Naim Issa

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.

Evaluation of Creatinine-Based Estimates of Glomerular Filtration Rate in a Large Cohort of Living Kidney Donors

Background. Accurate determination of kidney function is critical in the evaluation of living kidney donors and higher donor glomerular filtration rate (GFR) is associated with better allograft outcomes. However, among transplant centers donor kidney function evaluation varies widely. Methods. The performance of creatinine clearance (CrCl), Modification of Diet in Renal Disease (MDRD), the re-expressed MDRD equations with standardized creatinine, and the Cockcroft-Gault (CG) formula as compared with 125I-iothalamate GFR (iGFR) was analyzed in 423 donors. All methods of GFR measurement were then evaluated for their association with graft function at 1 year. Results. The MDRD and re-expressed MDRD equations underestimated iGFR whereas CG showed minimal bias (median difference=−11.0, −16.3, and −0.5 mL/min/1.73 m2, respectively). CrCl overestimated iGFR (10 mL/min/1.73 m2). The MDRD, re-expressed MDRD, and CG formulas were more accurate (88%, 86%, and 88% of estimates within 30% of iGFR, respectively) than CrCl (80% within 30% of iGFR). Interestingly, low bias and high accuracy were achieved by averaging the MDRD estimation with the CrCl result; both methods available to the clinician in most transplant centers. We also showed that predonation GFR as measured by isotopic renal clearance or any of the creatinine-based estimation formulas may be associated with allograft function at 1 year, whereas the widely used CrCl was not. Conclusions. Variable performance was seen among different GFR estimations, with CrCl being the poorest. Recent recommendations to use the MDRD equation with standardized serum creatinine did not improve its performance. However, recognizing the limited availability of GFR laboratories, these methods are still clinically useful if used with caution and understanding their limitations.

Donor factors influencing graft outcomes in live donor kidney transplantation

Living donor renal allograft survival is superior to that achieved from deceased donors, although graft outcome is suboptimal in some of these patients. In an effort to identify the subset of patients at high risk for poor outcomes we studied donor risk factors in 248 living kidney donor–recipient pairs. Unadjusted donor 125I-iothalamate GFR (iGFR), donor age more than 45 years, donor total cholesterol level less than 200 mg/dL, and donor systolic blood pressure (SBP) less than 120 mm Hg were correlated with allograft estimated glomerular filtration rate (eGFR), and incidence of acute rejection (AR), delayed graft function and/or graft loss at 2 years posttransplantation. Donor iGFR less than 110 mL/min (slope=−7.40, P<0.01), donors more than 45 years (slope=−8.76, P<0.01), donor total cholesterol levels more than 200 mg/dL (slope=−10.03, P<0.01), and SBP more than 120 mm Hg (slope=−5.60, P=0.03) were associated with lower eGFR. By multivariable linear regression analysis these variables remained independently associated with lower eGFR, and poorer outcomes. The increasing number of donor factors (age, iGFR, cholesterol, and blood pressure) was directly associated with worse posttransplant eGFR (P<0.01). In conclusion, our data suggest that routine assessment of living donor parameters could supplement the consideration of recipient characteristics in predicting posttransplant risk of graft injury/dysfunction.

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.

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.

Medical outcomes of adolescent live kidney donors

Living kidney donation from donors <18 yr of age is uncommon. The majority of donations from adolescents took place several decades ago providing a unique opportunity to study true long‐term consequences of donation. We compared survival, renal outcomes, and rates of hypertension and diabetes among 42 adolescent donors and matched older controls. Adolescent donors were matched with donors 18–30 yr on the following: gender, relation to the recipient, BMI at donation, eGFR at donation, and year of donation. After a mean follow‐up of 31.8 ± 8.0 yr, 94.9% of adolescent donors were alive vs. 93.8% of controls. There was no significant difference in having eGFR (MDRD) <60 mL/min/1.73 m2 (26.1% vs. 40.9%), hypertension (35.9% vs. 39.4%), diabetes (5.1% vs. 12.5%), or proteinuria (15.4% vs. 14.1%): adolescent donors vs. controls for all comparisons. These data suggest that adolescent donors are not at a higher risk of shortened survival, hypertension, diabetes, or proteinuria. Nevertheless, they probably should donate only when other options are exhausted as they have to live with a single kidney for decades and longer follow‐up is needed.

The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure

The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with GFR change, interstitial expansion and end-stage renal disease (ESRD) we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria or interstitial expansion. Losartan use, [HR 0.48 (95% CI 0.21–1.0), insignificant], and Caucasian donor, [HR 0.18 (95% CI 0.07–0.4), significant] were associated with less doubling of serum creatinine, death or ESRD. Hypertension, less than 3 HLA-matches, the combination of tacrolimus-rapamycin and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD, [HR 1.01 (95% CI 1.00–1.02)]. Thus, systemic RAAS is not overly activated in kidney transplant recipients but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.

Outcomes of Kidney Retransplantation in Recipients with Prior Post‐Transplant Lymphoproliferative Disorder

Post‐transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein–Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5–323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29–95 months) after PTLD diagnosis. After a median follow‐up of 62.5 months (range 2–125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted.