Brett Pinsky

Transplant Outcomes and Economic Costs Associated with Patient Noncompliance to Immunosuppression

We describe factors associated with immunosuppression compliance after kidney transplantation and examine relationships between compliance with allograft outcomes and costs. Medicare claims for immunosuppression in 15 525 renal transplant recipients with at least 1 year of graft function were used to calculate compliance as medication possession ratio. Compliance was categorized by quartiles as poor, fair, good and excellent. We modeled adjusted associations of clinical factors with the likelihood of persistent compliance by multiple logistic regressions (aOR), and estimated associations of compliance with subsequent graft and patient survival with Cox proportional hazards (aHR). Adolescent recipients aged 19–24 years were more likely to be persistently noncompliant compared to patients aged 24–44 years (aOR 1.49 [1.06–2.10]). Poor (aHR 1.80 [1.52–2.13]) and fair (aHR 1.63[1.37–1.93]) compliant recipients were associated with increased risks of allograft loss compared to the excellent compliant recipients. Persistent low compliance was associated with a

Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure.

12 840 increase in individual 3‐year medical costs. Immunosuppression medication possession ratios indicative of less than the highest quartile of compliance predicted increased risk of graft loss and elevated costs. These findings suggest that interventions to improve medication compliance among kidney transplant recipients should emphasize the benefits of maximal compliance, rather than discourage low compliance.

A Retrospective Analysis of Immunosuppression Compliance, Dose Reduction and Discontinuation in Kidney Transplant Recipients

Background. Mycophenolate mofetil (MMF) use in renal transplantation has steadily increased since 1995 because of its ability to lower the risks of rejection and chronic allograft nephropathy. However, significant gastrointestinal (GI) complications may lead to MMF dose reductions and discontinuations. Little is known of the association between MMF dose reductions and discontinuations following GI complications and graft survival. Methods. Using the United States Renal Data System, we identified 3,675 adult recipients (age ≥18) with a diagnosed GI complication who were prescribed MMF at the time of first GI diagnosis and had Medicare as their primary insurer. MMF doses were ascertained from Medicare payment records. We estimated risk of graft loss associated with MMF dose adjustments after GI diagnosis: dosage unchanged (reference), reduced <50%, reduced ≥50%, and MMF discontinued. Patients were followed until graft loss, death, last recorded immunosuppression prescription, or 3 years posttransplant. Results. Compared to those with no MMF dose reductions or discontinuations, the risk of graft failure increased with MMF doses reduction ≥50% (HR=2.36, 95% CI 1.23–4.54) and those with MMF discontinuation (2.72, CI 1.60–4.64). Conclusion. Renal transplant recipients who underwent MMF dose reduction or withdrawal following GI diagnosis are associated with increased risk of graft failure.

Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality.

We describe factors associated with poor compliance and dose reductions and examine the relative impact of compliance, dose reduction and discontinuation on graft outcome.

Predictive Ability of Pretransplant Comorbidities to Predict Long‐Term Graft Loss and Death

BACKGROUND Gastrointestinal complications after kidney transplantation are associated with inferior graft outcomes. We examined the incidence, risk factors, and outcomes of posttransplantation diarrhea. STUDY DESIGN Historic cohort study. SETTING & PARTICIPANTS We examined first kidney transplant recipients in the United States from 1995 to 2002, with follow-up through December 2002. Recipients of multiple organs were excluded. We limited our study population to Medicare beneficiaries. PREDICTORS Recipient, donor, and transplant characteristics were ascertained by means of US Renal Data System database inquiry. OUTCOMES Incidence of diarrhea, graft loss, and death after transplantation. First episodes of diarrhea after transplantation were ascertained by using International Classification of Disease, Ninth Revision, Clinical Modification codes using Medicare billing data. Cause of diarrhea was classified as infectious or not and according to specific cause. Graft loss and death were ascertained from the date of the first diarrhea episode. RESULTS We enrolled 41,442 patients. Mean follow-up was 758 +/- 399 days. We observed 7,103 diarrhea cases and 8,104 graft losses (4,201 deaths). The 3-year cumulative incidence of diarrhea was 22%, with 18% diagnosed as noninfectious diarrhea with an unspecified cause. Using multivariate Cox proportional hazards analysis, factors associated with increased risk of unspecified noninfectious diarrhea were female sex (hazard ratio [HR], 1.40; 95% confidence interval, 1.33 to 1.48), type 1 diabetes (HR, 1.20; 95% confidence interval, 1.06 to 1.37), and regimens containing tacrolimus and mycophenolate mofetil (HR, 1.37; 95% confidence interval, 1.28 to 1.46). Unspecified noninfectious diarrhea was associated with increased risk of graft failure (HR, 2.13; 95% confidence interval, 1.98 to 2.28) and patient death (HR, 2.04; 95% confidence interval, 1.85 to 2.24). LIMITATIONS Use of claims data to ascertain patient characteristics and events; inability to make causal inference based on retrospective designs. CONCLUSIONS Regimens containing tacrolimus and mycophenolate mofetil were associated with increased risk of noninfectious diarrhea. Episodes of noninfectious diarrhea doubled the hazard of graft loss and patient death.

Early outcomes of thymoglobulin and basiliximab induction in kidney transplantation: Application of statistical approaches to reduce bias in observational comparisons

Whether to include additional comorbidities beyond diabetes in future kidney allocation schemes is controversial. We investigated the predictive ability of multiple pretransplant comorbidities for graft and patient survival. We included first‐kidney transplant deceased donor recipients if Medicare was the primary payer for at least one year pretransplant. We extracted pretransplant comorbidities from Medicare claims with the Clinical Classifications Software (CCS), Charlson and Elixhauser comorbidities and used Cox regressions for graft loss, death with function (DWF) and death. Four models were compared: (1) Organ Procurement Transplant Network (OPTN) recipient and donor factors, (2) OPTN + CCS, (3) OPTN + Charlson and (4) OPTN + Elixhauser. Patients were censored at 9 years or loss to follow‐up. Predictive performance was evaluated with the c‐statistic.

Joint Association of Hyperuricemia and Reduced GFR on Cardiovascular Morbidity: A Historical Cohort Study Based on Laboratory and Claims Data From a National Insurance Provider

Background. Retrospective comparison of treatment-related kidney transplant outcomes may be facilitated by multivariable statistical adjustments and case-matching. Methods. We studied Organ Procurement and Transplantation Network registry data for kidney transplants in 2001 to 2005 managed with thymoglobulin, basiliximab, or no antibody induction and discharge maintenance immunosuppression regimens of tacrolimus and mycophenolate mofetil. The primary outcome was the 6 month, Food and Drug Administration-approved composite endpoint of rejection, graft failure, or death. Outcomes according to induction exposure were compared using logistic regression analysis, exposure likelihood matching, and outcome risk score matching. Results. All statistical approaches demonstrated lower rates of the 6-month triple endpoint with thymoglobulin compared with basiliximab when steroids were present, with approximately 22% adjusted, relative reduction by logistic regression analysis and 3% absolute reductions by matching approaches. When steroids were absent, risk reduction among thymoglobulin versus basiliximab-treated patients was of larger magnitude but borderline statistical significance. Triple endpoint incidence was lower with both induction regimens compared with no induction across methods. Estimated sample sizes necessary to detect the observed differences between induction types in the presence of steroids in a prospective trial ranged from 1600 to nearly 7000 patients. Conclusions. Consistency across statistical approaches suggests superiority of thymoglobulin compared with basiliximab or no antibody induction therapy for 6-month kidney transplant outcomes in the modern immunosuppression era. As the sample sizes necessary to power a prospective superiority trial are likely prohibitive, studies such as these provide clinically relevant information that may not be otherwise attainable.

Lack of Association Between Hepatitis C Infection and Chronic Kidney Disease

BACKGROUND Hyperuricemia is common in patients with chronic kidney disease (CKD). We assessed the relationship of increased serum uric acid levels with cardiovascular risk across levels of kidney function. STUDY DESIGN Historical cohort study. SETTING & PARTICIPANTS Study data were drawn from administrative records of a national private health insurer (2003-2006). We included all adult beneficiaries with concurrently measured serum creatinine and serum uric acid. Patients with acute kidney failure or undergoing renal replacement therapy at baseline were excluded. PREDICTORS Serum uric acid concentration and estimated glomerular filtration rate (eGFR). OUTCOMES & MEASUREMENTS Cardiovascular diagnoses (myocardial infarction, subacute coronary heart disease, heart failure, cerebrovascular disease, or peripheral arterial disease) ascertained from billing claims. Cox proportional hazard models were used to test the association of predictors with cardiovascular morbidity. Models were adjusted for sociodemographic characteristics, selected comorbid conditions, and laboratory results. RESULTS In 148,217 eligible patients, mean eGFR was 84 mL/min/1.73 m(2) and the prevalence of CKD stages 3-5 was 6.0%. Hyperuricemia (serum uric acid >7 mg/dL) was found in 15.6% of patients. The 40-month cumulative incidence of cardiovascular events (mean follow-up, 15.3 months) was 8.1%. Cardiovascular risk was associated independently with uric acid level, and this association was stronger in patients with lower eGFRs. LIMITATIONS Observational design, lack of information for mortality and potential confounders, single creatinine and uric acid assessment. CONCLUSIONS Serum uric acid concentration was an independent correlate of cardiovascular morbidity, and this association was stronger in patients with severely decreased eGFR. This investigation provides a rationale for further study of serum uric acid-lowering interventions on cardiovascular risk in the general population and patients with CKD.

Incremental value of the pancreas allograft to the survival of simultaneous pancreas-kidney transplant recipients.

BACKGROUND & AIMS Chronic kidney disease (CKD) can have a negative impact on the natural history of hepatitis C virus infection (HCV) infection; patients with HCV and CKD often have adverse outcomes. We evaluated a large and geographically diverse group of patients to determine whether HCV status has an independent effect on the risk of developing CKD. METHODS We conducted a cohort study of 167,569 patients included in a national health care claims database from January 1, 2003-December 31, 2006, with a mean follow-up of 25.3 months. We used multivariable logistic regression analyses to measure the independent effect of HCV status on the baseline prevalence of and progression to CKD (estimated glomerular filtration rate, <60 mL/min/1.73 m(2)). RESULTS The baseline prevalence of CKD was similar in patients with versus those without HCV (5.3% vs 5.1%, P = .3). Similarly, among patients with preserved renal function at baseline (n = 82,629), there was no difference in the overall progression to CKD in patients with versus those without HCV (3.8% vs 3.5%, P = .1). HCV status was not associated with progression to CKD, even after adjusting for patient demographics, comorbidities, and use of relevant medications (odds ratio, 0.92; 95% confidence interval, 0.79-1.08). CONCLUSIONS We found no association between HCV and risk of development of CKD. These data are relevant in counseling HCV patients regarding the impact of HCV on renal function.

Increased risk of graft failure in kidney transplant recipients after a diagnosis of dyspepsia or gastroesophageal reflux disease.

OBJECTIVE To quantify the incremental survival benefit of the pancreas allograft in simultaneous pancreas-kidney (SPK) transplant recipients. RESEARCH DESIGN AND METHODS Data from the national transplant database from 2000 to 2007 were analyzed. SPK recipients who had functioning allografts to 1-year post transplant (n = 3,304) were compared with those who had failure of the renal (n = 233) or pancreatic (n = 112) graft. The main outcome was a projection of 10 life-years of patient survival beyond the first transplant anniversary. RESULTS Recipients with function of both organs accrued 9.4 life-years following transplantation. Projected survival in patients with kidney failure was reduced to 2.5 life-years. Pancreas failure reduced predicted survival to 8 life-years. Renal allograft failure impacts life expectancy significantly (adjusted hazard ratio [aHR] 12.13). However, pancreas allograft failure was also associated with reduced survival (aHR 2.62). CONCLUSIONS Although the majority of the survival benefit of SPK transplant is due to the renal transplant, pancreas allograft function does contribute to patient survival.