Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.

Variants in apolipoprotein L1 (APOL1) gene are associated with nondiabetic kidney diseases in black subjects and reduced kidney transplant graft survival. Living and deceased black kidney donors (n = 107) were genotyped for APOL1 variants. To determine whether allografts from high-risk APOL1 donors have reduced podocyte densities contributing to allograft failure, we morphometrically estimated podocyte number, glomerular volume, and podocyte density. We compared allograft loss and eGFR trajectories stratified by APOL1 high-risk and low-risk genotypes. Demographic characteristics were similar in high-risk (n = 16) and low-risk (n = 91) donors. Podocyte density was significantly lower in high-risk than low-risk donors (108 ± 26 vs 127 ± 40 podocytes/106 um3 , P = .03). Kaplan-Meier graft survival (high-risk 61% vs. low-risk 91%, p-value = 0.049) and multivariable Cox models (hazard ratio = 2.6; 95% CI, 0.9-7.8) revealed higher graft loss in recipients of APOL1 high-risk allografts over 48 months. More rapid eGFR decline was seen in recipients of high-risk APOL1 allografts (P < .001). At 60 months, eGFR was 27 vs. 51 mL/min/1.73 min2 in recipients of APOL1 high-risk vs low-risk kidney allografts, respectively. Kidneys from high-risk APOL1 donors had worse outcomes versus low-risk APOL1 genotypes. Lower podocyte density in kidneys from high-risk APOL1 donors may increase susceptibility to CKD from subsequent stresses in both the recipients and donors.

Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.

BACKGROUND: Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. METHODS: We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. RESULTS: Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). CONCLUSIONS: Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant.

Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications.

BACKGROUND: Previous studies have demonstrated that donor-derived cell-free DNA (dd-cfDNA) found in circulating blood of transplant recipients may serve as a noninvasive biomarker of allograft rejection. To better interpret the clinical meaning of dd-cfDNA, it is essential to understand the biological variation of this biomarker in stable healthy recipients. This report establishes the biological variation and clinical reference intervals of dd-cfDNA in renal transplant recipients by using an analytically validated assay that has a CV of 6.8%. METHODS: We sampled venous blood at patient surveillance visits (typically at posttransplant months 1-4, 6, 9, and 12) in a 14-center observational study. Patients with stable renal allograft function spanning ≥3 serial visits were selected. We used AlloSure®, a targeted next-generation sequencing-based approach, to measure dd-cfDNA in the plasma and computed the intraindividual CV (CVI) and interindividual CV (CVG), the index of individuality (II), and reference change value (RCV). RESULTS: Of 93 patients, 61% were men, 56% were Caucasian, mean age was 49 years, and 63% were deceased donor kidney recipients. Of 380 blood samples, the dd-cfDNA median value was 0.21% (interquartile range 0.12%-0.39%) and the 97.5th percentile was 1.20%. In 18 patients with an average of 4.1 tests, the CVI was 21%, CVG was 37%, II was 0.57, and RCV was 61%. CONCLUSIONS: In a renal transplant recipient, a dd-cfDNA level above 1.2% is out of range and potentially abnormal. A serial increase of up to 61% in level of dd-cfDNA in a patient may be attributable to biological variation.Clinicaltrials.gov Identifier: NCT02424227.

Reverse Epidemiology of Blood Pressure in Peritoneal Dialysis Associated with Dynamic Deterioration of Left Ventricular Function.

UNLABELLED: ♦ BACKGROUND: Reverse epidemiology of blood pressure (BP) in end-stage kidney disease (ESKD) is manifested as higher mortality at lower blood pressure. We hypothesize that this phenomenon is partially mediated by deterioration of cardiac structure and function. ♦ METHODS: Seventy-seven prevalent ESKD patients starting renal replacement therapy on peritoneal dialysis (PD) from 2007 to 2012 were evaluated for the primary outcome of all-cause mortality. Longitudinal data were obtained from 1,930 patient-encounters including monthly clinic BP and serial echocardiograms. Generalized linear mixed models using data from the last observation moving backward, and time-to-event analysis using time-varying Cox-survival models to estimate mortality risk at different blood pressure categories were applied. ♦ RESULTS: There were 39 males (50.6%). Mean age was 51 years (standard deviation [SD] = 15). During follow-up, 20 patients (25%) died. As compared to systolic blood pressure (SBP) of 140-159 mmHg, unadjusted risk of mortality was 7.3 (95% confidence interval [CI]: 1.5-35.7, p = 0.008) at level < 120 mmHg. Systolic BP trended down to an average of 117 mmHg prior to death in non-survivors as compared to 141 mmHg in survivors (p < 0.05). In non-survivors, percentage with concentric left ventricular hypertrophy (LVH) decreased by 20% at the expense of a 20% reciprocal increase in eccentric hypertrophy associated with a 30% increase in percentage with low ejection fraction (EF) (< 50%). After adjusting for EF, risk of mortality at SBP < 120 mmHg attenuated to 3.4 (95% CI: 0.7-17.7, p = 0.14). ♦ CONCLUSION: We conclude that higher mortality associated with lower BP may be mediated in part by worsening heart function in ESKD patients receiving PD.

Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients.

BACKGROUND: The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear. METHODS: Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion. RESULT: After a median (interquartile range) of 3.1 (1.6-4.5) years of follow-up, serum creatinine decreased from 1.9 ± 0.8 to 1.8 ± 0.7 mg/dL (P=0.25) and eGFR increased from 40.8 ± 16.7 to 44.3 ± 20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0-155) to 382 (169-999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥ 1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1-9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6-11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2-2.2, P=0.003). CONCLUSION: Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥ 1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.

Lambda II immunoglobulin light chain protein in primary localized rectal amyloidosis.

Rectal involvement is usually part of a systemic amyloidosis, whereas, localized rectal amyloidosis is a rare entity. We present a case of asymptomatic localized rectal amyloidoma. Amyloid fibrils were isolated from rectal biopsy tissue and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) which showed bands at 17 kDa, 21 kDa and 28 kDa, a broad doublet band at 7-8 kDa and weaker bands at 15 kDa and 24 kDa. Edman sequence analysis of the isolated protein and its tryptic peptides showed that the amyloid protein was derived from an immunoglobulin lambdaII-light chain. To our knowledge, this is the first reported case to isolate and chemically characterize amyloid fibrils from a localized rectal amyloidoma. The development of specific therapies for patients with amyloid-associated disorders emphasizes the need to characterize the biochemical nature of the amyloid fibril protein.