Aleksandra Kukla

Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence.

Background: There is no doubt that acute calcineurin inhibitor (CNI) nephrotoxicity exists; however, chronic CNI nephrotoxicity is questionable at best. Methods: We reviewed the literature to identify original articles related to the use of CNIs in renal and nonrenal solid organ transplantation in order to examine the available evidence about their chronic nephrotoxicity and contribution to graft failure. Results: Early clinical experience and animal studies support the evidence of CNI nephrotoxicity. These findings evolved into the dogma that CNI nephrotoxicity is the major cause of late renal allograft failure. However, in transplanted kidneys the specific role of chronic CNI nephrotoxicity has been questioned. The emerging literature clearly highlights the lack of solid evidence for the role of CNIs as the sole and major injurious agents that cause chronic renal dysfunction and subsequent graft failure. Most of the evidence available to date is against complete CNI avoidance, and minimization appears to be a more viable strategy. It is becoming increasingly clear that the typical pathological lesions linked to chronic CNI use are highly nonspecific, and most of the chronic changes that have been attributed to chronic CNI nephrotoxicity are the consequences of previously unrecognized immunologic injuries. One needs to keep in mind that the potential risk of side effects of CNI use should be balanced against the risk of rejection. Conclusions: More research should focus on addressing the true causes of chronic graft dysfunction rather than focusing on the overexaggerated contribution of CNIs to late graft loss.

Ten-Year Outcome after Rapid Discontinuation of Prednisone in Adult Primary Kidney Transplantation

BACKGROUND AND OBJECTIVES Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied. RESULTS Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P<0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups. CONCLUSIONS Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Predictors of graft failure and death in elderly kidney transplant recipients.

Background The upper age limit to receive a kidney transplant has progressively risen, but the outcomes of elderly (ages ≥65 years) transplant recipients remain understudied. We therefore evaluated mortality, graft failure, and predictors of these outcomes in this population. Methods Three cohorts of recipients transplanted between 1963 and 2012 (ages <50 years [n=2900], 50–64 years [n=1218], and ≥65 years [n=364] at transplantation) were compared for allograft and patient outcomes. Three similar age cohorts transplanted after 2000 (n=1410) were studied separately to address era effect. Results Death-censored graft survival was higher in recipients ages ≥65 years: 5, 10, and 15 years was 90.7%, 80.4%, and 73.7%; for ages 50–64 years, it was 87.2%, 77.6%, and 71.5%; and for ages <50 years was 79.8%, 70.3%, and 60.8%. Risk factors for graft failure in those ages ≥65 years included panel-reactive antibody >10%, congestive heart failure (CHF), delayed graft function, and cellular rejection. The 5-, 10-, and 15-year patient survival rate was 69.7%, 36.0%, and 14.0% for those ages ≥65 years; 76.4%, 54.8%, and 34.0% for those ages 50–64 years; and 81.7%, 66.7%, and 52.2% for those ages <50 years. For the entire cohort of elderly recipients, coronary artery disease and CHF were associated with mortality, and in those recipients transplanted after 2000, the risk factors for mortality were coronary artery disease, graft failure, peripheral vascular disease, and cause of end-stage renal disease listed as other. For graft failure, only CHF and cellular rejection were associated with this outcome. Conclusions The overall outcomes of transplantation in elderly kidney transplant recipients ages ≥65 years are excellent, but the risk factors for mortality and graft failure are distinctly different than those observed in younger recipients.

Renal Function Profile in White Kidney Donors: The First 4 Decades

Previous studies reported the risk of ESRD after kidney donation, but not the renal outcomes that precede ESRD. Here, we estimated the risk of proteinuria, reduced GFR, and ESRD in 3956 white kidney donors, assessed the contribution of postdonation hypertension and diabetes to these outcomes, and developed a risk calculator. After a mean±SD follow-up of 16.6±11.9 years, 215 (6.1%) donors developed proteinuria. Men had a higher risk of proteinuria (hazard ratio [HR], 1.56; 95% confidence interval [95% CI], 1.18 to 2.05; P<0.001) as did those with higher body mass index (HR, 1.10; 95% CI, 1.06 to 1.13; P<0.001). In all, 1410 (36%) donors reached an eGFR<60 ml/min per 1.73 m(2), and 112 (2.8%) donors had either an eGFR<30 ml/min per 1.73 m(2) or ESRD (28 donors developed ESRD). An eGFR<30 ml/min per 1.73 m(2) or ESRD associated with older age (HR, 1.07; 95% CI, 1.05 to 1.09; P<0.001), higher body mass index (HR, 1.08; 95% CI, 1.04 to 1.13; P<0.001), and higher systolic BP (HR, 1.02; 95% CI, 1.00 to 1.04; P=0.01) at donation. Postdonation diabetes and hypertension associated with a fourfold higher risk of proteinuria and a >2-fold higher risk of ESRD. Models predicting proteinuria and reduced eGFR performed well (C-index 0.77-1.00). In conclusion, severe reduction in GFR and ESRD after kidney donation were uncommon and were highly associated with postdonation diabetes and hypertension. Furthermore, information available before donation may predict long-term renal outcomes in white living kidney donors.

Lymphoproliferative Disorders After Adult Kidney Transplant: Epidemiology and Comparison of Registry Report With Claims-Based Diagnoses

BACKGROUND Posttransplant lymphoproliferative disorder (PTLD) is a major complication of kidney transplant. STUDY DESIGN Retrospective cohort study comparing PTLD incidence rates using US Medicare claims and Organ Procurement and Transplantation Network (OPTN) data, examining risk factors for PTLD in OPTN data, and studying recipient and graft survival after PTLD diagnosis. SETTING & PARTICIPANTS All adult first-transplant patients who underwent deceased or living donor kidney-only transplants in 2000-2006 (n = 89,485) followed up through 3 years posttransplant. PREDICTORS Recipient and donor characteristics, HLA mismatches, viral serologic test results, and initial immunosuppression. OUTCOMES OPTN-reported or Medicare claims-based PTLD diagnosis, recipient and graft survival after OPTN-reported PTLD diagnosis. MEASUREMENTS Adjusted HRs for PTLD diagnosis estimated using a Cox proportional hazards model; probability of survival free of all-cause graft failure estimated using the Kaplan-Meier method. RESULTS The incidence rate of PTLD during the first posttransplant year was 2-fold higher in Medicare claims (0.46/100 patient-years; 95% CI, 0.39-0.53) than in OPTN data (0.22/100 patient-years; 95% CI, 0.17-0.27). Factors associated with increased rates of PTLD included older age, white race (vs African American), induction with T-cell-depleting antibodies, Epstein-Barr virus seronegativity at the time of transplant, and cytomegalovirus seronegativity at the time of transplant. The adjusted risk of death with graft function was 17.5 (95% CI, 14.3-21.4) times higher after a report of PTLD, and the risk of death-censored graft failure was 5.5 (95% CI, 3.9-7.7) times higher. LIMITATIONS Shortcomings inherent in large databases, including inconsistencies in patient follow-up, reporting, and coding practices by transplant centers; insufficient registry data to analyze acute rejection episodes and antirejection treatment; no available data for potential effects of different types of PTLD treatment on patient outcomes. CONCLUSIONS Despite the limitations of data collected by registries, PTLD clearly is an important complication; both mortality and death-censored graft failure increase after PTLD.

Recurrent Glomerulonephritis Under Rapid Discontinuation of Steroids

Background. Recurrent glomerulonephritis (GN) remains an important cause of kidney allograft loss and whether rapid discontinuation of steroids (RDS) is associated with a higher risk of recurrence is not known. Methods. We studied recurrence rate, and graft and patient survival in four groups of recipients: 216 recipients with GN transplanted under RDS (group 1), 978 concurrent non-GN recipients transplanted under RDS (group 2), 260 historic comparator group transplanted for GN between 1994 and 1999 with steroid maintenance (group 3), and 950 recipients who were also transplanted between 1994 and 1999 for non-GN and also maintained on steroids (group 4). Regression analysis adjusting for donor and recipient factors, steroid and sirolimus use, and also GN type was used to address factors associated with recurrent disease. Results. The 1-, 5-, and 7-year recurrence rate in the GN group under RDS was 6.7%, 13.7%, and 19.2% and in historic GN recipients maintained on steroids it was 2.4%, 3.8%, and 5.3%, respectively (P<0.0001). RDS was associated with a higher adjusted risk of recurrent disease for all GN types (hazard ratio 4.86; 95% confidence interval 2.34–10.07; P<0.0001). Graft and patient survival were similar in the two GN groups and both were highest among all groups. Notably, death-censored graft survival was not different among the groups. Conclusion. Steroid avoidance may be associated with a higher rate of recurrent GN but no apparent increase in risk of graft loss. This group of recipients needs to be studied more carefully, in larger numbers, and for a longer time period.

Diabetes after kidney donation.

Kidney donors, similar to the general population, are at risk for development of type 2 diabetes mellitus (T2DM). The course of donors who develop T2DM has not been studied. We surveyed 3777 kidney donors regarding the development of T2DM. Of the 2954 who responded, 154 developed T2DM 17.7 ± 9.0 years after donation. The multivariable risk of development of T2DM was associated with type 1 DM in the recipient, male gender and body mass index >30 kg/m2 at time of donation. Compared to age, gender, duration after donation and body mass index (BMI)‐matched non‐diabetic donor controls; diabetic donors were more likely to have hypertension (70.8% vs. 36.2%, p = 0.005), proteinuria (18.8% vs. 3.9%, p < 0.0001) but had a similar serum creatinine. eGFR change after T2DM development was −0.80 ± 0.94 mL/min/year, −0.70 ± 0.86 in nondiabetic donors with similar duration after donation and −0.61 ± 0.76 mL/min/year in age, gender, BMI and duration after donation matched nondiabetic donor controls. These preliminary and shor‐term data demonstrate that factors associated with T2DM in kidney donors are similar to those in the general population and donors screened carefully at the time of donation do not appear to have an acceleration of diabetic kidney disease.

Appraisal of GFR Estimating Equations Following Kidney Donation

BACKGROUND It is not clear which serum creatinine-based glomerular filtration rate (GFR)-estimating model performs best in kidney donors. STUDY DESIGN Study of diagnostic accuracy. SETTING & PARTICIPANTS From a population of 3,698 kidney donors, 255 donors underwent iohexol GFR measurement (mGFR). INDEX TEST (INTERVENTION): mGFR by means of plasma disappearance of iohexol. REFERENCE TEST OR OUTCOME GFR was estimated (eGFR) by using the Cockcroft-Gault equation (eGFR(CG)), Mayo Clinic equation (eGFR(MC)), and Modification of Diet in Renal Disease (MDRD) Study equation (eGFR(MDRD)). RESULTS Mean mGFR was 71.8 +/- 11.8 mL/min/1.73 m(2), and 85.5% had mGFR greater than 60 mL/min/1.73 m(2). eGFR(CG) underestimated mGFR by 3.96 +/- 13.3 mL/min/1.73 m(2) and was within 30% of mGFR 89.4% of the time. eGFR(MC) overestimated mGFR by 8.44 +/- 11.9 mL/min/1.73 m(2) and was within 30% of mGFR in 83.1% of cases. eGFR(MDRD) underestimated mGFR by only 0.43 +/- 11.7 mL/min/1.73 m(2), and the proportion within 30% of mGFR was greatest in the tested model; 94.1% of the time. However, eGFR(MC) was most accurate in classifying donors according to having eGFR less than 60 mL/min/1.73 m(2). LIMITATIONS Lack of ethnic diversity and response bias. CONCLUSIONS The MDRD Study equation is least biased, and because it is routinely reported by most laboratories, it is the best readily available model for estimating GFR in kidney donors.

Low birthweight and risk of albuminuria in living kidney donors.

Low birthweight is linked to hypertension, chronic kidney disease and even end‐stage renal disease. We hypothesized that living kidney donors born with lower birthweight may be at increased risk of hypertension, albuminuria, or reduced GFR beyond what is typical following uninephrectomy. Two hundred fifty‐seven living kidney donors who donated at the University of Minnesota between 1967 and 2005 underwent iohexol GFR and urinary albumin excretion measurements. Predictors of iohexol GFR <60 mL/min/1.73 m2, albuminuria, and hypertension were examined using logistic regression. Predictors examined include age at GFR measurement, time since donation, BMI, gender, serum creatinine level (at donation and GFR measurement), systolic and diastolic blood pressure, race, and birthweight. The latter was obtained through self‐report and verified through birth certificates and family members. Older age, higher BMI, and time from donation were associated with reduced GFR. Older age and higher BMI were also associated with hypertension. Birthweight was not associated with GFR <60 mL/min/1.73 m2: OR=0.70, 95% CI (0.28, 1.74), p = 0.45 or hypertension: OR=0.92, 95% CI (0.46, 1.84), p = 0.82 but was associated with albuminuria: OR=0.37, 95% CI (0.15, 0.92), p = 0.03. These data further strengthen the link between low birthweight and potential adverse renal outcomes.

Comparison of cystatin C and creatinine-based equations for GFR estimation after living kidney donation.

Background The performance of glomerular filtration rate (GFR) equations incorporating both cystatin C (CysC) and serum creatinine (Creat) in living kidney donors has not been studied before. Methods From a population of 3,698 living kidney donors, 257 donors were randomly selected to undergo GFR measurement (mGFR) by the plasma disappearance of iohexol. GFR was estimated with the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Collaboration study eGFR(CKD-EPI-Creat) in 257 donors and the two newly developed equations using CysC with and without Creat, eGFR(CKD-EPI-CysC) and eGFR(CKD-EPI-Creat+CysC), in 215 donors. Results Mean mGFR was 71.8±11.8 mL/min/1.73 m2. The eGFR(MDRD) exhibited least and only negative bias and the three other models were comparable in terms of bias. The eGFR(CKD-EPI-Creat+CysC) equation was most precise; r2=0.64. Both eGFR(MDRD) and eGFR(CKD-EPI-Creat+CysC) had high percentage (94.4% and 92.6%, respectively) of estimates falling within 30% of mGFR versus estimates by eGFR(CKD-EPI-Creat) and eGFR(CKD-EPI-CysC) equations (87.2% and 85.1%, respectively). The eGFR(MDRD) was by far most accurate in identifying those with mGFR less than 60 mL/min/1.73 m2 whereas the CKD-EPI models were extremely accurate in classifying those with mGFR greater than or equal to 60 mL/min/1.73 m2. Conclusions eGFR(CKD-EPI-Creat+CysC) equation provides comparable accuracy to the eGFR(MDRD) in overall estimation of mGFR, but with higher precision. However, eGFR(CKD-EPI-Creat+CysC) clearly misses many of those with a post-donation GFR less than 60 mL/min/1.73 m2 and therefore eGFR(MDRD) is preferable in detecting donors with GFR less than 60 mL/min/1.73 m2.