Clinical, pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study.

BACKGROUND: Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However, characteristics of those cases had not been intensively studied so far. METHODS: We retrospectively reviewed clinical, pathological, and genetic characteristics of 37 children (median age, 9.3 years) who underwent renal biopsy for persistent isolated proteinuria (urine protein-to-creatinine ratio: UP/C, > 0.2 g/g) between 2003 and 2019. Targeted next-generation sequencing (NGS) was utilized for all patients with FSGS, excluding those with secondary FSGS. RESULTS: At biopsy, all patients with FSGS (N = 14) had UP/C ≥ 0.5 g/g and the median UP/C was significantly higher in those with FSGS than those with minor glomerular abnormalities (MGA) (N = 23) (1.49 vs. 0.53 g/g, P < 0.001). Causative variants were found in seven patients with FSGS (TRPC6, WT1, ACTN4, and INF2 in 3, 2, 1, and 1 patient, respectively): all gene variants were in genes manifesting autosomal dominant inheritance mode. The proportion of the perihilar variant was significantly higher in the genetic FSGS patients than in the non-genetic FSGS patients (4/7 vs. 0/7, P < 0.05). Kaplan-Meier analysis showed that the renal survival rate after ASP diagnosis was significantly lower in the genetic FSGS patients than in the non-genetic FSGS and the MGA patients (P < 0.001). CONCLUSIONS: UP/C was a simple and useful predictive parameter for the diagnosis of FSGS. APS without nephrotic syndrome at onset may be associated with autosomal dominant causes of FSGS, especially in those with the perihilar variant.

Hydrogen-rich water reduced oxidative stress and renal fibrosis in rats with unilateral ureteral obstruction.

BACKGROUND: Congenital obstructive nephropathy (CKD) is commonly implicated in the pathophysiology of chronic kidney disease occurring in the pediatric and adolescent age groups and the release of reactive oxygen species contribute to the worsening of renal fibrosis. Molecular hydrogen (H2) protects against tissue injury by reducing oxidative stress. We evaluated the efficacy of oral H2-rich water (HW) intake in preventing unilateral ureteral obstruction (UUO)-induced renal injury in rats. METHODS: Male Sprague-Dawley UUO or control rats were administered with distilled water (DW) or HW for 2 weeks post-surgery. Histopathological and immunohistochemical analyses of kidney samples were performed. RESULTS: Histological changes were not apparent in the sham-operated kidneys. However, UUO kidneys were found to have widened interstitial spaces and tubular dilatation. Compared with the UUO + DW group, HW administration attenuated tubulointerstitial injury and reduced interstitial fibrotic area, causing a substantial decline in the frequency of α-SMA-, ED-1-, and TGF-ß1-positive cells in the UUO + HW group. The decrease in the klotho mRNA expression in the UUO + HW group was less pronounced than that in the UUO + DW group. CONCLUSION: Oral HW intake reduced oxidative stress and prevented interstitial fibrosis in UUO kidneys, potentially involving klotho in the underlying mechanism. IMPACT: Oral intake of hydrogen-rich water (HW) can reduce oxidative stress and suppress interstitial fibrosis in unilateral ureteral obstruction-induced renal injury in rats. This mechanism possibly involves klotho, which is known for its antiaging roles. The association between molecular hydrogen and klotho in renal fibrosis is well known; this is the first report on the association in a unilateral ureteral obstruction model. Drinking HW is a safe and convenient treatment for oxidative stress-induced pathologies, without side effects. As a prospect for future research, oral HW intake to treat oxidative stress may improve renal fibrosis in congenital obstructive nephropathy.

An extremely mild clinical course in a case with LAMB2-associated nephritis diagnosed with next-generation sequencing.

Biallelic pathogenic variants in the laminin ß2 (LAMB2) gene, which encodes laminin ß2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology.

BACKGROUND: Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes. METHODS: We retrospectively reviewed long-term outcomes (> 3 years; median follow-up, 9.1 years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine. RESULTS: At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116 days vs. 45 days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease. CONCLUSIONS: Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.

Preventive Effect of Tonsillectomy on Recurrence of Henoch-Schönlein Purpura Nephritis after Intravenous Methylprednisolone Pulse Therapy.

Henoch-Schönlein purpura (HSP) is regarded as a benign and self-limiting vasculitis characterized by purpura, arthritis, and gastrointestinal symptoms; however, about one third of the patients develop HSP nephritis (HSPN), the most serious long-term complication. Since 2013, we have proposed that tonsillectomy in addition to intravenous methylprednisolone pulse therapy (IVMP) be performed in all patients with HSPN, similar to immunoglobulin A nephropathy (IgAN) patients because both diseases are considered to a share common pathogenesis. Herein, we retrospectively reviewed the clinical courses of 71 Japanese children with HSPN (34 boys; median age at diagnosis, 6.7 years; median follow-up period, 5.6 years) who had received initial treatment with IVMP (15-20 mg/kg; on 3 consecutive days/week for 3 weeks) followed by oral prednisolone (initially 1 mg/kg; tapered off within 12 months) and achieved clinical remission (i.e., disappearance of both proteinuria and hematuria). The patients were divided into two groups: 31 patients receiving tonsillectomy after IVMP between 2013 and 2017 (tonsillectomy group) and 40 patients receiving IVMP monotherapy between 2003 and 2012 (IVMP group). For the 2 years after IVMP therapy, the rate of HSPN recurrence (i.e., persistent proteinuria combined with hematuria requiring additional treatments) after clinical remission was significantly lower in the tonsillectomy group than the IVMP group (0% vs. 19%, P < 0.05). Despite the short follow-up period in the tonsillectomy group, this study provides the evidence that tonsillectomy may be beneficial for preventing recurrence of HSPN from clinical remission with IVMP therapy in Japanese children.

Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is characterized by primary ciliary dysfunction (ciliopathy) and progresses to end-stage kidney disease (ESKD) during the second decade of life (juvenile and adolescent NPHP) or before the age of 3 years (infantile NPHP). Here we describe the case of an infant with NPHP who carries a homozygous mutation in SDCCAG8 (also called NPHP10 or BBS16) that encodes SDCCAG8 (serologically defined colon cancer antigen 8). SDCCAG8 is localized at the centrioles of both renal epithelial cells and retinal photoreceptor cells. A mutation in SDCCAG8 is also associated with Bardet-Biedl syndrome (BBS), characterized by NPHP, obesity, polydactyly, and rod-cone dystrophy. A 2-year-old boy was referred to our hospital due to kidney dysfunction of unknown etiology; the patient presented with delayed development and opsoclonus but did not exhibit the clinical characteristics of BBS. Histological findings such as dilatation of tubules and irregular thickness of tubular basement membrane confirmed the diagnosis of NPHP. Four months after referral, the patient's renal function was rapidly deteriorated, and emergency peritoneal dialysis was initiated. Next-generation sequencing (NGS) was performed, showing that the patient carries a homozygous four-base-pair deletion in SDCCAG8 (c.849_852delTTTG, p.Cys283Ter). The patient's parents were also found to be heterozygous for this loss-of-function mutation. To the best of our knowledge, the present patient is the first case of biopsy-proven infantile NPHP with a homozygous SDCCAG8 mutation. We conclude that NGS is extremely useful in the identification of SDCCAG8-related NPHP as a cause of sudden-onset ESKD during infancy.

Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis.

Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.

Optimal urinary protein-to-creatinine ratio as a renal biopsy criterion in children with asymptomatic proteinuria.

BACKGROUND: This retrospective case series aimed at exploring the optimal urinary protein-to-creatinine ratio (uP/uCr) cut-off value to determine the need for renal biopsy in pediatric patients with isolated asymptomatic proteinuria (ASP). METHODS: Data from 32 patients (16 boys, 16 girls) with persistent isolated ASP treated between January 2001 and September 2010 were analyzed. The uP/uCr cut-off value at which a renal biopsy is indicated was determined using the minimum p-value approach. An "optimal" cut-off value was selected to distinguish significant and non-significant glomerular changes. RESULTS: The minimum p-value approach using the χ2-test resulted in a peak uP/uCr of 0.5 g/g x Cr, which was then used to divide the patients into a low-proteinuria group and a high-proteinuria group. The proportion of significant glomerular changes was marginally higher (p = 0.097) in the high-proteinuria group than in the low-proteinuria group after adjustment for multiple tests. In addition, the number of patients with severe proteinuria at the most recent followup was higher in the high-proteinuria group than in the low-proteinuria group. CONCLUSION: The use of a uP/uCr >= 0.5 g/g x Cr may be a reasonable criterion for renal biopsy aimed at distinguishing renal outcomes in patients with persistent isolated ASP.

Increased urinary angiotensinogen is an effective marker of chronic renal impairment in very low birth weight children.

BACKGROUND: Recent advancements in perinatal and neonatal care have increased the survival of preterm infants with lower birth weight and very low birth weight (VLBW; < 1,500 g) infants. Such infants are exposed to a higher risk of renal insufficiency in later life due to congenitally fewer nephrons; however, urinalysis in order to detect renal insufficiency in those infants at school age has not yet been established. The aim of the study was to assess chronic renal impairment in VLBW infants during their childhood after discharge from the neonatal intensive care unit (NICU) until adolescence using urinary angiotensinogen (uAGT). METHODS: We compared serum levels of angiotensinogen (sAGT), creatinine, ß2-microglobulin (sß2MG) and cystatin C (sCysC), and urinary levels of uAGT, creatinine (uCre),ß2-microglobulin (uß2MG) and albumin between two infant groups-the VLBW group (50 children who were admitted to our NICU as infants), and a control group of 25 children who were born as full-term infants with birth weight ≥2,500 g. The median age of the VLBW group and control group infants was 60 months (range 7-135) and 57 months (range 5-144), respectively, at the time of evaluation. RESULTS: In the VLBW group, sCysC levels were high (p < 0.05) and estimated glomerular filtration rate (eGFR) was low (p < 0.05). There were no significant differences in the ratios of uß2MG to creatinine and urinary albumin to creatinine between the two groups. Although there were no differences in concentration of sAGT between the two groups (p = 0.062), the ratio of uAGT to creatinine was significantly higher in the VLBW group (p < 0.01). The examination of 19 VLBW infants (19/50) with eGFR ≤90 ml/min/1.73 m(2) showed a positive correlation between uAGT/creatinine and urinary albumin/creatinine (r = 0.531, p < 0.05). Furthermore, the analysis of correlation between the ratio of uAGT to creatinine and eGFR showed a reverse correlation in 19 VLBW infants (19/50) with eGFR ≤90 ml/min/1.73 m(2), 18 of whom had stage II chronic kidney disease and one who had stage III disease (r = -0.512, p ≤ 0.05). CONCLUSIONS: uAGT is an effective marker for predicting the progression of chronic renal impairment in preterm VLBW infants after their growth. uAGT measurement is easier to conduct, less invasive and more sensitive than conventional uß2MG or urinary albumin measurement.

Efficacy and safety of darbepoetin alfa for anemia in children with chronic kidney disease: a multicenter prospective study in Japan.

BACKGROUND: We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND). METHODS: A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 µg DA for 200 IU rHuEPO. The initial DA dose for naïve patients was determined by body weight, and intended not to exceed 0.5 µg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks. RESULTS: Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA. CONCLUSION: These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD.

Role of ultrasound in revealing complications following percutaneous renal biopsy in children.

BACKGROUND: This retrospective case series aimed to investigate the role of ultrasound immediately post-percutaneous renal biopsy (PRB) for detecting post-biopsy complications in pediatric patients. METHODS: Data from 380 (male/female = 209/171) consecutive biopsies of native kidney tissue of 344 children from January 2001 to October 2009 were analyzed to investigate the role of an ultrasound immediately post-PRB and the predictive value of demographic, clinical, and baseline chemistry factors in predicting the risk of post-PRB complications. RESULTS: Post-PRB ultrasound identified hematoma formation in 33 (8.7%) patients. Of the 19 (5.0%) patients whose hematomas were large (≥ 1 cm), post-biopsy courses of 16 patients were clinically complicated. On the other hand, of the 14 patients whose hematomas were small (< 1 cm), all patients but one showed an uncomplicated clinical course. Of the 17 complications, 79.1% were detected within the first 24 hours and 21.9% (cases of resorption fever) between 24 and 144 hours post-PRB. Age ≥ 10 is an independent risk factor for post-PRB complication. CONCLUSIONS: Age ≥ 10 is an independent risk factor for post-PRB complication. After the procedure, the formation of a large hematoma predicted a complicated clinical course.

Uncertainty in management of childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable?

Despite the recent establishment of clinical practice guidelines, many areas in the management of childhood idiopathic nephrotic syndrome (INS) remain uncertain. In this edition of Pediatric Nephrology Samuel et al. report significant differences between Canadian pediatric nephrologists' practice and guideline recommendations, including initial duration of glucocorticoid treatment, choice of glucocorticoid-sparing agents in cases of frequently relapsing or steroid-dependent INS, and biopsy timing. Although evidence is emerging that the incidence of subsequent relapse can be reduced with longer initial glucocorticoid therapy, even with this new regimen relapse occurs in more than half of the children with steroid-sensitive INS. Cyclosporine (CsA) as a glucocorticoid-sparing agent for children with frequently relapsing or steroid-dependent INS is believed to provide protection from steroid toxicity and significantly improve the quality of life. However, recent follow-up studies of the post-CsA era have revealed a high incidence of INS relapse in adulthood in patients treated with CsA in childhood, and CsA use itself is a significant predictor of recurrent relapses. Therefore, pediatric nephrologists must recognize the potential of adverse effects that may appear later in life because of prolonged immunosuppressive therapy in childhood.

Posterior reversible encephalopathy syndrome with exercise-induced acute kidney injury in renal hypouricemia type 1.

Renal hypouricemia type 1 is caused by mutations in the SLC22A12 gene, whereas type 2 is caused by defects in the SLC2A9 gene. Although both subtypes predispose to exercise-induced acute kidney injury (EIAKI), posterior reversible encephalopathy syndrome (PRES) occurring with this disorder is an uncommon phenomenon that has only been reported to date in a patient with renal hypouricemia type 2. We describe a 13-year-old boy with renal hypouricemia type 1 (serum uric acid, 0.9 mg/dL) with a homozygous W258X mutation in the SLC22A12 gene, presenting with EIAKI and PRES. On admission, his body weight was 61 kg (11 kg above the dry weight), and blood pressure was 153/88 mmHg. Cranial magnetic resonance imaging revealed high-intensity areas in the cortical and subcortical white matter of the occipital lobe. After admission, the patient responded well to a combination of hemodialysis and intravenous nicardipine. This is the first case of concurrent PRES and EIAKI in a patient with renal hypouricemia type 1. We suggest that PRES is not due to severe hypouricemia caused by SLC2A9 mutation but is a manifestation of severe EIAKI associated with renal hypouricemia.

Is there a pathogenic association between Fabry's disease and IgA nephropathy?

Several cases of concurrent Fabry's disease and IgA nephropathy have been reported, but the pathogenic association between these two diseases remains unclear. This is a report on the case of a girl with severe IgA nephropathy who was subsequently diagnosed with subclinical Fabry's disease. An 11-year-old girl was admitted to our hospital with massive proteinuria and hematuria detected by urinary screening. An initial renal biopsy revealed severe IgA nephropathy with diffuse mesangial proliferation. She was treated with intravenous methylprednisolone pulses followed by 2 years of oral steroids. The treatment improved both the urinary abnormalities and the second renal biopsy findings. At the age of 15 years, mild proteinuria prompted us to perform a third renal biopsy, and histology revealed minor glomerular abnormalities. In addition, numerous myelin-like bodies were detected in podocytes by electron microscopy. The histological findings combined with the low level of α-galactosidase A activity led to the diagnosis of concomitant Fabry's disease with IgA nephropathy. Our experience suggests that the initial massive proteinuria was not due to Fabry's disease, but was rather a manifestation of coincidental IgA nephropathy. We speculate that the coexistence of IgA nephropathy and Fabry's disease occurred by chance.

Hereditary renal hypouricemia: a cause of calcium oxalate urolithiasis in a young female.

Although renal hypouricemia is mostly asymptomatic, it is known to present a high risk of exercise-induced acute renal failure, especially in young males. However, there is little information regarding the clinical features of urolithiasis as a complication in childhood renal hypouricemia. Here we report a 4-year old female with idiopathic renal hypouricemia who presented with macroscopic hematuria due to obstructive calcium oxalate urolithiasis. She was treated successfully with percutaneous nephrolithotripsy and thereafter hematuria disappeared. Sequence analysis of the patient and her family's URAT1 gene confirmed a nonsense mutation in exon 4 (W258X). To the best of our knowledge, this is the youngest case of hereditary renal hypouricemia caused by URAT1 gene mutation, which was found by hematuria due to calcium oxalate urolithiasis.

Nephrotoxicity of once-daily cyclosporine A in minimal change nephrotic syndrome.

BACKGROUND: Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration. CASE-DIAGNOSIS/TREATMENT: A prospective study of the clinical efficacy and comparison between pre- and post-treatment renal biopsy findings in ten children (mean age, 8.8 years) with steroid-dependent MCNS who were administered once-daily CsA therapy for more than 24 months (mean ± SD, 30 ± 3.7) was performed in Saitama Children's Medical Center. Administration of once-daily CsA therapy (mean dose, 2.8 ± 0.6 mg/kg/day; mean C2 levels, 670 ± 64 ng/ml) resulted in a significant reduction in the median relapse rate from 4.6 to 0.2 times per year, and five patients did not experience a relapse of NS. Furthermore, mean threshold of prednisolone dose significantly reduced from 1.2 to 0.02 mg/kg on alternate days. However, two patients showed evidence of chronic CsA nephrotoxicity (CsAN). CONCLUSIONS: Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen.