Use of LCP-Tacrolimus (LCPT) in Kidney Transplantation: A Delphi Consensus Survey of Expert Clinicians.

BACKGROUND LCPT (Envarsus XR®) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings. MATERIAL AND METHODS Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as ≥75% agreement. RESULTS Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first-line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first-line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached. CONCLUSIONS When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.

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.

Counselling, Research Gaps, and Ethical Considerations Surrounding Pregnancy in Solid Organ Transplant Recipients.

Survival after solid-organ transplantation has improved significantly, and many contemporary transplant recipients are of childbearing potential. There are limited data to guide decision-making surrounding pregnancy after transplantation, variations in clinical practice, and significant knowledge gaps, all of which raise significant ethical issues. Post-transplant pregnancy is associated with an increased risk of maternal and fetal complications. Shared decision-making is a central aspect of patient counselling but is complicated by significant knowledge gaps. Stakeholder interests can be in conflict; exploring these tensions can help patients to evaluate their options and inform their deliberations. We argue that uniform, evidence-based recommendations for pregnancy after solid organ transplantation are needed. Conducting research, including patient-engaged studies, in this area should be priority for the transplant community.

Post-Transplant Pregnancy and Contraception.

Placed in a historical context, this overview focuses on post-transpant pregnancy, fatherhood, and contraception in women and men. The critical importance of early reproductive counseling because of improved sexual function and the early return of ovulation and menses post-transplant is emphasized. We explain the decision making regarding contraception choices. The available data on the safety of immunosuppressive drugs in pregnancy, and for men desiring fatherhood, are detailed. The risk of maternal ingestion of mycophenolate products on the in utero fetus is considered and contrasted with the lack of concern for their use by men fathering children. Pregnancy risks to the allograft, baby, and mother are discussed. An infant's exposure to specific immunosuppressant medications through breastfeeding is reviewed. The ethics and realities of post-transplant parenthood are explored.

Posttransplant Malignancy.

Posttransplant malignancy is a leading cause of death after solid organ transplantation (SOT). Recipients of SOT are at significantly higher risk of multiple cancers compared with the general population, most notably nonmelanoma skin cancer and posttransplant lymphoproliferative disorders. Risk factors for posttransplant malignancy include history of malignancy, immunosuppression, oncogenic viral infections, sun exposure, and disease-specific associations. Early detection and treatment of malignancies can improve survival.

Transmission of Babesia microti Parasites by Solid Organ Transplantation.

Babesia microti, an intraerythrocytic parasite, is tickborne in nature. In contrast to transmission by blood transfusion, which has been well documented, transmission associated with solid organ transplantation has not been reported. We describe parasitologically confirmed cases of babesiosis diagnosed ≈8 weeks posttransplantation in 2 recipients of renal allografts from an organ donor who was multiply transfused on the day he died from traumatic injuries. The organ donor and recipients had no identified risk factors for tickborne infection. Antibodies against B. microti parasites were not detected by serologic testing of archived pretransplant specimens. However, 1 of the organ donor's blood donors was seropositive when tested postdonation and had risk factors for tick exposure. The organ donor probably served as a conduit of Babesia parasites from the seropositive blood donor to both kidney recipients. Babesiosis should be included in the differential diagnosis of unexplained fever and hemolytic anemia after blood transfusion or organ transplantation.

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.

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.

Selection of induction therapy in kidney transplantation.

Currently available immunosuppressive agents can be classified into three categories: induction agents, maintenance therapy, and treatment for rejection. This review article will focus on induction immunosuppression. There are three antibodies which are used for induction therapy: the lymphocyte-depleting agents - anti-thymocyte globulin and alemtuzumab, and basiliximab which is nondepleting. Historically, immunosuppressant selection was solely based on efficacy for prevention of rejection. In the current era of transplantation, it is now common practice in the transplant community to select induction therapy on the basis of risk-benefit considerations for each patient. This article will focus on the efficacy of available induction agents and the selection of induction agent based on donor and recipient risk factors.

Impact of hepatorenal syndrome and liver transplantation.

PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) is an extremely detrimental complication of cirrhosis, with dismal survival in untreated patients. Continued advances in understanding the pathophysiology of HRS have improved HRS recognition and facilitated development of effective treatment strategies. In this article, we review current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver versus liver-kidney transplant in transplant candidates. RECENT FINDINGS: Published diagnostic criteria for HRS have improved early recognition and intervention in HRS. Increasing data support vasoconstrictor therapy for HRS reversal. Several randomized controlled trials clearly demonstrate efficacy of terlipressin therapy in HRS reversal; although comparable studies are lacking with norepinephrine, preliminary findings suggest that this regime may be the preferred alternative when terlipressin is unavailable for use. In transplant candidates without response to vasoconstrictor therapies, mounting evidence supports simultaneous liver-kidney transplantation if prolonged pretransplant dialysis is required. SUMMARY: Prompt identification and therapy initiation in transplant candidates with HRS may improve transplantation rates and posttransplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of simultaneous liver-kidney transplants in patients with HRS remains controversial and requires further analysis by the transplant community.

Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery.

INTRODUCTION: Interleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6. METHODS: Urine was collected in 25 consecutive pediatric patients undergoing cardiac bypass surgery (CPB). AKI was defined as a 50% increase in serum creatinine at 24 hours (RIFLE (Risk, Injury, Failure, Loss, End stage), R). Mouse models of AKI and freshly isolated proximal tubules were also studied. RESULTS: Urine IL-6 increased at six hours in patients with AKI versus no AKI (X2 = 8.1750; P < 0.0042). Urine IL-6 > 75 pg/mg identified AKI with a sensitivity of 88%. To assess whether increased urine IL-6 occurs in functional versus structural renal failure, mouse models of pre-renal azotemia after furosemide injection (no tubular injury), ischemic AKI (tubular injury) and cisplatin AKI (tubular injury) were studied. Urine IL-6 did not significantly increase in pre-renal azotemia but did increase in ischemic and cisplatin AKI. To determine if circulating IL-6 appears in the urine in AKI, recombinant human (h)IL-6 was injected intravenously and urine collected for one hour; urine hIL-6 increased in ischemic AKI, but not pre-renal azotemia. To determine the effect of AKI on circulating IL-6, serum hIL-6 was determined one hour post-intravenous injection and was increased in ischemic AKI, but not pre-renal azotemia. To directly examine IL-6 metabolism, hIL-6 was added to the media of normal and hypoxic isolated proximal tubules; hIL-6 was reduced in the media of normal versus injured hypoxic proximal tubules. CONCLUSIONS: Urine IL-6 increases early in patients with AKI. Animal studies demonstrate that failure of proximal tubule metabolism of IL-6 results in increased serum and urine IL-6. Impaired IL-6 metabolism leading to increased serum IL-6 may contribute to the deleterious systemic effects and increased mortality associated with AKI.

Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.

Patients with acute kidney injury frequently have pulmonary complications. Similarly ischemic acute kidney injury or bilateral nephrectomy in rodents causes lung injury characterized by pulmonary edema, increased pulmonary capillary leak and interstitial leukocyte infiltration. Interleukin-6 is a pro-inflammatory cytokine that is increased in the serum of patients with acute kidney injury and predicts mortality. Here we found that lung neutrophil infiltration, myeloperoxidase activity, the neutrophil chemokines KC and MIP-2 and capillary leak all increased within 4 h following acute kidney injury in wild-type mice. These pathologic factors were reduced in interleukin-6-deficient mice following acute kidney injury or bilateral nephrectomy. The lungs of mutant mice had reduced KC but MIP-2 was similar to that of wild type mice. Wild-type mice, treated with an interleukin-6 inactivating antibody, had decreased lung myeloperoxidase activity and KC levels following acute kidney injury. Our study shows that interleukin-6 contributes to lung injury following acute kidney injury.

Long-term renal outcomes after delayed graft function.

Delayed graft function (DGF) describes dysfunction of the kidney allograft immediately after transplantation and is the most common complication in the immediate posttransplantation period. Although a standardized definition for DGF is lacking, it is most commonly defined as the need for dialysis within the first week after transplant. DGF is caused by a variety of factors related to the donor and recipient as well as organ procurement techniques. The occurrence of DGF affects both allograft and patient outcomes. In addition to prolonging hospital stay and increasing the costs associated with transplantation, DGF is associated with an increased incidence of acute rejection after transplantation and is associated with poorer long-term graft outcomes. Both immunologic and nonimmunologic mechanisms contribute to DGF. The risk factors for DGF that have been identified are reviewed as well as the impact of DGF on long-term outcomes.

Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.

We have demonstrated that caspase-1-deficient (caspase-1(-/-)) mice are functionally and histologically protected against cisplatin-induced acute renal failure (ARF). Caspase-1 exerts proinflammatory effects via the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF. We first examined IL-1beta; renal IL-1beta increased nearly 2-fold in cisplatin-induced ARF and was reduced in the caspase-1(-/-) mice. However, inhibition with IL-1 receptor antagonist (IL-1Ra) did not attenuate cisplatin-induced ARF. Renal IL-18 increased 2.5-fold; however, methods to inhibit IL-18 using IL-18 antiserum and transgenic mice that overproduce IL-18-binding protein (a natural inhibitor of IL-18) did not protect. Renal IL-6 increased 3-fold; however, IL-6-deficient (IL-6(-/-)) mice still developed cisplatin-induced ARF. We next examined neutrophils; blood neutrophils increased dramatically after cisplatin injection; however, prevention of peripheral neutrophilia and renal neutrophil infiltration with the neutrophil-depleting antibody RB6-8C5 did not protect against cisplatin-induced ARF. In summary, our data demonstrated that cisplatin-induced ARF is associated with increases in the cytokines IL-1beta, IL-18, and IL-6 and neutrophil infiltration in the kidney. However, inhibition of IL-1beta, IL-18, and IL-6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin-induced ARF.

Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury.

BACKGROUND: Caspase-1 is a proinflammatory caspase via activation of the cytokine IL-18. We have recently demonstrated that the caspase-1-mediated production of IL-18 plays a deleterious role in ischaemic acute renal failure (ARF) which is independent of neutrophils and CD4+ T cells. The role of caspase-1 in hypoxia-induced membrane injury of proximal tubules (PT) in vitro is unknown. METHODS: Freshly isolated mouse PT exposed to 25 min of hypoxia were used to study the role of caspases, caspase-1 and IL-18 in hypoxia-induced membrane injury. Lactate dehydrogenase (LDH) release into the PT medium was used as a biochemical parameter of cell membrane damage. IL-18 was determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. RESULTS: PT pre-incubated with the novel pancaspase inhibitor IDN-8050 were protected; LDH release (%) was 35+/-3 in vehicle-treated hypoxic PT and 21+/-2 in IDN-8050-treated hypoxic PT (P<0.01, n=6). To investigate the mechanism of protection and examine the role of caspase-1 specifically, PT were isolated in parallel from wild-type and caspase-1- deficient (-/-) mice. PT from caspase-1-/-mice demonstrated less hypoxia-induced membrane injury. LDH release was 37+/-2 in wild-type hypoxic PT and 28+/-2 in caspase-1-/-hypoxic PT (P<0.01, n=12). IL-18 was detected in PT by immunoblotting and ELISA. PT pre-incubated with IL-18 binding protein, an inhibitor of IL-18, were not protected. CONCLUSIONS: These studies demonstrate a deleterious effect of the proinflammatory caspase, caspase-1, on PT in vitro in the absence of inflammatory cells and vascular effects.

Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury.

Clinical studies demonstrate that acute renal failure (ARF) is associated with increased mortality, which may be due to pulmonary complications. ARF may affect the lung via increased renal production or impaired clearance of mediators of lung injury, such as proinflammatory cytokines. Bilateral nephrectomy is a method to examine directly the deleterious systemic effects of absent renal clearance in ARF without the confounding effects that are associated with ischemia-reperfusion injury (e.g., ischemic ARF) or systemic toxicity (e.g., cisplatin-induced ARF). This study contrasts the effects of ischemic ARF and bilateral nephrectomy on serum cytokines and lung injury. It demonstrates that the acute absence of kidney function after both ischemic ARF and bilateral nephrectomy is associated with an increase in multiple serum cytokines, including IL-6 and IL-1beta, and that the cytokine profiles were distinct. Lung injury after ischemic ARF and bilateral nephrectomy was similar and was characterized by pulmonary vascular congestion and neutrophil infiltration. For investigation of the role of proinflammatory cytokines in pulmonary injury after ARF, the anti-inflammatory cytokine IL-10 was administered before bilateral nephrectomy. IL-10 treatment improved pulmonary architecture and was associated with a reduction in inflammatory markers, including bronchoalveolar lavage fluid total protein, pulmonary myeloperoxidase activity (a biochemical marker of neutrophils), and the chemokine macrophage inflammatory protein 2. These data demonstrate for the first time that the acute absence of kidney function results in pulmonary injury independent of renal ischemia and highlight the critical role of the kidney in the maintenance of serum cytokine balance and pulmonary homeostasis.