Impact of asymptomatic bacteriuria incidence and management post-kidney transplantation.

OBJECTIVE: Urinary tract infections (UTIs) are the most commonly occurring infectious complication following kidney transplantation. Questions remain regarding whether asymptomatic bacteriuria (ASB) should be treated. The aim was to evaluate the incidence and management of ASB in kidney transplant recipients at a large academic medical center. METHODS: All subjects receiving an isolated kidney transplant between September 2012 and October 2016, and with at least one ASB episode were included. Demographics, symptomatology, and urine culture data were collected on subjects with bacteriuria in the first year post-transplant. Cultures were classified by symptoms, ASB treatment trends were analyzed, and ASB-to-UTI progression was compared between ASB treatment and non-treatment. RESULTS: A total of 527 subjects were transplanted with 64 developing at least one ASB episode. The incidence of ASB was 12.1% and treated 74.6% of the time. Neither lack of ASB treatment (P = 0.463) nor ASB within the first month post-transplant (P = 0.303) were associated with ASB-to-UTI progression. CONCLUSION: Despite high ASB treatment rate, this was not found to be protective against ASB-to-UTI progression. ASB within the first month post-transplant also did not correlate with increased progression risk. These results suggest minimization of ASB treatment in kidney transplant recipients remains an important antimicrobial stewardship target.

Hidden selection bias deriving from donor organ characteristics does not affect performance evaluations of kidney transplant centers.

BACKGROUND: Transplant center performance evaluations have garnered substantial attention in recent years. Among sources of bias that may affect measured performance are underlying characteristics of donor organs. An unresolved question is whether centers accepting higher-risk donations are placed in jeopardy for lower evaluations independent of actual quality of care. OBJECTIVE: The primary aim was to assess whether unmeasured characteristics of donor organs impact risk-adjusted outcomes used for center performance evaluations. SUBJECTS: The study included adult kidney transplant recipients (n = 53,791) from 1994 to 2008 from a national registry. RESEARCH DESIGN: We compared adjusted graft survival with use of paired-donor kidneys (allocated to high- and low-performing centers) and unpaired donor kidneys to investigate whether measured center performance was consistent with organs derived from the same donor (minimizing the influence of noncodified risk factors). RESULTS: The primary finding was that differences between centers were unaffected by use of paired or unpaired donations (hazard ratio for patients transplanted at high performing centers with paired kidneys = 0.63 [95% CI, 0.53-0.74] and with unpaired kidneys = 0.66 [95% CI, 0.62-0.70], P value for interaction = 0.52). This finding was consistent over 5 consecutive cohorts, based on either concurrent or prospective outcomes and by altering the threshold criteria for identification of performance outliers. CONCLUSIONS: Results indicate that underlying selection bias from donor characteristics does not impact transplant center evaluations. This is important evidence that donor selection is not a primary driver for evaluated quality of care among transplant centers and acceptance of higher-risk kidneys should not be perceived as a primary threat to measured performance.

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.

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 (125)I-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 m(2), respectively). CrCl overestimated iGFR (10 mL/min/1.73 m(2)). 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.

Renal Transplant Acute Rejection with Lower Mycophenolate Mofetil Dosing and Proton Pump Inhibitors or Histamine-2 Receptor Antagonists.

BACKGROUND: Pharmacokinetic data show reduced mycophenolic acid levels in renal transplant recipients taking mycophenolate mofetil (MMF) and proton pump inhibitors (PPIs) concomitantly. This reduced exposure could increase rejection risk. The typical initial MMF dose post renal transplantation is 2 g/day, which often requires dose reduction secondary to side effects. Existing studies have not shown significant acute rejection differences for patients taking MMF-PPI versus patients taking MMF-ranitidine. OBJECTIVE: The purpose of this study was to evaluate clinical outcomes in renal transplant recipients receiving a lower MMF dose than previously studied (1.5 g/day) and either a PPI or histamine-2 receptor antagonist (H2RA). METHODS: This retrospective cohort study included adult subjects receiving a renal transplant between January 1, 2009, and June 30, 2013. Comparison groups were defined based on acid-suppressing therapy class prescribed at discharge from transplantation. The primary outcome was acute rejection incidence within 1 year posttransplantation. RESULTS: Of 728 renal transplant recipients screened, 522 were included: 183 taking a PPI and 339 taking an H2RA. There was no significant difference in acute rejection within 1 year (H2RA 19% versus PPI 14%, p=0.12) or 3 months (4% vs 5%, p=0.44, respectively) posttransplantation. Maintenance immunosuppression (MMF dose and tacrolimus troughs) was similar between groups at 3 months and 1 year. Graft and patient survivals were favorable (> 95%), and graft function at 1 year was stable and similar between groups. CONCLUSION: Despite taking lower MMF doses than previously studied, subjects on a PPI compared to an H2RA were not at increased risk of acute rejection within 1 year posttransplantation.

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 (> or =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/1.73 m, 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/1.73 m, 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/1.73 m, P > 0.05). Absence of proteinuria and a SRL-based regimen remained independently associated FS with 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.

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.

Patient participation in research among solid organ transplant recipients in the United States.

BACKGROUND: In many healthcare contexts, evidence exists that patients who participate in research protocols (PRP) significantly differ from nonparticipants. These differences may affect the external validity of study findings, reflect access to care, and potentially explain sources of difference in patient outcomes. There is no comprehensive study evaluating PRP among transplant recipients. METHODS: We evaluated the national Scientific Registry of Transplant Recipients from 2000 to 2008 for liver, kidney, heart, lung, and simultaneous pancreas/kidney transplant recipients in the United States for which PRP for immunosuppressive medications is reported at follow-up. Our primary aims were to evaluate participant characteristics, compare outcomes between participants and nonparticipants, and assess variability of PRP between centers and medications. RESULTS: The national proportions of PRP at 1 year by organ were kidney (8.2%), liver (2.9%), heart (5.0%), lung (2.6%), and simultaneous pancreas/kidney (2.8%). Factors associated with PRP included recipients' educational attainment, insurance, race/ethnicity, gender and age, donor age, transplant number, income, distance to center, and center volume. Graft and patient survivals were significantly higher among PRP for kidney, liver, and lung transplant recipients. PRP varied markedly between centers (range, 0%-58%) and by immunosuppressant medications. CONCLUSIONS: There are systematic differences between participants and nonparticipants in research in the transplant population that may affect the external validity of research findings. Superior outcomes among participants may suggest that participation in research itself affords certain benefits. Future research evaluating the mechanisms for differential participation rates and improved survival among participants is needed.

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.

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.

Absence of proteinuria predicts improvement in renal function after conversion to sirolimus-based immunosuppressive regimens in lung transplant survivors with chronic kidney disease.

BACKGROUND: Improvement in renal function has been noted in some lung allograft recipients with chronic kidney disease (CKD) converted from a calcineurin inhibitor (CNI)- to a sirolimus (SRL)-based immunosuppressive regimen. However, not all patients have such a positive response. We sought to investigate independent predictors of a favorable renal response in a cohort of lung transplant recipients. METHODS: We retrospectively studied 56 lung transplant recipients with CKD, defined as a pre-conversion estimated glomerular filtration rate (eGFR) < or =60 ml/min/1.73 m(2), who had been converted to CNI-sparing regimens using SRL (CNI-free: n = 10; CNI dose reduction + SRL: n = 46). Proteinuria prior to conversion, defined as > or =1(+) on urine dipstick, was determined when available (n = 51). Changes in mean eGFR post-conversion and independent predictors of a favorable renal response, defined as a rise in eGFR > or =20% within 1 month, were investigated. RESULTS: Mean eGFR at conversion was 35 +/- 14 ml/min/1.73 m(2), increasing by 8 +/- 14 ml/min/1.73 m(2) (p < 0.01) by 1 month post-conversion, a trend that remained significant out to 18 months. A total of 43% (n = 24) of patients had a rise in eGFR > or =20%. Forced expiratory volume in 1 second (FEV(1)) remained stable in survivors maintained on SRL and only 1 rejection episode occurred. When controlling for gender, age, pre-conversion eGFR and CNI-free vs CNI-dose reduction, the only variable that remained independently predictive of a favorable renal response was absence of proteinuria, with an odds ratio = 3.3 (95% confidence interval 1.0 to 12.5, p = 0.05). CONCLUSIONS: Non-proteinuric lung transplant survivors with CKD are more likely to respond favorably from a renal standpoint after conversion to SRL with CNI-dose reduction or elimination.