Anti-nephrin autoantibodies: novel predictors of post-transplant recurrence of focal segmental glomerular sclerosis.

Post-transplant recurrence of focal segmental glomerular sclerosis (FSGS) is a major challenge in the field of kidney transplantation. Currently, the most reliable predictor of FSGS recurrence is disease recurrence in a previous allograft. Recent studies suggest a possible causal role of anti-nephrin autoantibodies in the primary disease (primary FSGS and minimal change disease), as well as post-transplant recurrence of FSGS. In this issue of Kidney International, Batal et al. evaluate pretransplant anti-nephrin autoantibodies as a specific predictor of FSGS recurrence and demonstrate colocalization of nephrin and punctate IgG in anti-nephrin-positive patients with disease recurrence.

Primary Cilia Elongation in Early-Onset Polycystic Kidney Disease with 2 Hypomorphic PKD1 Alleles: A Case Report.

Recent studies have described several children with very early-onset polycystic kidney disease (PKD) that mimicked autosomal recessive polycystic kidney disease because of 2 hypomorphic PKD1 gene variants. However, no reports have described pathological changes in the primary cilia in these cases. We analyzed the primary cilia in the kidney tubules of an early elementary school child who had very early-onset PKD and a history of large, echogenic kidneys in utero. There was no family history of autosomal dominant PKD. The patient developed kidney failure and received a living-donor kidney transplant from his father. Genetic analysis revealed compound heterozygous variants in the PKD1 gene: c.3876C>A (p. Phe1292Leu) and c.5957C>T (p. Thr1986Met). These variants were likely pathogenic based on in silico analysis. The absence of kidney cysts in the parents suggested that these variants were hypomorphic alleles. Pathological examination of the patient's excised kidney showed prominent dilatation of the proximal and distal tubules. Immunofluorescence staining for α-tubulin showed pronounced elongation of the primary cilia. These findings suggest that the hypomorphic PKD1 variants expressed in this patient with very early-onset PKD were pathogenic.

Children and adolescents with severe motor and intellectual disabilities who underwent kidney transplantation.

BACKGROUND: Kidney transplantation (KT) in children and adolescents with severe motor and intellectual disabilities (SMID) has been a topic of controversy. A multicenter study in Japan showed that KT was not contraindicated for children with multiple handicaps, but no consensus has been reached on KT for patients with SMID. This study aimed to determine whether KT is a viable treatment option for children and adolescents with SMID. METHODS: A single-center, retrospective study was conducted on children and adolescents with SMID who underwent KT. SMID was defined based on Oshima's classification. Clinical information was collected through a review of medical records. RESULTS: Of 453 children and adolescents who underwent KT between 1983 and 2023 in our institution, six (1.3%) patients with SMID were identified. One patient received KT twice. All patients underwent living KT. Five patients used medical devices, including gastrostomy and a ventriculoperitoneal shunt, prior to KT. Perioperative complications, including hemothorax related to central venous catheter insertion, ventilator-associated pneumonia, and common iliac artery thrombosis requiring graftectomy, occurred in three patients. One patient required vesicostomy owing to refractory urinary tract infection. There was no significant difference in the graft survival rate between patients with SMID and those without SMID. One patient developed graft failure and died after selecting conservative kidney management. CONCLUSION: Our study showed a favorable graft survival in children and adolescents with SMID who underwent KT. Although careful perioperative management and continued medical care are required, KT may be a viable option for these patients.

MYH9-related disease with a normal platelet count.

MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, progressive kidney failure, and sensorineural hearing loss. We describe a patient with MYH9-RD and a normal platelet count. A 13-year-old boy with a normal platelet count presented with proteinuria and hematuria and underwent a kidney biopsy. Light microscopy showed mild mesangial matrix expansion. Electron microscopy showed thinning of the glomerular basement membrane and splitting of the lamina densa. A tentative diagnosis of Alport syndrome was made. Unexpectedly, genetic analysis revealed a de novo MYH9 gene variant (p.Gln1068_Leu1074dup). A peripheral blood smear examination showed giant platelets and leukocyte inclusion bodies, confirming a diagnosis of MYH9-RD. In summary, we described a patient with MYH9-RD without thrombocytopenia who showed glomerular basement membrane abnormalities similar to Alport syndrome. Peripheral blood smear examinations may be helpful for an appropriate diagnosis of MYH9-RD, even in patients with proteinuria and a normal platelet count.

Partial bladder transplantation with en bloc kidney transplant-long-term, 17 years, the outcome of a "bladder patch technique".

A transplant of a portion of the bladder with an en bloc kidney from a 2-year-old donor was previously reported in a 12-month-old girl due to her extremely small bladder. Bilateral kidneys were transplanted en bloc with their ureters connected to a patch of the donor bladder (bladder patch technique). The long-term outcomes and complications of this technique have not been documented. Here, we report a long-term, 17-year follow-up of this patient with an evaluation of whole bladder functions at 18 years of age. The patient has had no episodes of urinary tract infections. Cystoscopy showed a viable transplanted bladder with a well-perfused mucosa. We observed that the native bladder has stretched over time, forming more than half of the bladder wall. Urodynamic studies showed preserved bladder compliance at 43 mL/cmH2O, and native bladder contractility was preserved. Prolonged voiding time and postvoid residual urine were also observed. These findings were suggestive of detrusor underactivity. No reflux across the donor ureterovesical junctions was observed. The recipient was instructed to continue timed voiding and double voiding to empty the bladder. In conclusion, en bloc kidney transplantation with a bladder patch is a feasible and safe option for kidney transplant recipients with a small bladder capacity.

Clinical Course of Nonresponders With Recurrent Focal Segmental Glomerulosclerosis After Pediatric Kidney Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders. METHODS: We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018. RESULTS: Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1-2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add-on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group. CONCLUSIONS: Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders.

En bloc kidney transplantation from pediatric donors to teenage recipients: Two case reports.

Introduction: Since the implementation of the new selection criteria in 2018, kidney donations from pediatric patients have been prioritized for pediatric recipients and kidney donations from pediatric donors have increased in Japan. Herein, we present two cases of en bloc kidney transplantation. Case presentation: Case 1: A 19-year-old male patient who had been on hemodialysis for 5 years due to end-stage renal disease. After brain death, a graft from a 5-year-old boy was transplanted into the right iliac fossa. Case 2: A 19-year-old male patient, who had previously undergone a living kidney transplantation at the age of 3, received a secondary cadaveric kidney transplantation in the left iliac fossa. The graft was procured from a 17-month-old girl following cardiac death. Conclusion: This report will help surgeons perform en bloc kidney transplantation in the growing number of pediatric kidney donations, such as those in Japan.

A nationwide survey of MYH9-related disease in Japan.

BACKGROUND: MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, Döhle body-like granulocyte inclusions, and nephropathy, which may progress to end-stage kidney disease (ESKD). However, information on the effects of renin-angiotensin system (RAS) inhibitors on kidney survival is currently lacking and the outcomes of kidney replacement therapy (KRT) in MYH9-RD are largely unknown. METHODS: We conducted a cross-sectional nationwide survey by sending questionnaires to 145 institutions in Japan and analyzed data for 49 patients. RESULTS: The median patient age was 27 years. Genetic analysis was performed in 37 (76%) patients. Twenty-four patients (65%) had MYH9 variants affecting the motor domain of non-muscle myosin heavy chain-IIA, and these patients had poorer kidney survival than those with variants affecting the tail domain (P = 0.02). There was no significant difference in kidney survival between patients treated with and without RAS inhibitors. Hemodialysis and peritoneal dialysis were performed in 16 and 7 patients, respectively. There were no major bleeding complications during the perioperative period or during follow-up, except for one patient. Most of the 11 patients who underwent kidney transplantation required perioperative red cell concentrate transfusions, but there was no graft loss during the median posttransplant observational period of 2.0 (interquartile range, 1.3-6.8) years. CONCLUSION: Our study demonstrated no beneficial effect of RAS inhibitors on kidney function in patients with MYH9-RD, indicating the need for further studies with more patients. All modalities of KRT are feasible options for MYH9-RD patients who progress to ESKD, with adequate attention to bleeding complications.

A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

Case Report: Guanfacine and methylphenidate improved chronic lower back pain in autosomal dominant polycystic kidney disease with comorbid attention deficit hyperactivity disorder and autism spectrum disorder.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by the bilateral development of multiple cysts in the kidneys. Pain management is a clinically important issue, especially because approximately 60% of patients with ADPKD experience chronic pain related to hemorrhage from renal cysts, which significantly reduces their daily life. The cystic fibrosis transmembrane conductance regulator, the molecule responsible for cyst formation in ADPKD, is also the cause of cystic fibrosis. Since attention deficit hyperactivity disorder (ADHD) is known to occur frequently in conjunction with cystic fibrosis, ADPKD may be associated with ADHD. However, to our knowledge, no study has investigated 1) ADHD or autism spectrum disorder (ASD) as comorbidities with ADPKD, 2) the effects of ADHD medications on chronic pain in ADPKD, or 3) cerebral blood flow corresponding to guanfacine (GF) or methylphenidate (MP) treatment for chronic pain. We report the case of a 15-year-old girl with ADPKD, who had chronic back pain associated with ADPKD and had to withdraw from high school because the pain interfered with her daily life. Although she took antihypertensive medications to prevent bleeding, they did not provide adequate blood pressure control. The patient was referred to a child psychiatrist and diagnosed with ASD; however, the pain did not improve. Subsequently, she was referred to our pain center. The diagnosis of ADHD was confirmed and treatment with ADHD medications was initiated. Monotherapy with MP, atomoxetine, and GF resulted in hypertension and hypotension as side effects; however, a combination of MP 18 mg and GF 4 mg provided pain relief and moderate blood pressure control, and the patient was able to go on to college. During the course of treatment, there was an improvement in the distribution of cerebral blood flow in the prefrontal and insular cortices. Confirmation of an ADHD diagnosis comorbid with ASD enabled the use of ADHD medications. The combination of MP and GF improved chronic back pain and high blood pressure due to ADPKD and cerebral blood flow. Screening for ADHD is important in the treatment of ADPKD.

Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy.

Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot-Marie-Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes.

Successful administration of eltrombopag in preparation for peritoneal dialysis catheter placement in a girl with MYH9-related disease.

MYH9-related disease is an autosomal dominant disorder characterized by macrothrombocytopenia, nephropathy, inclusion bodies in leukocytes, sensorineural hearing loss, and cataract. Severe cases require kidney replacement therapy in the patient's second decade of life; thrombocytopenia constitutes a major risk factor for hemorrhagic complications during dialysis initiation or kidney transplantation. Prophylactic platelet transfusion prior to surgery is commonly administered to affected patients in these cases. However, transfusion in such patients has limitations other than the general risk of allergic reactions and blood-borne infections; it may also trigger alloimmunization, leading to platelet transfusion resistance or the development of anti-donor antibodies in potential kidney transplant recipients. Here, we describe prophylactic administration of eltrombopag, an oral thrombopoietin receptor agonist, prior to laparoscopic peritoneal dialysis catheter placement in a 15-year-old girl with MYH9-related disease. Her platelet count was approximately 30 × 103/µL at baseline; it increased to 61 × 103/µL on the day before surgery, thereby avoiding the need for platelet transfusions. There were no major bleeding or adverse events associated with eltrombopag administration. Thus, eltrombopag may be a safe and effective alternative to prophylactic platelet transfusions in patients with MYH9-related disease.

Depression and health-related quality of life in adolescents and young adults with childhood-onset end-stage kidney disease: a multicenter study in Japan.

BACKGROUND: Patient survival and physical outcomes among children with end-stage kidney disease (ESKD) have significantly improved, and recent research has focused on long-term depression symptoms and health-related quality of life (HRQOL). However, no studies have been conducted among adolescents and young adults with childhood-onset ESKD in Japan. METHODS: This multicenter study included 45 adolescents and young adults aged 16-39 years who developed ESKD at age < 20 years. Depression symptoms were measured using the Beck Depression Inventory (BDI)-II. The Short Form-36 Health Survey (SF-36) was used to assess HRQOL. Factors associated with depression and HRQOL were analyzed. RESULTS: Depression (BDI-II score ≥ 14) was observed in 13 (29%) patients. Patient's SF-36 physical component summary (PCS) and mental component summary (MCS) scores were comparable with those for the general population. Lower estimated glomerular filtration rate, higher BDI-II scores, and lower body mass index were associated with lower PCS scores. BDI-II scores were negatively correlated with MCS scores. We observed a trend that unemployment was associated with lower MCS scores. CONCLUSIONS: Depression is frequently observed among adolescents and young adults with childhood-onset ESKD. Regular screening for psychosocial concerns, maintaining stable graft functions, and achieving optimal nutritional status may contribute to improved well-being among these patients.

Medical and psychosocial outcomes in adolescents and young adults with childhood-onset end-stage kidney disease: a multicenter study in Japan.

BACKGROUND: Adolescents and young adults face various socio-emotional and behavioral challenges that can affect their medical and psychosocial outcomes. Pediatric patients with end-stage kidney disease (ESKD) often have extra-renal manifestations, including intellectual disability. However, limited data are available regarding the impact of extra-renal manifestations on medical and psychosocial outcomes among adolescents and young adults with childhood-onset ESKD. METHODS: Patients born between January 1982 and December 2006 that had developed ESKD in 2000 and later at age < 20 years were enrolled in this multicenter study in Japan. Data for patients' medical and psychosocial outcomes were retrospectively collected. Associations between extra-renal manifestations and these outcomes were analyzed. RESULTS: In total, 196 patients were analyzed. The mean age at ESKD was 10.8 years, and at last follow-up was 23.5 years. The first modality of kidney replacement therapy was kidney transplantation, peritoneal dialysis, and hemodialysis in 42, 55 and 3% of patients, respectively. Extra-renal manifestations were documented in 63% of patients and 27% had intellectual disability. Baseline height at kidney transplantation and intellectual disability significantly impacted final height. Six (3.1%) patients died, of which five (83%) had extra-renal manifestations. Patients' employment rate was lower than that in the general population, especially among those with extra-renal manifestations. Patients with intellectual disability were less likely to be transferred to adult care. CONCLUSIONS: Extra-renal manifestations and intellectual disability in adolescents and young adults with ESKD had considerable impacts on linear growth, mortality, employment, and transfer to adult care.

Overexpression of Plasmalemmal Vesicle-Associated Protein-1 Reflects Glomerular Endothelial Injury in Cases of Proliferative Glomerulonephritis with Monoclonal IgG Deposits.

Introduction: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) occasionally presents refractory nephrotic syndrome resulting in poor renal prognosis, but its etiology is not fully elucidated. Given that glomerular endothelial cell (GEC) stress or damage may lead to podocytopathy and subsequent proteinuria, as in thrombotic microangiopathy (TMA), diabetic kidney disease, and focal segmental glomerulosclerosis, we investigated the evidence of glomerular endothelial injury by evaluating the expression of plasmalemmal vesicle-associated protein-1 (PV-1), a component of caveolae in the cases of PGNMID. Methods: We measured the immunofluorescent PV-1 intensities of 23 PGNMID cases and compared with those of primary membranoproliferative glomerulonephritis (MPGN) (n = 5) and IgA nephropathy (IgAN) (n = 54) cases. PV-1 localization was evaluated with Caveolin-1, and CD31 staining, and the ultrastructural analysis was performed using a low-vacuum scanning electron microscope (LVSEM). To check the association of podocyte injury, we also conducted 8-oxoguanine and Wilms tumor 1 (WT1) double stain. We then evaluated PV-1 expression in other glomerulitis and glomerulopathy such as lupus nephritis and minimal change disease. Results: The intensity of glomerular PV-1 expression in PGNMID is significantly higher than that in the other glomerular diseases, although the intensity is not associated with clinical outcomes such as urinary protein levels or renal prognosis. Immunostaining and LVSEM analysis revealed that glomerular PV-1 expression is localized in GECs in PGNMID. 8-oxoguanine accumulation was detected in WT1-positive podocytes but not in PV-1-expressing GECs, suggesting GEC-derived podocyte injury in PGNMID. Conclusion: PV-1 overexpression reflects glomerular endothelial injury, which could be associated with podocyte oxidative stress in PGNMID cases.

Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is a common pediatric kidney disease, yet current treatments for complicated NS are only partially effective and have significant toxicity. There is no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved safe and effective treatment for NS. Thiazolidinediones (TZDs) have been shown to reduce proteinuria in both diabetic and non-diabetic kidney disease and in preclinical studies to directly protect podocytes from injury and reduce proteinuria. Here, we report on the potential utility of the addition of the TZD pioglitazone (PIO) to enhance proteinuria reduction in 8 children and young adults with steroid dependent NS and steroid resistant NS. METHODS: Clinical data were analyzed in comparable time periods before and after the addition of PIO to their medical regimens. Eight NS patients with minimal change NS (n = 2), focal segmental glomerulosclerosis (FSGS) (n = 4), or collapsing FSGS (n = 2) were evaluated. RESULTS: Prior to PIO initiation, all children and young adults had already received multiple immunosuppressive medications (mean = 3.75). Five of eight patients (63%; "Responders") had notable proteinuria reduction within 1 month of PIO initiation (62% reduction; P = 0.04) and normalization within 6 months (97% reduction; P = 0.04). PIO-related benefits among the responders included notable increases in serum albumin (2.5 to 3.7 g/dl; P = 0.08), dramatic reductions in hospitalizations for IV albumin infusions and diuresis (11 to 0; P < 0.01), and considerable reduction in total immunosuppression (43% reduction; P > 0.1). Importantly, no patients experienced any adverse events attributable to PIO during a total of 136 patient-months of treatment. CONCLUSIONS: While confirmatory safety and efficacy studies are needed, these findings suggest pioglitazone (a non-immunosuppressive drug) may be useful to enhance proteinuria reduction in some children and young adults with complicated NS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Survival analysis among pediatric patients receiving kidney replacement therapy: a Japanese nationwide cohort study.

BACKGROUND: Limited data are available on the survival and causes of death in pediatric patients with chronic kidney disease (CKD) stage 5 receiving kidney replacement therapy (KRT) in Asia. METHODS: Data were obtained from the Japanese nationwide cross-sectional CKD stage 5 survey on pediatric patients (<20 years of age) who started KRT from 2006 to 2013. The cohort was divided into three groups according to age at the start of KRT: <1, 1-5, and 6-19 years. RESULTS: Among the 701 children who were included, 59.3% were boys. Peritoneal dialysis was the most common initial modality of KRT (60.3%). Median age at KRT initiation was 10.2 years. Infants (<1 year old) accounted for 16.0% of the total cohort. Overall survival at 1 and 5 years was 97.2% and 92.5%, respectively. Infants had significantly lower survival rates than the other groups (hazard ratio, 5.35; 95% CI, 2.60-11.03; P < 0.001). In contrast, after the age of 1 year, the survival rate improved and did not differ from that of other age groups. The most common causes of death were infection (35.9%) and sudden death (15.4%). CONCLUSIONS: The overall survival rate of pediatric patients with CKD stage 5 in Japan is like that in other high-income countries. Age at initiation of KRT is an important factor affecting survival since the poorest survival rate was observed in infants. Further improvement in infant dialysis therapy is still needed to improve survival of the youngest children. A higher resolution version of the Graphical abstract is available as Supplementary information.