (34.7%) and malignant neoplasms (31.8%) were the leading causes of death, with malignancy-related deaths more common among those with earlier stages of kidney disease. After adjusting for covariates, each 5 ml/min per 1.73 m(2) decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio [HR], 1.10; 95% confidence interval [95% CI], 1.08 to 1.12) and non-cardiovascular/non-malignancy diseases (HR, 1.12; 95% CI, 1.09 to 1.14) but not to malignancy. In the adjusted models, blacks had overall-mortality hazard ratios similar to those of whites but higher hazard ratios for cardiovascular deaths. Further studies to confirm these findings and explain the mechanisms for differences are warranted. In addition to lowering cardiovascular burden in CKD, efforts to target known risk factors for cancer at the population level are needed.

Latest consensus and update on protein-energy wasting in chronic kidney disease.

Protein-energy wasting (PEW) is a state of metabolic and nutritional derangements in chronic disease states including chronic kidney disease (CKD). Cumulative evidence suggests that PEW, muscle wasting and cachexia are common and strongly associated with mortality in CKD, which is reviewed here. The malnutrition-inflammation score (KALANTAR Score) is among the comprehensive and outcome-predicting nutritional scoring tools. The association of obesity with poor outcomes is attenuated across more advanced CKD stages and eventually reverses in the form of obesity paradox. Frailty is closely associated with PEW, muscle wasting and cachexia. Muscle loss shows stronger associations with unfavorable outcomes than fat loss. Adequate energy supplementation combined with low-protein diet for the management of CKD may prevent the development of PEW and can improve adherence to low-protein diet, but dietary protein requirement may increase with aging and is higher under dialysis therapy. Phosphorus burden may lead to poor outcomes. The target serum bicarbonate concentration is normal range and at least 23 mEq/l for nondialysis-dependent and dialysis-dependent CKD patients, respectively. A benefit of exercise is suggested but not yet conclusively proven. Prevention and treatment of PEW should involve individualized and integrated approaches to modulate identified risk factors and contributing comorbidities.

Hemoglobin Outcomes during Administration of Continuous Erythropoietin Receptor Activator (C.E.R.A): A Prospective, Observational, Multicenter Study

Objective: To evaluate Hb outcomes in patients with dialysis-dependent or non-dialysis dependent chronic kidney disease (CKD) receiving continuous erythropoietin receptor activator (C.E.R.A.) therapy under routine conditions at specialist nephrology centers in Germany. Methods: In a 12-month, prospective, observational, multicenter study, Hb outcomes were assessed in 1,580 patients with CKD (1,184 dialysis-dependent, 326 non-dialysis dependent) given once-monthly C.E.R.A. under routine conditions. Results: Across the total study population, mean hemoglobin was in the range 11.4–11.6 g/dL at all post-baseline visits. In the 962 patients on hemodialysis who were pretreated with ESA including C.E.R.A., mean (SD) hemoglobin was 11.4 (1.2) g/dL at baseline and 11.5 (1.1) g/dL at month 12; the mean (SD) number of C.E.R.A. dose changes was 3.0 (2.4). For the 227 non-dialysis dependent patients without prior ESA therapy, mean hemoglobin values were 10.6 (1.1) g/dL at baseline and 11.6 (1.3) g/dL at month 12, with a mean of 1.0 (1.4) dose changes. Presence of diabetic nephropathy showed no clinically relevant effect on hemoglobin response in either group. Overall, the proportion of patients with every hemoglobin measurement within narrow (≤ 2 g/dL) pre-specified ranges was low (<10%), but higher for the range 10.0–13.0 g/dL (28.7%), reflecting the known fluctuation in hemoglobin values over time. Patients managed at large centers were more likely to have hemoglobin range in the range 10–13 g/dL throughout the 12-month study, suggesting closer anemia management. In total, five patients (0.3%) discontinued C.E.R.A. due to adverse events. Conclusion: Switching dialysis-dependent patients from more frequent ESA regimens to once-monthly C.E.R.A. therapy or initiating once-monthly C.E.R.A. de novo in predialysis CKD patients appears to be an effective therapeutic strategy regardless of diabetic status.

Brain Atrophy in Peritoneal Dialysis and CKD Stages 3-5: A Cross-sectional and Longitudinal Study

Brain atrophy has been reported in patients with end-stage renal disease receiving hemodialysis, although its mechanism is unknown. However, little is known regarding brain atrophy in patients receiving peritoneal dialysis (PD). Therefore, we examined brain volume and its annual change over 2 years in PD patients compared with patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Cross-sectional and longitudinal cohort. 62 PD patients and 69 patients with NDD-CKD with no history of cerebrovascular disease who underwent brain magnetic resonance imaging (MRI) were recruited in a cross-sectional study. Among them, 34 PD patients and 61 patients with NDD-CKD, who underwent a second brain MRI after 2 years, were recruited in a longitudinal study. PD therapy versus NDD-CKD. T1-weighted magnetic resonance images were analyzed. Total gray matter volume (GMV), total white matter volume (WMV), and cerebrospinal fluid space volume were segmented, and each volume was quantified using statistical parametric mapping software. Normalized GMV and WMV values were calculated by division of GMV and WMV by intracranial volume to adjust for variations in head size. We compared normalized GMV and normalized WMV between PD patients and patients with NDD-CKD in the cross-sectional study and the annual change in normalized GMV in the longitudinal study. In the cross-sectional study, normalized GMV, which was correlated inversely with age, was lower in PD patients than in patients with NDD-CKD. However, normalized WMV, which was not correlated with age, was comparable between the groups. Annual change in normalized GMV was significantly higher in PD patients than in patients with NDD-CKD. These differences remained significant even after adjustment for potential confounding factors. A short observation period and high dropout rate in the longitudinal study. Decline in normalized GMV is faster in PD patients than in patients with NDD-CKD.

Erythropoiesis-Stimulating Agent Use Among Non–Dialysis-Dependent CKD Patients Before and After the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Using a Large US Health Plan Database

In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo. A retrospective observational design was used to determine the impact of TREAT on clinical practice. A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and4. ESA prescribing 2 years before and after publication of TREAT. Rate of ESA prescribing for ESA-naive and -prevalent cohorts. (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (χ(2) test). For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing ofESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage3:change of slope,-0.08 [P<0.001]; stage 4: change of slope,-0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels<10g/dL, only 25%of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67). The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT. TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD.

Breath Analysis of Ammonia, Volatile Organic Compounds and Deuterated Water Vapor in Chronic Kidney Disease and During Dialysis

The volatile metabolites present in trace amounts in exhaled breath of healthy individuals and patients, for example those with advanced chronic kidney disease (CKD), can now be detected and quantified by sensitive analytical techniques. In this review, special attention is given to the major retention metabolites resulting from dialysis-dependent CKD stage 5 and especially ammonia, as a potential estimator of the severity of uremia. However, other biomarkers are important, including the hydrocarbons isoprene, ethane and pentane, in that they are likely to indicate tissue injury associated with the dialysis treatment itself. Evaluation of over-hydration, a serious complication of CKD stage5 can be improved by analysis of deuterium in exhaled water vapor after ingestion of a known amount of deuterated water, so providing total body water measurements at the bedside to support clinical management of volume status.

B-type natriuretic peptide predicts an ischemic etiology of acute heart failure in patients with stage 4–5 chronic kidney disease

ObjectivesThe non-invasive differentiation of ischemic and non-ischemic acute heart failure (AHF) not resulting from acute myocardial infarction is difficult and has therapeutic and prognostic implications. The aim of this study was to assess whether plasma B-type natriuretic peptide (BNP) can identify ischemic etiology in patients with stage 4–5 chronic kidney disease (CKD) presenting with AHF. Design and methodsWe prospectively analyzed 61 patients. The diagnosis of ischemic AHF was confirmed by coronary angiography or stress myocardial perfusion imaging. Plasma levels of BNP were measured at admission (BNP1) and 48h after admission (BNP2). ResultsThe mean age of the study patients was 67years. In these patients, 70.5% had diabetes and 47.5% had dialysis-dependent CKD; 28 of these patients (45.9%) had an ischemic etiology with significantly higher concentrations of BNP1 and BNP2 than did patients without ischemia. The area under the receiver operating characteristic curve was 0.755 (P=0.001) for BNP1 and 0.868 (P<0.001) for BNP2 to detect ischemic etiology of AHF. Plasma BNP1 >2907ng/L (odds ratio [OR], 10.9; 95% confidence interval [CI] 2.5–48.4; P=0.002) and BNP2 >2322ng/L (OR 93.1, 95% CI 7.0–1238.7; P=0.001) were independently associated with an ischemic etiology of AHF. ConclusionsPlasma BNP may represent a clinically useful non-invasive tool for identification of ischemic etiology of AHF in patients with stage 4–5 CKD.

Safety and Effectiveness of Ferumoxytol in Hemodialysis Patients at 3 Dialysis Chains in the United States Over a 12-Month Period

BackgroundIntravenous (IV) iron is the treatment of choice for iron-deficiency anemia (IDA) in patients with dialysis-dependent chronic kidney disease (DD-CKD). However, IV iron products have been associated with serious adverse events (SAEs), including anaphylactoid reactions. Ferumoxytol is an IV iron preparation that can be injected over a short period of time. Although randomized clinical trials support ferumoxytol’s efficacy and safety, additional insights may be drawn from the acquisition of long-term, repeat dosing efficacy and safety data in a real-world setting. ObjectiveThe goal of this study was to characterize the effectiveness and safety profile of ferumoxytol as administered to adult DD-CKD patients with IDA in a real-world setting. The ability of ferumoxytol to maintain hemoglobin (Hb), transferrin saturation (TSAT), and ferritin treatment targets established by the 2006 Kidney Disease Outcomes Quality Initiative guidelines was determined in 3 medium-sized US-based dialysis chains. MethodsThis retrospective, observational study was conducted to examine laboratory and dosing data for all patients who received any dose of ferumoxytol at 3 US-based dialysis chains over a 12-month period. Investigators and/or physicians from each of the chains also made independent determinations regarding the seriousness of any adverse event (AE). Special attention was paid to the incidence and types of AEs and SAEs that were potentially associated with ferumoxytol. ResultsOver the 12-month observation period, 8666 patients (mean [SD] age in chains A, B and C, 63.9 [14.8], 63.9 [14.9] and 63.6 [15.1], respectively), were treated with 33,358 doses of ferumoxytol across the 3 chains. Treatment with ferumoxytol corresponded to an increased mean monthly Hb level relative to baseline (0.13–0.69 g/dL) and led to an increase in the proportion of patients maintained within the target Hb range of 10 to 12 g/dL (61%–72%). Ferumoxytol was also associated with increases in TSAT and ferritin that stabilized throughout the observation period. Incidence of AEs was similar across the 3 chains; between 0.07% and 1.77% of all patients treated at each chain experienced an AE associated with ferumoxytol administration. SAEs were reported in 0.2% of patients. The most common AEs reported (≥6 patients) were nausea (0.37% of patients), pruritus (0.29%), vomiting (0.25%), hypotension (0.21%), and dyspnea (0.20%). Two patients (0.02%) experienced anaphylactoid reactions. The AE profile of ferumoxytol remained consistent with that reported from controlled clinical trials. ConclusionsThese long-term data, which include repeat dosing in a large number of DD-CKD patients with IDA in a real-world setting, confirm the effectiveness of ferumoxytol in increasing and maintaining Hb levels within the target range and with favorable assessments of long-term safety.

Hemoglobin Stability and Patient Satisfaction After Switch to C.E.R.A. Therapy: A Multicenter, Observational Study

Clinical Drug Investigation published the results of a study by Heidenreich et al. [1] in which the authors described efficacy and safety outcomes in a cohort of patients with chronic kidney disease (CKD) not on dialysis receiving C.E.R.A., a continuous erythropoietin receptor activator (Mircera , Roche Registration Limited, Welwyn Garden City, UK), at monthly intervals. Reduced frequency of erythropoiesis stimulating agent (ESA) dosing is a wellestablished clinical objective in nephrology, with the potential to improve patient satisfaction and compliance, as well as reducing outpatient staffing or hospital time. Encouragingly, the efficacy and safety of once-monthly dosing with C.E.R.A. versus shorter-acting ESA therapies has been convincingly demonstrated in randomized trials in dialysis-dependent [2–4] and non-dialysis [1, 3, 5, 6] patients with CKD. Subsequently, multicenter observational studies have confirmed that hemoglobin control is maintained after conversion of dialysis [7, 8] and nondialysis [1] CKD patients to C.E.R.A. under routine clinical conditions, and is well-tolerated. Heidenreich et al. [1] described the results of a patient satisfaction survey, which indicated that more than half of the patients who had previously received another ESA were more satisfied with C.E.R.A. Their analysis, however, did not specify the method of administration of prior ESA agents, which may have influenced patient attitudes. Epoetin beta and darbepoetin are available as multi-dose pen application systems (epoetin beta is also offered in multi-dose vials), which are convenient for patients and staff and reduce pain at the injection site [9]. These systems also permit small adjustments in dose (250 IE) that can be performed every time these shorter-acting ESAs are administered. C.E.R.A. is provided only as pre-filled syringes with a minimum incremental dose difference of 20 lg. We undertook a non-interventional, observational study at 15 nephrology centers in Germany, in which dialysisdependent CKD patients previously receiving ESA administered by multi-dose application systems using special vials or pens were followed up for 9 months after their physician had decided to switch to once-monthly C.E.R.A. therapy using pre-filled syringes. C.E.R.A. was initiated and prescribed at the investigator’s discretion. Patients were required to have serum ferritin [200 ng/mL and anemia caused only by CKD, and with no acute blood loss or hemoglobin decrease within the preceding 4 weeks. The key endpoints were hemoglobin stability and patient satisfaction regarding ESA therapy (‘satisfied’, ‘undecided’, and ‘not satisfied’). In total, 238 patients were enrolled and received at least one dose of C.E.R.A. Of these, 201 (84.5 %) completed the 9-month study on-treatment. Overall, 221 patients (92.9 %) met the criteria for inclusion in the patient satisfaction analysis and 142 patients (59.7 %) were eligible for the efficacy analysis (missing data was the main reason for exclusion from the efficacy analysis). Prior to study entry, 87 patients (36.6 %) were receiving epoetin beta using a pen system (NeoRecormon , Roche Registration Limited, Welwyn Garden City, UK), 34 patients (14.3 %) were receiving epoetin beta using multidose vials (NeoRecormon Multidose 50,000, Roche Registration Limited, Welwyn Garden City, UK), 52 F. Bozkurt (&) Nephrologisches Zentrum, Daun, Germany e-mail: 065927275@t-online.de

Use of Blood Tests to Predict Upper Gastrointestinal Lesions in Patients With Chronic Kidney Disease

ObjectiveAnemia and iron deficiency are common complications in patients with chronic kidney disease (CKD). However, information about the diagnostic indicators of bleeding-related upper gastrointestinal (GI) tract lesions is sparse and...

Insights From the Use in Clinical Practice of Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome Affecting the Native Kidneys: An Analysis of 19 Cases

Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys. A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 μmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included. 19 patients were identified through a query sent to all French nephrology centers. Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy. All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls. Retrospective study and use of historical controls. Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.

Blood Pressure and Mortality in U.S. Veterans With Chronic Kidney Disease

Chinese translation Background: The ideal blood pressure (BP) to decrease mortality rates in patients with non–dialysis-dependent chronic kidney disease (CKD) is unclear. Objective: To assess the association of BP (defined as the combination of systolic BP [SBP] and diastolic BP [DBP] at the individual level) with death in patients with CKD. Design: Historical cohort between 2005 and 2012. Setting: All U.S. Department of Veterans Affairs health care facilities. Patients: 651 749 U.S. veterans with CKD. Measurements: All possible combinations of SBP and DBP were examined in 96 categories from lowest (<80/<40 mm Hg) to highest (>210/>120 mm Hg), in 10–mm Hg increments. Associations with all-cause mortality were examined in time-dependent Cox models with adjustment for relevant confounders. Results: Patients with SBP of 130 to 159 mm Hg combined with DBP of 70 to 89 mm Hg had the lowest adjusted mortality rates, and those in whom both SBP and DBP were concomitantly very high or very low had the highest mortality rates. Patients with moderately elevated SBP combined with DBP no less than 70 mm Hg had consistently lower mortality rates than did patients with ideal SBP combined with DBP less than 70 mm Hg. Results were consistent in subgroups of patients with normal and elevated urinary microalbumin–creatinine ratios. Limitation: Mostly male patients, inability to establish causality, and large number of patients missing proteinuria measurement. Conclusion: The optimal BP in patients with CKD seems to be 130 to 159/70 to 89 mm Hg. It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and U.S. Department of Veterans Affairs.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of "acceptability" that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD

In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.

Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy—A meta-analysis of 11 randomized controlled trials involving 21,295 participants

The available studies have reported the benefits of statins on all-cause and cardiovascular mortality in chronic kidney disease (CKD) patients. However studies in end-stage renal disease patients on dialysis yielded conflicting results. Therefore, we performed a meta-analysis and provide the most reliable trial data to date on the impact of statin therapy on cardiovascular events and death from all causes in CKD patients. Data from PubMed, Web of Science, Cochrane Library, and Scopus for the years 1966 to October 2012 were searched. The final meta-analysis included 11 randomized controlled trials involving 21,295 participants with CKD. Among them 6857 were on dialysis. The use of statins in subjects with non-dialysis-dependent CKD resulted in a marked reduction in death from all causes (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.55–0.79; p<0.0001), cardiac causes (RR: 0.69; 95%CI: 0.55–0.68; p=0.0012), cardiovascular events (RR: 0.55; 95%CI: 0.4–0.75; p=0.0001) and stroke (RR: 0.66; 95%CI: 0.5–0.88; p=0.0022). The use of statins in dialysis-dependent CKD patients resulted in a non-significant effect on death from all causes (RR: 0.99; 95%CI: 0.88–1.11; p=0.85) and stroke (RR: 1.31; 95%CI: 0.9–1.89; p>0.05), but had the effect of reducing death from cardiac causes (RR: 0.79; 95%CI: 0.64–0.98; p<0.05) and cardiovascular events (RR: 0.81; 95%CI: 0.7–0.94; p<0.05). In conclusion, the use of statins should be indicated in cardiovascular disease prevention especially in patients with non-dialysis-dependent CKD. According to the very limited data the obtained results suggest caution in expecting a reduction in cardiovascular events in patients on dialysis.

Micromethod for Quantification of Cinacalcet in Human Plasma by Liquid Chromatography–Tandem Mass Spectrometry Using a Stable Isotope-Labeled Internal Standard

Cinacalcet hydrochloride is a calcimimetic agent indicated for the treatment of secondary hyperparathyroidism in dialysis-dependent patients with chronic kidney disease. In the context of a pharmacokinetic (PK)/pharmacodynamic study of cinacalcet in dialysis-dependent chronic kidney disease children with secondary hyperparathyroidism, we describe the development and validation of a new, rapid, simple, and economical liquid chromatography-tandem mass spectrometry (LC-MS/MS) micromethod for quantifying cinacalcet plasma concentrations. Cinacalcet was analyzed in 50-μL plasma samples over a wide range of concentrations (0.1-100 ng/mL) by LC-MS/MS after protein precipitation and addition of deuterated cinacalcet as the internal standard. Cinacalcet was quantified using selective reaction monitoring of the specific transition m/z 358.1 > 155.1, with the 361.1 > 158.1 transition used for the internal standard. The suitability of the assay for clinical PK studies was evaluated using data from a pilot PK study in a pediatric patient. The overall turnaround time for the assay was 20 minutes. The lower limit of quantification of the method was 0.1 ng/mL. Intraassay imprecision and inaccuracy for quality control samples ranged from 2.8% to 9% and 100% to 102%, respectively. Interassay imprecision and inaccuracy ranged from 6.9% to 8.5% and 99% to 103%, respectively. The overall recovery ranged from 90% to 106%. No ion suppression due to matrix effects was found with different preanalytical conditions, such as hemolysis, lipemia, and hyperuricemia. This LC-MS/MS micromethod provides high specificity, precision, and accuracy for rapid quantification of cinacalcet plasma concentrations, and it is suitable for application in pediatric PK studies; it also has potential for use in the establishment of target ranges and ultimately routine therapeutic drug monitoring to optimize cinacalcet dosing.

Survival Advantage in Black Versus White Men With CKD: Effect of Estimated GFR and Case Mix

Black dialysis patients have significantly lower mortality compared with white patients, in contradistinction to the higher mortality seen in blacks in the general population. It is unclear whether a similar paradox exists in patients with non-dialysis-dependent chronic kidney disease (CKD), and if it does, what its underlying reasons are. Historical cohort. 518,406 white and 52,402 black male US veterans with non-dialysis-dependent CKD stages 3-5. Black race. We examined overall and CKD stage-specific all-cause mortality using parametric survival models. The effect of sociodemographic characteristics, comorbid conditions, and laboratory characteristics on the observed differences was explored in multivariable models. During a median follow-up of 4.7 years, 172,093 patients died (mortality rate, 71.0 [95% CI, 70.6-71.3] per 1,000 patient-years). Black race was associated with significantly lower crude mortality (HR, 0.95; 95% CI, 0.94-0.97; P < 0.001). The survival advantage was attenuated after adjustment for age (HR, 1.14; 95% CI, 1.12-1.16), but was magnified after full multivariable adjustment (HR, 0.72; 95% CI, 0.70-0.73; P < 0.001). The unadjusted survival advantage of blacks was more prominent in those with more advanced stages of CKD, but CKD stage-specific differences were attenuated by multivariable adjustment. Exclusively male patients. Black patients with CKD have lower mortality compared with white patients. The survival advantage seen in blacks is accentuated in patients with more advanced stages of CKD, which may be explained by changes in case-mix and laboratory characteristics occurring during the course of kidney disease.