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.

Efficacy of combined rituximab and daratumumab treatment in posttransplant recurrent focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of kidney failure and it is characterized by a high rate of recurrence after kidney transplant. Moreover, FSGS recurrence is worsened by an increased risk of graft failure. Common therapies for FSGS recurrence mostly consist of plasma exchange treatments, also for prolonged time, and rituximab, with variable efficacy. We report 5 cases of early FSGS recurrence after kidney transplant, resistant to plasma exchange and rituximab treatment that subsequently resolved after combined therapy with rituximab and daratumumab. All cases were negative for genetic FSGS. The combined treatment induced a complete response in all the cases and was well tolerated. We also performed a comprehensive flow cytometry analysis in 2 subjects that may suggest a mechanistic link between plasma cells and disease activity. In conclusion, given the lack of viable treatments for recurrent FSGS, our reports support the rationale for a pilot trial testing the safety/efficacy profile of combined rituximab and daratumumab in posttransplant FSGS recurrence.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Incidence, risk factors, and outcomes of recurrent focal segmental glomerulosclerosis in pediatric kidney transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Focal segmental glomerulosclerosis is the most prevalent acquired kidney disease leading to end-stage renal disease in children and has a propensity for recurring in the transplanted kidney. The recurrence of FSGS after kidney transplantation in children varies greatly. In addition, the risk factors and outcomes of recurrence of FSGS remain controversial. This study evaluated the recurrence rate, risk factors, and prognosis of FSGS after kidney transplantation in order to provide advice and assistance in clinical decision-making for pediatric kidney transplantation. METHODS: PubMed, Embase, Web of Science, CNKI, and other databases were searched from the establishment of the repository to March 2022. We extracted data on incidence, risk factors, and outcomes. RESULTS: The results showed that the recurrence rate of primary FSGS in children after renal transplantation was 48% (95% CI 36%-59%) and the recurrence rate of FSGS (all forms) was 35% (95% CI 17%-52%). The graft loss rate of primary FSGS in children after kidney transplantation was 29% (95% CI 17%-42%) and the graft loss rate of FSGS (all forms) was 29% (95% CI 4%-62%). 57% (95% CI 42%-73%) of pediatric patients with recurrent primary FSGS showed complete remission. Risk factor analyses showed that age of onset (SMD .69, 95% CI .20-1.19, p = .006) was related to the recurrence of primary FSGS, whereas the living related donor was not a risk factor for recurrent primary FSGS in pediatrics after kidney transplantation (OR 1.22, 95% CI .48-3.10, p = .674). CONCLUSIONS: The recurrence rate and graft loss rate of FSGS in children after kidney transplantation were relatively high. Age at onset was associated with a risk for recurrent primary FSGS, whereas the living related donor was not a risk factor for recurrent FSGS in pediatric kidney recipients.

Stage lighting on PAR-1: a step further in the understanding of acquired focal and segmental glomerulosclerosis.

The pathogenic mechanisms of acquired focal and segmental glomerular sclerosis are only partially known and represent a medical challenge in nephrology. The article by May et al. sheds additional light on previous data indicating the key role of the protease-activated receptor 1. The new evidence is based on in vivo studies in relevant animal models and on patient biopsies and represents a significant step forward in the understanding of this pathologic condition.

Incidence and risk factors for recurrent focal segmental glomerulosclerosis after kidney transplantation: a meta-analysis.

AIMS: To systematically review the incidence and risk factors for recurrent FSGS after kidney transplantation. METHODS: We searched PubMed, Embase, Medline, Web of Science, the Cochrane Library, CNKI, CBMdisc, Wanfang, and Weipu for case-control studies related to recurrent FSGS from the establishment until October 2022. The protocol was registered on PROSPERO (CRD42022315448). Data were analyzed using Stata 12.0, with odds ratios (counting data) and standardized mean difference (continuous data) being considered as effect sizes. If the I2 value was greater than 50%, the random-effects model was used; otherwise, a fixed-effects model was used. A meta-analysis on the incidence and risk factors for recurrent FSGS after kidney transplantation was performed. RESULTS: A total of 22 studies with 966 patients and 12 factors were included in the meta-analysis. There were 358 patients with recurrent FSGS and 608 patients without FSGS after kidney transplantation. The results showed that the recurrence rate of FSGS after kidney transplantation was 38% (95% CI: 31%-44%). Age at transplantation (SMD = -0.47, 95% CI -0.73 to -0.20, p = .001), age at onset (SMD = -0.31, 95% CI -0.54 to -0.08, p = .008), time from diagnosis to kidney failure (SMD = -0.24, 95% CI -0.43 to -0.04, p = .018), proteinuria before KT (SMD = 2.04, 95% CI 0.91 - 3.17, p < .001), related donor (OR 1.99, 95% CI 1.20 - 3.30, p = .007) and nephrectomy of native kidneys (OR 6.53, 95% CI 2.68 - 15.92, p < .001) were associated with recurrent FSGS, whereas HLA mismatches, duration of dialysis before KT, sex, living donor, tacrolimus use and previous transplantation were not associated with recurrent FSGS after kidney transplantation. CONCLUSIONS: The recurrence of FSGS after kidney transplantation remains high. Clinical decision-making should warrant further consideration of these factors, including age, original disease progression, proteinuria, related donor, and nephrectomy of native kidneys.

Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. We have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (P < 0.01) and weight loss (P < 0.01), and ameliorated histopathological damage (P < 0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repositioning candidate for clinical trial in FSGS.

Clinical and histopathologic predictors of recurrent glomerulonephritis after kidney transplantation.

INTRODUCTION: We evaluated the long-term outcomes of recurrent glomerulonephritis (RGN) using clinical, histopathological, and demographic predictors. METHODS: A retrospective cohort study of kidney transplant recipients (KTR) in two renal centers between 2005 and 2020. Clinical and native kidney histological data were analyzed. The risk factors and outcomes of each primary glomerulonephritis subtype were assessed using Cox methods. RESULT: 336 recipients with primary glomerulonephritis were analyzed. RGN was diagnosed in 17%, 20%, 25%, and 13% of recipients with IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and membranoproliferative glomerulonephritis (MPGN), respectively. Median time to recurrence was shortest in FSGS (.6 years IQR .2-2.9) and longest in MN (6.3 years IQR 3.3-8.0) whereas time to graft loss after diagnosis was shortest in MPGN (.3 years IQR .1-1.7) and longest in IgAN (2.9 year IQR 1.3-4.3). Recipients with recurrent IgAN were likely to be younger, have higher proteinuria at diagnosis, receive living donor allografts, receive cyclosporine treatment, have a history of acute rejection, and have segmental sclerosis in native glomeruli. Younger age of the donors, higher proteinuria at diagnosis, alemtuzumab, proteinuria within the first 12 months, acute rejection, low baseline eGFR, mesangial proliferation, and IgG and IgA deposits were associated with FSGS recurrence. MPGN recurrence was predicted by lower BMI at transplantation, and crescentic native disease. Death-censored graft survival at 5-, 10-, and 15-years was 83%, 51%, and 29% in the RGN group and 95%, 93%, and 84%, respectively in the non-RGN group. Over 15 years, recipients with RGN are nine times more likely than those without RGN to lose their grafts, regardless of donor type, acute rejection, and baseline eGFR. Transplant recipients of related donor allograft were not more likely to have recurrent GN than non-related donors.

Post-operative recurrence of focal segmental glomerulosclerosis according to pre-transplant treatment after kidney transplantation.

BACKGROUND: Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) is a serious complication and a significant risk factor for graft failure. However, there is no clear evidence of the effectiveness of pre-transplant treatment using plasmapheresis (PP) or rituximab in preventing post-operative FSGS recurrence after KT. METHODS: This single-center retrospective study included 99 adult patients with biopsy-proven primary FSGS who underwent KT between 2007 and 2018. The patients were divided into the pre-treatment group (N = 53, 53.5%) and no pre-treatment group (N = 46, 46.5%). In the pre-transplant group, prophylactic PP was administered before KT in patients undergoing living donor transplantation and the day after KT in those undergoing deceased donor transplantation. RESULTS: The rate of immediate post-operative recurrence was significantly higher in the no pre-treatment group (16 [34.8%]) than in the pre-treatment group (5 [9.4%]; P = 0.002). There were three cases of graft failure due to recurrent FSGS, all of which were in the no pre-treatment group. After adjusting for possible confounding factors, age (per 10-year increase; OR = 0.61, CI, 0.42-0.90; P = 0.012) and pre-transplant treatment (vs. no pre-transplant treatment; OR = 0.17, CI, 0.05-0.54; P = 0.003) were identified as significant factors associated with FSGS recurrence. The rate of death-censored graft survival was significantly superior in the pretransplant treatment group (P = 0.042). CONCLUSION: Pre-transplant treatment with PP was associated with beneficial effects on preventing FSGS recurrence after KT.

Can Kunxian Capsule, a Novel Tripterygium Preparation be Used as an Adjuvant Treatment of Early Recurrent Focal Segmental Glomerular Sclerosis After Renal Transplantation? A Case Report.

Focal segmental glomerular sclerosis (FSGS) tends to recur after kidney transplantation, particularly when genetic testing is negative. Once the recurrence happens, the renal graft function can rapidly become impaired, following a massive urine protein loss. Despite intensive plasmapheresis and high-dose rituximab treatment, the complete remission rate remains below 50%. The Kunxian capsule, representing a new generation of tripterygium preparation, has shown promising results in controlling proteinuria in patients with IgA nephropathy. It is unclear whether Kunxian capsule treatment would also produce a favorable response in cases of FSGS recurrence. Here we report favorable results with this approach in a patient with early recurrent FSGS after kidney transplantation; we treated this patient successfully with a Kunxian capsule, a low dose of rituximab (200 mg), and reduced sessions of plasmapheresis. Complete remission, with a 90% reduction in total urine protein (0.81 g/24 h vs 8.3 g/24 h), was achieved within 2 weeks post-treatment. Of interest, the complete remission state in this patient has been maintained over 20 months with continuous administration of Kunxian capsules after the cessation of plasmapheresis. The potential mechanisms involved here include direct podocyte protection and the anti-inflammatory and immunosuppressive properties of triptolide in the Kunxian capsule. Our case may offer a new reference option for treating recurrent FSGS in the future.

Early recurrence of focal segmental glomerulosclerosis as an unusual cause of primary kidney transplant malfunction.

Recurrence of the primary disease is one of the most common causes of graft failure in the first decade after kidney transplantation. We present a case of a patient with an unusually rapid recurrence of focal segmental glomerulonephritis in the graft, the recognition of its occurrence was hampered by the primary graft affection and oligoanuria and by insignificant histological changes in the first two biopsy samples in the early post-transplant period, as well as by unawareness of the disease leading to terminal renal failure, as no renal biopsy was performed due to grade 3 obesity. Only worsening of hypoalbuminemia and finding of massive proteinuria despite oligoanuria were crucial for further management. Disease recurrence in the graft was confirmed by electron microscopy. However, complex targeted therapy did not result in restoration of graft function and decrease in proteinuria. This case history was aimed to draw attention to the knowledge of the importance of the primary disease confirmed by renal biopsy and early (so called pre-emptive) treatment in case of diseases with a high potential of recurrence (Fig. 7, Ref. 10). Text in PDF www.elis.sk Keywords: kidney transplantation, recurrence, minimal changes in glomeruli, focal segmental glomerulosclerosis.

Unexpected Late Response to Ofatumumab in Adult Post-Transplantation Recurrent Focal Segmental Glomerulosclerosis, Case Report.

BACKGROUND: Idiopathic focal segmental glomerulosclerosis is an important cause of kidney failure in adults, which is associated with a high risk of disease recurrence after transplantation. Plasmapheresis, rituximab, immunoadsorption, and high-dose cyclosporine are used to treat post-transplant recurrent focal segmental glomerulosclerosis (rFSGS). However, the response rate is variable, and few options remain for unresponsive patients. CASE REPORT: We present a 44-year-old man with an early post-transplant rFSGS. After peritransplant plasmapheresis, rituximab, and abatacept treatments failed, we employed ofatumumab. After 9 months without apparent benefit, we observed an unexpected partial remission thereafter, without severe side effects. Furthermore, remission has been sustained in 30-month follow-up. CONCLUSIONS: We believe ofatumumab can be considered an alternative for patients with plasmapheresis and rituximab-resistant post-transplant rFSGS.

A Rare Case Report of Postoperative Paraneoplastic Glomerulopathy in Kidney Transplant.

Kidney transplant recipients are more likely to develop posttransplant renal cell carcinoma than the general population. Symptoms of renal cell carcinoma are often nonspecific, such as nausea, vomiting, and weight loss, and tend to occur syndrome caused by the release of peptides and hormones by the cancer itself. However, there have been rare case reports of postoperative paraneoplastic glomerulopathy associated with renal cell carcinoma in kidney transplant recipients. Here, we report the case of a 54-year-old male who presented with subnephrotic range proteinuria with a urine protein-to-creatinine ratio of 1.0 within 1 year after a deceased donor kidney transplant without kidney function decline. The transplant team decided to perform a biopsy of the transplanted kidney, and the ultrasonography before intervention revealed a right- side native renal mass. The result of the kidney biopsy revealed focal segmental glomerulosclerosis. At the same time, computed tomography was done to find the cause of the renal mass, and we found that the right native kidney mass had features highly suspicious for renal cell carcinoma. The urologist subsequently performed a right radical nephrectomy. The pathology diagnosis of the kidney mass was renal cell carcinoma. After the cancer had been eliminated, clinical improvement of proteinuria was achieved. Hence, we diagnosed a rare secondary focal segmental glomerulosclerosis from renal cell carcinoma (paraneoplastic glomerulopathy) about which, to our knowledge, there are no previous reports. To date, there is no consensus recommendation for screening postoperative renal cell carcinoma in organ transplant recipients. The potential postoperative diagnosis of paraneoplastic glomerulopathy-associated renal cell carcinoma in kidney transplant recipients must be recognized.

Good outcomes after pediatric intraperitoneal kidney transplant.

BACKGROUND: Kidney transplantation in small children is technically challenging. Consideration of whether to use intraperitoneal versus extraperitoneal placement of the graft depends on patient size, clinical history, anatomy, and surgical preference. We report a large single-center experience of intraperitoneal kidney transplantation and their outcomes. METHODS: We conducted a retrospective review of pediatric patients who underwent kidney transplantation from April 2011 to March 2018 at a single large volume center. We identified those with intraperitoneal placement and assessed their outcomes, including graft and patient survival, rejection episodes, and surgical or non-surgical complications. RESULTS: Forty-six of 168 pediatric kidney transplants (27%) were placed intraperitoneally in children mean age 5.5 ± 2.3 years (range 1.6-10 years) with median body weight 18.2 ± 5 kg (range 11.4-28.6 kg) during the study period. Two patients (4%) had vascular complications; 10 (22%) had urologic complications requiring intervention; all retained graft function. Thirteen patients (28%) had prolonged post-operative ileus. Eight (17%) patients had rejection episodes ≤6 months post-transplant. Only one case resulted in graft loss and was associated with recurrent focal segmental glomerular sclerosis (FSGS). Two patients (4%) had chronic rejection and subsequent graft loss by 5-year follow-up. At 7-year follow-up, graft survival was 93% and patient survival was 98%. CONCLUSIONS: The intraperitoneal approach offers access to the great vessels, which allows greater inflow and outflow and more abdominal capacity for an adult donor kidney, which is beneficial in very small patients. Risk of graft failure and surgical complications were not increased when compared to other published data on pediatric kidney transplants.

Treatment of Focal and Segmental Glomerulosclerosis Secondary to High Altitude Polycythemia with Acetazolamide.

Vizcarra-Vizcarra, Cristhian A., Eduardo Chávez-Velázquez, Carmen Asato-Higa, and Abdías Hurtado-Aréstegui. Treatment of focal and segmental glomerulosclerosis secondary to high altitude polycythemia with acetazolamide. High Alt Med Biol. 23:286-290, 2022.-Focal segmental glomerulosclerosis (FSGS) is a morphological pattern, caused by glomerular injury and is the leading cause of nephrotic syndrome in adults. We present the case of a 59-year-old female patient, resident of a high-altitude city (3,824 m), who had polycythemia and nephrotic syndrome. A renal biopsy was performed, and the findings were compatible with FSGS. The patient received phlebotomy 500 ml three times, which reduced, partially, the hemoglobin concentration. However, she had refractory proteinuria, despite the use of enalapril and spironolactone. We observed that proteinuria worsened with the increase in hemoglobin levels. So, she was treated with acetazolamide 250 mg bid for 4 months, which reduced proteinuria and hemoglobin. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not take acetazolamide and again, she had an increase in hemoglobin and proteinuria levels. We conclude that acetazolamide may be an effective treatment in FSGS due to high altitude polycythemia.

Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy.

Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed-chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans-hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements.

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

BACKGROUND: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). METHODS: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. RESULTS: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites. CONCLUSION: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.