Amane Endo

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.

Evaluation of kidney dysfunction and angiotensinogen as an early novel biomarker of intrauterine growth restricted offspring rats

Background:Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring.Methods:Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed.Results:The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin–angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring.Conclusion:Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.

The Synergistic Effect of Mizoribine and a Direct Renin Inhibitor, Aliskiren, on Unilateral Ureteral Obstruction Induced Renal Fibrosis in Rats

PURPOSE Renal fibrosis, the major histopathological change in various renal disorders, is closely related to renal dysfunction. Unilateral ureteral obstruction is a well established model of experimental renal disease that results in tubulointerstitial fibrosis. Previous studies showed that aliskiren and mizoribine ameliorated unilateral ureteral obstruction induced renal fibrosis. However, to our knowledge the protective effect of combination therapy with aliskiren and mizoribine against renal fibrosis is unknown. We investigated the synergistic effects of aliskiren and mizoribine combination therapy on unilateral ureteral obstruction induced fibrosis in rats. MATERIALS AND METHODS Male Sprague Dawley® rats underwent unilateral ureteral obstruction followed by aliskiren and/or mizoribine treatment. Kidney samples were fixed for histopathology and immunohistochemistry of myofibroblasts (α-SMA) and macrophages (ED-1). Real-time quantitative reverse transcription-polymerase chain reaction was performed to measure α-SMA, TGF-β1, osteopontin, MCP-1 and renin expression. RESULTS After unilateral ureteral obstruction the tubular dilatation, interstitial volume and α-SMA expression scores were significantly decreased by combination therapy compared with monotherapy with aliskiren or mizoribine. Combination therapy caused a significant decrease in the number of ED-1 positive cells and in TGF-β1 gene expression compared with monotherapy with either drug (each p <0.05). Combination therapy also decreased OPN and MCP-1 gene expression (p <0.05). CONCLUSIONS Aliskiren and mizoribine combination therapy provides increased renal protection against renal fibrosis and unilateral ureteral obstruction induced inflammation.

Evaluation of Urinary Aquaporin 2 and Plasma Copeptin as Biomarkers of Effectiveness of Desmopressin Acetate for the Treatment of Monosymptomatic Nocturnal Enuresis

Purpose: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome. Materials and Methods: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 &mgr;g or 240 &mgr;g desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 &mgr;g) and nonresponders (at 240 &mgr;g). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment. Results: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 &mgr;g was significantly lower than in the 240 &mgr;g nonresponder group (p = 0.02). Conclusions: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.

Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats

Background:Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats.Methods:Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated.Results:Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity.Conclusion:These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.

Long‐term renal tubular damage in intrauterine growth‐restricted rats

Intrauterine growth restriction (IUGR) has been shown to be associated with increased risk of renal disease or hypertension in later life. Glomerular dysfunction, however, has mainly been reported, and limited information is available to link IUGR with renal tubular damage. The aim of this study was therefore to investigate urinary markers of tubular damage in a rat model of IUGR induced by bilateral uterine artery ligation.

Impaired nephrogenesis in neonatal rats with oxygen-induced retinopathy

Preterm neonates are born while nephrogenesis is ongoing, and are commonly exposed to factors in a hyperoxic environment that can impair renal development. Oxidative stress has also been implicated in the development of retinopathy of prematurity (ROP). The rat model of oxygen‐induced retinopathy (OIR) is the most clinically relevant model of ROP because its biologic features closely resemble those of ROP in preterm infants. We investigated impaired renal development in a rat model of OIR.

Congenital glucose-galactose malabsorption diagnosed from macrohematuria in an infant

Congenital glucose–galactose malabsorption (CGGM) is a rare autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. Macrohematuria has not previously been reported to be associated with CGGM. We report the case of a 2-month-old girl with macrohematuria secondary to hypercalcemia caused by CGGM. A 2-month-old girl with CGGM had macrohematuria, diarrhea, and failure to thrive. No abnormalities were detected during the pregnancy or at delivery at 38 weeks. Birthweight was 2734 g. The infant did not have consanguineous parents or a family history of hereditary disease. She was breast-fed from birth and defecated within 24 h of birth. She developed frequent diarrhea when she was 1 month old. At 35 days old, macrohematuria was observed. On admission to hospital, her weight was 3310 g, indicating an average weight gain of 16 g/day since birth. She was moderately dehydrated with abdominal distention. Laboratory examinations showed elevated blood urea nitrogen (32 mg/dL), calcium (14.4 mg/dL), and sodium (150 mmol/L). Creatinine (0.32 mg/dL), phosphate, and magnesium were all within the normal ranges. 1,25-(OH)2D and 25-(OH)D and parathyroid hormone were also normal. Blood gas analysis indicated acidemia (pH 7.336), bicarbonate 13.0 mmol/L, and base excess – 11.3 mmol/L. Fecal electrolyte levels were normal and carbohydrate test was positive. Urinalysis indicated non-glomerular hematuria with a 3 + reaction for red blood cells, numerous red blood cells, and mild proteinuria but normal uric acid level with no reaction to glucose. The urinary calcium to creatinine (Ca/Cre) ratio was increased (to 1.24 mg/mg). Renal ultrasonography (Fig. 1a,b) and abdominal computed tomography (Fig. 1c) showed normal-sized kidneys and bilateral nephrocalcinosis in the renal pelvis. It was suspected that macrohematuria was caused by nephrocalcinosis with hypercalcemia and hypercalciuria, rather than being due to abnormal parathyroid function, abnormal vitamin D metabolism, or malignancy. Therefore, carbohydrate malabsorption was expected because of the incident diarrhea and the constantly positive fecal carbohydrate tests. Carbohydrate absorption analysis using lactose-loading tests showed no serum glucose increase, while sucrose-loading test indicated an increasing glucose curve. Glucoseand galactose-loading tests showed no increase in the glucose curve, but a fructose-loading test showed increased glucose within 60 min. The clinical sequence and laboratory findings indicated CGGM. Treatment with a carbohydrate-free diet formula with fructose immediately relieved the diarrhea and hematuria and the negative urinary red blood cell count and fecal carbohydrate tests. Urinary Ca/Cre ratio and serum calcium improved to 0.11 mg/mg and 8.2 mg/dL after treatment, respectively. Mutation analysis of the sodium– glucose cotransporter type 1 gene, performed at our hospital, indicated that the patient expressed a compound heterozygous mutation of R379R/X (exon 11) and R499R/H (exon 13). Informed consent was obtained from her parents. There is one previous report of lactose intolerance with renal calcification and hematuria. Saarela et al. reported renal calcification in fice of 10 lactose-intolerant children. There are some previous reports of renal calcification in patients with CGGM. Abdullah et al. reported that 12.5% of these patients had renal calcification and risk factors for nephrocalcinosis (metabolic acidosis and chronic dehydration). There are no reports, however, on macrohematuria with CGGM. The present hypothesis is that the observed macrohematuria in the present case may have been caused by nephrolithiasis due to CGGM, with dehydration leading to hypercalcemia, thereby increasing urinary calcium excretion. Several reports have noted that CGGM causes hypercalcemia because of the intestinal calcium absorption increase, with the intestinal lactose accumulation due to malabsorption resulting from congenital lactase deficiency. Similarly, glucose and galactose accumulation in the intestinal tract increases the intestinal calcium absorption, leading to the hypercalcemia associated with CGGM. Additionally, hypercalcemia is caused by a combination of excess H from metabolic acidosis due to Correspondence: Tohru Fujii, MD PhD, Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyoku, Tokyo 113-8421, Japan. Email: fujii-j@juntendo.ac.jp Received 3 March 2016; revised 15 May 2016; accepted 2 June 2016.