Francis L. Weng

Association of Hepatitis C with Posttransplant Diabetes in Renal Transplant Patients on Tacrolimus

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Race and Electronically Measured Adherence to Immunosuppressive Medications after Deceased Donor Renal Transplantation

Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26 to 0.72; P = 0.001). Cause of renal disease, Powerful Others health locus of control, transplant center, and dosing frequency were also associated with adherence. After adjustment for transplant center and dosing frequency, the association between black race and decreased adherence was substantially attenuated (OR, 0.65; 95% CI, 0.38 to 1.14, P = 0.13). Transplant center (P = 0.003) and increased dosing frequency (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P = 0.003) remained independently associated with adherence. Other baseline demographic, socioeconomic, medical, surgical, and psychosocial characteristics were not associated with adherence. The transplant center and dosing frequencies of immunosuppressive medications are associated with adherence and explain a substantial proportion of the race-adherence relationship.

Renal transplantation in patients with pre-transplant donor-specific antibodies and negative flow cytometry crossmatches.

The clinical significance of pre‐transplant donor‐specific antibodies (DSA), despite negative cytotoxicity and flow cytometry crossmatches (FCXMs), is unknown. We performed a retrospective cohort study of 60 living donor renal transplant recipients, all with pre‐transplant cytotoxicity and T‐cell and B‐cell FCXMs that were negative. Twenty recipients had pre‐transplant DSA detected by enzyme‐linked immunosorbent assays (ELISA) and/or microbead methods. Forty contemporaneous DSA‐negative controls were selected. In the DSA‐positive group, after a median follow‐up of 8.2 months (25–75% range, 5.4–22.8 months), patient survival was 100% and allograft survival was 95.0%. Acute humoral rejection (AHR) developed in four patients (20.0%). Three of the AHR episodes occurred within the first month post‐transplant. Median serum creatinine at last follow‐up was 1.3 mg/dL (25–75% range, 1.0–1.6 mg/dL), versus 1.1 mg/dL (25–75% range, 0.9–1.4 mg/dL) in the DSA‐negative controls (p = 0.29). Only one of the 40 controls developed AHR (2.5%). Pre‐transplant DSA was associated with a significantly increased incidence of AHR (p = 0.02 by log‐rank test). In conclusion, despite negative pre‐transplant cytotoxicity and FCXMs, renal transplant recipients with pre‐transplant DSA detected by solid‐phase methods may have an increased incidence of AHR and require close monitoring post‐transplant.

Oral ganciclovir versus low-dose valganciclovir for prevention of cytomegalovirus disease in recipients of kidney and pancreas transplants.

Background. The optimal regimen for prophylaxis of cytomegalovirus (CMV) disease after kidney and/or pancreas transplantation remains unclear. We compared the effectiveness of three months of oral ganciclovir (3 g/day) versus low-dose valganciclovir (450 mg/day) for CMV prophylaxis. Methods. We performed a retrospective cohort study of patients at our center who received kidney and/or pancreas transplants between January 2000 and April 2003. We used a Cox proportional hazards model to examine the relationship between baseline covariates, including type of CMV prophylaxis, and time to development of CMV disease. Results. Of the 500 patients (295 ganciclovir, 205 valganciclovir), 22 patients (4.4%) developed CMV disease (mean time to CMV disease, 163±85 days). Sixteen of the ganciclovir patients (5.4%) and six of the valganciclovir patients (2.9%) developed CMV disease (P=0.18). By CMV serostatus, the incidence of CMV disease during the first posttransplant year was 8.5% among donor-seropositive, recipient-seronegative (D+/R−) patients, 8.6% among D+/R+ patients, 2.9% among D−/R+ patients, 1.0% among D−/R− patients, and 0.9% among patients for whom documentation of CMV serostatus was incomplete. In the unadjusted Cox proportional hazards analysis, race/ethnicity, type of transplant, type of antiviral prophylaxis, CMV serostatus, and use of mycophenolate mofetil were each associated with risk of developing CMV disease. In the adjusted, multivariable model, only CMV serostatus was associated with development of CMV disease. Conclusions. Three months of low-dose valganciclovir (450 mg/day) was as effective as ganciclovir (3 g/day) for prophylaxis of CMV disease after kidney and/or pancreas transplantation.

Associations of Perfusate Biomarkers and Pump Parameters With Delayed Graft Function and Deceased Donor Kidney Allograft Function

Hypothermic machine perfusion (HMP) is increasingly used in deceased donor kidney transplantation, but controversy exists regarding the value of perfusion biomarkers and pump parameters for assessing organ quality. We prospectively determined associations between perfusate biomarkers (neutrophil gelatinase–associated lipocalin [NGAL], kidney injury molecule 1, IL‐18 and liver‐type fatty acid–binding protein [L‐FABP]) and pump parameters (resistance and flow) with outcomes of delayed graft function (DGF) and 6‐mo estimated GFR (eGFR). DGF occurred in 230 of 671 (34%) recipients. Only 1‐h flow was inversely associated with DGF. Higher NGAL or L‐FABP concentrations and increased resistance were inversely associated with 6‐mo eGFR, whereas higher flow was associated with higher adjusted 6‐mo eGFR. Discarded kidneys had consistently higher median resistance and lower median flow than transplanted kidneys, but median perfusate biomarker concentrations were either lower or not significantly different in discarded compared with transplanted kidneys. Notably, most recipients of transplanted kidneys with isolated “undesirable” biomarker levels or HMP parameters experienced acceptable 6‐mo allograft function, suggesting these characteristics should not be used in isolation for discard decisions. Additional studies must confirm the utility of combining HMP measurements with other characteristics to assess kidney quality.

Preimplant Histologic Acute Tubular Necrosis and Allograft Outcomes

BACKGROUND AND OBJECTIVES The influence of deceased-donor AKI on post-transplant outcomes is poorly understood. The few published studies about deceased-donor preimplant biopsy have reported conflicting results regarding associations between AKI and recipient outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This multicenter study aimed to evaluate associations between deceased-donor biopsy reports of acute tubular necrosis (ATN) and delayed graft function (DGF), and secondarily for death-censored graft failure, first adjusting for the kidney donor risk index and then stratifying by donation after cardiac death (DCD) status. RESULTS Between March 2010 and April 2012, 651 kidneys (369 donors, 4 organ procurement organizations) were biopsied and subsequently transplanted, with ATN reported in 110 (17%). There were 262 recipients (40%) who experienced DGF and 38 (6%) who experienced graft failure. DGF occurred in 45% of kidneys with reported ATN compared with 39% without ATN (P=0.31) resulting in a relative risk (RR) of 1.13 (95% confidence interval [95% CI], 0.9 to 1.43) and a kidney donor risk index-adjusted RR of 1.11 (95% CI, 0.88 to 1.41). There was no significant difference in graft failure for kidneys with versus without ATN (8% versus 5%). In stratified analyses, the adjusted RR for DGF with ATN was 0.97 (95% CI, 0.7 to 1.34) for non-DCD kidneys and 1.59 (95% CI, 1.23 to 2.06) for DCD kidneys (P=0.02 for the interaction between ATN and DCD on the development of DGF). CONCLUSIONS Despite a modest association with DGF for DCD kidneys, this study reveals no significant associations overall between preimplant biopsy-reported ATN and the outcomes of DGF or graft failure. The potential benefit of more rigorous ATN reporting is unclear, but these findings provide little evidence to suggest that current ATN reports are useful for predicting graft outcomes or deciding to accept or reject allograft offers.

Associations of deceased donor kidney injury with kidney discard and function after transplantation.

Deceased donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing admission‐to‐terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6‐month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08–1.52), 1.82 (1.45–2.30) and 2.74 (2.0–3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09–1.49), 1.70 (1.37–2.12) and 2.25 (1.74–2.91), respectively. Six‐month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 [interquartile range: 31–61] vs. 58 [45–75] ml/min/1.73m2 for no DGF, p < 0.001). There was significant favorable interaction between donor AKI and DGF such that 6‐month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 [29–60], 49 [32–64], 52 [36–59] and 58 [39–71] ml/min/1.73m2 for no AKI, stage 1, 2 and 3, respectively; interaction p = 0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6‐month allograft function, clinicians should consider cautious expansion into this donor pool.

Associations between Deceased-Donor Urine Injury Biomarkers and Kidney Transplant Outcomes

Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m(2) In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant.

Recurrence of lupus nephritis after renal transplantation: if we look for it, will we find it?

Recurrence of lupus nephritis after kidney transplantation is often regarded as rare, and transplantation of patients with end-stage renal disease secondary to this condition is common. Several studies, however, have reported a higher incidence of recurrence of lupusnephritis after renal transplantation than the 1–4% which is usually quoted. Weng and Goral discuss reasons for the variation in reported incidence of recurrent lupus nephritis and consider the potential clinical impact of recurrence.

Fatal Graft-Versus-Host Disease Presenting as Fever of Unknown Origin in a Pancreas-After-Kidney Transplant Recipient

Acute graft‐versus‐host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54‐year‐old male with type 1 diabetes who received a zero‐antigen mismatched pancreas‐after‐kidney transplant from a pancreas donor who was homozygous at the HLA‐B, ‐Cw, ‐DR, and ‐DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low‐grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants.