Ryuichiro Konda

Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan.

PURPOSE We evaluate clinical characteristics of primary vesicoureteral reflux in infants in a multicenter study in Japan with special reference to the relation of renal parenchymal damage to urinary tract infection and gender. MATERIALS AND METHODS Infants younger than 1 year old with primary vesicoureteral reflux were recruited from 14 hospitals during the 3-year registration period beginning in January 1996 and ending in December 1998. Various clinical parameters as well as renal parenchymal lesion on dimercaptosuccinic acid scintigraphy were evaluated. RESULTS Of 356 infants enrolled 296 (83%) were male and 60 (17%) were female. In 85% of infants presenting symptom was febrile urinary tract infection. There were 204 bilateral (57%) and 152 unilateral (43%) cases. Reflux was bilateral in 56% of males versus 65% of females, and high grade (grades IV and V) in 58% of males versus 55% of females. Diffuse parenchymal lesion was similarly noted in infants with or without prior urinary tract infection (38% and 46%, respectively) and was more often noted in male than in female infants (42% versus 25%). CONCLUSIONS Despite the current use of screening prenatal ultrasound, many infants are still diagnosed as having vesicoureteral reflux only after the occurrence of urinary tract infection. The greater severity of renal parenchymal lesion in male infants combined with similar incidence of diffuse parenchymal lesion in those with or without prior infection suggests preexisting congenital abnormalities in the male refluxing kidney.

Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese population.

Aim:  Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D3 (1,25(OH)2D3) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)2D3 and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population.

Ultrasound Grade of Hydronephrosis and Severity of Renal Cortical Damage on 99mTechnetium Dimercaptosuccinic Acid Renal Scan in Infants With Unilateral Hydronephrosis During Followup and After Pyeloplasty

PURPOSE We performed ultrasonography and (99m)technetium dimercaptosuccinic acid (DMSA) renal scan in infants with unilateral hydronephrosis during followup and after pyeloplasty to examine the correlation of ultrasound hydronephrosis grade with the severity of renal cortical damage and assess the recovery of renal function in the obstructed kidneys after surgery. MATERIALS AND METHODS We studied 80 boys and 19 girls with unilateral hydronephrosis detected in the first year of life, including 75 (76%) in whom it was detected prenatally. Ultrasound images were graded according to the Society for Fetal Urology grading system. The severity of renal cortical damage was assessed by DMSA renal scan. Absolute function of the right and left kidneys was estimated by DMSA uptake and relative DMSA uptake was calculated by the formula, relative uptake = uptake in obstructed kidney/total uptake in right and left kidneys x 100%. RESULTS On ultrasonography grades 1 to 4 hydronephrosis were diagnosed in 9, 21, 19 and 50 kidneys, respectively. On DMSA renal scan cortical damage was detected in 10 kidneys (53%) with grade 3 and 49 (98%) with grade 4 hydronephrosis but not in kidneys with grade 1 or 2 disease. Dysfunction in the obstructed kidney, defined as relative DMSA uptake less than 40%, was noted in 13 patients with grade 4 hydronephrosis. Relative DMSA uptake significantly increased after successful pyeloplasty compared with preoperative uptake (44% +/- 2% versus 40.1% +/- 2%, p <0.01). CONCLUSIONS Ultrasound grading of hydronephrosis correlates with the severity of cortical damage or the decrease in renal function on DMSA renal scan. Differential renal function on DMSA renal scan may be a useful and less invasive tool for determining surgical indications and examining changes in renal function after surgery.

Expression of Platelet-Derived Endothelial Cell Growth Factor and its Potential Role in Up-Regulation of Angiogenesis in Scarred Kidneys Secondary to Urinary Tract Diseases

The mechanism of neovascularization secondary to renal interstitial fibrosis is not well understood. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to promote angiogenesis. We examined the expression of PD-ECGF immunohistochemically in 9 normal kidneys and 26 scarred kidneys secondary to urinary tract diseases. To estimate up-regulation of angiogenesis, microvessels were counted by immunostaining endothelial cells for CD34. Immunostaining of PD-ECGF was observed in most Bowmans capsules, occasional tubules, and some interstitial mononuclear cells in normal kidneys. A remarkable increase of immunostained PD-ECGF was found in the tubules and interstitial mononuclear infiltrates in the scarred kidneys. The predominant cell type in the infiltrate was T cells (CD3(+)). The microvessel count and mean numbers of PD-ECGF(+) tubular and interstitial mononuclear cells increased with increasing interstitial fibrosis. A significant correlation was noted between microvessel count and the number of PD-ECGF(+) tubular cells (P = 0.0002) or PD-ECGF(+) interstitial mononuclear cells (P < 0.0001). Immunostaining of endogrin, a marker of endothelial proliferation, increased in the microvessels located in the fibrotic interstitial spaces. These results suggest that angiogenesis may play a critical role in the progression of tubulointerstitial injuries and that up-regulation of PD-ECGF may contribute to neovascularization.

Followup Study of Renal Function in Children With Reflux Nephropathy After Resolution of Vesicoureteral Reflux

PURPOSE We evaluated data collected for 10 years on children with reflux nephropathy to identify a means of predicting the prognosis. MATERIALS AND METHODS A total of 15 boys and 13 girls were enrolled in this study at least 2 years after surgical and spontaneous resolution of vesicoureteral reflux in 25 and 3 patients, respectively. They were followed for more than 10 years and renal function was periodically evaluated. Urinary beta 2-microglobulin, alpha 1-microglobulin, N-acetyl-beta-D-glucosaminidase, microalbumin and 99mtechnetium dimercapto-succinic acid uptake were measured. RESULTS Of the 28 patients 12 had high levels of urinary alpha 1-microglobulin during followup, including all 7 in whom renal function deteriorated. In 3 children with elevated alpha 1-microglobulin urinary microalbumin gradually increased after puberty. Although elevated levels of urinary beta 2-microglobulin, N-acetyl-beta-D-glucosaminidase and microalbumin were also observed, they were less predictive of renal function than alpha 1-microglobulin. CONCLUSIONS These results suggest that elevated urinary levels of alpha 1-microglobulin may predict the risk of abnormal renal function in children with reflux nephropathy even before the appearance of significant proteinuria.

CLINICAL SIGNIFICANCE OF URINARY INTERLEUKIN-6 IN CHILDREN WITH REFLUX NEPHROPATHY

PURPOSE We determined urinary interleukin-6 (IL-6) in children with reflux nephropathy to evaluate the clinical significance of this cytokine in the progression of renal injury. MATERIALS AND METHODS Enrolled in this study were 34 boys and 32 girls in whom 99mtechnetium dimercapto-succinic acid renal scan showed renal scarring. Vesicoureteral reflux had been corrected surgically at least 3 years before study entry. Urinary IL-6 was determined by enzyme-linked immunosorbent assay using spot urine samples. Simultaneously we measured serum creatinine, beta2-microglobulin, alpha1-microglobulin, urinary alpha1-microglobulin and albumin. In addition, IL-6 expression was assessed by immunohistochemical study in the scarred kidneys of 3 boys and 1 girl who underwent nephrectomy due to severe reflux nephropathy with little function on renal scan. RESULTS Urinary IL-6 was significantly higher in children with severe bilateral renal scarring than in those with mild scarring and normal controls. Urinary IL-6 correlated significantly with serum alpha1-microglobulin (Spearman test p <0. 03), beta2-microglobulin (p <0.003), creatinine (p <0.02) and urinary albumin (p <0.0001). Histological evaluation revealed that IL-6 was predominantly expressed in the tubules in and adjacent to fibrotic areas. CONCLUSIONS Our observations indicate that tubular IL-6 may be involved in the pathogenesis of tubulointerstitial injury in reflux nephropathy and urinary IL-6 may be a useful tool for monitoring the progression of reflux nephropathy.

Standardized Prevalence Ratios for Chronic Hepatitis C Virus Infection Among Adult Japanese Hemodialysis Patients

Background Many studies have estimated the prevalence of anti-hepatitis C virus (HCV) antibody among hemodialysis (HD) patients; however, the prevalence of HCV core antigen—which indicates the presence of chronic HCV infection—is not known. Methods Standardized prevalence ratios (SPRs) for anti-HCV antibody and HCV core antigen among HD patients (n = 1214) were calculated on the basis of data from the general population (n = 22 472) living in the same area. Results The prevalences of anti-HCV antibody and HCV core antigen were 12.5% and 7.8%, respectively, in male hemodialysis patients, and 8.5% and 4.1% in female hemodialysis patients. The SPRs (95% confidence interval) for anti-HCV antibody and HCV core antigen were 8.39 (6.72–10.1) and 12.9 (9.66–16.1), respectively, in males, and 5.42 (3.67–7.17) and 8.77 (4.72–12.8) in females. Conclusions The prevalences of chronic HCV infection among male and female HD patients were 13-fold and 9-fold, respectively, those of the population-based controls. Further studies should therefore be conducted to determine the extent of chronic HCV infection among HD patients in other populations and to determine whether chronic HCV infection contributes to increased mortality in HD patients.

The distribution of renin containing cells in scarred kidneys.

PURPOSE To evaluate changes in renal renin synthesis secondary to renal scarring from urinary tract disease, we investigated the immunohistochemical distribution of renin in normotensive children with scarred kidneys and determined whether renal renin content correlates with the degree of interstitial fibrosis. MATERIALS AND METHODS We performed semiquantitative analysis of the immunohistochemical distribution of renin using rabbit anti-human renin antibody in the scarred kidneys of 3 boys and 17 girls with urinary tract disease. RESULTS Immunoreactive renin was mainly present within the afferent arteriole. Immunostaining of the juxtaglomerular apparatuses, interlobular arteries and renin containing cells increased with the degree of interstitial fibrosis. Glomeruli disjointed from proximal tubules, that is atubular glomeruli, were observed in fibrosed areas and renin was distinctly noted in the juxtaglomerular apparatus of atubular glomeruli. CONCLUSIONS Scarred areas may be responsible for the hyperproduction of renin and angiotensin II, which in turn promotes renal scarring and an increase in atubular glomeruli. This cycle may lead to progressive renal scarring.

RENIN CONTAINING CELLS ARE PRESENT PREDOMINANTLY IN SCARRED AREAS BUT NOT IN DYSPLASTIC REGIONS IN MULTICYSTIC DYSPLASTIC KIDNEY

PURPOSE Hypertension is an important complication of multicystic dysplastic kidney and it has been suggested that it is induced by renin. Little information is available on renin production in this disease. To assess renin production we examined the distribution of renin containing cells in multicystic dysplastic kidneys using immunohistochemical methods. MATERIALS AND METHODS Immunohistochemical examination of renin was performed in 29 multicystic dysplastic kidneys from 14 boys and 15 girls 1 month to 10 years old using rabbit anti-human renin antibodies. In all cases normal renal function was confirmed by the serum creatinine level and no proteinuria on urinalysis. Two patients had the complication of hypertension before removal of the multicystic dysplastic kidney but plasma renin activity was normal. RESULTS Immunostaining of renin was observed in 26 of 29 multicystic dysplastic kidneys (90%). Histologically multicystic dysplastic kidney involved scarred and dysplastic areas. Renin positive cells were observed predominantly in the scarred areas, mainly in the juxtaglomerular apparatus of mature glomeruli, interlobular arteries and some mature tubules. Immunopositive renin was sparsely noted in the juxtaglomerular apparatus or Bowmans capsules of occasional immature glomeruli in dysplastic areas. CONCLUSIONS Our observations suggest that multicystic dysplastic kidney may have the ability to produce renin. Renin producing cells in the juxtaglomerular apparatus of mature glomeruli and interlobular arteries in the scarred areas may be the predominant source of renin production in this organ.

Brain-Specific Angiogenesis Inhibitor 1 is a Putative Factor for Inhibition of Neovascular Formation in Renal Cell Carcinoma

PURPOSE Renal cell carcinoma is a typical hypervascular tumor in which neovascularization may have a large part in progression. We examined expression of the cancer regulating, p53 targeted angiogenesis inhibitor brain-specific angiogenesis inhibitor 1 in renal cell carcinoma tissue to elucidate the clinical significance of its expression. MATERIALS AND METHODS We examined brain-specific angiogenesis inhibitor 1 mRNA and protein expression in 47 renal cell carcinoma and 10 normal kidney tissues using real-time quantitative polymerase chain reaction and immunohistochemistry, respectively. Levels of VEGF and bFGF mRNA, and immunohistochemical expression of p53 protein were also investigated in the same renal cell carcinoma tissues. RESULTS A significant decrease in BAI1 mRNA was noted in renal cell carcinoma tissue compared with that in normal kidney tissue (p <0.001). Immunostaining for brain-specific angiogenesis inhibitor 1 was also decreased in carcinoma tissue compared with normal kidney tissue. BAI1 mRNA and protein expression were lower in advanced renal cell carcinoma (pT3-4) than in localized renal cell carcinoma (pT1-2) tissues (p <0.03 and 0.003, respectively). A significant negative correlation was observed between microvessel density and brain-specific angiogenesis inhibitor 1 protein expression (r = -0.4056, p = 0.002). No significant correlation was noted between BAI1 and VEGF or bFGF mRNA levels. Brain-specific angiogenesis inhibitor 1 protein expression did not correlate with p53 protein expression. CONCLUSIONS These observations suggest that down-regulation of brain-specific angiogenesis inhibitor 1 expression may be a critical factor in renal cell carcinoma development and BAI1 may be a promising candidate for gene therapy of renal cell carcinoma.