Christina M. Yuan

Progressive Multifocal Leukoencephalopathy and Use of Mycophenolate Mofetil After Kidney Transplantation

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Early Renal Insufficiency and Hospitalized Heart Disease after Renal Transplantation in the Era of Modern Immunosuppression

Renal insufficiency has been identified as a risk factor for graft loss and death after renal transplantation but has not been consistently linked to early, nonfatal, hospitalized heart disease (HHD). With the United States Renal Data System database, 29,597 patients who received a kidney transplant between January 1, 1996, and July 31, 2000, with Medicare as the primary payer, and were monitored until December 31, 2000, were studied. Cox proportional-hazards regression models were used to calculate the association of recipient estimated GFR (eGFR) at 1 yr after renal transplantation, as determined with the Modification of Diet in Renal Disease formula, with hospitalization for treatment of acute coronary syndromes (ACS) (International Classification of Diseases, version 9, code 410.x or 411.x) or congestive heart failure (CHF) (code 428.x) 1 to 3 yr after renal transplantation. Rates of ACS and CHF were 2.2 and 4.9%, respectively, for patients with eGFR of <44.8 ml/min per 1.73 m(2), compared with 1.2 and 1.4% for patients with eGFR of >69.7 ml/min per 1.73 m(2). Reduced eGFR (<44.8 ml/min per 1.73 m(2), compared with >69.7 ml/min per 1.73 m(2)) at the end of the first 1 yr after transplantation was independently associated with increased risks of both ACS (adjusted hazard ratio, 2.16; 95% confidence interval, 1.39 to 3.35) and CHF (adjusted hazard ratio, 2.95; 95% confidence interval, 2.24 to 3.90). It was concluded that early renal insufficiency (approximately stage 3 chronic kidney disease) was associated with higher rates of HHD 1 to 3 yr after kidney transplantation. Preservation of renal function after renal transplantation may reduce the rates of HHD, and renal transplant recipients with reduced eGFR should be considered at high risk of developing cardiovascular disease.

Cardiovascular Risk Assessment Among Potential Kidney Transplant Candidates: Approaches and Controversies

Cardiovascular disease is the most common cause of death after kidney transplantation. However, uncertainties regarding the optimal assessment of cardiovascular risk in potential transplant candidates have produced controversy and inconsistency in pretransplantation cardiac evaluation practices. In this review, we consider the evidence supporting cardiac evaluation in kidney transplant candidates, generally focused on coronary artery disease, according to the World Health Organization principles for screening. The importance of pretransplant cardiac evaluation is supported by the high prevalence of coronary artery disease and the incidence and adverse consequences of acute coronary syndromes in this population. Testing for coronary artery disease may be performed noninvasively by using modalities that include nuclear myocardial perfusion studies and dobutamine stress echocardiography. These tests have prognostic value for mortality, but imperfect sensitivity and specificity for detecting angiographically defined coronary artery disease in patients with end-stage renal disease. Associations of angiographically-defined coronary artery disease with subsequent survival also are inconsistent, likely because plaque instability is more critical for infarction risk than angiographic stenosis. The efficacy and best methods of myocardial revascularization have not been examined in large contemporary clinical trials in patients with end-stage renal disease. Biomarkers, such as cardiac troponin, have prognostic value in end-stage renal disease, but require further study to determine clinical applications in directing more expensive and invasive cardiac evaluation.

Effect of Pentoxifylline on GFR Decline in CKD: A Pilot, Double-Blind, Randomized, Placebo-Controlled Trial

BACKGROUND Pentoxifylline is a nonspecific phosphodiesterase inhibitor with anti-inflammatory properties. It reduces proteinuria in patients with glomerular disease, although its impact on glomerular filtration rate (GFR) is unknown. We hypothesized that pentoxifylline would slow the estimated GFR decrease in patients with chronic kidney disease at high risk of progression. STUDY DESIGN Pilot randomized double-blind placebo-controlled trial. SETTING & PARTICIPANTS 40 outpatients with decreased GFR, hypertension, and proteinuria greater than 1 g/24 h currently treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or the combination and followed up in a nephrology clinic at a tertiary medical care facility. INTERVENTION Pentoxifylline, 400 mg twice daily, or matching placebo. OUTCOMES Difference in rates of estimated GFR change during the 1-year study period between the 2 groups. MEASUREMENTS Estimated GFR (4-variable Modification of Diet in Renal Disease Study equation) and proteinuria by 24-hour urine collection were assessed at baseline and 6 and 12 months after enrollment. RESULTS Baseline characteristics were similar between the 2 groups. At 1 year, the mean estimated GFR decrease was significantly less in the pentoxifylline group than the placebo group (-1.2 +/- 7.0 versus -7.2 +/- 8.2 mL/min/1.73 m2/y; mean difference, -6.0 mL/min/1.73 m2/y; 95% confidence interval, -11.4 to -0.6; P = 0.03). For pentoxifylline-treated participants, the mean estimated GFR decrease during treatment was slower compared with the year before study enrollment (-9.6 +/- 11.9 mL/min/1.73 m2/y; mean difference, -8.4 mL/min/1.73 m2/y; 95% confidence interval, -14.8 to -2.1; P = 0.01). Proteinuria was not different between the pentoxifylline and placebo groups at baseline, 6 months, or 1 year. LIMITATIONS Small sample size and incomplete follow-up. CONCLUSIONS Pentoxifylline may slow the estimated GFR decrease in high-risk patients. This may be independent of its antiproteinuric properties and warrants further investigation.

Damned If You Do, Damned If You Don't: Potassium Binding Resins in Hyperkalemia

Sodium polystyrene sulfonate (SPS) potassium binding resins increase colonic potassium excretion and are approved by the U.S. Food and Drug Administration (FDA) for the treatment of hyperkalemia. In 2009, the FDA recommended that sorbitol, a cathartic often given with SPS to prevent obstipation, not be added to SPS powder because of associated colonic necrosis. A premixed oral suspension of SPS in 33% sorbitol was not included in this warning. SPS resins increase stool potassium excretion in normokalemic subjects, but proportionately more potassium is excreted due to cathartics when the two are combined. In hyperkalemic patients, oral SPS mixed in water significantly decreases serum potassium within 24 hours. SPS/sorbitol-associated colonic necrosis is most commonly seen in patients who have received enemas in the setting of recent abdominal surgery, bowel injury, or intestinal dysfunction. It is a rare event, on the order of 0.2 to 0.3%, almost exclusively present in patients at risk. The agent most likely associated with colonic necrosis is 70% sorbitol, and animal data support that etiology. There is very little data to suggest that oral SPS given with 33% sorbitol (in the premixed form) or SPS powder in water orally or as an enema causes colonic necrosis. SPS ion-exchange resins are the only agents, other than dialysis and diuretics, available to increase potassium excretion in hyperkalemia, and when used appropriately, they appear to be clinically effective and reasonably safe.

Asymptomatic Autoantibodies Associate with Future Anti-glomerular Basement Membrane Disease

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.

Transjugular renal biopsy in high-risk patients: an American case series

BackgroundIn the United States, transjugular renal biopsies using the Quickcore™ side cut needle system have previously been described primarily for transjugular renal biopsy in patients with concurrent liver and kidney disease.MethodsWe describe transjugular renal biopsy with the Quickcore™ system in 9 patients with nephrotic syndrome and contraindications to percutaneous renal biopsy, who underwent biopsy between 23 October 1996 and 12 April 2001. The most common contraindication was oral anticoagulation with coumadin (40%). Other contraindications included horseshoe kidney, severe renal failure, and spontaneous coagulopathy. A 62 cm straight catheter and 60 cm side-cut Quickcore™ biopsy needle were used to obtain cortical tissue. Packing of the biopsy tract with Gelfoam™ was used for venographically identified capsular perforation.ResultsTen procedures were performed on 9 patients with one requiring re-biopsy (5% of all renal biopsies performed at our institution). There were 9 transjugular renal biopsy and one combined liver-kidney biopsy. A mean of 4 ± 2 passes were made, with a mean of 3 ± 1 cores obtained per procedure. Histologic diagnosis was made in 90% of biopsies and in 100% of patients. Two patients developed transient hydronephrosis associated with gross hematuria; both required transfusion. Capsular perforation occurred in 90%. One patient died of bacterial sepsis, unrelated to the biopsy, several days after the procedure.ConclusionsTransjugular renal biopsy appears to be efficacious in high-risk patients, for whom the percutaneous approach is contraindicated, including patients on oral anticoagulation. The transfusion rate in the present study was similar to other American reports using this technique.

Distribution of the cellular uptake of phosphorothioate oligodeoxynucleotides in the rat kidney in vivo

Previous animal studies have demonstrated that following systemic administration phosphorothioate oligodeoxynucleotides (S-ODNs) are primarily excreted by the kidneys and that renal tissue levels of S-ODNs exceed that of other organs. Thus, the kidney may be an ideal target organ for application of antisense S-ODNs in vivo. We examined which cells within the rat kidney have uptake of radiolabeled S-ODNs following intravenous infusion. A 20-base 35S-ODN was infused into 6 adult male Wistar rats. Three animals each were sacrificed 30 min and 4 h after infusion. The kidneys were then removed, fixed, and tissue autoradiography was performed. Similar results were obtained in both groups. The highest level of radioactivity was seen within the proximal tubules. Lower levels of activity were seen within the glomerulus, the parietal epithelial cells of Bowmans space, and distal tubular cells. Very weak activity was also detected within the cells of the loop of Henle and the medullary collecting ducts. These results demonstrated that within the kidney S-ODNs were taken up primarily by proximal tubular cells, with much lower uptake by cells in other segments of the nephron.

Hospitalized valvular heart disease in patients on renal transplant waiting list: incidence, clinical correlates and outcomes.

BACKGROUND Patients with ESRD are at increased risk for heart valve calcification. It has not been established whether hospitalized valvular heart disease (VHD) is a substantial barrier to renal transplantation (RT) after transplant listing, or whether VHD progresses after RT. METHODS Using data from the USRDS, we studied 35,215 patients with ESRD enrolled on the renal transplant waiting list from July 1994 to June 1997. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for RT and VHD. RESULTS In comparison to maintenance dialysis (2.2/1,000 person years), RT was independently associated with a lower hazard for hospitalization for VHD (0.7/1,000 person years, HR 0.28, 95% confidence interval 0.17 - 0.47). Renal transplant recipients had much lower rates of VHD after transplant than before (rate ratio (RR) 0.49, 95% Cl 0.47 - 0.52). Patients with VHD were significantly less likely to receive RT (adjusted rate for RT 0.38, 95% CI 0.20 - 0.45) but patients who received valve replacement surgeries (VRS) were not affected (adjusted rate for RT 1.10, 95% CI 0.52 - 2.32, not significant). CONCLUSIONS VHD is an uncommon but serious barrier to RT after listing, while VRS is not a significant barrier to RT. Established VHD does not appear to worsen after RT. Clinicians should consider giving increased attention to the detection and treatment of VHD during the pre-transplant evaluation.

The prevalence of BK polyomavirus infection in outpatient kidney transplant recipients followed in a single center

Abstract: Background:  BK polyomavirus (BKV) infection has emerged as an important cause of renal allograft loss. There is no proven therapy, and much basic clinical information is still lacking.