Development of immune response to tissue-restricted self-antigens in simultaneous kidney-pancreas transplant recipients with acute rejection.

Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment for end-stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue-restricted kidney and pancreas self-antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen-IV, Col-IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas-associated protein-1) by ELISA. KSAg-specific IFN-γ, IL-17, and IL-10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney-only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas-only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg-specific IFN-γ and IL-17 with reduction in IL-10-secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg-specific IFN-γ and IL-17-secreting cells with reduced IL-10, suggesting loss of peripheral tolerance to SAgs.

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.

BACKGROUND/AIMS: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. METHODS: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. RESULTS: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). CONCLUSION: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Cytomegalovirus-induced thrombotic microangiopathy after renal transplant successfully treated with eculizumab: case report and review of the literature.

De novo thrombotic microangiopathy (TMA) after renal transplant is rare. Cytomegalovirus (CMV)-related post-transplant TMA has only been reported in 6 cases. We report an unusual case of a 75-year-old woman who developed de novo TMA in association with CMV viremia. The recurrence of TMA with CMV viremia, the resolution with treatment for CMV, and the lack of correlation with a calcineurin inhibitor (CNI) in our case support CMV as the cause of the TMA. What is unique is that the use of eculizumab without plasmapheresis led to prompt improvement in renal function. After a failure to identify a genetic cause for TMA and the clear association with CMV, eculizumab was discontinued. This case provides insight into the pathogenesis and novel treatment of de novo TMA, highlights the beneficial effects of complement inhibitors in this disease, and shows that they can be safely discontinued once the inciting etiology is addressed.

Fertility Management in Cystinosis: A Clinical Perspective.

Cystinosis is a rare, inherited, lysosomal storage disorder characterized by the progressive accumulation of intralysosomal cystine and subsequent organ and tissue damage. The kidneys are the first and most severely impacted organ. Although cystinosis was once considered a fatal pediatric disease, patients with cystinosis are living well into adulthood with advances in medical care, including kidney transplant and early and continuous use of cysteamine therapy. This increase in life expectancy has revealed an extrarenal phenotype of cystinosis that emerges in adolescence and adulthood, affecting nearly all body systems, including the endocrine and reproductive systems. As individuals with cystinosis are planning for the future, reproductive health and fertility have become areas of increased focus. This narrative review aims to summarize the current understanding of reproductive health and fertility in patients with cystinosis and discuss practical considerations for monitoring and managing these complications.

Sitagliptin Versus Placebo to Reduce the Incidence and Severity of Posttransplant Diabetes Mellitus After Kidney Transplantation-A Single-center, Randomized, Double-blind Controlled Trial.

BACKGROUND: Postkidney transplant diabetes mellitus (PTDM) affects cardiovascular, allograft, and recipient health. We tested whether early intervention with sitagliptin for hyperglycemia (blood glucose >200 mg/dL) within the first week of transplant and discontinued at 3 mo could prevent development of PTDM in patients without preexisting diabetes. METHODS: The primary efficacy objective was to improve 2-h oral glucose tolerance test (OGTT) by > 20 mg/dL at 3 mo posttransplant. The secondary efficacy objective was to prevent new onset PTDM, defined as a normal OGTT at 3 mo. RESULTS: Sixty-one patients consented, and 50 patients were analyzed. The 3-mo 2-h OGTT (end of treatment) was 141.00 ± 62.44 mg/dL in the sitagliptin arm and 165.22 ± 72.03 mg/dL ( P = 0.218) in the placebo arm. The 6-mo 2-h OGTT (end of follow-up) was 174.38 ± 77.93 mg/dL in the sitagliptin arm and 171.86 ± 83.69 ng/dL ( P = 0.918) in the placebo arm. Mean intrapatient difference between 3- and 6-mo 2-h OGTT in the 3-mo period off study drug was 27.56 + 52.74 mg/dL in the sitagliptin arm and -0.14 + 45.80 mg/dL in the placebo arm ( P = 0.0692). At 3 mo, 61.54% of sitagliptin and 43.48% of placebo patients had a normal 2-h OGTT ( P = 0.2062), with the absolute risk reduction 18.06%. There were no differences in HbA1c at 3 or 6 mo between sitagliptin and placebo groups. Participants tolerated sitagliptin well. CONCLUSIONS: Although this study did not show a significant difference between groups, it can inform future studies in the use of sitagliptin in the very early posttransplant period.

Obesity and kidney transplant candidates: how big is too big for transplantation?.

Obesity impacts many inter-related, and sometimes conflicting, considerations for transplant practice. In this article, we describe an approach for applying available data on the importance of body composition to the kidney transplant population that separates implications for candidate selection, risk stratification among selected candidates, and interventions to optimize health of the individual. Transplant recipients with obesity defined by elevated body mass index (BMI) have been shown in many (but not all) studies to experience an array of adverse outcomes more commonly than normal-weight transplant recipients, including wound infections, delayed graft function, graft failure, cardiac disease, and increased costs. However, current studies have not defined limits of body composition that preclude clinical benefit from transplantation compared with long-term dialysis in patients who have passed a transplant evaluation. Formal cost-effectiveness studies are needed to determine if payers and society should be compensating centers for clinical and financial risks of transplanting obese end-stage renal disease patients. Recent studies also demonstrate the limitations of BMI alone as a measure of adiposity, and further research should be pursued to define practical measures of body composition that refine accuracy for outcomes prediction. Regarding individual management, observational registry studies have not found beneficial associations of pretransplant weight loss with patient or graft survival. However, association studies cannot distinguish purposeful from unintentional weight loss as a result of illness and comorbidity. Prospective evaluations of the impact of targeted risk modification efforts in this population including dietary changes, monitored exercise programs, and bariatric surgery are urgently needed.

Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation.

Background: Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here, we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods: A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: seven TCMR, ten ABMR, and one mixed rejection. The second validation set included eight quiescence and 11 rejection samples: seven TCMR, two ABMR, and two mixed rejection. AlloSure donor-derived cell-free DNA (dd-cfDNA) was also evaluated. Results: AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median, 9.49; IQR, 7.68-11.53) and rejection (median, 13.09; IQR, 11.25-15.28), with P<0.001. In the second validation set, the cohorts were statistically different (P=0.03) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC, 0.894). Conclusion: Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunologic activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.

Cardiac evaluation prior to kidney transplantation.

Kidney transplantation is the treatment of choice for most patients with stage 5 chronic kidney disease and end-stage renal disease (ESRD), offering improved quality of life and overall survival rates. However, the limited supply of available organs makes this a scarce resource. Cardiovascular complications continue to be the leading cause of mortality in the kidney transplant population, accounting for over 30% of deaths with a functioning allograft. Thus, preoperative cardiac risk assessment is critical to optimize patient selection and outcomes. Currently there is no consensus for cardiovascular evaluation in the chronic kidney disease and ESRD population prior to kidney transplantation; the recommendations of the American Society of Nephrology and American Society of Transplantation differ from those of the American Heart Association and the American College of Cardiology. Previously developed risk scores have also been used to risk stratify this population. In this review, we discuss two cases that illustrate the difficulties of interpreting the prognostic value of current testing strategies. We also discuss the importance of different tests for cardiovascular evaluation as well as previous nonkidney transplant specific risk scores used in the pre-kidney transplant population.

Management of Post-transplant Hyperparathyroidism and Bone Disease.

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

Effect of Frequent Dialysis on Renal Recovery: Results From the Acute Renal Failure Trial Network Study.

INTRODUCTION: The optimal frequency of intermittent hemodialysis (IHD) in the treatment of acute kidney injury (AKI) remains unclear. Increasing the frequency of IHD, while offering the possible advantage of reduced ultrafiltration requirement and less hemodynamic instability per session, amplifies patient contact with an extracorporeal circuit with possible deleterious cardiovascular and immunological consequences. A recent study suggested that intensive renal replacement therapy (RRT) is associated with a decrease in urine output during AKI. We hypothesized that increased frequency of IHD may be associated with delayed renal recovery. METHODS: This is a post hoc analysis of the Acute Renal Failure Trial Network (ATN) study. The ATN study was a large randomized multicenter trial of intensive versus less-intensive RRT in critically ill patients with AKI. This study used either continuous RRT or IHD, depending on the hemodynamic status of the patient. Of 1124 patients, 246 were treated solely with IHD during the study period and were included in this analysis. The participants were randomized to receive IHD 3 days per week (L-IntRRT) or 6 days per week (IntRRT). The primary outcome of interest was renal recovery at day 28. RESULTS: L-IntRRT was associated with higher number of RRT-free days through day 28 than IntRRT (mean difference 2.5 days; 95% confidence interval [CI]: -4.79 to -0.27 days; P = 0.028). The likelihood for renal recovery at day 28 was lower in the IntRRT group (OR: 0.49; 95% CI: 0.28-0.87; P = 0.016). CONCLUSION: In hemodynamically stable patients with AKI, intensifying the frequency of IHD from 3 to 6 days per week may be associated with impaired renal recovery.

Accelerated humoral renal allograft rejection due to HLA-C14 mediated allosensitization to HLA-Bw6.

OBJECTIVES: To investigate immunological mechanisms underlying accelerated antibody-mediated rejection (AMR) of a living-related renal allograft in a patient with no detectable antibodies to donor human leukocyte antigens (HLA) in pre-transplant sera. METHODS: Pre- and post-transplant HLA antibody specificities were determined by single-antigen bead assay, and crossmatching was performed by flow cytometry- and complement-dependent cytotoxicity-based methods. Intermediate- and high-resolution HLA typing were performed by molecular methods. RESULTS: Pre-transplant patient serum reacted weakly against Bw6-positive beads; cytotoxicity and flow crossmatches were negative. The patient was mismatched for the donor antigens B62 and C10 (Bw6-positive). Following transplantation, strong antibody responses against B62, C10, and all Bw6-positive beads were detected. This reactivity was initially masked by complement interference, but became apparent at 1:20 dilution. High-resolution typing suggested that the anti-C16 antibody reactivity detected was an allele-specific response to donor C∗16:01 (Bw6-positive) but not recipient C∗16:02 (Bw6-negative). Alloimmunization likely occurred during pregnancy, during which HLA-C14 (Bw6-positive) was the only mismatched paternal HLA Class I allele. CONCLUSIONS: Sensitization to HLA-Bw6 via exposure to paternal HLA-C14 during pregnancy likely predisposed this patient to AMR. The case demonstrates the immunogenicity of HLA-C14-associated Bw6 epitopes in vivo and the clinical significance of low-level antibodies to HLA-Bw6.

The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation.

BACKGROUND: White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. METHODS: We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. RESULTS: There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). CONCLUSIONS: This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Tacrolimus-Induced Cardiomyopathy in an Adult Renal Transplant Recipient.

Tacrolimus-induced cardiomyopathy (TICM) is a rare but serious adverse effect of tacrolimus, which has been described primarily in pediatric non-renal transplant recipients. We describe a case of TICM in an adult renal transplant recipient that resulted in allograft dysfunction and multiple hospital admissions for heart failure exacerbation. Prompt and complete reversal of TICM occurred after tacrolimus discontinuation. Although tacrolimus-induced cardiomyopathy is reversible, availability of alternative immunosuppressants is limited, particularly in the setting of renal dysfunction. Available studies and patient-specific factors must be considered when determining an alternative maintenance immunosuppression regimen. We chose to use belatacept as alternative immunosuppression in this patient with TICM. Over the next 3 years, the patient remained free of hospital admissions and acute rejection, and demonstrated superior renal allograft function than was observed before her first heart failure admission. We believe that belatacept is an acceptable alternative to tacrolimus therapy for resolution of TICM.

The efficacy and safety of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in chronic kidney disease, dialysis, and transplant patients.

Coronary heart disease (CHD) is the leading cause of death in Western civilizations, in particular in chronic kidney disease (CKD) patients. Serum total cholesterol and LDL have been linked to the development of atherosclerosis and progression to CHD in the general population. However, the reductions of total and LDL cholesterol in the dialysis population have not demonstrated the ability to reduce the morbidity, mortality, and cost burden associated with CHD. The patients at greatest risk include those with pre-existing CHD, a CHD-risk equivalent, or multiple risk factors. However, data in the dialysis population are much less impressive, and the relationship between plasma cholesterol, cholesterol reduction, use of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and reduction in incidence of CHD or effect on progression of renal disease have not been proven. Adverse event information from published trials indicates that agents within this class share similar tolerability and adverse event profiles. Hepatic transaminase elevations may occur in 1 to 2% of patients and is dose related. Myalgia, myopathy, and rhabodmyolysis occur infrequently and are more common in kidney transplant patients and patients with CKD. This effect appears to be dose related and may be precipitated by administration with agents that inhibit cytochrome P-450 isoenzymes. Caution should be exercised when coadministering any statin with drugs that metabolize through cytochrome P-450 IIIA-4 in particular fibrates, cyclosporine, and azole antifungals. Elderly patients with CKD are at greater risk of adverse drug reactions, and therefore the lowest possible dose of statins should be used for the treatment of hyperlipidemia.