Richard Spong

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 Chronic Kidney Disease in Long-Term Survivors of Lung and Heart-Lung Transplantation

Renal insufficiency is common after non‐renal organ transplants. The predictors of long‐term renal outcomes are not well established. A total of 219 lung and heart‐lung transplant recipients surviving more than 6 months after transplantation were studied to determine predictors of time to doubling of serum creatinine and end‐stage kidney disease (ESKD) with death as a competing risk. Median follow‐up was 79 months (range 9–222 months). Baseline estimated glomerular filtration rate (GFR) was 96.3 ± 34.5 mL/min/1.73 m2. One hundred twenty‐two recipients (55%) doubled their serum creatinine, 16 (7.3%) progressed to ESKD and 143 (65%) died. The majority of recipients who survived >6 years had a GFR < 60 mL/min at both 1 and 7 years. Most of the loss of renal function occurred in the first year post‐transplant. Older age at transplant, lower GFR at 1 month and cyclosporine use in the first 6 months predicted shorter time to doubling of serum creatinine when death was handled as a competing risk. Based on this prevalence data and using GFR decay and death as study endpoints, we offer sample size estimates for a prospective, interventional trial that is aimed at slowing or preventing the progression of kidney disease.

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.

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1—c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)—both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

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.

Quality of life in elderly kidney transplant recipients

To evaluate quality of life (QOL) in kidney transplant recipients aged 65 and older, identify predictors of impaired physical and mental QOL cross‐sectionally and compare QOL over time with that of younger transplant recipients and general population controls.

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.

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.

Uric acid and allograft loss from interstitial fibrosis/tubular atrophy: post hoc analysis from the angiotensin II blockade in chronic allograft nephropathy trial.

Background Uric acid has been linked to the progression of native kidney disease. Studies evaluating its contribution to allograft function in kidney transplant recipients, among whom hyperuricemia is common, have yielded mixed results. Methods We evaluated the association between baseline uric acid and the primary composite outcome of doubling of interstitium or ESRD from interstitial fibrosis and tubular atrophy (IF/TA) in the Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN) Trial participants. Subjects underwent uric acid, iothalamte GFR, and urine albumin to creatinine (ACR) measurements annually for 5 years in addition to an allograft biopsy at baseline and 5 years. Results Baseline uric acid was 5.57±1.48 mg/dL; male sex, higher BMI, diuretic use, and lower GFR were associated with higher uric acid, whereas older age, less than 3 HLA matches and having a female donor were associated with lower levels. In multivariate analysis adjusting for baseline GFR, uric acid was associated with doubling of interstitium or ESRD from IF/TA (OR 1.83, 95% CI, 1.06–3.17, P=0.03). Over time, a 1 mg/dL increase in time-varying uric acid was associated with a 2.39 mL/min lower final GFR (P<0.001) but not with the secondary outcome of creatinine doubling, ESRD, or death. Conclusions These data suggest that uric acid is associated with IF/TA and thus may be a viable target for intervention.