Roberto S. Kalil

Older donor livers show early severe histological activity, fibrosis, and graft failure after liver transplantation for hepatitis C.

Background. In hepatitis C virus (HCV)-positive liver transplant recipients, infection of the allograft and recurrent liver disease are important problems. Increased donor age has emerged as an important variable affecting patient and graft survival; however, specific age cutoffs and risk ratios for poor histologic outcomes and graft survival are not clear. Methods. A longitudinal database of all HCV-positive patients transplanted at our center during an 11-year period was used to identify 111 patients who received 124 liver transplants. Graft survival and histological endpoints (severe activity and fibrosis) of HCV infection in the allografts were compared as a function of donor age at transplantation. Results. By Kaplan-Meier analyses, older allografts showed earlier failure and decreased time to severe histological activity and fibrosis as compared with allografts from younger donors. By Cox proportional hazards analysis, older allografts were at greater risk for all severe histologic features and decreased graft survival as compared with younger allografts (P≤0.02 for all outcomes). Analysis of donor age as a dichotomous variable showed that donors greater than 60 yr were at high risk for deleterious histologic outcomes and graft failure. An age cutoff of 60 yr showed a sensitivity of 94% and specificity of 67% for worse graft survival by receiver operating characteristics curve. Conclusions. Advanced donor age is associated with more aggressive recurrent HCV and early allograft failure in HCV-positive liver transplant recipients. Consideration of donor age is important for decisions regarding patient selection, antiviral therapy, and organ allocation.

A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation

Background. For stable kidney-transplant recipients receiving triple drug therapy with cyclosporine (CsA), prednisone, and mycophenolate mofetil (MMF), it remains unclear what is the optimal dose of CsA beyond the first 6 to 12 months after transplantation. Complete CsA withdrawal has been associated with a significant incidence of acute rejection and, in some studies, chronic rejection as well. Methods. We performed an open, prospectively randomized, controlled clinical trial to determine whether CsA could be safely reduced by 50%. At 1 year or more posttransplant, 64 patients were randomized to either continue their stable-maintenance CsA dose (control group, n=32) or to lower their CsA dose by 50% over a 2 month period (CsA reduction group, n=32). All patients had stable renal-allograft function at the time of enrollment. Results. Within 6 months of randomization, no episode of acute rejection or graft loss occurred in either group. Patients in the CsA reduction group had a slight but significant increase in their glomerular filtration rate and a trend towards lower serum creatinine. There was also a significant decrease in mean systolic blood pressure, triglycerides, and serum uric acid levels in the CsA reduction group. No significant changes in any of these parameters were observed in the control group. Conclusions. This study suggests that a strategy consisting of a 50% CsA reduction is safe and is not associated with the increased risk of acute rejection observed in CsA withdrawal studies. It also has the potential to improve short-term allograft function and appears to reduce cardiovascular risk factors such as hypertension and hyperlipidemia.

A Prospective Controlled Study of Living Kidney Donors: Three-Year Follow-up

BACKGROUND There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. STUDY DESIGN Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS 3-year follow-up of kidney donors and paired controls suitable for donation at their donors center. PREDICTOR Kidney donation. OUTCOMES Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. RESULTS At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36±7.55mL/min per year in 194 controls, but increased 1.47±5.02mL/min per year in 198 donors (P=0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0±11.2 [SD] vs 120.7±9.7mmHg [P=0.6]; mean diastolic blood pressure, 73.4±7.0 vs 74.5±6.5mmHg [P=0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% ± 6.6% of controls and 11.3% ± 6.1% of donors (P=0.9). Urinary protein-creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. LIMITATIONS Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. CONCLUSIONS Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function.

A Prospective Controlled Study of Kidney Donors: Baseline and 6-Month Follow-up

BACKGROUND Most previous studies of living kidney donors have been retrospective and have lacked suitable healthy controls. Needed are prospective controlled studies to better understand the effects of a mild reduction in kidney function from kidney donation in otherwise healthy individuals. STUDY DESIGN Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS Consecutive patients approved for donation at 8 transplant centers in the United States were asked to participate. For every donor enrolled, an equally healthy control with 2 kidneys who theoretically would have been suitable to donate a kidney also was enrolled. PREDICTOR Kidney donation. MEASUREMENTS At baseline predonation and at 6 months after donation, medical history, vital signs, measured (iohexol) glomerular filtration rate, and other measurements were collected. There were 201 donors and 198 controls who completed both baseline and 6-month visits and form the basis of this report. RESULTS Compared with controls, donors had 28% lower glomerular filtration rates at 6 months (94.6 ± 15.1 [SD] vs 67.6 ± 10.1 mL/min/1.73 m(2); P < 0.001), associated with 23% greater parathyroid hormone (42.8 ± 15.6 vs 52.7 ± 20.9 pg/mL; P < 0.001), 5.4% lower serum phosphate (3.5 ± 0.5 vs 3.3 ± 0.5 mg/dL; P < 0.001), 3.7% lower hemoglobin (13.6 ± 1.4 vs 13.1 ± 1.2 g/dL; P < 0.001), 8.2% greater uric acid (4.9 ± 1.2 vs 5.3 ± 1.1 mg/dL; P < 0.001), 24% greater homocysteine (1.2 ± 0.3 vs 1.5 ± 0.4 mg/L; P < 0.001), and 1.5% lower high-density lipoprotein cholesterol (54.9 ± 16.4 vs 54.1 ± 13.9 mg/dL; P = 0.03) levels. There were no differences in albumin-creatinine ratios (5.0 [IQR, 4.0-6.6] vs 5.0 [IQR, 3.3-5.4] mg/g; P = 0.5), office blood pressures, or glucose homeostasis. LIMITATIONS Short duration of follow-up and possible bias resulting from an inability to screen controls with kidney and vascular imaging performed in donors. CONCLUSIONS Kidney donors have some, but not all, abnormalities typically associated with mild chronic kidney disease 6 months after donation. Additional follow-up is warranted.

Abnormalities in biomarkers of mineral and bone metabolism in kidney donors

Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors.

Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study

BACKGROUND Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. STUDY DESIGN Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. SETTING & PARTICIPANTS Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. PREDICTOR Uric acid concentration. OUTCOMES The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. RESULTS 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). LIMITATIONS Unknown use of uric acid-lowering agents among study participants. CONCLUSIONS Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C

Background. Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. Methods. Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non–HVC-related deaths and graft losses censored) were analyzed. Results. By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). Conclusions. CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.

Treatment for presumed BK polyomavirus nephropathy and risk of urinary tract cancers among kidney transplant recipients in the United States

Recent case series describe detection of BK polyomavirus (BKV) in urinary tract cancers in kidney transplant recipients, suggesting that BKV could contribute to the development of these cancers. We assessed risk for urinary tract cancers in kidney recipients with or without treatment for presumed BKV nephropathy (tBKVN) using data from the United States Transplant Cancer Match Study (2003‐2013). Among 55 697 included recipients, 2015 (3.6%) were reported with tBKVN. Relative to the general population, incidence was similarly elevated (approximately 4.5‐fold) for kidney cancer in recipients with or without tBKVN, and incidence was not increased in either group for prostate cancer. In contrast, for invasive bladder cancer, incidence was more strongly elevated in recipients with versus without tBKVN (standardized incidence ratios 4.5 vs. 1.7; N = 48 cases), corresponding to an incidence rate ratio (IRR) of 2.9 (95% confidence interval [CI] 1.0‐8.2), adjusted for sex, age, transplant year, and use of polyclonal antibody induction. As a result, recipients with tBKVN had borderline increased incidence for all urothelial cancers combined (renal pelvis, ureter, and bladder cancers: adjusted IRR 2.2, 95% CI 0.9‐5.4; N = 89 cases). Together with reports describing BKV detection in tumor tissues, these results support an association between BKV and urothelial carcinogenesis among kidney transplant recipients.

The Disadvantage of Being Fat

Given the epidemic of obesity in the United States, it is not surprising that an increasing fraction of patients who are considered for and receiving kidney transplants are also overweight. Friedman et al. [1][1] found a 41.9% decrease in the fraction of patients with normal body mass index (BMI)

Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.