Late-Onset Allograft Aspergillosis in an HIV-Positive Renal Transplant Recipient: A Case Report.

Aspergillus infection of the allograft in renal transplant patients is rare and associated with a high mortality. We report a case of a 21-year-old, human immunodeficiency virus-positive, deceased-donor kidney recipient who presented 1 year after transplant with oliguric kidney injury. A nuclear medicine renal scan revealed absence of flow to the transplanted kidney, and a urine fungal culture was positive for Aspergillus flavus. The diagnosis was confirmed with the presence of fungal hyphae along with thrombosis in the vascular structures in renal allograft pathology. We found no evidence of disseminated aspergillosis or involvement of any other organ in the patient. To our knowledge, this case is the first reported in the literature of late-onset non-disseminated renal-limited aspergillosis in a human immunodeficiency virus-positive renal transplant patient.

Eculizumab and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. CASE REPORT: We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. CONCLUSION: This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.

Complete Remission of Post-transplantation Recurrence of Focal Segmental Glomerulosclerosis With the Use of Adrenocorticotrophic Hormone Gel: Case Report.

BACKGROUND: Post-transplantation recurrence of primary focal and segmental glomerulosclerosis (FSGS) is estimated to occur in 30%-50% of cases and doubles the risk of allograft failure. Treatment of recurrent FSGS is challenging because specific pathogenic targets are unknown and available therapeutic options have limited efficacy. CASE REPORT: We report a case of recurrent FSGS with nephrotic-range proteinuria (urine protein creatinine ratio [UPCR], >50) and debilitating edema that was resistant to rituximab and plasmapheresis. The patient had a remarkable response to adrenocorticotropic hormone (ACTH) gel and achieved complete remission (UPCR, 0.5; serum albumin, 4.1 g/dL; serum creatinine, 1.0 mg/dL) which was maintained over 10 months on this treatment. CONCLUSIONS: We conclude that ACTH gel is a potential therapeutic option for post-transplantation recurrence of FSGS and warrants further evaluation.

Case Report: Successful Living Donor Kidney Transplantation in a Highly Human Leukocyte Antigen-Sensitized Recipient With a Positive Cytotoxic Crossmatch Using Bortezomib-Based Desensitization Without Intravenous Immunoglobulin.

BACKGROUND: Highly sensitized patients, who produce antibodies against multiple anti-human leukocyte antigens, have significantly reduced chances for renal transplantation. Traditionally, desensitization protocols to reduce the levels of antibodies have relied on the use of intravenous immunoglobulin and plasmapheresis. RESULTS: Here we report the case of a patient with a calculated panel-reactive antibody level of 100% who was desensitized using multiple courses of bortezomib, a proteasome inhibitor, in an intravenous immunoglobulin-free regimen. The patient underwent a successful transplantation with an allograft from a living donor and has continued to do well post-transplantation. CONCLUSIONS: The expression of anti-human leukocyte antigen antibodies decreases the likelihood of transplantation for patients by restricting the available donor pool. New protocols that reduce antibody expression in these patients and allow for renal transplantation are needed. Bortezomib, as used in the patient reported here, represents a promising new medication for successful desensitization and transplantation.

Prospective iterative trial of proteasome inhibitor-based desensitization.

A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRß3, HLA DRß4 and HLA DRß5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization.

The NHE1 Na+/H+ exchanger regulates cell survival by activating and targeting ezrin to specific plasma membrane domains.

NHE1 is a ubiquitously expressed Na+/H+ exchanger, which is important for vital cell functions. Using in vivo models of kidney podocyte injury and renal tubular epithelial cell (RTC) culture systems, we previously demonstrated that NHE1 defends against apoptosis by a mechanism involving ezrin binding to the NHE1 cytoplasmic domain. We now extend the NHE1 role to diabetic mouse models and refine the mechanism of NHE1-dependent ezrin activation. Streptozotocin induced diabetes resulted in greater azotemia, albuminuria and tubulointerstitial pathology in NHE1-deficient swe/swe compared to wild-type control mice. Increased RTC apoptosis was noted in swe/swe mice, suggesting that loss of NHE1 function leads to tubular atrophy, which predicts kidney disease progression. In vitro, proximal RTC derived from swe/swe mice also underwent increased apoptosis in response to staurosporine or a hypertonic environment. Activated ezrin normally resides in the apical domain of the proximal RTC, while NHE1 is a basolateral protein. After NHE1 activation by intracellular acidification or extracellular hypertonicity, confocal immunofluorescence microscopy in polarized LLC-PK1 cells demonstrated transient ezrin localization to lateral membrane domains, where it is positioned to interact with NHE1. We conclude that cell stresses promote NHE1-ezrin interaction, which activate cell survival pathways to prevent apoptosis in diabetic and non-diabetic kidney diseases.