Anuria after kidney transplantation diagnosed as early recurrence of focal segmental glomerulosclerosis combined with acute calcineurin inhibitor nephrotoxicity: a case report and literature review.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that sometimes recurs in patients after kidney transplantation (KT) and increases the risk of graft loss. Proteinuria is a common early sign of recurrent FSGS, but an abrupt decrease in urine volume is rare. Herein, we report a patient with early recurrence of FSGS with anuria following KT. CASE PRESENTATION: A 55-year-old man with end-stage kidney disease caused by primary FSGS experienced anuria on postoperative day 2 following deceased donor KT. Laboratory results revealed that serum tacrolimus trough levels were consistently elevated at the time of anuria. At first, we considered acute calcineurin inhibitor (CNI) nephrotoxicity based on graft biopsy on light microscopy, laboratory findings, and clinical courses. However, the allograft function did not recover even after discontinuation of CNI, and recurrent FSGS was diagnosed 2 weeks later on electron microscopy. A total of 13 sessions of plasmapheresis and two administrations of rituximab (375 mg/m2) were required to treat recurrent FSGS. The patient achieved a partial response, and the spot urine protein-to-creatinine ratio decreased from 15.5 g/g creatinine to 5.2 g/g creatinine. At 5 months following KT, the serum creatinine level was stable at 1.15 mg/dL. CONCLUSIONS: These findings highlight that anuria can occur in cases of early recurrence of FSGS combined with acute CNI nephrotoxicity.

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of the CYP3A5 and ABCB1 genes.

BACKGROUND: Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background. METHODS: PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients. RESULTS: PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype. CONCLUSIONS: Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.

Renal histopathological lesions after liver transplantation: What can we find besides calcineurin inhibitor-induced nephrotoxicity?

BACKGROUND: Chronic kidney disease (CKD) is a common complication after liver transplantation and is traditionally considered to be secondary to calcineurin inhibitors (CNIs). However, several studies have reported that the etiology of CKD after liver transplantation is broad and may only be assessed accurately by renal biopsy. The current study aimed to explore the usefulness of renal biopsies in managing CKD after liver transplantation in daily clinical practice. METHOD: This retrospective analysis enrolled all post-liver transplantation patients who had a renal biopsy in a single center from July 2018 to February 2021. RESULTS: Fourteen renal biopsies were retrieved for review from 14 patients at a median of 35.7 (minimum-maximum: 2.80-134.73) months following liver transplantation. The male-to-female ratio was 13:1 (age range, 31-75 years). The histomorphological alterations were varied. The predominant glomerular histomorphological changes included focal segmental glomerular sclerosis (FSGS) (n = 4), diabetic glomerulopathy (n = 4), and membranoproliferative glomerulonephritis (n = 4). Thirteen (92.9%) patients had renal arteriolar sclerosis. Immune complex nephritis was present in six patients, of whom only two had abnormal serum immunological indicators. Despite interstitial fibrosis and tubular atrophy being present in all the patients, only six (42.9%) presented with severe interstitial injury. No major renal biopsy-related complications occurred. After a mean follow-up of 11.8 months (range: 1.2-29.8), three patients progressed to end-stage renal disease (ESRD). CONCLUSION: The etiology of CKD after liver transplantation might be more complex than originally thought and should not be diagnosed simply as calcineurin inhibitors(CNI)-related nephropathy. Renal biopsy plays a potentially important role in the diagnosis and treatment of CKD after liver transplantation and might not be fully substituted by urine or blood tests. It may help avoid unnecessary changes to the immunosuppressants and inadequate treatment of primary diseases.

The Irish experience of kidney transplantation among recipients with prior non-renal solid organ transplants: A retrospective study on short- and long-term outcomes.

BACKGROUND: This study aims to evaluate allograft and patient outcomes among recipients of kidney transplants after non-renal solid organ transplants. We also aim to compare our findings with recipients of a repeat kidney transplant. METHODS: We performed an analysis on kidney transplant recipients who underwent kidney transplantation after a non-renal solid organ transplant. Survival data were stratified into 2 groups: Group A (n = 37) consisted of recipients of a kidney transplant after prior non-renal solid organ transplant, and Group B (n = 330) consisted of recipients of a repeat kidney transplant. RESULTS: The 1-,5-, and 10-year graft survival (death-censored) for recipients of a kidney transplant post-non-renal solid organ transplant (Group A) were 97.3%, 91.5%, and 86.9%, compared with 97.9%, 90.2%, and 83.4% for recipients of a repeat kidney transplant (Group B) (p = .32). The 1-, 5-, and 10-year patient survival rates were 97.3%, 82.7%, and 79.1% in Group A compared to 97.9%, 90.2%, and 83.4% in Group B. Unadjusted overall patient survival was significantly lower for Group A (p = .017). CONCLUSION: Kidney transplant recipients who have undergone a previous non-renal solid organ transplant have similar allograft survival outcomes, but higher long-term mortality rates compared to repeat kidney transplant recipients.

Characterizing the frequency of modifiable histological changes observed on surveillance biopsies in pediatric kidney allograft recipients.

BACKGROUND: Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. Early identification and treatment of allograft injury, specifically modifiable pathologies such as subclinical rejection (SCR), calcineurin inhibitor toxicity, and BK virus nephropathy, may improve allograft survival. Protocol surveillance biopsy (SB) currently offers the earliest opportunity for targeted interventions. METHODS: This is a single-center retrospective review of 215 kidney SBs obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. SBs were obtained at 6, 12, and 24 months post-transplantation. Frequency of abnormal histologic findings, estimated glomerular filtration rate at time of SB, and SB-related complications were recorded. Data were analyzed to investigate possible time trends and the presence of demographic or clinical associations with abnormal histologic findings. RESULTS: Potentially modifiable histologic findings were seen in 38.1% of all SBs. SCR was found with increasing frequency across all time points with an estimated 49% increase in the odds of a SCR finding per additional 6 months post-transplantation (aOR 1.49, 95% CI 1.06-2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for SCR, 50% had no SCR and 18.8% showed histologic improvement. The complication rate associated with SB was 1.9% (4/215 SBs) and consisted of only minor complications. CONCLUSIONS: SBs are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population. The performance of SBs for up to 2 years after transplantation can have meaningful clinical impact.

Microvascular inflammation is a risk factor in kidney transplant recipients with very late conversion from calcineurin inhibitor-based regimens to belatacept.

BACKGROUND: In de novo kidney transplant recipients (KTR) treatment with belatacept has been established as a comparable option as maintenance immunosuppression, preferably as a strategy to convert from calcineurin inhibitor (CNI)- to belatacept-based immunosuppression. Switch to belatacept demonstrated improved renal function in patients with CNI-induced nephrotoxicity, but risk of transplant rejection and the development of donor-specific antibodies (DSA) are still a matter of debate. Only few data are available in patients at increased immunological risk and late after transplantation. METHODS: We analyzed 30 long-term KTR (including 2 combined pancreas-KTR) converted from CNI to belatacept > 60 months after transplantation with moderate to severe graft dysfunction (GFR ≤ 45 mL/min). Biopsies were classified according to the Banff 2015 criteria. Group differences were assessed in a univariate analysis using Mann Whitney U or Chi square test, respectively. Multivariate analysis of risk factors for treatment failure was performed using a binary logistic regression model including significant predictors from univariate analysis. Fifty-six KTR matched for donor and recipient characteristics were used as a control cohort remaining under CNI-treatment. RESULTS: Patient survival in belatacept cohort at 12/24 months was 96.7%/90%, overall graft survival was 76.7 and 60.0%, while graft survival censored for death was 79.3%/66.7%. In patients with functioning grafts, median GFR improved from 22.5 mL/min to 24.5 mL/min at 24 months. Positivity for DSA at conversion was 46.7%. From univariate analysis of risk factors for graft loss, GFR < 25 mL/min (p = 0.042) and Banff microvascular inflammation (MVI) sum score ≥ 2 (p = 0.023) at conversion were significant at 24 months. In the analysis of risk factors for treatment failure, a MVI sum score ≥ 2 was significant univariately (p = 0.023) and in a bivariate (p = 0.037) logistic regression at 12 months. DSA-positivity was neither associated with graft loss nor treatment failure. The control cohort had comparable graft survival outcomes at 24 months, albeit without increase of mean GFR in patients with functioning grafts (ΔGFR of - 3.6 ± 8.5 mL/min). CONCLUSION: Rescue therapy with conversion to belatacept is feasible in patients with worsening renal function, even many years after transplantation. The benefit in patients with MVI and severe GFR impairment remains to be investigated.

Incidence, etiology, and significance of acute kidney injury in the early post-kidney transplant period.

Little is known about the incidence, causes, and significance of acute kidney injury (AKI) in the early transplant period. This study used a definition as >26 µmol/L increase in creatinine within 48 h or >50% increase over a period >48 h. In 326 adult consecutive recipients of a solitary kidney transplant from 2006 to 2014 followed at this center, 21% developed AKI within the first six months. Most etiologies were CNI toxicity (33%) or unknown (26%), whereas acute rejection accounted for 17% and urinary tract obstruction for 10%. Those with AKI had a significantly lower glomerular filtration rate (GFR) at one-yr post-transplant (adjusted beta coefficient -5.5 mL/min/1.73 m(2) , 95% CI: -10.4, -0.7, p = 0.025) in a multivariable linear regression model. However, the AKI definition missed 6 of 19 episodes of acute rejection and 4 of 10 episodes of urinary tract obstruction. When acute rejection (including those that did not satisfy AKI criteria) was included in the model, other causes of AKI were not significantly associated with GFR at year 1. Although AKI, using current criteria, is likely to be a significant predictor of later outcomes, important causes are missed and the criteria are not sensitive for clinical decision-making.

Recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation.

Post-transplant hyperglycaemia of diabetic patients may cause recurrent diabetic kidney disease (DKD) in kidney allografts. We report a patient with slowly progressive DKD with calcineurin inhibitor toxicity (CNI) toxicity after the kidney transplantation. A 28-year-old female with type 1 diabetes mellitus underwent successful kidney transplantation from her mother in April 2003, and the kidney graft survived for more than 10 years. She was treated with combined immunosuppressive therapy consisting of cyclosporine and mycophenolate mofetil. After transplantation, she continued to take insulin injection four times per day, but her glycosylated haemoglobin (HbA1c) was above 10%. Protocol allograft kidney biopsies performed 5 and 10 years after transplantation revealed the recurrence of slowly progressive diabetic kidney disease. In addition, arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity (CNI) was detected with progression. Post-transplant hyperglycaemia causes recurrent diabetic kidney disease (DKD) in kidney allografts, but its progression is usually slow. For long-term management, it is important to prevent the progression of the calcineurin inhibitor arteriolopathy, as well as maintain favourable glycaemic control.

The use of extended-release tacrolimus twice a day might be beneficial for selected kidney transplant recipients: a case report.

The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration-time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient's high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.

Kidney disease in non-kidney solid organ transplantation.

Kidney disease after non-kidney solid organ transplantation (NKSOT) is a common post-transplant complication associated with deleterious outcomes. Kidney disease, both acute kidney injury and chronic kidney disease (CKD) alike, emanates from multifactorial, summative pre-, peri- and post-transplant events. Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types. The aim of this review is to summarize the current literature describing kidney disease in NKSOT. We conducted a narrative review of pertinent studies on the subject, limiting our search to full text studies in the English language. Kidney disease after NKSOT is prevalent, particularly in intestinal and lung transplantation. Management strategies in the peri-operative and post-transplant periods including proteinuria management, calcineurin-inhibitor minimization/ sparing approaches, and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation. Kidney disease after NKSOT is an important consideration in organ allocation practices, ethics of transplantation. Kidney disease after SOT is an incipient condition demanding further inquiry. While some truths have been revealed about this chronic disease, as we have aimed to describe in this review, continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.