Jeffrey S. Berns

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5–7.1; P = 4 × 10−23, n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5–3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.

APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

To the Editor: We have read the letter to the editor by Jerzy Przedlacki1 and the response from the authors2 of the Kidney Disease-Improving Global Outcomes (KDIGO) clinical practice guidelines for bisphosphonate (BP) treatment in chronic kidney disease (CKD), and would like to share our concerns regarding the use of BP treatment of CKD. The kidney is the organ that excretes many drugs, and any change in renal function will affect the pharmacology of these drugs. Existing or residual renal function of the patient will have to be taken into account while prescribing drugs. This is just as important for the patient with CKD 4 or 5, including those with CKD 5 already on peritoneal dialysis or hemodialysis, who may still have residual renal function. Nephrotoxic drugs including nonsteroidal anti-inflammatory drugs can very readily destroy whatever residual renal function patients may still have. Residual renal function is important to preserve as it contributes to less patient morbidity and mortality3 in the dialysis patient. Recently, there have been adverse reports of a certain BP that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. As of 14 August 2009, there have been 139 post-marketing reports of renal impairment following its use as an infusion worldwide. Many of these occur in patients with pre-existing medical conditions or risk factors (elderly, renal impairment, and/or concurrent dehydration), or in those on nonsteroidal anti-inflammatory drugs or other concurrent exposure to other nephrotoxic agents. There have also been cases requiring dialysis, and occasional fatal outcomes have been reported in patients with pre-existing renal impairment and concomitant risk factors.4, 5, 6, 7

KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

This commentary provides a US perspective on the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). KDIGO is an independent international organization with the primary mission of the promotion, coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for the care of patients with kidney disease. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI), recognizing that international guidelines need to be adapted for each country, convened a group of experts to comment on the application and implementation of the KDIGO guideline for patients with CKD in the United States. This commentary puts the KDIGO guideline into the context of the supporting evidence and the setting of care delivered in the United States and summarizes important differences between prior KDOQI guidelines and the newer KDIGO guideline. It also considers the potential impact of a new bundled payment system for dialysis clinics. The KDIGO guideline addresses the evaluation and treatment of abnormalities of CKD-MBD in adults and children with CKD stages 3-5 on long-term dialysis therapy or with a kidney transplant. Tests considered are those that relate to laboratory, bone, and cardiovascular abnormality detection and monitoring. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. Limitations of the evidence are discussed. The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas.

Definition and Classification of CKD: The Debate Should Be About Patient Prognosis—A Position Statement From KDOQI and KDIGO

m g e 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 AQ:1 n 2002 the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative KDOQI) published a guideline on chronic kidey disease (CKD) covering evaluation, classifiation, and stratification of risk. The workgroup eveloping this guideline provided a new concepual framework for a diagnosis of CKD indepenent of cause, and developed a classification cheme of kidney disease severity based on the evel of glomerular filtration rate (GFR). Before his new system for defining and staging CKD as developed, vague and variable terminology, uch as “chronic renal failure,” “chronic renal nsufficiency,” “pre-dialysis,” and “pre-endtage renal disease” prevented the use of a comon and precise language. The new system also epresented a significant conceptual change, since idney disease historically had been categorized ainly by cause. The definition is based on 3 omponents: (1) an anatomical or structural comonent (markers of kidney damage, including lbuminuria), (2) a functional component (based n GFR), and (3) a temporal component (at least months’ duration of structural and/or funcional alterations). The diagnosis of CKD relies n markers of kidney damage and/or a reduction n GFR. Stages 1 and 2 define conditions of idney damage in the presence of a GFR of at east 90 mL/min/1.73 m or 60 to 89 mL/min/ .73 m, respectively, and stages 3 to 5 define onditions of moderately and severely reduced FR irrespective of markers of kidney damage Table 1). The impact that this classification system has ad in only 6 years on the awareness of CKD in ndividuals and populations, on research activiies, research support, and public health policy as been tremendous. There has been an exponenial increase in the amount of research performed n patients with kidney disease not receiving ong-term dialysis therapy since the guidelines ere released, and the common definition of KD has facilitated comparisons between studes. Thus, this new diagnostic classification of KD has likely been one of the most profound onceptual developments in the history of nehrology.

Reviews: Use of Insulin and Oral Hypoglycemic Medications in Patients with Diabetes Mellitus and Advanced Kidney Disease

Diabetes mellitus is recognized as a leading cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in the United States. There is a vast array of medications used to treat diabetes, including insulin and the sulfonylureas, as well as newer classes of drugs such as the thiazolidinediones and biguanides. In patients with reduced glomerular filtration rate (GFR), it is necessary to decrease the dosage of some of these drugs, while others are best avoided altogether. Accumulation of either the parent compound or its metabolites can result in symptomatic hypoglycemia, or in the case of metformin, significant lactic acidosis. In this article we will review the use of insulin and the various classes of oral medications used to treat type 2 diabetes mellitus, focusing on their pharmacokinetic properties and dosing in patients with advanced kidney disease.

The Renal Manifestations of Thyroid Disease

Thyroid hormones influence renal development, kidney structure, renal hemodynamics, GFR, the function of many transport systems along the nephron, and sodium and water homeostasis. These effects of thyroid hormone are in part due to direct renal actions and in part are mediated by cardiovascular and systemic hemodynamic effects that influence kidney function. As a consequence, both hypothyroidism and hyperthyroidism associate with clinically important alterations in kidney function and have relevance to its assessment. Disorders of thyroid function have also been linked to development of immune-mediated glomerular injury, and alterations in thyroid hormones and thyroid hormone testing occur in patients with kidney disease.

A Survey-Based Evaluation of Self-Perceived Competency after Nephrology Fellowship Training

BACKGROUND AND OBJECTIVES There have been no recent analyses of the adequacy of training in U.S. nephrology training programs or the importance of specific aspects of fellowship training in the careers and practices of nephrologists who recently completed training. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS An internet-based survey was sent to members of the American Society of Nephrology who completed nephrology training in 2004 to 2008. Respondents were asked to rate their fellowship training (little or no training, some training but not enough to feel competent, well trained and competent) in specific areas and the importance of each area to their current careers and practices. RESULTS Among 133 recent adult nephrology trainees, most felt well trained and competent in many areas of patient care and core content. A significant percentage of respondents reported receiving little or no training, or some training but not enough to feel competent in other specific areas, such as genetic renal disease, care of adults with childhood kidney disease, pregnancy complications, poisoning, nutrition, end-of-life care, clinical pharmacology, home and self-care hemodialysis, peritoneal dialysis, plasmapheresis, interpretation and performance of renal ultrasound and other renal imaging, renal biopsy pathology interpretation, business and administrative aspects of nephrology, research, and research funding. Many of these areas were also identified as somewhat or very important to the careers and practices of respondents. CONCLUSIONS Nephrology training programs are perceived as doing an excellent job training fellows in many areas. Gaps in training should be addressed in fellowship training and post-training education.

History-Adjusted Marginal Structural Analysis of the Association between Hemoglobin Variability and Mortality among Chronic Hemodialysis Patients

BACKGROUND AND OBJECTIVES Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin. RESULTS In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively. CONCLUSIONS Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.

Single-center Experience with the Arrow-Trerotola Percutaneous Thrombectomy Device in the Management of Thrombosed Native Dialysis Fistulas

PURPOSE The present study sought to evaluate the performance of the Arrow-Trerotola Percutaneous Thrombolytic Device (PTD) in the treatment of native fistula thrombosis in a U. S. hemodialysis population. Specifically, the technical success, clinical success, complication rate and type, primary and secondary patency rates, effect of adjunctive thrombolytic therapy, and any variables that affected outcomes of procedures in which this device was used were analyzed. MATERIALS AND METHODS Forty-two patients with 44 thrombosed native fistulas (17 radiocephalic, 10 brachiocephalic, 10 transposed or superficialized, five graft/fistula hybrids, and two leg fistulas) were treated with 62 mechanical thrombolysis procedures with use of the PTD. All patients had large clot burden. The device type was recorded in 43 procedures: standard (n = 21), over-the-wire (OTW; n = 19), or both (n = 3). No device was used in two cases because of inability to cross the anastomosis. Adjunctive therapies (n = 18) included the use of tissue plasminogen activator (tPA; n = 16) and deployment of the AngioJet device with (n = 1) or without tPA (n = 1). Stents were inserted in four procedures. Outcome variables included technical and clinical success, complications, and primary and secondary patency. Cox proportional-hazards regression and Kaplan-Meier analyses were performed. RESULTS The technical success rate was 87% (54 of 62) and the clinical success rate was 79% (49 of 62). Percutaneous transluminal angioplasty was performed in all but two procedures. Complications occurred in 13% of procedures (n = 8); three resulted in technical failure. The primary patency rates were 38% at 6 months and 18% at 12 months; secondary patency rates were 74% and 69%, respectively. Outcomes were not affected by adjunctive techniques, fistula type, age of fistula, device type (ie, OTW vs standard), or patient sex. Secondary patency was superior when no residual clot or stenosis was present (P = .003). CONCLUSIONS The PTD is effective for percutaneous treatment of thrombosed hemodialysis fistulas, with good short- and long-term outcomes in a U.S. population. Within the limitations of a retrospective study with a small sample size, use of an adjunctive thrombolytic agent did not appear to improve results compared with the use of the device alone.