RARE DISEASE
Rare disorder potentially indicated for kidney transplant
Rare disorder potentially indicated for kidney transplant
Rare disorder potentially indicated for kidney transplant
Drug discovery
4
drugs
With orphan designations
Overview
Rare kidney disorders such as primary hyperoxaluria, atypical hemolytic uremic syndrome (aHUS), nephronophthisis, and hereditary complement C3 deficiency may necessitate kidney transplantation due to end-stage kidney disease (ESKD) caused by genetic or metabolic defects [1][7][16]. These conditions often require combined liver-kidney transplantation (CLKT) to correct underlying hepatic abnormalities or address systemic complications [1][13].
Burden
High morbidity: Rapid progression to ESKD in ~50% of adults with rare glomerulopathies (e.g., C3 glomerulopathy) [16].
Economic impact: Frequent hospitalizations, dialysis dependence, and lifelong immunosuppression post-transplant [14][17].
Multi-organ risks: Systemic manifestations (e.g., cardiac, ocular, or hepatic involvement) increase complexity and mortality [1][16].
Therapies
Transplantation: CLKT for metabolic defects (e.g., primary hyperoxaluria) [1]; kidney-alone transplants for glomerular diseases (e.g., focal segmental glomerulosclerosis) [16].
Pharmacotherapy: Targeted therapies (e.g., eculizumab for aHUS, sparsentan for IgA nephropathy) [1][11], RAAS inhibitors, and SGLT2 inhibitors to delay progression [5][11].
Supportive care: Dialysis, dietary modifications, and management of complications (e.g., hypertension, proteinuria) [13][16].
Categories: rare transplant-related disorders
Research Papers
26 drug discovery papers about Rare disorder potentially indicated for kidney transplant, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
26 drug discovery papers about Rare disorder potentially indicated for kidney transplant, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-06-18 | Post-meal loss of consciousness in an adult patient with carbamoyl phosphate synthetase 1 deficiency and two newly identified heterozygous variants: a case report.
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder characterized by urea cycle dysfunction and secondary hyperammonemia. Although primarily observed in neonates, adult cases are exceedingly rare and warrant reporting due to their novelty and potential for misdiagnosis. We present a case of a 34-year-old male who presented with post-meal loss of consciousness, a symptom atypical of the disease's usual manifestation. A 34-year-old man was admitted with a 2-day history of general fatigue that escalated to unconsciousness over half a day. He also experienced vomiting, bilateral limb convulsions, and a history of epilepsy. Upon admission, he exhibited coma with a Glasgow Coma Scale score of 5/15. Biochemical investigations revealed normal liver and kidney function but a significantly elevated blood ammonia concentration of 597.6 µmol/L. Cranial imaging showed diffuse swelling of the brain parenchyma indicative of encephalopathy. Gene sequencing identified three heterozygous variants in theCPS1 gene, including two novel variants sites. Despite ammonia-lowering treatments, his condition rapidly deteriorated, and he succumbed to hyperammonemia-induced encephalopathy on day 9 of admission. This case highlights the importance of recognizing CPS1D as a potential diagnosis in adults presenting with neurological symptoms, particularly those involving consciousness changes. The rarity and atypical presentation of adult CPS1D underscore the need for early diagnosis through comprehensive evaluation, including blood ammonia measurement and genetic analysis. This case expands the spectrum of clinical manifestations and genetic variants associated with CPS1D and emphasizes the urgency of ammonia-lowering therapy and consideration for liver transplantation in eligible patients.
2026-05-07 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation
Introduction and importance: Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. Case presentation: On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver–kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. Clinical discussion: PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions – high fluid intake, crystallization inhibitors, and pyridoxine – can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. Conclusion: This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2025-10-31 | Human Urine-Derived SIX2-Positive Renal Progenitor Cells Partially Improve Kidney Fibrosis by Paracrine Signaling.
Cells with renal progenitor cells characteristics are shed in urine. This study aimed to investigate whether these SIX2-positive urine-derived renal progenitor cells (UdRPC) have therapeutic potential in treating or managing acute to chronic kidney injuries, which are increasing worldwide and currently affect one in ten people. Human UdRPC were obtained from a 35-year-old woman, expanded, and characterized in vitro before being transplanted unilaterally under the renal capsule of mouse kidneys that had undergone ischemia reperfusion injury (IRI). The blood sera of the mice were examined for kidney injury markers such as blood-urea-nitrogen and creatinine, and proteome changes over the 21-day study period using proteome arrays and bioinformatic methods. At the end of the study period, connective tissue deposition in the kidneys was examined histologically through Sirius Red staining, and the expression of fibrosis- and inflammation-associated genes was determined by reverse transcription quantitative polymerase chain reaction. The blood serum analysis revealed that the transplanted human UdRPC transiently influenced the secretome in mice. Furthermore, the transplanted cells improved renal fibrosis resulting from IRI, indicating therapeutic relevance. Deposition of extracellular matrix proteins and the expression of fibrosis-associated genes, such as connective tissue growth factor as well as collagen 1α2 and 3α1 chains, significantly decreased in the injured kidney after UdRPC transplantation. The expression of genes linked to inflammation and chronic kidney disease, such as monocyte chemoattractant protein 1 and intercellular adhesion molecule 1, was also reduced in mouse kidneys in the presence of UdRPC. K-means cluster analysis of the serum proteome from mice with IRI and transplanted UdRPC at different time points revealed a transient increase in immunomodulatory, antifibrotic, and angiogenic factors that could have triggered these positive effects on acute to chronic mouse kidney disease. Transplanted human UdRPC alleviated the kidney injury severity through ameliorating fibrosis; however, they could not restore complete kidney function within 21 days.
2025-06-01 | Unraveling Abdominal Distention: A Rare Presentation of Giant Pancreatic Mucinous Cystic Neoplasm in a Patient With Cystic Fibrosis
CASE REPORT Patients with cystic fibrosis (CF) exhibit diverse pancreatic disorders, encompassing functional insufficiency, structural abnormalities (fibrofatty parenchymal replacement, pancreatic cysts), and endocrine/exocrine dysfunction.1 In this study, we present a case of pancreatic mucinous cystic neoplasm in a patient with CF, recognized as a premalignant lesion for pancreatic adenocarcinoma. A 22-year-old woman with CF with genetic mutations F508del/G551D on elexacaftor/tezacaftor/ivacaftor and exocrine pancreatic insufficiency on pancreatic enzyme replacement therapy presented with abdominal distention. Computed tomography imaging revealed a large cystic lesion with mildly enhancing internal septations anterior to the left kidney between the stomach and the spleen, measuring 14.5 × 15.5 × 18 cm (Figure 1). After a multidisciplinary team consultation and discussion, the patient underwent surgery, with excision of a 15-pound cystic mass from the pancreas along with distal pancreatectomy (Figure 2). Histopathological analysis identified a mucinous cystic neoplasm of the pancreas with multifocal low-grade and high-grade dysplasia and intestinal metaplasia (Figures 3 and 4). A systematic review has shown that patients with CF demonstrate an increased risk of gastrointestinal malignancies.2,3 Cystic lesions of the pancreas in CF, although rare, need close follow-up due to the potential risk of malignancy. With increased lifespan due to cystic fibrosis transmembrane conductance regulator modulator drugs, and transplantation, vigilance for premalignant lesions, especially pancreatic cancers, is crucial.Figure 1.: Computed tomography of the abdomen/pelvis image with arrow pointing to a cystic lesion with mildly enhancing internal septations, measuring 18 cm in the coronal plane, between the stomach and the spleen, and displacing bowel loops to the right.Figure 2.: Intraoperative picture of the surgically excised mass from the pancreas (100×).Figure 3.: High-power microscopic view of the excised mass showing the classical histopathology of mucinous cystic neoplasm. The black arrow points toward the mucinous epithelium seen as columnar cells with pale pink apical mucin. The star points to the spindled, dense “ovarian-type” stroma (200×).Figure 4.: High-power microscopic view of the same specimen with black arrows pointing to cells with elongated, penicillate, and pseudostratified nuclei (low-grade dysplasia) and scattered goblet cells, indicating areas of intestinal metaplasia (200×).DISCLOSURES Author contributions: G. Nageswaran, L. Ton, VT Chandrasekar, JEL Yap made substantial contributions to the conception or design of the work; the acquisition, analysis, and interpretation of data for the work; drafting the work and critically reviewing it for important intellectual content, and gave final approval for the work to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JEL Yap is the article guarantor. Financial disclosure: None to report. Previous presentation: Abstract accepted and presented as a poster in the American College of Gastroenterology Annual Meeting held in Vancouver, Canada between October 20–25, 2023. Informed consent was obtained for this case report.
2025-02-06 | Clinical advances in kidney autotransplantation: a review.
Kidney autotransplantation is a surgical procedure with multiple indications and advancing technological approaches. Kidney autotransplantation is used to address complex kidney-related diseases including renal vascular lesions, ureteral diseases, tumors, loin pain-hematuria syndrome, and conditions affecting a solitary kidney or both kidneys. Renal artery lesions, including aneurysms and stenoses, often necessitate kidney autotransplantation in cases involving renal artery bifurcation or distant failure of endovascular repair. Complex ureteral lesions such as ureteral avulsions are commonly treated with kidney autotransplantation. Renal tumors, especially centrally located tumors or those involving the renal hilum, are treated using this technique while preserving renal function. It is worth emphasizing that this would be a rarely used last-resort technique in the modern era of minimally invasive nephron-sparing surgery. Kidney autotransplantation may be indicated for the rare condition of loin pain-hematuria syndrome when conservative measures fail. Additionally, individuals with solitary or bilateral kidney disease benefit from kidney autotransplantation to preserve their renal function. Traditional open-kidney autotransplantation involves renal extraction, workbench repair, and renal reimplantation. Technological advancements have introduced minimally invasive techniques including laparoscopic- and robot-assisted kidney autotransplantation, which reduce surgical trauma and recovery times. These techniques have shown promising outcomes, and robotic platforms have the potential to further reduce complications. In this study, we reviewed diverse indications and recent technological innovations in the field of kidney autotransplantation.
proteins
2026-03-06 | Immunoglobulin A Nephropathy With Associated Thrombotic Microangiopathy: Biopsy and Clinical Case Series.
IgA nephropathy (IgAN) with concurrent thrombotic microangiopathy (TMA) is an unusual combination of pathological findings that is associated with severe hypertension, proteinuria, and lower estimated glomerular filtration rate (eGFR). This series presents 7 patients with kidney biopsies demonstrating IgAN and concomitant TMA and presents a link by way of complement disorder. Seven patients all presented as IgAN with associated TMA coinciding with hypertension, proteinuria, and low eGFR. Six patients showed tubular atrophy or interstitial fibrosis and 5 of those 6 showed >50% of renal cortex containing tubular atrophy or interstitial fibrosis. Variations of low serum C3, high serum C4, elevated IgA or IgM proteins, and elevated CH50 were found in 6 of the 7 patients. Chronic changes seen like interstitial fibrosis and tubular atrophy appear to show a subacute or chronic nature of IgAN with TMA. The low serum C3, high C4, elevated CH50, suggests complement activation in endothelial and mesangial from IgG-IgA complexes known to occur in IgAN. This phenotype of IgAN with TMA may represent a more unique IgAN phenotype with a more severe clinical course and be indicative of underlying complement dysregulation.
2025-01-30 | Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.
2021-10-01 | Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.
Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
small molecules
2025-08-01 | Iptacopan treatment for recurrent dense deposit disease after kidney transplant: A case report
C3 glomerulopathies, including dense deposit disease, are rare kidney disorders caused by dysregulation of the alternative complement pathway. Recurrence after kidney transplantation is common and can threaten graft survival. Iptacopan, an oral factor B inhibitor, was recently Food and Drug Administration-approved as the first targeted therapy for C3 glomerulopathies. We describe a 19-year-old woman with childhood-onset dense deposit disease who progressed to kidney failure and underwent deceased donor transplantation. Post-transplant, she experienced delayed graft function and persistently low serum C3. A biopsy on day 7 revealed C3-only deposits, indicating early recurrent disease. Iptacopan was initiated at 200 mg twice daily. Her serum C3 normalized within 1 week and remained stable over 6 months. Proteinuria decreased significantly, and renal function improved and stabilized. This case highlights the potential of iptacopan as a disease-specific therapy for post-transplant C3 glomerulopathies recurrence, reinforcing its clinical utility and mirroring outcomes from the APPEAR-C3G trial.
2024-12-19 | SGLT2-Inhibition in Patients With Alport Syndrome.
Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts. This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i. The study's primary end point was change of albuminuria in albumin/g creatinine from the start of therapy. Compared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (aged 38 ± 14 years) and had a better estimated glomerular filtration rate (eGFR, 63 ± 35 ml/min per 1.73 m2; n = 98). Maximum follow-up was 32 months. Compared to baseline, at the first 3 follow-up visits (months 1 to 3, 4 to 8, and 9 to 15) after initiation of SGLT2i therapy, a significant reduction of albuminuria in mg albumin/g creatinine (>30%) was observed. Mean loss of eGFR was 9 ± 12 ml/min per 1.73 m2 almost 1 year after initiation of SGLT2i therapy (n = 35). At a total of 71 patient-years at risk, 0.24 adverse events (AEs) per patient-year on SGLT2i were reported. This study indicates that, additive to renin-angiotensin system (RAS)-inhibition (RASi), SGLT2i have the potential to reduce the amount of albuminuria in patients with AS. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with AS to assess whether the observed reduction in albuminuria translates to a delay in kidney failure (KF).
2024-10-24 | Second transplantation after kidney graft loss in primary hyperoxaluria type 2: a pedigree study and mutation analysis.
Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by GRHPR mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment. We report a case of PH2 with a three-generational pedigree. The GRHPR genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization. The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (p < 0.001), whereas p.P203Rfs*7 not only suppressed expression (p < 0.001) and reduced activity (p < 0.001), but also facilitated protein aggregation. Based on our results, the variant p.G160E was classified as 'pathogenic' according to ACMG guidelines. Our findings suggest that treatment strategies for the long-term prevention of oxalate nephropathy should be developed for patients with PH2 receiving isolated kidney transplantation. Moreover, the pathogenicity of the compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7 was also validated.
2023-03-24 | Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.
Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns-/- female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns-/- mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.
2023-02-15 | Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.
Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.
antibodies
2026-05-05 | Hepatic Manifestations and Response to Treatment in Deficiency of Adenosine Deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-04-14 | Efficacy and Safety of Rituximab in Antiglomerular Basement Membrane Disease.
Anti-glomerular basement membrane (GBM) disease is caused by pathogenic antibodies usually targeting the noncollagenous domain of the α3 chain of type IV collagen and frequently presents as rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage (DAH). Rapid reduction of these antibodies is imperative for kidney survival and the mainstay of therapy is the combination of plasma exchange (PLEX), glucocorticoids, and cyclophosphamide. Rituximab has been postulated as a potential treatment for anti-GBM disease; however, data on efficacy and safety are lacking. We performed a review of case reports and series (n = 28) providing individual patient-level data on the efficacy and safety of rituximab in adult and pediatric anti-GBM disease. In addition, we have received data from authors on 18 patients which stem from 4 studies that did not report on patient-level outcomes or were not previously reported. A search strategy of studies indexed in PubMed/MEDLINE was performed, followed by synthesis and analysis of the data. Sixty-seven patients [37 female (55%); 14 pediatric (21%); median age: 37 years] were followed-up with for a total of 87.1 person-years (median follow-up time: 9.5 months). They received rituximab as first-line (n = 39) or second-line (n = 28). Median serum creatinine was 416 μmol/l with 32 patients (48%) being dialysis-dependent at presentation and 24 (36%) having DAH. Intravenous pulse, oral glucocorticoids and PLEX were used in 85%, 98%, and 93%, respectively; and 54% of them received cyclophosphamide. Patients received a median of 4 (2-4) doses of rituximab with 11 patients (16%) having transient adverse effects. Patient survival was 91% and kidney survival was 67% (53% in adults and 71% in pediatric patients). Kidney survival was lower in initially dialysis-dependent patients (34% vs. 81%, P < 0.001). Patients receiving second-line rituximab had better kidney survival compared with those receiving it as first-line (73% vs. 46%, P = 0.03). Acknowledging the limitations of our study, including publication and selection bias, rituximab had a favorable toxicity and efficacy profile. The results indicate that rituximab can be considered as a second-line therapy in anti-GBM disease when cyclophosphamide is contraindicated.
2022-10-31 | C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease.
C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.
cell therapies
2026-06-18 | Post-meal loss of consciousness in an adult patient with carbamoyl phosphate synthetase 1 deficiency and two newly identified heterozygous variants: a case report.
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder characterized by urea cycle dysfunction and secondary hyperammonemia. Although primarily observed in neonates, adult cases are exceedingly rare and warrant reporting due to their novelty and potential for misdiagnosis. We present a case of a 34-year-old male who presented with post-meal loss of consciousness, a symptom atypical of the disease's usual manifestation. A 34-year-old man was admitted with a 2-day history of general fatigue that escalated to unconsciousness over half a day. He also experienced vomiting, bilateral limb convulsions, and a history of epilepsy. Upon admission, he exhibited coma with a Glasgow Coma Scale score of 5/15. Biochemical investigations revealed normal liver and kidney function but a significantly elevated blood ammonia concentration of 597.6 µmol/L. Cranial imaging showed diffuse swelling of the brain parenchyma indicative of encephalopathy. Gene sequencing identified three heterozygous variants in theCPS1 gene, including two novel variants sites. Despite ammonia-lowering treatments, his condition rapidly deteriorated, and he succumbed to hyperammonemia-induced encephalopathy on day 9 of admission. This case highlights the importance of recognizing CPS1D as a potential diagnosis in adults presenting with neurological symptoms, particularly those involving consciousness changes. The rarity and atypical presentation of adult CPS1D underscore the need for early diagnosis through comprehensive evaluation, including blood ammonia measurement and genetic analysis. This case expands the spectrum of clinical manifestations and genetic variants associated with CPS1D and emphasizes the urgency of ammonia-lowering therapy and consideration for liver transplantation in eligible patients.
2026-05-07 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation
Introduction and importance: Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. Case presentation: On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver–kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. Clinical discussion: PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions – high fluid intake, crystallization inhibitors, and pyridoxine – can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. Conclusion: This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2025-10-31 | Human Urine-Derived SIX2-Positive Renal Progenitor Cells Partially Improve Kidney Fibrosis by Paracrine Signaling.
Cells with renal progenitor cells characteristics are shed in urine. This study aimed to investigate whether these SIX2-positive urine-derived renal progenitor cells (UdRPC) have therapeutic potential in treating or managing acute to chronic kidney injuries, which are increasing worldwide and currently affect one in ten people. Human UdRPC were obtained from a 35-year-old woman, expanded, and characterized in vitro before being transplanted unilaterally under the renal capsule of mouse kidneys that had undergone ischemia reperfusion injury (IRI). The blood sera of the mice were examined for kidney injury markers such as blood-urea-nitrogen and creatinine, and proteome changes over the 21-day study period using proteome arrays and bioinformatic methods. At the end of the study period, connective tissue deposition in the kidneys was examined histologically through Sirius Red staining, and the expression of fibrosis- and inflammation-associated genes was determined by reverse transcription quantitative polymerase chain reaction. The blood serum analysis revealed that the transplanted human UdRPC transiently influenced the secretome in mice. Furthermore, the transplanted cells improved renal fibrosis resulting from IRI, indicating therapeutic relevance. Deposition of extracellular matrix proteins and the expression of fibrosis-associated genes, such as connective tissue growth factor as well as collagen 1α2 and 3α1 chains, significantly decreased in the injured kidney after UdRPC transplantation. The expression of genes linked to inflammation and chronic kidney disease, such as monocyte chemoattractant protein 1 and intercellular adhesion molecule 1, was also reduced in mouse kidneys in the presence of UdRPC. K-means cluster analysis of the serum proteome from mice with IRI and transplanted UdRPC at different time points revealed a transient increase in immunomodulatory, antifibrotic, and angiogenic factors that could have triggered these positive effects on acute to chronic mouse kidney disease. Transplanted human UdRPC alleviated the kidney injury severity through ameliorating fibrosis; however, they could not restore complete kidney function within 21 days.
2025-06-01 | Unraveling Abdominal Distention: A Rare Presentation of Giant Pancreatic Mucinous Cystic Neoplasm in a Patient With Cystic Fibrosis
CASE REPORT Patients with cystic fibrosis (CF) exhibit diverse pancreatic disorders, encompassing functional insufficiency, structural abnormalities (fibrofatty parenchymal replacement, pancreatic cysts), and endocrine/exocrine dysfunction.1 In this study, we present a case of pancreatic mucinous cystic neoplasm in a patient with CF, recognized as a premalignant lesion for pancreatic adenocarcinoma. A 22-year-old woman with CF with genetic mutations F508del/G551D on elexacaftor/tezacaftor/ivacaftor and exocrine pancreatic insufficiency on pancreatic enzyme replacement therapy presented with abdominal distention. Computed tomography imaging revealed a large cystic lesion with mildly enhancing internal septations anterior to the left kidney between the stomach and the spleen, measuring 14.5 × 15.5 × 18 cm (Figure 1). After a multidisciplinary team consultation and discussion, the patient underwent surgery, with excision of a 15-pound cystic mass from the pancreas along with distal pancreatectomy (Figure 2). Histopathological analysis identified a mucinous cystic neoplasm of the pancreas with multifocal low-grade and high-grade dysplasia and intestinal metaplasia (Figures 3 and 4). A systematic review has shown that patients with CF demonstrate an increased risk of gastrointestinal malignancies.2,3 Cystic lesions of the pancreas in CF, although rare, need close follow-up due to the potential risk of malignancy. With increased lifespan due to cystic fibrosis transmembrane conductance regulator modulator drugs, and transplantation, vigilance for premalignant lesions, especially pancreatic cancers, is crucial.Figure 1.: Computed tomography of the abdomen/pelvis image with arrow pointing to a cystic lesion with mildly enhancing internal septations, measuring 18 cm in the coronal plane, between the stomach and the spleen, and displacing bowel loops to the right.Figure 2.: Intraoperative picture of the surgically excised mass from the pancreas (100×).Figure 3.: High-power microscopic view of the excised mass showing the classical histopathology of mucinous cystic neoplasm. The black arrow points toward the mucinous epithelium seen as columnar cells with pale pink apical mucin. The star points to the spindled, dense “ovarian-type” stroma (200×).Figure 4.: High-power microscopic view of the same specimen with black arrows pointing to cells with elongated, penicillate, and pseudostratified nuclei (low-grade dysplasia) and scattered goblet cells, indicating areas of intestinal metaplasia (200×).DISCLOSURES Author contributions: G. Nageswaran, L. Ton, VT Chandrasekar, JEL Yap made substantial contributions to the conception or design of the work; the acquisition, analysis, and interpretation of data for the work; drafting the work and critically reviewing it for important intellectual content, and gave final approval for the work to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JEL Yap is the article guarantor. Financial disclosure: None to report. Previous presentation: Abstract accepted and presented as a poster in the American College of Gastroenterology Annual Meeting held in Vancouver, Canada between October 20–25, 2023. Informed consent was obtained for this case report.
2025-02-06 | Clinical advances in kidney autotransplantation: a review.
Kidney autotransplantation is a surgical procedure with multiple indications and advancing technological approaches. Kidney autotransplantation is used to address complex kidney-related diseases including renal vascular lesions, ureteral diseases, tumors, loin pain-hematuria syndrome, and conditions affecting a solitary kidney or both kidneys. Renal artery lesions, including aneurysms and stenoses, often necessitate kidney autotransplantation in cases involving renal artery bifurcation or distant failure of endovascular repair. Complex ureteral lesions such as ureteral avulsions are commonly treated with kidney autotransplantation. Renal tumors, especially centrally located tumors or those involving the renal hilum, are treated using this technique while preserving renal function. It is worth emphasizing that this would be a rarely used last-resort technique in the modern era of minimally invasive nephron-sparing surgery. Kidney autotransplantation may be indicated for the rare condition of loin pain-hematuria syndrome when conservative measures fail. Additionally, individuals with solitary or bilateral kidney disease benefit from kidney autotransplantation to preserve their renal function. Traditional open-kidney autotransplantation involves renal extraction, workbench repair, and renal reimplantation. Technological advancements have introduced minimally invasive techniques including laparoscopic- and robot-assisted kidney autotransplantation, which reduce surgical trauma and recovery times. These techniques have shown promising outcomes, and robotic platforms have the potential to further reduce complications. In this study, we reviewed diverse indications and recent technological innovations in the field of kidney autotransplantation.
proteins
2026-03-06 | Immunoglobulin A Nephropathy With Associated Thrombotic Microangiopathy: Biopsy and Clinical Case Series.
IgA nephropathy (IgAN) with concurrent thrombotic microangiopathy (TMA) is an unusual combination of pathological findings that is associated with severe hypertension, proteinuria, and lower estimated glomerular filtration rate (eGFR). This series presents 7 patients with kidney biopsies demonstrating IgAN and concomitant TMA and presents a link by way of complement disorder. Seven patients all presented as IgAN with associated TMA coinciding with hypertension, proteinuria, and low eGFR. Six patients showed tubular atrophy or interstitial fibrosis and 5 of those 6 showed >50% of renal cortex containing tubular atrophy or interstitial fibrosis. Variations of low serum C3, high serum C4, elevated IgA or IgM proteins, and elevated CH50 were found in 6 of the 7 patients. Chronic changes seen like interstitial fibrosis and tubular atrophy appear to show a subacute or chronic nature of IgAN with TMA. The low serum C3, high C4, elevated CH50, suggests complement activation in endothelial and mesangial from IgG-IgA complexes known to occur in IgAN. This phenotype of IgAN with TMA may represent a more unique IgAN phenotype with a more severe clinical course and be indicative of underlying complement dysregulation.
2025-01-30 | Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.
2021-10-01 | Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.
Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
small molecules
2025-08-01 | Iptacopan treatment for recurrent dense deposit disease after kidney transplant: A case report
C3 glomerulopathies, including dense deposit disease, are rare kidney disorders caused by dysregulation of the alternative complement pathway. Recurrence after kidney transplantation is common and can threaten graft survival. Iptacopan, an oral factor B inhibitor, was recently Food and Drug Administration-approved as the first targeted therapy for C3 glomerulopathies. We describe a 19-year-old woman with childhood-onset dense deposit disease who progressed to kidney failure and underwent deceased donor transplantation. Post-transplant, she experienced delayed graft function and persistently low serum C3. A biopsy on day 7 revealed C3-only deposits, indicating early recurrent disease. Iptacopan was initiated at 200 mg twice daily. Her serum C3 normalized within 1 week and remained stable over 6 months. Proteinuria decreased significantly, and renal function improved and stabilized. This case highlights the potential of iptacopan as a disease-specific therapy for post-transplant C3 glomerulopathies recurrence, reinforcing its clinical utility and mirroring outcomes from the APPEAR-C3G trial.
2024-12-19 | SGLT2-Inhibition in Patients With Alport Syndrome.
Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts. This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i. The study's primary end point was change of albuminuria in albumin/g creatinine from the start of therapy. Compared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (aged 38 ± 14 years) and had a better estimated glomerular filtration rate (eGFR, 63 ± 35 ml/min per 1.73 m2; n = 98). Maximum follow-up was 32 months. Compared to baseline, at the first 3 follow-up visits (months 1 to 3, 4 to 8, and 9 to 15) after initiation of SGLT2i therapy, a significant reduction of albuminuria in mg albumin/g creatinine (>30%) was observed. Mean loss of eGFR was 9 ± 12 ml/min per 1.73 m2 almost 1 year after initiation of SGLT2i therapy (n = 35). At a total of 71 patient-years at risk, 0.24 adverse events (AEs) per patient-year on SGLT2i were reported. This study indicates that, additive to renin-angiotensin system (RAS)-inhibition (RASi), SGLT2i have the potential to reduce the amount of albuminuria in patients with AS. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with AS to assess whether the observed reduction in albuminuria translates to a delay in kidney failure (KF).
2024-10-24 | Second transplantation after kidney graft loss in primary hyperoxaluria type 2: a pedigree study and mutation analysis.
Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by GRHPR mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment. We report a case of PH2 with a three-generational pedigree. The GRHPR genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization. The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (p < 0.001), whereas p.P203Rfs*7 not only suppressed expression (p < 0.001) and reduced activity (p < 0.001), but also facilitated protein aggregation. Based on our results, the variant p.G160E was classified as 'pathogenic' according to ACMG guidelines. Our findings suggest that treatment strategies for the long-term prevention of oxalate nephropathy should be developed for patients with PH2 receiving isolated kidney transplantation. Moreover, the pathogenicity of the compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7 was also validated.
2023-03-24 | Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.
Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns-/- female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns-/- mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.
2023-02-15 | Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.
Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.
antibodies
2026-05-05 | Hepatic Manifestations and Response to Treatment in Deficiency of Adenosine Deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-04-14 | Efficacy and Safety of Rituximab in Antiglomerular Basement Membrane Disease.
Anti-glomerular basement membrane (GBM) disease is caused by pathogenic antibodies usually targeting the noncollagenous domain of the α3 chain of type IV collagen and frequently presents as rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage (DAH). Rapid reduction of these antibodies is imperative for kidney survival and the mainstay of therapy is the combination of plasma exchange (PLEX), glucocorticoids, and cyclophosphamide. Rituximab has been postulated as a potential treatment for anti-GBM disease; however, data on efficacy and safety are lacking. We performed a review of case reports and series (n = 28) providing individual patient-level data on the efficacy and safety of rituximab in adult and pediatric anti-GBM disease. In addition, we have received data from authors on 18 patients which stem from 4 studies that did not report on patient-level outcomes or were not previously reported. A search strategy of studies indexed in PubMed/MEDLINE was performed, followed by synthesis and analysis of the data. Sixty-seven patients [37 female (55%); 14 pediatric (21%); median age: 37 years] were followed-up with for a total of 87.1 person-years (median follow-up time: 9.5 months). They received rituximab as first-line (n = 39) or second-line (n = 28). Median serum creatinine was 416 μmol/l with 32 patients (48%) being dialysis-dependent at presentation and 24 (36%) having DAH. Intravenous pulse, oral glucocorticoids and PLEX were used in 85%, 98%, and 93%, respectively; and 54% of them received cyclophosphamide. Patients received a median of 4 (2-4) doses of rituximab with 11 patients (16%) having transient adverse effects. Patient survival was 91% and kidney survival was 67% (53% in adults and 71% in pediatric patients). Kidney survival was lower in initially dialysis-dependent patients (34% vs. 81%, P < 0.001). Patients receiving second-line rituximab had better kidney survival compared with those receiving it as first-line (73% vs. 46%, P = 0.03). Acknowledging the limitations of our study, including publication and selection bias, rituximab had a favorable toxicity and efficacy profile. The results indicate that rituximab can be considered as a second-line therapy in anti-GBM disease when cyclophosphamide is contraindicated.
2022-10-31 | C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease.
C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.
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Drug Discovery Landscape
4 orphan drug designations for Rare disorder potentially indicated for kidney transplant, including 1 approved therapy.
4 orphan drug designations for Rare disorder potentially indicated for kidney transplant, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
tacrolimus [Envarsus XR] | small molecules | FDA | Approved | Veloxis Pharmaceuticals, Inc. |
anti-thymocyte globulin [rabbit] | antibodies | FDA | Genzyme Corporation | |
humanized monocloncal antibody against human integrin alphaVbeta6 | antibodies | FDA | Stromedix, Inc. | |
Anti-CD45 monoclonal antibodies | antibodies | FDA | — | Baxter Healthcare Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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