Should Transplant Nephrology Pursue Recognition from the Accreditation Council for Graduate Medical Education (ACGME)?

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis.

Pretransplant Psoas Muscle Cross-Sectional Area and Postkidney Transplant Outcomes.

BACKGROUND: Sarcopenia is associated with adverse outcomes in end-stage kidney disease. We evaluated if pretransplant sarcopenia affects posttransplant outcomes in kidney transplant (KT) recipients. METHODS: In this single-center retrospective study of adult patients with end-stage kidney disease, we analyzed the association between pre-KT psoas muscle cross-sectional area and critical posttransplant outcomes of decline in estimated glomerular filtration rate (eGFR), graft loss, rehospitalization, and mortality using Cox proportional hazard model adjusted for age, sex, and race. RESULTS: Pre-KT abdomen and pelvic computed tomography scans performed during evaluation for KT eligibility were available for 573 KT recipients. Of these, 465 KT recipients received kidney alone transplant, 71 received simultaneous liver kidney transplant (SLK), and 37 received simultaneous pancreas kidney transplant (SPK). Patients were 49 (SD, 13) years old, 16% Black, and 60% men. For kidney alone transplant recipients, a higher psoas muscle cross-sectional area was associated with a shorter length of hospitalization (ß coefficient = -0.003; 95% CI, -0.005 to -0.0007). Conversely, pre-KT psoas muscle cross-sectional area did not predict decline in eGFR, graft loss, mortality, or early rehospitalization. For SLK recipients, psoas muscle cross-sectional area did not predict any of the priori outcomes. For SPK recipients, higher pretransplant psoas muscle cross-sectional area predicted a longer length of hospitalization (ß coefficient = 0.03; 95% CI, 0.01-0.05). There was no association between psoas muscle cross-sectional area and other outcomes assessed. CONCLUSIONS: Pretransplant psoas muscle cross-sectional areas are not predictive of post-transplant decline in eGFR, graft loss, rehospitalization or mortality in kidney alone, SPK, or SLK transplants.

Pre-transplant cognitive screening is a poor predictor of post-transplant cognitive status.

INTRODUCTION: Transplant centers hesitate to transplant patients with cognitive impairment. It is unclear if pre-kidney transplant (KT) cognitive screening can predict post-KT cognitive function. METHODS: We evaluated pre- to post-KT cognitive function with the Montreal Cognitive Assessment (MoCA) in a cohort of 108 patients. We used an adjusted logistic regression model to assess pre- to post-KT changes in cognitive status (continuous variable) and a linear mixed model to assess changes in MoCA scores (categorical variable) pre- to post- KT. RESULTS: The average pre- and post-KT MoCA scores were 25.3 ± 3.0 and 26.4 ± 2.8, respectively. Final pre-KT score did not predict post-KT cognitive status (OR = 1.08; 95% CI: .92-1.26; P = .35). 32% of the patients with a final pre-KT score ≥26 had at least one post-KT score < 26. Conversely, 61% of the patients with a final pre-KT score < 26 had at least one post KT score ≥26. In the linear mixed model analysis, the final pre-KT score was associated with a small, clinically insignificant (ß = .34; 95% CI: .19-.49; P < .001) effect on the post-KT score. CONCLUSION: A low pre-KT MoCA score is not a strong independent predictor of post-KT cognitive function and should not preclude patients from receiving a KT.

Posttransplant proteinuria due to Apolipoprotein E2 deposition in a kidney allograft.

Lipoprotein deposition disorders limited to the kidney and causing proteinuria are rare. We present a case of nephrotic range proteinuria presenting within 4 months after deceased donor renal transplantation in a patient with end-stage kidney disease presumed secondary to hypertension. Two transplant kidney biopsies were performed sixteen weeks after transplantation, and one year after the first biopsy, both showing lipoprotein deposits in the glomeruli, progressive focal segmental glomerulosclerosis, and effacement of visceral foot processes. The patient had a normal lipid profile. Based on previous case reports of Apolipoprotein E variants causing proteinuria in native kidneys, Apolipoprotein E genotyping was performed. Genotyping showed Apolipoprotein E2 homozygosity. This Apolipoprotein E variant has been associated with lipoprotein deposition, proteinuria, and progressive kidney disease in the native kidneys. However, this is the first case of Apolipoprotein E2 homozygosity-related kidney disease in a transplant recipient. The patient was treated with fenofibrate, angiotensin enzyme inhibition, and angiotensin receptor blockade with reduction in proteinuria, and he kept good stable kidney function.

Nonoperative management of gastrointestinal bleeding after a simultaneous pancreas and kidney transplant.

With a shift toward enteric drainage techniques, the complications associated with simultaneous pancreas and kidney (SPK) transplant have also changed. Gastrointestinal (GI) bleeding is one of the most common complications associated with SPK. This case report describes the treatment of a postoperative GI hemorrhage using the push endoscopy technique. A 48-year-old male underwent an uneventful SPK transplant with entero-systemic drainage and developed hematochezia. The push enteroscopy technique was utilized to treat the bleeding ulcer. Historically, the use of the push enteroscopy technique to treat GI bleeding from the small bowel is not described in the literature. One of the limitations of duodenojejunostomy is that standard endoscopy cannot be readily used to visualize the duodenojejunostomy. However, the use of push enteroscopy may prove to be a minimal invasive and cost-effective intervention for GI bleeding after SPK.

Podocyte stress and detachment measured in urine are related to mean arterial pressure in healthy humans.

Hypertension-associated progressive glomerulosclerosis is a significant driver of both de novo and all-cause chronic kidney disease leading to end-stage kidney failure. The progression of glomerular disease proceeds via continuing depletion of podocytes from the glomeruli into the ultrafiltrate. To non-invasively assess injury patterns associated with mean arterial pressure (MAP), we conducted an observational study of 87 healthy normotensive individuals who were cleared for living kidney donation. Urine pellet podocin and aquaporin2 mRNAs normalized to the urine creatinine concentration (UPod:Creat ratio and UAqp2:Creat ratio) were used as markers of podocyte detachment and tubular injury, respectively. The ratio of two podocyte mRNA markers, podocin to nephrin (UPod:Neph) as well as the ratio of podocin to the tubular marker aquaporin2 (UPod:Aqp2) estimated the relative rates of podocyte stress and glomerular vs. tubular injury. The MAP was positively correlated with the UPod:Neph and UPod:Aqp2, thereby confirming the relationship of MAP with podocyte stress and the preferential targeting of the glomerulus by higher MAP. In multivariable linear regression analysis, both UPod:Neph and UPod:Creat, but not UAqp2:Creat or proteinuria, were both significantly related to a range of normal MAP (70 to 110 mm Hg). Systolic, as opposed to diastolic or pulse pressure was associated with UPod:Creat. Thus, higher podocyte stress and detachment into the urine are associated with MAP even in a relatively "normal" range of MAP. Hence, urine pellet mRNA monitoring can potentially identify progression risk before the onset of overt hypertension, proteinuria or chronic kidney disease.

Subclinical Cognitive Impairment and Listing for Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Cognitive impairment is common in patients with kidney disease and can affect physicians' perception and/or patients' ability to complete the pretransplant evaluation. We examined whether cognitive impairment influences the likelihood for transplant listing and whether patients with cognitive impairment take longer to be listed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a single-center longitudinal cohort study. Patients presenting for their index kidney transplant evaluation were screened for cognitive impairment using the Montreal Cognitive Assessment. A score <26 indicated cognitive impairment. The transplant selection committee was blinded to the scores. Kaplan-Meier analysis assessed time to active listing by level of cognition. A Cox proportional hazards model that included age, sex, race/ethnicity, smoking, coronary artery disease, and diabetes was constructed to evaluate the association between Montreal Cognitive Assessment score and listing for transplant. RESULTS: In total, 349 patients who underwent Montreal Cognitive Assessment testing at their initial visit were included in the analysis. Patients with cognitive impairment were more likely to be older, black, and smokers. The time to listing in patients with cognitive impairment was longer than the time to listing in those with no cognitive impairment (median time, 10.6 versus 6.3 months; log rank test P=0.01). Cognitive impairment was independently associated with a lower likelihood of being listed for transplant (hazard ratio, 0.93 per unit lower Montreal Cognitive Assessment score; 95% confidence interval, 0.88 to 0.99; P=0.02). A lower proportion of patients with cognitive impairment were listed compared with patients without cognitive impairment at 1 month (2% versus 11%), 6 months (17% versus 37%), and 1 year (23% versus 41%), (P<0.001 for all). CONCLUSIONS: Cognitive impairment is associated with a lower likelihood of being listed for kidney transplant, and is associated with longer time to transplant listing.

Accelerated podocyte detachment early after kidney transplantation is related to long-term allograft loss of function.

BACKGROUND: Kidney allograft half-life has not improved despite excellent short-term survival. Recent long-term surveillance biopsy studies identify accumulating glomerulosclerosis (GS) to be associated with late allograft loss. While podocyte depletion is well known to drive proteinuria and GS in animal models and human glomerular diseases, its role in renal allograft loss of function is generally not recognized. METHODS: To address these questions, we collected urine from 125 kidney allograft recipients in the first posttransplant year for urine pellet messenger RNA (mRNA) and protein analysis, with a median follow up of 4.5 years. RESULTS: Using multivariable linear models adjusted for proteinuria, transplant, recipient and donor factors, we observed that the average urine pellet podocin mRNA normalized to urine creatinine (UPodCR) in the first posttransplant year was significantly associated with an estimated glomerular filtration rate (eGFR) decline (P = 0.001). The relationship between UPodCR and eGFR decline persisted even among recipients who were nonproteinuric and who had no recurrent or de novo glomerular disease identified on 1-year protocol biopsy. Finally, we identified recipient, donor and recipient:donor body surface area mismatch ratio to be independently associated with UPodCR early after transplantation. A larger donor was protective, while a larger recipient and increased recipient:donor size mismatch ratio were associated with increased UPodCR. CONCLUSIONS: These findings support the concept that in kidney allografts, accelerated podocyte loss precedes proteinuria and is associated with inferior long-term allograft outcomes as measured by eGFR decline and may be initiated by recipient:donor size mismatch. Modulating factors driving early podocyte detachment after kidney transplantation may help improve long-term outcomes.

Temporal trends, center-level variation, and the impact of prevalent state obesity rates on acceptance of obese living kidney donors.

The impact of pre-donation obesity on long-term outcomes of living kidney donors remains controversial. Published guidelines offer varying recommendations regarding BMI (kg/m2 ) thresholds for donor acceptance. We examined temporal and center-level variation in BMI of accepted donors across US transplant centers. Using national transplant registry data, we performed multivariate hierarchical logistic regression modeling using pairwise comparisons (overweight, BMI: 25-29.9; mildly obese, BMI: 30-34.9; very obese, BMI: ≥35; versus normal BMI: 18.5-24.9). Metrics of heterogeneity, including median odds ratio (MOR), were calculated. Among 90 013 living kidney donors, 2001-2016, proportions who were very obese decreased and proportions who were mildly obese or overweight increased. Significant center-level heterogeneity was noted in BMI of accepted donors; the MOR varied from 1.10 for overweight to 1.93 for very obese donors. At centers located in the 10 states with the highest general population obesity rates, adjusted odds of very obese donor status were 185% higher (reference: normal BMI) than in states with the lowest obesity rates. Although there is a declining trend in acceptance of very obese living kidney donors, variation across centers is significant. Furthermore, local population obesity rates may affect the decision to accept obese individuals as donors.

A LASSO Method to Identify Protein Signature Predicting Post-transplant Renal Graft Survival.

Identifying novel biomarkers to predict renal graft survival is important in post-transplant clinical practice. Serum creatinine, currently the most popular surrogate biomarker, offers limited information of the underlying allograft profiles. It is known to perform unsatisfactorily to predict renal function. In this paper, we apply a LASSO machine-learning algorithm in the Cox proportional hazards model to identify promising proteins that are associated with the hazard of allograft loss after renal transplantation, motivated by a clinical pilot study that collected 47 patients receiving renal transplants at the University of Michigan Hospital. We assess the association of 17 proteins previously identified by Cibrik et al. [5] with allograft rejection in our regularized Cox regression analysis, where the LASSO variable selection method is applied to select important proteins that predict the hazard of allograft loss. We also develop a post-selection inference to further investigate the statistical significance of the proteins on the hazard of allograft loss, and conclude that two proteins KIM-1 and VEGF-R2 are important protein markers for risk prediction.

Quantitative podocyte parameters predict human native kidney and allograft half-lives.

BACKGROUND: Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives. METHODS: Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries. RESULTS: With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate. CONCLUSION: Native kidneys are designed to have a limited average life span of about 100-140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention. FUNDING: National Institutes of Health.

The Impact of Obesity on Allograft Failure After Kidney Transplantation: A Competing Risks Analysis.

BACKGROUND: The impact of pretransplant body mass index (BMI) on long-term allograft outcomes after kidney transplantation remains controversial. The conventional approach of using Kaplan-Meier method to calculate the cumulative risk of death-censored allograft failure may overestimate the risk of failure especially when competing failure risks are present. METHOD: A retrospective cohort of adult first-time kidney transplant recipients was drawn from the Organ Procurement and Transplantation Network database (2001 to 2009). Based on World Health Organization obesity classification, BMI was categorized as: less than 18.5, 18.5 to <25, 25 to < 30, 30 to < 35, 35 to <40 and ≥40 kg/m. Both unadjusted and adjusted risk models were used to assess for risk of allograft failure in the presence of death as a competing event. RESULTS: A total of 108 654 recipients were studied. In both unadjusted and adjusted models, increasing BMI level was associated with increased risk of long-term allograft failure. In the adjusted model with BMI 18.5 to less than 25 as the reference, the subhazards ratios (SHRs) for BMI were: less than 18.5: SHR, 0.96; P = 0.41; 25 to less than 30: SHR, 1.05; P = 0.01; 30 to less than 35: SHR, 1.15; P = <0.001; 35 to less than 40: SHR, 1.21; P < 0.001; and greater than 40: SHR, 1.13; P = 0.002. CONCLUSIONS: Handling of death as a competing event demonstrates a graded, detrimental impact of increasing pretransplant BMI on the risk of graft failure after kidney transplantation in both unadjusted and adjusted models. Compared with previous studies, a lower BMI was not associated with an increased risk of graft loss in a competing risk model.

Population pharmacokinetics of mycophenolic acid in lung transplant recipients with and without cystic fibrosis.

PURPOSE: The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant. METHODS: Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed. RESULTS: For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CF patients had a slower absorption rate (Ka), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates. CONCLUSIONS: The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V2/F and V3/F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.

Mycophenolic acid pharmacokinetics in lung transplant recipients with cystic fibrosis.

BACKGROUND: Lung transplantation is an established treatment for cystic fibrosis (CF) patients with end-stage lung disease. Current immunosuppression includes the prodrug mycophenolate mofetil (MMF), which has led to improved transplant outcomes. Given the pancreatic insufficiency and malabsorption in CF patients, some transplant centers give higher doses of MMF to these patients based on lower predose levels (C(0)), even though C(0) values correlate poorly with mycophenolic acid (MPA) exposure. The focus of this pilot study was to determine the pharmacokinetics (PK) of MPA in CF when compared with noncystic fibrosis (NCF) lung transplant recipients. METHODS: Five CF and 5 NCF patients had 3 separate PK analyses performed through our clinical research center. In addition to MMF, all patients were on tacrolimus and prednisone and were diabetic on insulin. Twelve-hour total serum concentration-time profiles of MPA and MPA glucuronide (MPAG) were obtained after oral administration of MMF. Concentrations of total MPA and MPAG were determined by a validated liquid chromatography-tandem mass spectrometry method. PK parameters of MPA were calculated by the noncompartmental method. Student t test or Mann-Whitney test was used to assess the differences in the PK parameters between the 2 cohorts. RESULTS: CF patients were significantly younger (30.6 versus 59.4 years; P < 0.001) and had significantly lower serum albumin (3.8 versus 4.1 g/dL; P = 0.0018) than NCF patients. CF patients had significantly lower MPA area under the curve (47.7 versus 83.1 mg·h·L(-1); P = 0.016) and MPAG area under the curve (569 versus 911 mg·h·L(-1); P = 0.047) when compared with NCF patients. In addition, C(0) (2.6 versus 4.6 mg/L; P = 0.026) and maximum serum concentration (9.2 versus 20.3 mg/L; P = 0.016) were significantly lower, and apparent oral clearance (0.26 versus 0.13 L·h·kg(-1); P = 0.009) was significantly higher in CF patients. T(max) was delayed in CF patients but not significantly. No difference between CF and NCF patients was observed for intra- and interindividual variability. CONCLUSIONS: Given these results, the lower MPA exposure in CF patients may impact transplant outcome in this lung transplant population.

Identification of a protein signature in renal allograft rejection.

PURPOSE: Serum creatinine functions as a poor surrogate marker of renal allograft dysfunction and long-term graft survival. By measuring multiple proteins simultaneously in the serum of transplant patients, we can identify unique protein signatures of graft dysfunction. EXPERIMENTAL DESIGN: We utilized training and validation cohorts composed of healthy and volunteer subjects, stable renal transplant patients, and renal transplant patients experiencing acute allograft rejection. Utilizing our antibody microarray, we measured 108 proteins simultaneously in these groups. RESULTS: Using Mann-Whitney tests with Bonferroni correction, we identified ten serum proteins from 19 renal transplant patients with stable renal function, which are differentially expressed, compared to healthy control subjects. In addition, we identified 17 proteins that differentiate rejecting renal transplant recipients from stable renal transplant. Validation cohorts substantiated these findings. CONCLUSION AND CLINICAL RELEVANCE: Our preliminary results support that a specific pattern of protein expression or "protein signature" may be able to differentiate between stable transplant patients from those with rejection. Future studies will focus on other etiologies of renal allograft dysfunction and the effect of treatment on protein expression and long-term outcome.

A history of chronic opioid usage prior to kidney transplantation may be associated with increased mortality risk.

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.

Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation.

BACKGROUND: Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. METHODS: A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3-8 or 6-12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab ± corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. RESULTS: Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (-2.2%, 13.0%), 26.9% (-7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3-8 and 6-12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (-2.1, 5.5 mL/min/1.73 m(2)), 49.4 (-4.8, 2.7 mL/min/1.73 m(2)), and 50.5 mL/min/1.73 m(2), respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P = 0.03 vs. MPA), 30.6% (P = 0.007 vs. MPA), and 20.5% of patients receiving everolimus 3-8 and 6-12 ng/mL and MPA, respectively. CONCLUSIONS: Everolimus trough concentrations targeted to 3-8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine.

BACKGROUND: The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored. METHODS: In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations. RESULTS: The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3 ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ≥ 12 ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8 ng/mL and CsA <100 ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations. CONCLUSIONS: These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.