Brian R. Stephany

Donor Kidney Volume and Outcomes Following Live Donor Kidney Transplantation

Pre‐donation kidney volume and function may be crucial factors in determining graft outcomes in kidney transplant recipients. We measured living donor kidney volumes by 3D helical computed tomography scanning and glomerular filtration rate (GFR) by 125I‐iothalamate clearances in 119 donors, and correlated these values with graft function and incidence of acute rejection at 2 years post‐transplantation. Kidney volume strongly correlated with GFR (Pearson r= 0.71, p < 0.001). Body size and male gender were independent correlates of larger kidney volumes, and body size and age were predictors of kidney function. The effects of transplanted kidney volume on graft outcome were studied in 104 donor‐recipient pairs. A transplanted kidney volume greater than 120 cc/1.73 m2 was independently associated with better estimated GFR at 2 years post‐transplant when compared to recipients of lower transplanted kidney volumes (64 ± 19 vs. 48 ± 14 mL/min/1.73 m2, p < 0.001). Moreover, recipients of lower volumes had a higher incidence of acute cellular rejection (16% vs. 3.7%, p = 0.046). In conclusion, kidney volume strongly correlates with function in living kidney donors and is an independent determinant of post‐transplant graft outcome. The findings suggest that (1) transplantation of larger kidneys confers an outcome advantage and (2) larger kidneys should be preferred when selecting from otherwise similar living donors.

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m(2) is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by (125)I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m(2) for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49+/-0.61 ml/min per 1.73 m(2) per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

The Role of Proteasome Inhibition With Bortezomib in the Treatment of Antibody-Mediated Rejection After Kidney-Only or Kidney-Combined Organ Transplantation

Background. We report our initial experience in using the proteasome inhibitor, bortezomib, to treat established antibody-mediated rejection (AMR) in 20 patients. Methods. There were 16 kidney-only and 4 kidney-combined organ recipients with de novo donor-specific antibody (DSA) and histologic evidence of AMR with peritubular capillaries C4d deposition. AMR was diagnosed 19.8 months (range 1-71 months) posttransplant. Patients received intravenous corticosteroids followed by a 2-week cycle on days 1-4-8-11 of plasmapheresis and 1.3 mg/m2 bortezomib; then 0.5 mg/kg intravenous immunoglobulin four times. Results. De novo class I DSA was detected in 11 (55%) and class II DSA in 18 (90%) recipients. The absolute mean difference between peak-nadir dominant DSA was 68,171 molecules of equivalent soluble fluorochrome (P<0.0001), representing 55%±22%. Only two patients (10%) had undetectable DSA after treatment. Patient survival is 100%, and graft survival is 85% with a mean follow-up of 9.8 months (range 2-20 months). The treatment was generally well tolerated but caused fatigue, gastrointestinal complaints, fluid retention, and thrombocytopenia in a number of patients. The last follow-up estimated glomerular filtration rate was 41.9±16.8 mL/min (range 20.6-72.2 mL/min). However, only 25% returned to their baseline renal function before AMR, and many have proteinuria with urine protein/creatinine more than 0.5 in 41% and more than 1.0 in 18%. Conclusions. The bortezomib-containing regimen demonstrated activity in AMR but seems to be most effective before the onset of significant renal dysfunction (serum creatinine <3 mg/dL) or proteinuria (<1 g/day). The best use of bortezomib to treat AMR should be evaluated in controlled trials using dosing strategies that include longer courses or retreatment schedules.

Utility of leflunomide in the treatment of complex cytomegalovirus syndromes.

Background. Cytomegalovirus (CMV) viremia that is resistant or refractory to the standard antiviral therapy still constitutes a major threat to high-risk transplant recipients. In addition, multiple CMV recurrences may lead to neutropenia because of repeated courses of therapy with ganciclovir derivatives. Leflunomide, a drug for rheumatoid arthritis, has been reported to have anti-CMV activity. This study reports on its use in 17 transplant recipients with complex CMV syndromes who had failed or were intolerant to other therapies. Methods. Single-center, retrospective study. Clinical data were extracted from the electronic medical record. CMV DNA viral loads were performed by quantitative hybrid capture assay. Results. Leflunomide was initiated after a median of three episodes of CMV viremia, with a mean peak viral load of 245,826 copies/mL. Initial clearance of CMV viremia was observed in 14 of 17 patients (82%), and 9 of 17 (53%) patients achieved a long-term suppression of CMV recurrences. Higher peak viral load and higher viral load at the start of leflunomide therapy were associated with failure to suppress viremia. The duration of leflunomide therapy ranged from 1 to 24 months (median 3.5 months, interquartile range 2.6–7 months), and the mean time to an undetectable CMV-DNA was 1.9 months. Adverse effects included diarrhea (35%), anemia (18%), and increased liver function tests (12%). Conclusions. Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.

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.

Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation.

Background. Calcineurin inhibitor(CNI)-free protocols using sirolimus (SRL) in kidney transplantation have proven effective, although reports have linked SRL to proteinuria. We sought to investigate this link and its impact on graft function. Methods. We retrospectively analyzed 184 live donor kidney transplant recipients who exclusively received de novo CNI-based (n=106) or SRL-based (n=78) regimens. Estimated glomerular filtration rate (GFR) and semi-quantitative dipstick proteinuria measurements were obtained at one, six, 12, and 24 months and six and 12 months, respectively. Results. SRL-treated patients had higher frequencies of proteinuria (≥1+) at 6 months (40.8% vs. 21.4%, P=0.006) and 12 months (37.8% vs. 18.4%, P=0.004) than those treated with CNI. Independent predictors of proteinuria at 12 months were GFR at one month (OR 0.62 per 10 ml/min/1.73m2, P<0.001), delayed graft function (OR 11.5, P=0.02), and a SRL-based regimen (OR 4.18, P=0.002). By univariable analysis, SRL vs. CNI patients had higher GFR at each point. SRL-treated patients without proteinuria had higher GFR at 12 months compared to CNI-treated patients with and without proteinuria (66 vs. 50 or 56 ml/min/1.73m2, P<0.05). No difference in GFR was seen between SRL-treated patients with proteinuria vs. CNI-treated patients without proteinuria (57 vs. 56 ml/min/1.73m2, P>0.05). Absence of proteinuria and a SRL-based regimen remained independently associated FSwith higher GFR at 12 months by multivariable analyses. Conclusions. De novo SRL-based immunosuppression is associated with a higher frequency of semi-quantitative proteinuria, however, estimated graft function at 1 year posttransplant remains superior to that of CNI-treated patients. Nevertheless, the long-term implications of these findings need to be determined.

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.

An Emerging Population: Kidney Transplant Candidates Who Are Placed on the Waiting List after Liver, Heart, and Lung Transplantation

BACKGROUND AND OBJECTIVES ESRD has an adverse impact on patients who have had previous nonrenal solid-organ transplants (NRTxs; liver, heart, lung) and may be referred for a kidney transplant (KTx). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using Scientific Registry of Transplant Recipients data for all KTx candidates who had NRTx and were listed between 1995 and 2008, incidence of NRTx listings were compared with trends in KTx without NRTX. The efficacy of kidney transplantation relative to dialysis was measured in time-dependent Cox models that incorporated candidates with the applicable previous organ transplant as a reference group. RESULTS Overall, 4904 NRTx candidates were listed during the study period, growing from <1% of candidates before 1995 to 3.3% in 2008. A total of 38% of NRTx candidates were listed preemptively versus 21% of other candidates. NRTx candidates had dramatically shorter half-lives (≤ 4 years) after listing compared with previous KTx recipients (9.2 years). KTx demonstrated a survival advantage for each type of NRTx candidate relative to maintenance dialysis. Listing for expanded-criteria donor kidneys averaged 47% and did not differ significantly by previous transplant category. CONCLUSIONS KTx candidates who are placed on the waiting list after NRTx constitute a significant and more rapidly growing cohort compared with the general KTx candidate population. NRTx candidates are frequently listed preemptively but have rapid decline once placed on the waiting list. Targeted use of expanded-criteria donor and living-donor transplants in the NRTx population may be particularly important given their high mortality on the waiting list.

Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease: An Open-Label Randomized Controlled Pilot Study

BACKGROUND AND OBJECTIVES The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography. RESULTS Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01). CONCLUSION Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.

Short-term and long-term outcomes of acute kidney injury after lung transplantation

BACKGROUND The effect of acute kidney injury (AKI) after lung transplantation has been described infrequently and with inconsistent results. Using a newly adopted and validated definition of AKI proposed by the Acute Kidney Injury Network (AKIN), we examined the incidence of AKI and associated renal morbidity and short-term and long-term mortality. METHODS We retrospectively evaluated data of 657 patients who underwent lung transplantation from 1997 to 2009. Outcomes analyzed were the incidence of AKI, as defined and categorized into 3 stages according to creatinine criteria from the AKIN classification (AKIN 1, AKIN 2, and AKIN 3), cumulative incidence of chronic kidney disease (CKD), as defined by an estimated glomerular filtration rate ≤ 29 ml/min/1.73 m(2), and/or the onset of end-stage renal disease, as defined by the need for renal replacement therapy for 8 weeks with no recovery on follow-up or need for kidney transplant, and long-term mortality. RESULTS We identified 424 patients (65%) who had at least 1 AKI (309 [47%] AKIN 1 and 115 [17%] AKIN 2-3) event in the first 2 weeks after transplantation. At 1 year, the cumulative incidence of CKD was 5.8%, 12.8%, 24.5 % in the no-AKI, AKIN 1, and AKIN 2-3 patients, respectively. After a median follow-up of 2.2 years, 277 (42%) died. One-year patient survival was 91%, 82%, 66% in the no-AKI, AKIN 1, and AKIN 2-3 patients, respectively. Adjusting for age, sex, race, type and cause of lung transplant, diabetes, and hypertension, the hazard ratio for death was 1.7 (95% confidence interval, 1.2-2.2; p = 0.0002) for AKIN 1 and 2.9 (95% confidence interval, 1.7-3.7; p < 0.001) for AKIN 2-3. CONCLUSIONS AKI is a common complication after lung transplantation and is associated with increased risk of CKD and all cause-mortality on long-term follow-up.