Orly F. Kohn

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39–0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Fractional Excretion of Urea as a Guide to Renal Dysfunction

The use of fractional excretion of sodium as a guide to renal perfusion is hampered by the prior use of natriuretic agents. The fractional excretion of urea (FEUr) has been shown to be affected by volume status. We, therefore, determined the value of the FEUr as a guide to renal perfusion. In 6 patients evaluated prospectively and in 87 patients evaluated retrospectively, a low FEUr (less than or equal to 35%) was found to be a sensitive index to renal perfusion, despite the prior administration of furosemide.

Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy

BACKGROUND African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans. STUDY DESIGN Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. SETTING & PARTICIPANTS Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls. PREDICTORS Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes. OUTCOMES APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1. RESULTS The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001). LIMITATIONS Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy. CONCLUSIONS This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.

Solute kinetics with short-daily home hemodialysis using slow dialysate flow rate.

“NxStage System One™” is increasingly used for daily home hemodialysis. The ultrapure dialysate volumes are typically between 15 L and 30 L per dialysis, substantially smaller than the volumes used in conventional dialysis. In this study, the impact of the use of low dialysate volumes on the removal rates of solutes of different molecular weights and volumes of distribution was evaluated. Serum measurements before and after dialysis and total dialysate collection were performed over 30 times in 5 functionally anephric patients undergoing short‐daily home hemodialysis (6 d/wk) over the course of 8 to 16 months. Measured solutes included β2 microglobulin (β2M), phosphorus, urea nitrogen, and potassium. The average spent dialysate volume (dialysate plus ultrafiltrate) was 25.4±4.7 L and the dialysis duration was 175±15 min. β2 microglobulin clearance of the polyethersulfone dialyzer averaged 53±14 mL/min. Total β2M recovered in the dialysate was 106±42 mg per treatment (n=38). Predialysis serum β2M levels remained stable over the observation period. Phosphorus removal averaged 694±343 mg per treatment with a mean predialysis serum phosphorus of 5.2±1.8 mg/dL (n=34). Standard Kt/V averaged 2.5±0.3 per week and correlated with the dialysate‐based weekly Kt/V. Weekly β2M, phosphorus, and urea nitrogen removal in patients dialyzing 6 d/wk with these relatively low dialysate volumes compared favorably with values published for thrice weekly conventional and with short‐daily hemodialysis performed with machines using much higher dialysate flow rates. Results of the present study were achieved, however, with an average of 17.5 hours of dialysis per week.

Thrombotic Thrombocytopenic Purpura in Pregnancy: Successful Treatment with Plasma Exchange

Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome which presents typically with thrombocytopenia, microangiopathic hemolytic anemia, central nervous system symptoms, fever, and renal abnormalities. The diagnosis of TTP in pregnancy previously carried a poor prognosis and a high fetal mortality when presenting early in gestation. This case report describes the earliest presentation of TTP in pregnancy (6 weeks of gestation) we could identify in the literature treated successfully with a prolonged course of plasma exchange. The differential diagnosis and the pathogenesis of TTP in pregnancy are reviewed. Therapeutic options and data regarding the removal of pregnancy-related hormones by plasma exchange are presented.

Renal Malacoplakia With Papillary Necrosis and Renal Failure

Renal parenchymal malacoplakia is a rare cause of renal failure. Patients presenting with renal failure carry a poor prognosis, the majority either dying or requiring chronic dialysis. In this report, we describe an alcoholic man who presented with renal failure due to bilateral renal parenchymal malacoplakia and papillary necrosis. The patient, who initially required dialysis, partially recovered renal function following prolonged antibiotic treatment with a fluoroquinolone antibiotic.

Patient-specific phosphorus mobilization clearance during nocturnal and short daily hemodialysis.

The kinetics of plasma phosphorus during different hemodialysis (HD) modalities are incompletely understood. We recently demonstrated that a pseudo one‐compartment kinetic model including phosphorus mobilization from various body compartments into extracellular fluids can describe intradialytic and postdialytic rebound kinetics of plasma phosphorus during conventional and short 2‐hour HD treatments. In this model, individual patient differences in phosphorus kinetics were characterized by a single parameter, the phosphorus mobilization clearance (KM). In this report we determined KM in patients treated by in‐center nocturnal HD (ICNHD) and short daily HD (SDHD) with low dialyzer phosphate clearance. In the ICNHD study, eight patients underwent 8‐hour HD treatments where intradialytic and postdialytic plasma samples were collected; KM values were determined by nonlinear regression of plasma concentration as a function of time. In the SDHD study, five patients were studied during 28 treatments for approximately 3 hours. Here, KM was calculated using only predialytic and postdialytic plasma phosphorus concentrations. Dialyzer phosphate clearances were 134 ± 20 (mean ± SD) and 95 ± 16 mL/min during ICNHD and SDHD, respectively. KM values for the respective therapies were 124 ± 83 and 103 ± 33 mL/min, comparable to those determined previously during conventional and short HD treatments of 98 ± 44 mL/min. When results from ICNHD, SDHD, and previous HD modalities were combined, KM was directly correlated with postdialytic body weight (r = 0.38, P = 0.025) and inversely correlated with predialytic phosphorus concentration (r = −0.47, P = 0.005). These findings suggest that phosphorus kinetics during various HD modalities can be described by a pseudo one‐compartment model.

Evaluation of Renal Blood Flow in Chronic Kidney Disease Using Arterial Spin Labeling Perfusion Magnetic Resonance Imaging

Introduction Chronic kidney disease (CKD) is known to be associated with reduced renal blood flow. However, data in humans are limited to date. Methods In this study, noninvasive arterial spin labeling magnetic resonance imaging data were acquired in 33 patients with diabetes and stage 3 CKD as well as in 30 healthy controls. Results A significantly lower renal blood flow in both the cortex (108.4 ± 36.4 vs. 207.3 ± 41.8; P < 0.001, d = 2.52) and medulla (23.2 ± 8.9 vs. 42.6 ± 15.8; P < 0.001, d = 1.5) was observed. Both cortical (ρ = 0.67, P < 0.001) and medullary (ρ = 0.62, P < 0.001) blood flow were correlated with estimated glomerular filtration rate, and cortical blood flow was found to be confounded by age and body mass index. However, in a subset of subjects who were matched for age and body mass index (n = 6), the differences between CKD patients and control subjects remained significant in both the cortex (107.4 ± 42.8 vs. 187.51 ± 20.44; P = 0.002) and medulla (15.43 ± 8.43 vs. 39.18 ± 11.13; P = 0.002). A threshold value to separate healthy controls and CKD patients was estimated to be a cortical blood flow of 142.9 and a medullary blood flow of 24.1. Discussion These results support the use of arterial spin labeling in the evaluation of renal blood flow in patients with a moderate level of CKD. Whether these measurements can identify patients at risk for progressive CKD requires further longitudinal follow-up.

Thrombotic thrombocytopenic purpura after cephalosporin administration: a possible relationship

BACKGROUND:  Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder. The pathogenesis is believed to be mediated by an autoantibody directed against the metalloproteinase responsible for the degradation of the very‐high‐molecular‐weight multimers of the vWF. The syndrome can be precipitated by a variety of conditions, and certain medications also have been implicated.