Changes in the small bowel of symptomatic kidney transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium.

BACKGROUND/AIMS: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions. METHODS: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. RESULTS: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. CONCLUSION: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

Effects of antibody induction on transplant outcomes in human leukocyte antigen zero-mismatch deceased donor kidney recipients.

BACKGROUND: We aimed to investigate the impact of antibody induction on outcomes in human leukocyte antigen (HLA) 0-mismatched deceased donor kidney recipients. METHODS: Using the Organ Procurement and Transplant Network/United Network of Organ Sharing database as of November 2009, we identified 44,008 adult deceased donor kidney recipients who received primary kidney transplants alone between 2003 and 2008 (HLA 0 mismatch, n = 6274; ≥ 1 mismatch, n=37,734; median follow-up: 834 days). The impact of induction (thymoglobulin, interleukin-2 receptor antagonists [IL-2RA], or alemtuzumab; vs. no induction) on rejection (initial hospitalization, 6 months, first year), death-censored graft failure, and mortality were analyzed using multivariate logistic and Cox regression in the two groups. The impact of individual agents on outcomes was further analyzed in 0-mismatch recipients. RESULTS: There was a decreased risk of rejection over the first 6 months for HLA 0-mismatch recipients of antibody induction (adjusted odds ratio=0.71, P=0.003), but this effect was not observed at 1 year; in comparison, induction was associated with a reduced risk of rejection over the first year for HLA-mismatched recipients (0.87, P<0.001). The use of thymoglobulin (0.72, P=0.02) and IL-2RA (0.67, P=0.004) was associated with a decreased risk of rejection compared with no-induction at 6 months but was not different at 1 year (thymoglobulin: 0.77, P=0.05; IL-2RA:0.81, P=0.11) in HLA 0-mismatched recipients. Induction was not associated with improved graft or patient survival in HLA 0-mismatch recipients. CONCLUSION: In HLA 0-mismatch deceased donor recipients, antibody induction was associated with a decreased risk of rejection at 6 months posttransplant. Its use did not improve graft and patient survival over the follow-up period.

ABO blood type-incompatible kidney transplantation and access to organs.

OBJECTIVE: To determine whether ABO-incompatible (ABOi) kidney transplantation can be performed safely and result in acceptable posttransplantation outcomes. DESIGN: Prospective study. SETTING: Transplantation center. PATIENTS: In the 1½ years of a new program, 18 patients with renal failure and an ABOi living kidney donor were included in the study. All donors and recipients were of incompatible blood types and underwent transplantation beginning in June 2008. INTERVENTIONS: Patients received immunomodulation (anti-CD20 antibody, intravenous immunoglobulin, and plasmapheresis) until an acceptable isoagglutinin titer was obtained on the date of transplantation. All the kidneys were transplanted heterotopically, and all the patients received induction immunosuppression followed by a combination of prednisone, mycophenolate mofetil, and tacrolimus. Isoagglutinin titers were monitored, and postoperative plasmapheresis was initiated if titers increased. MAIN OUTCOME MEASURES: Patient and allograft survival; length of stay; 1-, 3-, and 6-month and 1-year renal function; and incidence of rejection. RESULTS: Patient survival was 100%, with allograft survival of 94.4%. Mean (SD) length of stay was 6.9 (1.9) days. Donor to recipient transplantation was A to O in 11 cases, A2 to B in 1, B to A in 3, B to O in 1, and AB to B in 2. Mean (SD) creatinine levels, a measure of graft function, were 1.2 (0.5) mg/dL at discharge, 1.4 (0.4) mg/dL at 1 month, 1.3 (0.45) mg/dL at 3 months, 1.1 (0.3) mg/dL at 6 months, and 1.2 (0.2) mg/dL at 1 year. One episode of cellular rejection occurred. CONCLUSIONS: These short-term results suggest that with a straightforward regimen, ABOi kidney transplantation is possible, acceptable results and graft function are obtainable, and access to kidney transplantation for those with a blood type-incompatible donor can be expanded.

Management of renal dysfunction in the liver transplant recipient.

PURPOSE OF REVIEW: Acute and chronic kidney injury following orthotopic liver transplantation (OLT) is associated with increased morbidity and mortality. With the increasing longevity of liver transplant recipients, chronic kidney disease (CKD) has become an increasingly prevalent complication among long-term survivors. This article provides an overview of the literature on suggested risk factors for acute and CKD following OLT and a discussion of an approach to their medical management. RECENT FINDINGS: In OLT candidates with pretransplant renal dysfunction, the use of interleukin-2 receptor blockers or antithymocyte globulin induction therapy in conjunction with delayed introduction of calcineurin inhibitors may preserve early renal function. In long-term stable OLT recipients with established calcineurin inhibitor nephrotoxicity, calcineurin inhibitor minimization or withdrawal protocols may halt or ameliorate renal dysfunction without compromising patient and graft survival. However, large-scale, multicenter, randomized controlled trials are still needed. SUMMARY: The occurrence of acute kidney injury is common immediately after OLT, whereas the incidence of CKD and end-stage renal disease increases with time. Identifying patients at risk for acute kidney injury and CKD following OLT and early implementation of measures to preserve, halt, or ameliorate the progression of renal dysfunction should be an integral part in the management of OLT recipients.

New onset diabetes mellitus after solid organ transplantation.

This article presents an overview of the literature on the current diagnostic criteria for new onset diabetes mellitus after transplantation (NODAT) and discusses suggested risk factors for the development of NODAT, its potential pathogenic mechanisms, and its impact on post-transplant outcomes after solid organ transplantation. Suggested guidelines for early identification and management of NODAT are also discussed.

Pancreas-kidney and pancreas transplantation for the treatment of diabetes mellitus.

Kidney transplantation is the treatment of choice for end-stage diabetic nephropathy, but the ultimate treatment today for type 1 diabetes mellitus is the whole vascularized pancreas transplant. Although its use is increasing, pancreas transplantation remains an uncommonly used therapeutic option that normalizes glucose levels and results in stabilization or improvement in secondary complications far better than any other strategy available for treatment of type 1 diabetes. These documented benefits of a simultaneous kidney and pancreas transplant are the basis for its acceptance as an appropriate therapy for patients who have type 1 diabetes mellitus and end-stage renal disease.

Renal function outcomes following liver transplantation and combined liver-kidney transplantation.

Acute renal failure (ARF) is common immediately after orthotopic liver transplantation (OLT), whereas the incidences of chronic kidney disease (CKD) and end-stage renal disease increase with time. Introduction of the Model for End-stage Liver Disease (MELD) score-intended to prioritize patients with more-severe pretransplantation liver disease in general, and worse pretransplantation renal function in particular-for the allocation of liver grafts led to concerns about compromised patient and allograft survival and increased incidence of postoperative ARF and CKD. Nonetheless, it has been suggested that early OLT of candidates with baseline renal dysfunction improves post-transplantation renal outcomes. For OLT candidates with mild to moderate chronic renal impairment or recent-onset ARF, the decision of whether to perform OLT alone or combined liver-kidney transplantation (CLKT) can be challenging because no single factor has been shown to be predictive of the degree of renal function recovery or CKD progression following successful OLT. In this article, we provide an overview of the literature on renal function outcomes following OLT and CLKT, share our perspectives on the potential predictors of renal dysfunction or nonrecovery of renal function after OLT, and present United Network for Organ Sharing data on patient and allograft outcomes in CLKT recipients in the pre-MELD and post-MELD eras. Mechanisms that might underlie immunological protection of kidney grafts by liver allografts are also discussed.

Noninvasive diagnosis of cellular and antibody-mediated rejection by perforin and granzyme B in renal allografts.

A major milestone in transplantation would be the use of biomarkers to monitor rejection. We examined the association between perforin and granzyme-B gene expression detected in the peripheral blood of renal allograft recipients with cellular and antibody-mediated rejection. Furthermore, we judged the appropriateness of assigning negative rejection statuses to persons without a biopsy whose grafts were functioning well clinically. Of the 46 patients who completed the study, recipients with cellular rejection had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.006). Interestingly, recipients with antibody-mediated rejection also had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.04). Patients with high levels of granzyme B had a probability of rejecting that was 26.7 times greater than those patients with low levels of granzyme B. Perforin and granzyme B had sensitivities of 50% and specificities of 95% in predicting rejection (cutoff value = 140). Assigning negative rejection statuses to recipients without a biopsy whose grafts were functioning well did not have a major effect on the direction or significance of covariate values. This study suggests that perforin and granzyme-B gene expressions in peripheral blood are accurate in detecting both cellular and antibody-mediated rejection.

Long-term analysis of combined liver and kidney transplantation at a single center.

OBJECTIVE: To analyze use of combined liver and kidney transplantation (CLKT) for patients with chronic primary diseases of both organs and for patients with hepatorenal syndrome. DESIGN: Retrospective case series. SETTING: Multiorgan transplantation service in a large university medical center. PATIENTS: A total of 98 patients underwent 99 CLKTs during a 16-year period; 76 had primary renal diseases, and 22 had hepatorenal syndrome. Patients receiving isolated liver and kidney transplants were analyzed for comparison. MAIN OUTCOME MEASURES: Patient and graft survival, rejection rates, and need for hemodialysis before and after transplantation. RESULTS: Overall patient survival was 76%, 72%, and 70% at 1, 3, and 5 years, respectively; liver graft survival was 70%, 65%, and 65%; and kidney graft survival was 76%, 72%, and 70%. No risk factors analyzed for recipients or donors were associated significantly with early posttransplantation mortality or graft loss. In 28 patients who received monoclonal antibody induction therapy with interleukin 2 blockers, there were significantly fewer episodes of acute liver rejection. For patients with hepatorenal syndrome, CLKT did not confer a survival advantage over liver-only transplantation (1-year patient survival was 72% vs 66%; P = .88). The 1-year acute kidney rejection rate in the adult CLKT group was 14% vs 23% in a 5-year cadaveric renal transplantation cohort (P<.01). CONCLUSIONS: First, CLKT is indicated in patients with dual organ disease and achieves excellent results. Second, CLKT for hepatorenal syndrome is indicated in patients receiving hemodialysis for longer than 8 weeks and confers advantages in patient survival and use of hospital resources. Third, the liver is immunoprotective for the kidney.

Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature.

Scleroderma renal crisis (SRC) can lead to end-stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1-2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987-July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5-year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new-onset anemia and cardiac complications.

Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction.

BACKGROUND: The goal of this study was to determine whether the production of posttransplant antibodies directed against donor HLA mismatches (donor specific antibody; DSA) is associated with renal allograft rejection and early graft dysfunction. METHODS: Forty-nine adult renal allograft recipients with increased risk of rejection were enrolled during the period of October 2001 through May 2003 and were prospectively monitored for the development of anti-HLA antibodies. RESULTS: Of 49 patients, eight (16.3 %) patients were diagnosed with acute humoral rejection (AHR) and 11/49 (22.4%) patients were diagnosed with acute cellular rejection (ACR). A strong association between pretransplant HLA sensitization and AHR was found (P=0.005). Of the eight patients diagnosed with AHR, the majority developed DSA before or concomitant with episodes of rejection (P<0.001). Only 3 of 41 patients (7.3%) without AHR developed DSA. The pathogenic role of alloantibodies was further substantiated by analyzing their association with graft function as measured by serum creatinine levels. The average serum creatinine after the third month posttransplantation in DSA producers was 2.24+/-1.01 mg/dL, while in non-DSA patients the average serum creatinine was 1.41+/-0.37 mg/dL (P<0.01). CONCLUSION: This study reveals a strong association between the production of DSA, AHR, and early graft dysfunction. Our findings indicate that prospective monitoring for anti-HLA antibodies following transplantation is a useful test for the diagnosis and classification of AHR for identifying patients at risk of early graft dysfunction.

A novel flow assay for the detection of cytokine secreting alloreactive T cells: application to immune monitoring.

The direct and indirect allorecognition pathways play an important role in graft rejection. We hypothesized that the presence of alloreactive memory T cells in the recipient's circulation increases the risk of rejection after transplantation. The objective of this study was to develop a noninvasive, immune monitoring tool that simultaneously measures donor-specific responses via both the direct and indirect recognition pathways. Our laboratory developed a whole blood flow cytometric cytokine secretion assay to identify interferon (IFN)-gamma secreting memory T cells in whole blood of renal transplant patients. The assay readily detected IFN-gamma producing CD3+ T cells in response to recall antigens tetanus toxoid, purified protein derivative, and alloantigens in whole blood from healthy controls. Analysis of sequential posttransplant blood samples from 19 renal allograft recipients showed that alloimmune responses were higher in transplant recipients who had undergone acute rejection than in those without acute rejection episodes. In addition, patients showing increased creatinine levels 3 months after transplantation were more likely to exhibit alloimmune responses than recipients with stable graft function. The flow cytokine secretion assay provides a reliable and simple method for identification of patients at risk of acute rejection and early graft dysfunction.

Sirolimus-associated pulmonary toxicity.

BACKGROUND: Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. METHODS: We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. RESULTS: Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. CONCLUSION: The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation.

BACKGROUND: Acute rejection remains a major problem in renal transplantation. Immunoprophylaxis with basiliximab (Simulect) has achieved significant reductions in acute rejection episodes in renal allograft recipients receiving dual immunosuppression. This study explored the tolerability and cumulative benefit of combining basiliximab with triple-drug therapy-cyclosporine (USP Modified, Neoral), mycophenolate mofetil, and steroids. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 123 kidney transplant recipients received either basiliximab at 20 mg before transplantation (day 0) and 20 mg on day 4 (n=59), or placebo (n=64). All received triple-drug immunosuppression and were followed for 6 months. RESULTS: Tolerability of basiliximab was equivalent to placebo, with no increase in serious adverse events, infection, malignancy, or posttransplant lymphoproliferative disorder. At 6 months, there were trends in favor of basiliximab over placebo in the incidences of first biopsy-confirmed acute rejection (15.3% vs. 26.6%, P=NS) and of acute rejection treated with antibody (5.1% vs. 15.6%, P=NS). Kaplan-Meier estimates at 4 weeks and 6 months were significantly in favor of basiliximab treatment for first acute rejection, biopsy-confirmed rejection, rejection episodes treated with antibody therapy, and treatment failure. Renal function improved more rapidly in the basiliximab group, with mean creatinine clearance at week 2 being 54.7 mL/min versus 43.2 mL/min for placebo (P=0.034). At 12 months, patient survival was 100% in both groups; graft survival was 94.9% with basiliximab and 92.2% with placebo. CONCLUSIONS: Basiliximab immunoprophylaxis is safe, well tolerated, and shows a trend toward reduction in number of acute rejection episodes in renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

Inhibitors of ADAMTS13: a potential factor in the cause of thrombotic microangiopathy in a renal allograft recipient.

BACKGROUND: Thrombotic microangiopathy (TMA) is a well-known complication after renal allograft transplantation. In most cases, calcineurin inhibitor is believed to play a role in the development of this disorder. Recent studies have shown that a deficiency in the activity of the von Willebrand factor-cleaving metalloprotease ADAMTS13 causes thrombotic thrombocytopenic purpura. A similar mechanism occurring in patients who develop TMA after renal transplantation has not been described. METHODS: Analysis of plasma samples from a patient who developed TMA after receiving a cadaveric renal allograft revealed undetectable ADAMTS13 activity and the presence of its inhibitors. RESULTS: Discontinuation of cyclosporine and daily plasma exchange increased the ADAMTS13 activity, which was followed by resolution of the microangiopathic hemolysis and improvement of the graft function. At 3-month follow-up, the ADAMTS13 activity remained in the normal range and no inhibitors were detected. CONCLUSIONS: This is the first case to demonstrate a correlation between the presence of ADAMTS13 inhibitors and transplant-associated TMA. Autoimmune inhibitors of ADAMTS13 should be considered in patients with transplant-associated thrombotic microangiopathy. The role of calcineurin inhibitor in the formation of autoantibodies to ADAMTS13 remains to be explored.

Identification of patients best suited for combined liver-kidney transplantation: part II.

Liver-kidney transplantation (LKT) should be reserved for those recipients with primary disease affecting both organs. However, increasing transplant list waiting times have increased the development and duration of acute renal failure before liver transplantation. Furthermore, the need for posttransplant calcineurin inhibitors can render healing from acute renal failure difficult. Because of the increasing requests for and controversy over the topic of a kidney with a liver transplant (OLT) when complete failure of the kidney is not known, the following article will review the impact of renal failure on liver transplant outcome, treatment of peri-OLT renal failure, rejection rates after LKT, survival after LKT, and information on renal histology and progression of disease into the beginnings of an algorithm for making a decision about combined LKT.

Pathophysiology of renal disease associated with liver disorders: implications for liver transplantation. Part I.

Renal and hepatic function are often intertwined through both the existence of associated primary organ diseases and hemodynamic interrelationships. This connection occasionally results in the chronic failure of both organs, necessitating combined liver-kidney transplantation (LKT). Since 1988, more than 850 patients in the United States have received such transplants, with patient survival somewhat less than that for patients receiving either organ alone. Patients with renal failure caused by acute injury or hepatorenal syndrome have classically not been included as candidates for combined transplantation because of the reversibility of renal dysfunction after liver transplantation. However, the rate and duration of renal failure before liver transplantation is increasing in association with prolonged waiting list times. Thus, the issue of acquired permanent renal damage in the setting of hepatic failure continues to confront the transplant community. The following article and its sequel (Part II, to be published in vol 8, no 3 of this journal) attempt to review the problem of primary and secondary renal disease in patients with end-stage liver disease, elements involved in renal disease progression and recovery, the impact of renal disease on liver transplant outcome, and results of combined LKT; outline the steps in the pretransplantation renal evaluation; and provide the beginnings of an algorithm for making the decision for combined LKT.