Donor-Recipient Matching in Kidney Transplant: We're Not There Yet.

BACKGROUND: Strategic organ allocation is expected to prolong patient and graft survival after transplant. This study explored differences in graft survival when kidneys are allocated based on strategic donor-recipient (D-R) pairing vs with the existing Kidney Allocation System (KAS). METHODS: Using the Scientific Registry of Transplant Recipients from 2000 to 2014, we used a multivariable Cox model to assess the hazard ratios (HRs) for death or graft failure among 3 hypothetical donor kidneys transplanted into 3 hypothetical recipients, relative to an ideally matched D-R pair. Median predicted survival for each of the 9 possible D-R pairing combinations was determined, and outcomes for strategic D-R pairing were compared with those obtained using the KAS for allocation. RESULTS: A total of 31,607 patients (29.7%) died or developed graft loss over the study period. Strategic allocation of kidneys resulted in HRs for graft loss of 1.74 (95% confidence interval [CI], 1.41-2.14), 1.82 (95% CI, 1.46-2.26), and 1.74 (95% CI 1.38-2.19) for recipients 1, 2 and 3 respectively, whereas by following the KAS, HRs were 1.93 (95%, CI 1.63-2.28), 2.06 (95% CI, 1.74-2.44), and 1.93 (95% CI, 1.58-2.37); corresponding to 3.84, 11.39, and 7.40 months longer predicted patient or graft survival for recipients 1, 2 and 3 with strategic D-R pairing compared with the KAS. CONCLUSIONS: Allocation of kidneys by strategic D-R pairing may improve graft survival relative to allocation using the KAS.

Hepatitis C virus-infected kidney waitlist patients: Treat now or treat later?

Currently many but not all centers transplant hepatitis C virus (HCV) viremic positive (+) donor kidneys into HCV+ recipients. Directed donation of HCV+ organs reduces the wait time to transplantation for HCV+ patients. Direct-acting antiviral (DAA) therapy can cure HCV in virtually all who are infected. Some have suggested that treatment of HCV+ waitlisted patients be deferred with the hope that earlier transplantation will provide better outcomes than early DAA therapy. However, there are not enough organs to guarantee prompt transplantation for the current waitlist of infected candidates. A Markov medical decision analysis model was created to compare the overall outcomes of delayed DAA therapy (Option 1) to immediate DAA therapy (Option 2) in waitlisted HCV+ patients. Option 1 patients were modeled to be transplanted 1 year earlier, with a higher cumulative transplant incidence (54% at 5 years post-listing vs 45% for Option 2). Despite this, Option 2 provided 0.43 (95% confidence interval [CI] 0.38-0.49) more life years than Option 1. However, Option 1 was preferred for regions with much greater access to HCV+ organs or in patients with very low HCV+-associated mortality. The best option from an individual patient's perspective will differ by region and candidate.

De Novo Donor-Specific Human Leukocyte Antigen Antibody Screening in Kidney Transplant Recipients After the First Year Posttransplantation: A Medical Decision Analysis.

Screening for de novo donor-specific antibodies (dnDSA) in stable kidney transplant recipients is routine practice in some centers. Patients with DSA are at increased risk of graft loss and early intervention may improve outcomes. However, the costs and benefits of dnDSA surveillance are unknown. A medical decision analysis to examine a screening strategy was developed for kidney transplant recipients who had stable graft function and were DSA negative 1 year posttransplant. In the base case, a modest 25% reduction in graft loss in dnDSA-positive patients treated with increased immunosuppression resulted in 0.04618 quality-adjusted years (QALYs) gained. However, benefits from reduced graft loss were eliminated if there was a small increased risk of death from added therapy. The incremental cost effectiveness was marginal at approximately $120 000-250 000 per QALY, but could be more or less favorable depending on several key variables such as efficacy of treatment, screening costs, incidence rate of subclinical dnDSA, and patient survival. Screening performed the best in patients with lower mortality rates and higher baseline incidence rates of dnDSA. Further study is warranted to gather the necessary high-quality evidence to justify screening.

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Screening to prevent polyoma virus nephropathy in kidney transplantation: a cost analysis.

Polyoma virus nephropathy is an important cause of graft dysfunction in kidney transplant recipients and screening to prevent disease has been advocated. Although screening incurs new costs, our hypothesis is that savings from less immunosuppression in those with positive screening tests could pay for overall costs of screening. In 134 consecutive recipients, polyoma virus (positive decoy cells) was detected in the urine of 34 (25.4%) individuals over a 2-year follow-up. Of these 34, 11 had a plasma BK PCR of >7700 copies/mL. Immunosuppression was reduced stepwise in these patients until viral loads fell <1000/mL. Overall screening costs (including extra plasma PCR testing) were estimated at $33,450. Those with positive PCR had greater reductions in annual immunosuppression costs by year 2 ($6452 vs. $2799, p = 0.0015) compared to those with negative screens. At the end of the 2-year period, 61% of the screening costs were covered by less immunosuppressant costs. At the end of 30 months there were net savings. In summary, reductions in immunosuppression cover the cost of screening for polyoma viral infection. Longer-term follow-up is needed to ensure patient outcomes remain acceptable.

Cancer mortality in kidney transplantation.

Immunosuppression is associated with an increased risk of cancer in kidney transplant recipients compared to the general population. It is less clear whether standardized cancer mortality ratios (SMRs) are also increased. This study's hypothesis is that SMRs are not increased because of competing risks of death. During the median follow-up of 5.05 years (Q1-Q3: 2.36-8.62), there were 1937 cancer deaths and 36 619 noncancer deaths among 164 078 first kidney-only transplant recipients captured in the United States Renal Data System between January 1990 and December 2004. The observed cancer death rate was 206 per 100 000 patient-years compared to an expected rate of 215 per 100,000 patient-years in the general population. The overall age- and sex-adjusted SMR was only 0.96 (95% CI 0.92-1.00). However, patients <50 years had SMRs significantly greater than unity while patients >60 had SMRs lower than unity. Up to 25% of cancer-related deaths occurred after allograft failure. These findings challenge the notion that cancer is a major cause of premature death in all kidney transplant recipients and has implications for design of cancer prevention strategies in kidney transplant recipients.

MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene correlate with the intestinal function of P-glycoprotein (PGP). PGP serves as a hydrophobic export pump that extrudes cyclosporine (CsA) across the luminal membrane thus preventing CsA absorption. These genetic variants may predict CsA exposure levels in the early posttransplantation period. METHODS: CsA absorption profiles were established in 75 renal transplant patients using total daily dose and body weight adjusted 4-hour area under the time-concentration curve, AUC(0-4)/mg dose/kg body weight, on posttransplant day 3. These patients were subsequently genotyped for C3435T and G2677T polymorphisms using real-time polymerase chain reaction. An analysis was conducted to assess the independent impact of C3435T and G2677T SNPs on CsA bioavailability. RESULTS: C3435T polymorphisms were found to be an independent predictor of CsA AUC(0-4)/mg dose/kg levels on postoperative day 3. An inverse correlation was found between the number of T alleles and AUC values such that every T allele was associated with an approximate 15% decrement in AUC(0-4)/mg dose/kg (P = .034). A similar nonsignificant trend was observed for G2677T polymorphisms. CONCLUSIONS: MDR1 SNPs are correlated with CsA exposure in the early post-transplant period. Polymorphisms, in conjunction with other criteria, may become a useful tool to optimize initial drug dosing in renal transplantation.

BK virus nephropathy in a heart transplant recipient: case report and review of the literature.

The human polyomavirus BK virus (BKV) remains latent in the urinary tract and may be reactivated in immunocompromised states. BKV is noted to be the etiologic agent of polyomavirus-associated nephropathy (PVAN), which is a significant cause of allograft failure in renal transplant patients. Renal dysfunction following non-renal solid organ transplantation is common and is typically attributed to drug toxicity or patient comorbidities. In this article we describe a case of PVAN in the native kidneys of a heart transplant recipient and review the literature. Although this is only the fourth case reported, BKV nephropathy should be considered in the differential diagnosis of new renal failure following non-kidney solid organ transplantation, as early diagnosis of PVAN is necessary to prevent irreversible renal damage.

Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period.

UNLABELLED: Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. METHODS: This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine (n = 116) or tacrolimus (n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. RESULTS: There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g (n = 22) compared to 2-g (n = 94) daily doses (AUC([0-12]) 33.8 +/- 10.0 mg*h/L versus 30.1 +/- 9.7 mg*h/L, P = .20, respectively). About half the patients in both groups had AUC([0-12]) <30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g (n = 21) compared to 2 g (n = 29) daily (AUC([0-12]) 43.1 +/- 9.0 mg*h/L versus 36.8 +/- 11.1 mg*h/L, P = .016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC([0-12]) of <30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level (P = .068). The AUC([0-12]) levels were not different on day 5. CONCLUSIONS: Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.

Treatment of hypercholesterolemia with ezetimibe in the kidney transplant population.

BACKGROUND: Given the high incidence of lipid abnormalities, high burden of cardiovascular disease, and high proportion who do not achieve target levels despite therapy in the kidney transplant population, additional lipid lowering strategies are needed. METHODS: This was a nonrandomized, open-label, single-cohort evaluation of ezetimibe, a novel cholesterol absorption inhibitor, in 40 stable kidney transplant recipients with hypercholesterolemia. RESULTS: After 4 weeks of therapy total and LDL cholesterol were reduced by 23 +/- 13% (P < .0001) and 33 +/- 15% (P < .0001), respectively. The drug was equally effective in patients on cyclosporine (19), tacrolimus (13), or sirolimus (8), but more effective (P = .0006) when used in combination with a statin (41 +/- 13% reduction in LDL, n = 22) compared with monotherapy (24% +/- 13%, n = 18). There were no significant effects on serum creatinine, drug levels, body weight, or liver function tests. CONCLUSIONS: Ezetimibe is an effective LDL cholesterol-lowering agent in the kidney transplant population. Further studies are warranted in a larger population not only to examine the extent of cardiovascular risk reduction but also to detect unwarranted toxicity.

Importance of peak PRA in predicting the kidney transplant survival in highly sensitized patients.

Do patients with high historic peak panel-reactive antibodies (PRA) remain high risk if their PRA levels fall before transplantation? We examined retrospectively 406 first and repeat kidney recipients with a peak PRA of >50%, who were transplanted from our center between January 1990 and December 2001. Univariate analysis by log-rank test was performed for variables that affect graft survival. The factors tested included current PRA, peak PRA, difference between peak and current PRA (DeltaPRA), HLA mismatch, gender, age, transplant number, and donor source. Receiver operator characteristic curves (ROC) were generated to obtain the best cutpoints for current PRA and DeltaPRA. Current PRA (P < .0001), peak PRA (P = .0004), and DeltaPRA (P = .0015) were significant predictors by univariate analysis. However, in a multivariate model, peak PRA was not significant. Current PRA (P < .0001) was significantly associated with graft survival, while DeltaPRA showed a strong trend to significance (P = .05). Current PRA of <26% and DeltaPRA of >37% were the best cutpoints for separating good and poor outcomes. This study shows that current PRA and DeltaPRA impact on graft survival in highly sensitized (>50%) patients. Sensitized patients with peak PRA >50% who subsequently have a drop in PRA to <26% are at lower risk of graft loss than those with a persistently high PRA. A fall in peak PRA of >37% at the time of transplant appears to be of benefit only in those patients who achieve a current PRA of <26%.

Adequate early cyclosporin exposure is critical to prevent renal allograft rejection: patients monitored by absorption profiling.

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration-time curve during the first 4h after cyclosporin-microemulsion dosing (AUC0-4) and cyclosporin (CyA) levels immediately before and at 2 and 3h after dosing (C0, C2 and C3) to predict the risk of biopsy-proven acute rejection (AR) at 6 months. Ninety-eight kidney transplant recipients treated with CyA-microemulsion-based triple therapy immunosuppression were studied on post-transplant days 3, 5, and 7, and at increasing intervals thereafter. The most sensitive and specific predictor of AR was AUC0-4. Of the single time-point measurements, the measurement properties of C2 were closest to those of AUC0-4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0-4 > or = 4,400 ng.h/mL and C2 > or = 1,700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR. Adequate exposure within the first 3days post transplantation may be critically important in preventing subsequent rejection.

Cardiovascular risk reduction in renal transplantation. Strategies for success.

One of the aims of transplantation is to restore the potential for a full life to individuals with ESRD. To obtain this strategies that allow better and longer allograft function and a reduction in adverse events that lead to premature death are required. To this end, the recommendations below showed reduce cardiovascular disease and help present and future transplant recipients live a full life. Focusing on traditional risk factors (hypertension, hyperlipidemia, discontinuation of smoking, and prevention and treatment of diabetes mellitus) in patients at risk and striving for the recommended targets will have the greatest clinical benefit. These strategies should begin in the pre-dialysis and dialysis phases in order to reduce the cumulative burden of disease. Failing this, early and hopefully pre-emptive transplantation should be the goal.

Cardiac risk factors and the use of cardioprotective medications in patients with chronic renal insufficiency.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with chronic renal insufficiency (CRI). beta-Adrenergic blockers, acetylsalicylic acid (ASA), angiotensin-converting enzyme (ACE) inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) all reduce CVD mortality, but little is known about the extent to which these medications are used in patients with CRI. This study, a prospective cross-sectional study of consecutive patients seen by nephrologists in four Canadian centers for follow-up of progressive CRI in 1999, was performed to investigate the prevalence of coronary risk factors and use of cardioprotective medications among patients with CRI. Patients had creatinine clearances of 75 mL/min or less but were not on dialysis therapy. Three hundred four consecutive patients meeting the inclusion criteria were enrolled. Mean age was 60.8 +/- 15.7 years, mean creatinine clearance was 30.3 +/- 18 mL/min, and the case mix of kidney diseases was similar to that in the Canadian Organ Replacement Registry data. One hundred seventeen of 304 patients (38.5%) had a history of previous CVD, and the prevalence of CVD was greater in patients with more severe CRI. Two hundred forty-three patients (79.9%) had a history of hypertension, 132 patients (43.4%) had hyperlipidemia, 114 patients (37.5%) had diabetes mellitus, and 71 patients (27.3%) were smokers. Thirty-five percent of the patients with CVD had blood pressures greater than 140/90 mm Hg; 103 patients (33.9%) were administered beta-blockers; 196 patients (64.5%), ACE inhibitors or angiotensin-receptor blockers; 83 patients (27.3%), ASA; and 56 patients (18.4%), statins. Patients with diabetes were not more likely than those without diabetes to be prescribed cardioprotective medications. CVD is common in the predialysis population, and its prevalence increases with more severe kidney failure. Despite this, the use of cardioprotective medications is relatively low, and many patients had suboptimal blood pressure control. Given the high burden of disease in these patients, beta-blockers and ACE inhibitors should be used to control hypertension and/or for cardioprotection, and the increased use of ASA and statins should be considered.

Estimating the benefits of solitary pancreas transplantation in nonuremic patients with type 1 diabetes mellitus: a theoretical analysis.

BACKGROUND: The goal of early pancreas transplantation in type 1 diabetes mellitus is to achieve euglycemia and thereby prevent the renal, retinal, and vascular complications of this disease. The purpose of this analysis was to examine the conditions and assumptions that would make early solitary pancreas a viable therapeutic option. METHODS: A Markov model was constructed to compare outcomes for patients with type 1 diabetes mellitus and early overt nephropathy assigned to either standard insulin therapy or solitary pancreas transplantation. Probabilities for development of end stage renal disease (ESRD), blindness, mortality, and direct health care costs were taken from the literature. Utility scores for the relevant health states were determined by the standard gamble method on 16 type 1 diabetic patients suitable for pancreas transplantation. RESULTS: Assuming a baseline graft life expectancy for the pancreas of 10 years, early pancreas transplantation could provide 0.42 more life years and 2.2 more quality adjusted life years (discounted at 3%) to patients above standard insulin therapy. The model was sensitive to estimates of pancreas graft life expectancy (<8 years being inadequate to extend patient life), timing of pancreas transplantation with respect to rate of progression to ESRD, and drug nephrotoxicity rates. The incremental costs (charges) for early pancreas transplantation over standard therapy were estimated to be modestly high (about $56,600/quality adjusted life year for the baseline case). Pancreas transplant costs were also a very sensitive parameter in the cost utility analysis. CONCLUSIONS: The success of early solitary pancreas transplantation may well be at the stage to consider a trial in selected type 1 diabetic patients at risk for renal and retinal disease.

Should all Pima Indians with type 2 diabetes mellitus be prescribed routine angiotensin-converting enzyme inhibition therapy to prevent renal failure?

OBJECTIVE: To determine how effective angiotensin-converting enzyme (ACE) inhibitors must be in preventing diabetic nephropathy to warrant early and routine therapy in all Pima Indians with type 2 diabetes mellitus. DESIGN: A computerized medical decision analysis model was used to compare strategy 1, screening for microalbuminuria and treatment of incipient nephropathy as currently recommended with ACE inhibitor therapy, with strategy 2, a protocol wherein all patients were routinely administered an ACE inhibitor 1 year after diagnosis of type 2 diabetes mellitus. The model assumed that ACE inhibitors can block, at least in part, the pathogenic mechanisms responsible for early diabetic nephropathy (microalbuminuria). RESULTS: The model predicted that strategy 2 would produce more life-years at less cost than strategy 1, if routine drug therapy reduced the rate of development of microalbuminuria by 21% in all patients. Only a 9% reduction in the rate of development of microalbuminuria was cost-effective at $15,000 per additional life-year gained, and only a 2.4% reduction was cost-effective at $75,000 per additional life-year gained for strategy 2 over strategy 1. CONCLUSIONS: Routine ACE inhibitor therapy in Pima Indians with type 2 diabetes mellitus could prove more effective and even cost saving than the currently recommended approach of microalbuminuria screening. A prospective trial examining this goal should be considered.

Routine treatment of insulin-dependent diabetic patients with ACE inhibitors to prevent renal failure: an economic evaluation.

The objective of this study was to determine how effective angiotensin-converting enzymes (ACEs) must be in preventing diabetic nephropathy to warrant routine administration to insulin-dependent diabetic patients. A Markov model was used to compare three strategies designed to prevent the development of end-stage renal disease in insulin-dependent diabetic patients. Strategy I, screening for microalbuminuria and treatment of incipient nephropathy as currently recommended, was compared with strategy II, a protocol in which patients were routinely administered an ACE inhibitor 5 years after diagnosis of diabetes, and strategy III, in which patients at high risk for nephropathy were routinely treated and low-risk patients followed a protocol in which patients were treated with an ACE inhibitor if they developed hypertension and/or macroproteinuria. The model predicted that strategy II would produce as many quality-adjusted life-years as strategy I at nearly the same cost if routine drug therapy reduced the rate of development of microalbuminuria by 26% in all patients. Strategy III produced as many quality-adjusted life-years at less cost than strategy I if a high-risk cohort could be identified with a rate of developing microalbuminuria at four times the rate of low-risk patients and if drug therapy reduced the rate of developing microalbuminuria in this high-risk group by 20%. In conclusion, routine ACE inhibitor therapy could prove to be cost-effective, especially if high-risk individuals could be identified. A prospective trial examining this goal should be considered.