Michele H. Mokrzycki

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.

Therapeutic Plasma Exchange: Complications and Management

Therapeutic plasma exchange is a treatment modality used in a variety of disease states, some of which are characterized by renal involvement (ie, Goodpastures syndrome, multiple myeloma, cryoglobulinemia, and thrombotic thrombocytopenic purpura). To investigate the safety of this procedure we evaluated all patients receiving plasma-pheresis at the University of Connecticut from January 1988 to June 1991. Sixty-eight adverse reactions occurred in 699 treatments, resulting in an incidence of 9.7%. The most frequent complications were symptoms of hypocalcemia, hypovolemia, and anaphylactoid reactions. The incidence of hypocalcemic symptoms was lowered with the prophylactic administration of calcium. Without calcium prophylaxis the incidence of symptoms was 9.1% (six in 66 treatments), whereas with calcium prophylaxis the incidence was reduced to 1% (six in 633 treatments) (P < 0.01). Treatments in which albumin was administered as volume replacement were associated with fewer adverse reactions when compared with those using fresh-frozen plasma (1.4% v 20%). Our experience, combined with the 15,658 procedures reported in the literature, reveals that serious complications do not commonly occur. These are characterized by cardiovascular events (0.2%), respiratory events (0.2%), and anaphylactoid reactions (0.25%). Hemorrhage and infection are rare, each occurring at a rate of 0.02%. Death was reported in eight of 15,658 procedures (0.05%). We conclude that therapeutic plasma exchange is relatively safe and alterations in plasma proteins generally are well tolerated. Prophylactic calcium administration lowers the incidence of hypocalcemic symptoms. Adverse reactions are associated more commonly with the administration of fresh-frozen plasma.

Prevention and management of catheter-related infection in hemodialysis patients

Central venous catheter-related infections have been associated with high morbidity, mortality, and costs. Catheter use in chronic hemodialysis patients has been recognized as distinct from other patient populations who require central venous access, leading to recent adaptations in guidelines-recommended diagnosis for catheter-related bacteremia (CRB). This review will discuss the epidemiology and pathogenesis of hemodialysis CRB, in addition to a focus on interventions that have favorably affected CRB outcomes. These include: (1) the use of prophylactic topical antimicrobial ointments at the catheter exit site, (2) the use of prophylactic catheter locking solutions for the prevention of CRB, (3) strategies for management of the catheter in CRB, and (4) the use of vascular access managers and quality initiative programs.

Standardized Definitions for Hemodialysis Vascular Access

Vascular access dysfunction is one of the leading causes of morbidity and mortality among end‐stage renal disease patients. Vascular access dysfunction exists in all three types of available accesses: arteriovenous fistulas, arteriovenous grafts, and tunneled catheters. To improve clinical research and outcomes in hemodialysis (HD) access dysfunction, the development of a multidisciplinary network of collaborative investigators with various areas of expertise, and common standards for terminology and classification in all vascular access types, is required. The North American Vascular Access Consortium (NAVAC) is a newly formed multidisciplinary and multicenter network of experts in the area of HD vascular access, who include nephrologists and interventional nephrologists from the United States and Canada with: (1) a primary clinical and research focus in HD vascular access dysfunction, (2) national and internationally recognized experts in vascular access, and (3) a history of productivity measured by peer‐reviewed publications and funding among members of this consortium. The consortium’s mission is to improve the quality and efficiency in vascular access research, and impact the research in the area of HD vascular access by conducting observational studies and randomized controlled trials. The purpose of the consortium’s initial manuscript is to provide working and standard vascular access definitions relating to (1) epidemiology, (2) vascular access function, (3) vascular access patency, and (4) complications in vascular accesses relating to each of the vascular access types.

Introduction and overview of therapeutic apheresis

Chidi Okafor, David M. Ward, Michele H. Mokrzycki, Robert Weinstein, Pamela Clark, and Rasheed A. Balogun* Department of Medicine, Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia Department of Medicine, University of California, San Diego, California Department of Medicine, Albert Einstein College of Medicine, Bronx, New York Departments of Medicine and Pathology, University of Massachusetts, Amherst, Massachusetts Department of Pathology, University of Virginia, Charlottesville, Virginia

Who should be referred for a fistula? A survey of nephrologists

BACKGROUND There is marked variation in the use of the arteriovenous fistula (AVF) across programmes, regions and countries not explained by differences in patient demographics or comorbidities. The lack of clear criteria of who should or should not get a fistula may contribute to this, as well as barriers to creating AVFs. METHODS We conducted a survey of Canadian and American nephrologists to assess the patient variables considered to determine the timing and type of access requested. Perceived barriers and absolute contraindications to access were also collected. RESULTS An immediate referral for a fistula was more highly preferred when patients are <65 years old, have minimal comorbidities or have no history of failed accesses. In older patients, and in those with increased comorbidities or a previously failed fistula, US nephrologists selected arteriovenous grafts as an alternative to the fistula, while Canadian nephrologists selected primarily catheters. Referral for vascular mapping was more common in the USA than in Canada. Gender did not influence the timing or the type of access. Perceived barriers to establishing a mature fistula included patient refusal for creation (77%) or cannulation (58%), delay in decision regarding dialysis modality (71%), wait time for surgical creation (55%) and high failure-to-mature rate (52%). We found that 27% of Canadian and 43% of American nephrologists indicated no absolute contraindications for permanent vascular access. CONCLUSIONS This study demonstrated marked variability in timing and criteria used to select patients for referral for a vascular access between nephrologists practicing within Canada and the USA. Establishing minimal eligibility criteria for fistulae is an important area of future research.

Large atrial thrombus formation associated with tunneled cuffed hemodialysis catheters.

AIMS In the existing literature, there is a paucity of data regarding large atrial thrombus (AT) formation occurring as a complication of tunneled cuffed hemodialysis catheter (TCC) use. This study was performed to determine the risk factors, mortality and the appropriate management of TCC-AT. METHODS We report 6 new cases of TCC-AT and have amalgamated these data with data from 16 previously published cases of TCC-AT found by performing a PubMed literature search (total of 22 cases). Demographic data were collected prospectively over 2 years in 85 consecutive patients initiating hemodialysis who were using a TCC as their primary vascular access, so that comparisons could be made between the 6 patients with TCC-AT versus all patients with a TCC at our center. RESULTS In patients with TCC-AT, the mean time from TCC insertion was 4.5 months, and infection was present at the time of diagnosis in 68% of cases. The mean thrombus size was 3.7 cm, range 1.5-8 cm. All but 1 case were visualized by echocardiography; the remaining case required magnetic resonance imaging. Management included TCC removal and thrombectomy (n = 9), TCC removal and anticoagulation (AC) (n = 6), TCC removal alone (n = 5), and no intervention (n = 2). The overall mortality was 27%, and 5 of the 6 deaths (83%) occurred in patients with bacteremia. The mortality associated with each management strategy was as follows: TCC removal and thrombectomy (0%), TCC removal and AC (33%), TCC removal alone (40%), and no intervention (100%). CONCLUSIONS AT is a serious complication of TCC use in hemodialysis patients and may be associated with a high mortality rate. TCC-AT may occur more commonly than previously reported and therefore warrants a high index of suspicion.

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.

Therapeutic Apheresis: A Review of Complications and Recommendations for Prevention and Management

Therapeutic apheresis procedures are a form of extracorporeal therapy that use different techniques to separate blood into the different components out of which the part containing the etiological agent in a disease process is discarded and the rest of the components of blood are re‐infused into the patient, frequently with the addition of a replacement fluid or volume. These complex procedures have inherent risks of adverse events and factors that may impact on the incidence these events include the underlying disease state, anticoagulation techniques, replacement fluid type including the volume, issues related to the vascular access used, and the therapeutic apheresis procedure type and technique. We present a representative case based review of common complications of therapeutic apheresis and suggestions about how to prevent or manage these as presented at the 2010 Therapeutic Apheresis Academy. J. Clin. Apheresis, 2011.