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Background: We assessed the accuracy of different GFR estimating equations in kidney transplant recipients across diverse racial backgrounds, addressing the previously identified validation gap in multiethnic populations predominantly studied in White cohorts., Methods: In this single-center study, eGFR was compared to the measured GFR (mGFR) one year following kidney transplantation., Results: The 1-year eGFR and mGFR data from 1145 participants (54% Whites, 23% Hispanics, 9% Blacks, 7% Native Americans, and 6% Asians) revealed varied correlations across racial groups. For Whites, the combined 2021 CKD-EPI creatinine-cystatin C formulas demonstrated a stronger correlation (r = 0.72, [0.65, 0.78]) compared to the 2021 CKD-EPI creatinine and EKFC cystatin C equation. This equation also achieved the highest accuracy (P30: 77.1%). In Black recipients, both the 2009 CKD-EPI (r = 0.56 [0.42, 0.68]) and the 2021 CKD-EPI creatinine (r = 0.56 [0.41, 0.68]) exhibited modest correlations. The 2021 CKD-EPI creatinine-cystatin C equation showed improved correlation (r = 0.63 (0.43, 0.77)] and an accuracy of 62.7% (P30), which was slightly lower than the EKFC cystatin C equation (P30: 64.7%). However, neither the EKFC (rescaled) cystatin C nor the race-free kidney-specific equations outperformed existing eGFR equations for Black participants In Hispanic patients, combined creatinine-cystatin C equations outperformed creatinine-only equations. Among Native Americans, the combined creatinine-cystatin, EKFC (rescaled) cystatin C, and race-free kidney-specific equations achieved an accuracy rate exceeding 85%. In Asians, the CKD-EPI creatinine-cystatin C equation showed the highest correlation, while the race-free kidney-specific equation had the most accuracy., Conclusion: Our findings indicate that creatinine-cystatin C combined equations outperformed single-marker formulas across all racial groups, with negligible differences between the 2009 CKD EPI and the race-neutral 2021 CKD-EPI version., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

This single-center retrospective study investigated subclinical rejection prevalence and significance in simultaneous pancreas and kidney transplant (SPKT) recipients. We analyzed 352 SPKT recipients from July 2003 to April 2022. Our protocol included pancreas allograft surveillance biopsies at 1, 4, and 12months post-transplant. After excluding 153 patients unable to undergo pancreas biopsy, our study cohort comprised 199 recipients. Among the 199 patients with protocol pancreas biopsies, 107 had multiple protocol pancreas biopsies in the first year, totaling 323. Subclinical rejection was identified in 132 episodes (41%). Of these, 72% were Grade 1, 20% were indeterminate, and 8% were Banff Grade 2 or higher. All episodes of subclinical rejection were treated. Rates of pancreas graft loss (10% vs. 7%) and clinical rejection (21% vs. 20%) at 3 years were similar between those with and without subclinical rejection. Subclinical rejection Banff Grade 2 or more was associated with poor pancreas graft survival HR of 5.5 (95% CI: 1.24-24.37, p = 0.025). Of 236 simultaneous protocol kidney and pancreas biopsies, 102 (43%) showed pancreas subclinical rejection, while only 17% had concurrent kidney subclinical rejection. Our findings suggest limited predictive value of pancreatic enzymes and euglycemia in detecting pancreas rejection. Furthermore, poor concordance existed between pancreas and kidney subclinical rejection., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The evaluation of living kidney donor candidates is a complex and lengthy process. Donor candidates face geographic and socioeconomic barriers to completing donor evaluation. Inequities in access to living donations persist. With a growing demand for kidney transplants and a shortage of living donors, transplant centers are more permissive of accepting less-than-ideal donor candidates. Donors have an increased lifetime risk of kidney failure, but the absolute risk increase is small. Efforts are needed to support donor candidates to complete donor nephrectomy safely and efficiently and receive optimal follow-up care to prevent risk factors for kidney disease and detect complications early. In this article, the authors address key elements of donor kidney evaluation, including current living donation policy requirements and transplant center practices. The authors present a simplified comprehensive practical approach to help guide providers in completing donor evaluation and follow-up care with best outcomes possible., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: More solid organ transplant (SOT) patients are undergoing total knee arthroplasty (TKA). This study identifies risk factors for complications, implant survivorship, and mortality in TKA patients who had prior SOT., Methods: We identified 176 TKAs in patients who had prior SOT. Of these, 77 had a prior renal (RT), 77 had a prior liver (LT) transplant, and 22 had multiple prior transplants (MT). Median survival was estimated using Kaplan-Meier. Univariate analyses were assessed with mixed-effects logistic regressions for complications and Cox-regressions for mortality. Median follow-up was 63 months (range, 24 to 109)., Results: At least one acute medical complication occurred in 25, 13, and 27% of cases with prior RT, LT, and MT, respectively (P = .12). None of the variables were significantly associated with acute medical complications. At least one surgical complication occurred in 14, 13 and 14% of cases with prior RT, LT, and MT, respectively (P = 1). Vitamin D supplementation (Odds Ratio [OR] = 0.38, P < .03) was associated with lower risk of surgical complications. Reoperation and revision rates were 5 and 3%, respectively. Older age at time of transplantation and greater level of serum creatinine at time of TKA were associated with lower risk (OR = 0.96, P = .01), and higher risk of reoperation (OR = 4.9, P = .01), respectively. Coronary artery disease was associated with higher mortality (Hazard Ratio = 2.35, P = .01)., Conclusions: Vitamin D was associated with lower surgical complications, whereas a younger age at time of transplantation increased the risk of reoperation. Additionally, SOT patients with coronary artery disease demonstrated higher mortality after TKA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Over the last 7 decades, kidney transplantation has evolved from an experiment between identical twins to becoming the gold standard treatment for end-stage kidney disease. To date, mycophenolate and calcineurin inhibitors, with or without prednisone, continue to constitute the backbone of modern maintenance immunosuppression. Despite major strides in improving acute rejection, long-term outcomes remain suboptimal with current regimens. Alternatives to calcineurin inhibitors such as belatacept and mammalian targets of rapamycin inhibitors exist; however, their wider-scale adoption remains relatively delayed due to concerns about increased rejection rates. In addition to continuing the investigation of steroid and calcineurin inhibitor sparing protocols, it is time to identify measurable surrogates for meaningful long-term graft survival. iBOX, a dynamic risk-prediction tool that predicts long-term death-censored graft failure could be a potential surrogate end point for future immunosuppression clinical trials. In this review, we summarize the landmark studies supporting current immunosuppression protocols and briefly discuss challenges and future directions., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 has led to the death of about 7 million people worldwide. When infected, older individuals and those with diabetes, hypertension, cardiovascular disease, and compromised immune system are at higher risk for unfavorable outcomes. These comorbidities are prevalent in kidney transplant candidates and recipients making them inherently vulnerable to severe acute respiratory syndrome coronavirus 2 infection, hence, the significant burden the pandemic has exerted on kidney transplant programs. With the swift discovery and wide-scale availability of vaccines and therapeutics against severe acute respiratory syndrome coronavirus 2, the pandemic is currently behind us allowing transplant programs to relieve their restrictions and resume normal pre-COVID-19 operations. In the aftermath of the pandemic, we discuss the implications for immunosuppression and vaccination, COVID-19-induced kidney injury phenotypes and long COVID-19 symptoms. We also discuss some of the operational aspects the pandemic brought about - mainly the utilization of telemedicine - that are now here to stay., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: JC polyomavirus (JCPyV) is a ubiquitous virus that can be latent in the brain and the kidney. It is the etiologic agent responsible for progressive multifocal leukoencephalopathy, a fatal, demyelinating disease of the central nervous system, and rarely causes polyomavirus nephropathy in immunocompromised kidney transplant recipients., Case Description: We present the first case of JCPyV nephropathy in a simultaneous heart-kidney transplant patient, where viral-specific in situ hybridization staining of the kidney tissue was utilized to confirm the diagnosis. The patient was diagnosed 6 years after simultaneous heart-kidney transplantation and was treated with immunosuppression reduction and intravenous immunoglobulin., Discussion: JCPyV nephropathy should be considered in the differential diagnosis of kidney allograft injury, particularly, with suggestive light microscopy histologic features in the absence of BK polyomavirus viremia and/or viruria. In addition to obtaining JCPyV PCR in the blood, in situ hybridization staining may have a utility in confirming the diagnosis. To date, we lack effective JCPyV-specific therapies, and prompt initiation of immunosuppression reduction remains the mainstay of treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abu Jawdeh, Smith, Hudson, Mour, Budhiraja and Rosenthal.)

Purpose: Atypical hemolytic uremic syndrome (aHUS) is a genetic-based thrombotic microangiopathy (TMA) that is mediated by the activation of the alternative complement pathway. Heterozygous deletion in CFHR3-CFHR1 occurs in 30% of the general population and has not been classically linked to aHUS. Post-transplant aHUS has been associated with a high rate of graft loss. Herein, we report our case series of patients who developed aHUS after solid-organ transplantation., Materials and Methods: Five consecutive cases of post-transplant aHUS were identified at our center. Genetic testing was performed in all but one., Results: One patient had a presumed TMA diagnosis before transplant. One heart and 4 kidney (KTx) transplant recipients were diagnosed with aHUS based on the clinical picture of TMA, acute kidney injury, and normal ADAMTS13 activity. Genetic mutation testing revealed heterozygous deletion in CFHR3-CFHR1 in 2 patients and a heterozygous complement factor I (CFI) variant of uncertain clinical significance (VUCS) (Ile416Leu) in a third. Four patients were on tacrolimus, 1 had anti-HLA-A68 donor-specific antibody (DSA), and another had borderline acute cellular rejection at the time of aHUS diagnosis. Four responded to eculizumab, and 1 out of 2 patients came off renal replacement therapy. One KTx recipient died from severe bowel necrosis in the setting of early post-transplant aHUS., Conclusion: Calcineurin inhibitors, rejection, DSA, infections, surgery, and ischemia-reperfusion injury are common triggers that could unmask aHUS in solid-organ transplant recipients. Heterozygous deletion in CFHR3-CFHR1 and CFI VUCS may be important susceptibility factors acting as the first hit for alternative complement pathway dysregulation.

Introduction: This study describes patient characteristics and examines graft function of kidney transplant recipients (without primary hyperoxaluria) with elevated plasma oxalate (POx) and enteric risk factors prior to transplant at our institution., Methods: Kidney transplant recipients between 2012 and 2020 with elevated POx at the time of kidney transplant evaluation were included. A matched control cohort was gathered using patient/donor age, living/deceased donor type, panel reactive antibody, kidney donor profile index, and human leukocyte antigen mismatch as matching variables. Graft function at 1 year and at last follow-up was reported., Results: A total of 106 patients with elevated POx were identified. A third of the patients had Roux-en-Y gastric bypass, a third had other enteric risks, and a third did not have an identifiable enteric risk. Median eGFR (estimated glomerular filtration rate) at 1 year and at last follow-up was similar between cases and controls except for subgroup of patients with pre-transplant POx >30 µmol/L where 1-year eGFR was lower compared to controls. Across eGFR categories, more cases were in eGFR category <30 mL/min/1.73 m2 compared to controls., Conclusion: Roux-en-Y gastric bypass is the most common identifiable risk for elevated POx in kidney transplant candidates. 1-year graft function was not inferior in cases compared to matched controls except for subgroup with POx >30 µmol/L pre-transplant., (© 2023 S. Karger AG, Basel.)

Emphysematous pyelonephritis (EPN) is a severe, acute necrotizing infection that is defined by the presence of gas in the kidney parenchyma. Multiple case reports have described the radiological findings and clinical course of EPN. Herein, we report on EPN including the histopathological findings in a kidney transplant recipient. Our patient presented with EPN complicated by multiorgan failure and was successfully managed with transplant nephrectomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abu Jawdeh, Nguyen, Ryan and Vikram.)

Acute antibody-mediated rejection (AMR) is mediated by the activation of the classical complement system in addition to noncomplement-dependent inflammatory pathways. Complement fixation by donor-specific antibodies leads to cleavage of the complement proteins C4, C3, and C5 to produce multiple complement split-products (CSP) and the end-effector membrane attack complex, C5b-9. In this study, we investigate CSP as potential biomarkers for AMR., Methods: In an Institutional Review Board-approved, prospective, controlled study, CSP levels were measured in blood and urine samples from consecutive kidney transplant recipients with biopsy-proven AMR (n = 10), acute cellular rejection (ACR) (n = 5), or no rejection (n = 5). After obtaining informed consent, samples were collected at the time of biopsy (day 0) and days 15 (end of rejection treatment) and 30 postbiopsy for AMR and ACR patients. ELISA was used to measure C5a, C4d, and soluble C5b-9 concentrations in blood and urine, in addition to factor Bb (Bb) concentration in blood only. Kidney transplant histopathology was evaluated using the Banff 2013 classification. Rejection treatment and follow-up were performed per standard of care., Results: Blood and urine CSP levels adjusted to urine creatinine were not elevated in AMR compared to no rejection and ACR arms. There was significant variability in CSP concentration within each of the study groups., Conclusion: Our study does not support the utility of CSP as surrogate biomarkers of AMR; however, it is limited by the small sample size and larger studies may be warranted., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival., Methods: Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015., Results: A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P < 0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction > 50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01)., Conclusions: In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2, has led to the death of hundreds of thousands of people worldwide. If infected, older individuals and those with diabetes, hypertension, cardiovascular disease, and compromised immune systems are at higher risk for unfavorable outcomes. These comorbidities are prevalent in patients with kidney disease, hence the significant burden of COVID-19 on kidney transplant programs. Multiple case series of kidney transplant recipients with COVID-19 have shown increased mortality compared to nontransplant patients. To date, we do not have high-level evidence to inform immunosuppression minimization strategies in infected transplant recipients. Most centers however have adopted early antimetabolite withdrawal in addition to other interventions. This review summarizes the published COVID-19 literature as it relates to outcomes and immunosuppression management in kidney transplant recipients. It also discusses challenges pertaining to pretransplant evaluation and wait-listed patients., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Apolipoprotein L1 gene (APOL1) variants predispose to nondiabetic kidney disease in African American (AA) patients. Here, we share our experience with APOL1 genotyping of AA potential living kidney donors and offer a perspective on its utility and cost-effectiveness in this population., Methods: Since May 2017, all potential AA living kidney donors at our center underwent APOL1 genotyping early in the donor evaluation process. APOL1 high-risk individuals were declined, whereas those with low-risk genotype continued with further evaluation and testing., Results: One out of 26 potential donors had high-risk genotype and was therefore declined. The rest were eligible to continue the donor evaluation process and 7 of them underwent donor nephrectomy without any complications. A crude cost analysis utilizing our sample suggested probable cost-effectiveness of APOL1 genotyping as it can prevent earlier onset of chronic kidney disease in AA donors., Conclusion: We propose a role for systematically incorporating APOL1 genotyping in the evaluation and informed consent process of potential AA donors while acknowledging the controversial considerations associated with it., (© 2020 S. Karger AG, Basel.)

BK polyomavirus mostly manifests as polyomavirus-associated nephropathy (PyVAN) in kidney transplant patients and polyoma virus-associated hemorrhagic cystitis (PyVHC) in bone marrow transplant patients. PyVHC in kidney transplant patients is only reported in four cases in the literature. Our patient had severe hemorrhagic cystitis without renal involvement. We postulate that our patient's exposure to ifosfamide and radiation 8 years prior transplantation might predispose him to this disease., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow-up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) C max , T max , AUC, and half-life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is common in kidney transplant recipients. In addition to the usual causes of AKI in native kidneys, certain features and risk factors are unique to kidney allografts. In this article, we will present an overview of the common transplant-specific AKI etiologies that include increased susceptibility to hemodynamic-mediated AKI, acute rejection, medication-induced AKI, recurrence of native kidney disease, infections, urinary tract obstruction, vascular thrombosis and post-transplant lymphoproliferative disorder. AKI is independently associated with allograft loss and patient mortality. It is, therefore, prudent for transplant centers to address it as a major quality measure., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Contrast-induced nephropathy (CIN) in native kidneys is associated with a significant increase in mortality and morbidity. Data regarding CIN in renal allografts are limited, however. We retrospectively studied CIN in renal allografts at our institution: its incidence, risk factors, and effect on long-term outcomes including allograft loss and death., Methods: One hundred thirty-five renal transplant recipients undergoing 161 contrast-enhanced computed tomography (CT) scans or coronary angiograms (Cath) between years 2000 and 2014 were identified. Contrast agents were iso- or low osmolar. CIN was defined as a rise in serum creatinine (SCr) by >0.3 mg/dl or 25% from baseline within 4 days of contrast exposure. After excluding 85 contrast exposures where patients had no SCr within 4 days of contrast administration, 76 exposures (CT: n  = 45; Cath: n  = 31) in 50 eligible patients were analyzed. Risk factors assessed included demographics, comorbid conditions, type/volume of contrast agent used, IV fluids, N -acetylcysteine administration, and calcineurin inhibitor use. Bivariate and multivariable analyses were used to assess the risk of CIN., Results: Incidence of CIN was 13% following both, CT (6 out of 45) and Cath (4 out of 31). Significant bivariate predictors of CIN were IV fluid administration ( p  = 0.05), lower hemoglobin ( p  = 0.03), and lower albumin ( p  = 0.02). In a multivariable model, CIN was predicted by N -acetylcysteine ( p  = 0.03) and lower hemoglobin ( p  = 0.01). Calcineurin inhibitor use was not associated with CIN. At last follow-up, CIN did not affect allograft or patient survival., Conclusion: CIN is common in kidney transplant recipients, and there is room for quality improvement with regards to careful renal function monitoring post-contrast exposure. In our study, N -acetylcysteine exposure and lower hemoglobin were associated with CIN. Calcineurin inhibitor use was not associated with CIN. Our sample size is small, however, and larger prospective studies of CIN in renal allografts are needed.

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR)., Methods: A prospective institutional review board-approved database was queried to identify biopsy-proven first AR episodes occurring from January 2005 to October 2012. The ACR was defined by Banff criteria; borderline AR was excluded. The AMR was defined as 3 of 4 criteria: renal dysfunction, donor specific antibody, C4d positivity on biopsy, and histological changes. The MAR met criteria for both ACR and AMR. Early AR occurred within six months post-transplant. AR episodes were then assigned to 1 of the 6 categories--early AMR, early ACR, early MAR, late AMR, late ACR, and late MAR., Results: One hundred eighty-two kidney transplant recipients identified with a first AR episode. Mean follow-up was 773 days (± 715 days). No difference was observed in patient survival. Death-censored graft survival was 84%. Death-censored graft loss was higher with late versus early AMR (P = 0.01) and late versus early ACR (P = 0.03), but not late versus early MAR (P = 0.3)., Conclusions: The AR type demonstrated a hierarchy for graft survival with ACR better than MAR better than AMR, which persisted for both early and late AR. Improvement in long-term results of AR may require development of specific treatment for individual AR types.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses., Methods: Antibody-mediated rejection was diagnosed using Antibody Working Group criteria and Banff component scoring, and C4d staining data were analyzed. Statistics included independent and paired samples t test, χ(2), Fisher exact, or the Wilcoxon-signed rank test. Fifty-five AMR patients were analyzed. Early AMR was defined as occurring within 6 months after transplantation and treated with a single rituximab dose and 4 bortezomib doses preceded by plasmapheresis. Allograft biopsies were performed within 48 hours of treatment; repeat biopsy was performed 14 to 21 days later., Results: Early AMR demonstrated histologic improvement in mean scores for acute Banff components glomerulitis (g), C4d, g+ peritubular capillaritis (ptc) and acute composite score, but showed deterioration in chronic Banff components tubular atrophy and interstitial fibrosis. Late AMR showed improved mean scores for acute Banff components tubulitis, interstitial inflammation, g, ptc, g + ptc, C4d, and acute composite score, but chronic scores did not change. Significant changes in distribution of Banff scores after treatment were observed for g, C4d, tubular atrophy, and interstitial fibrosis scores in early AMR patients and tubulitis, interstitial inflammation, g, ptc, and C4d in late AMR., Conclusions: These results show that: (1) Banff component scoring provides insights into histologic responses to AMR therapy and may provide a potential endpoint for clinical AMR trials. (2) Early and late AMR demonstrate differences in acute and chronic Banff components at the time of the AMR diagnostic biopsy, as well as differential responses to AMR therapy.

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 DRβ3, HLA DRβ4 and HLA DRβ5). 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., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR., Methods: Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength., Results: Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06)., Conclusions: A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Chronic kidney disease progression can be predicted based on the degree of tubular atrophy, which is the result of proximal tubule apoptosis. The Na+/H+ exchanger NHE1 regulates proximal tubule cell survival through interaction with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], but pathophysiologic triggers for NHE1 inactivation are unknown. Because glomerular injury permits proximal tubule luminal exposure and reabsorption of fatty acid/albumin complexes, we hypothesized that accumulation of amphipathic, long-chain acyl-CoA (LC-CoA) metabolites stimulates lipoapoptosis by competing with the structurally similar PI(4,5)P2 for NHE1 binding. Kidneys from mouse models of progressive, albuminuric kidney disease exhibited increased fatty acids, LC-CoAs, and caspase-2-dependent proximal tubule lipoapoptosis. LC-CoAs and the cytosolic domain of NHE1 directly interacted, with an affinity comparable to that of the PI(4,5)P2-NHE1 interaction, and competing LC-CoAs disrupted binding of the NHE1 cytosolic tail to PI(4,5)P2. Inhibition of LC-CoA catabolism reduced NHE1 activity and enhanced apoptosis, whereas inhibition of proximal tubule LC-CoA generation preserved NHE1 activity and protected against apoptosis. Our data indicate that albuminuria/lipiduria enhances lipotoxin delivery to the proximal tubule and accumulation of LC-CoAs contributes to tubular atrophy by severing the NHE1-PI(4,5)P2 interaction, thereby lowering the apoptotic threshold. Furthermore, these data suggest that NHE1 functions as a metabolic sensor for lipotoxicity.

Tubular atrophy predicts chronic kidney disease progression, and is caused by proximal tubular epithelial cellcaused by proximal tubular epithelial cell (PTC) apoptosis. The normally quiescent Na(+)/H(+) exchanger-1 (NHE1) defends against PTC apoptosis, and is regulated by PI(4,5)P(2) binding. Because of the vast array of plasma membrane lipids, we hypothesized that NHE1-mediated cell survival is dynamically regulated by multiple anionic inner leaflet phospholipids. In membrane overlay and surface plasmon resonance assays, the NHE1 C terminus bound phospholipids with low affinity and according to valence (PIP(3) > PIP(2) > PIP = PA > PS). NHE1-phosphoinositide binding was enhanced by acidic pH, and abolished by NHE1 Arg/Lys to Ala mutations within two juxtamembrane domains, consistent with electrostatic interactions. PI(4,5)P(2)-incorporated vesicles were distributed to apical and lateral PTC domains, increased NHE1-regulated Na(+)/H(+) exchange, and blunted apoptosis, whereas NHE1 activity was decreased in cells enriched with PI(3,4,5)P(3), which localized to basolateral membranes. Divergent PI(4,5)P(2) and PI(3,4,5)P(3) effects on NHE1-dependent Na(+)/H(+) exchange and apoptosis were confirmed by selective phosphoinositide sequestration with pleckstrin homology domain-containing phospholipase Cδ and Akt peptides, PI 3-kinase, and Akt inhibition in wild-type and NHE1-null PTCs. The results reveal an on-off switch model, whereby NHE1 toggles between weak interactions with PI(4,5)P(2) and PI(3,4,5)P(3). In response to apoptotic stress, NHE1 is stimulated by PI(4,5)P(2), which leads to PI 3-kinase activation, and PI(4,5)P(2) phosphorylation. The resulting PI(3,4,5)P(3) dually stimulates sustained, downstream Akt survival signaling, and dampens NHE1 activity through competitive inhibition and depletion of PI(4,5)P(2).

Ischemia-reperfusion (IR) injury plays a significant role in the pathogenesis of both delayed graft function (DGF) in allografts and hemodynamic mediated acute kidney injury (AKI) of native kidneys. IR injury involves the interplay of several factors, including both the innate and adaptive immune systems. Though the final effector mechanisms causing injury are likely similar in both allograft and native kidneys, DGF is confounded by various donor, recipient and graft-handling factors. DGF is becoming increasingly important because of the growing number of patients awaiting kidney transplant. Identifying mediators, new diagnostics and therapeutics for DGF is important to provide more kidneys for transplant and improve outcomes. Furthermore, given that DGF occurs in a tightly controlled scenario, studying DGF is useful for early studies of proof of principle for biomarkers and therapeutics prior to launching into less wellcontrolled studies in large numbers of native kidney AKI patients., (Copyright © 2011 S. Karger AG, Basel.)

Current guidelines recommend a blood pressure goal of less than 130/80 mm Hg in patients with chronic kidney disease. Considerable epidemiologic observational data, post hoc analyses of clinical trials, and meta-analyses support this goal, particularly in patients with proteinuria. Although prospective clinical trials have not shown a clear benefit, recent data indicate that a longer duration of follow-up may be needed to assess the effects of different blood pressure goals. While we await the results of several ongoing and planned studies in this area, the current recommendations of a blood pressure goal less than 130/80 mm Hg appear reasonable.

The frequency of radiocontrast administration is dramatically increasing, with over 80 million doses delivered annually worldwide. Although recently developed radiocontrast agents are relatively safe in most patients, contrast nephropathy (CN) is still a major source of in-hospital and long-term morbidity and mortality, particularly in patients with preexisting kidney disease. Multiple protocols for CN prevention have been studied; however, strict guidelines have not been established, in part because of conflicting efficacy data for most prevention approaches. In this work, we critically review the major trials that have addressed common CN prophylaxis strategies, including type of radiocontrast media, N-acetylcysteine administration, extracellular fluid volume expansion, and hemofiltration/hemodialysis. We conclude with evidence-based recommendations for CN prevention, which emphasize concurrent NaHCO3 infusion and N-acetylcysteine administration. These guidelines should be helpful to hospitalists, who frequently order radiocontrast studies, and could therefore have a significant impact on prevention of CN., (Copyright 2009 Society of Hospital Medicine)

Na(+)/H(+) exchanger-1 (NHE1) is a ubiquitous plasma membrane Na(+)/H(+) exchanger typically associated with maintenance of intracellular volume and pH. In addition to the NHE1 role in electroneutral Na(+)/H(+) transport, in renal tubular epithelial cells in vitro the polybasic, juxtamembrane NHE1 cytosolic tail domain acts as a scaffold, by binding with ezrin/radixin/moesin (ERM) proteins and phosphatidylinositol 4,5-bisphosphate, which initiates formation of a signaling complex that culminates in Akt activation and opposition to initial apoptotic stress. With robust apoptotic stimuli renal tubular epithelial cell NHE1 is a caspase substrate, and proteolytic cleavage may permit progression to apoptotic cell death. In vivo, genetic or pharmacological NHE1 loss of function causes renal tubule epithelial cell apoptosis and renal dysfunction following streptozotocin-induced diabetes, ureteral obstruction, and adriamycin-induced podocyte toxicity. Taken together, substantial in vivo and in vitro data demonstrate that NHE1 regulates tubular epithelial cell survival. In contrast to connotations of NHE1 as an unimportant "housekeeping" protein, this review highlights that NHE1 activity is critical for countering tubular atrophy and chronic renal disease progression.

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.