Factors influencing the development of Multicystic Dysplastic Kidney (MCDK) following urinary tract obstruction in the fetal lamb.

BACKGROUND: Creating obstructive uropathy (OU) during glomerulogenesis in the fetal lamb results in multicystic dysplastic kidney (MCDK) at term. We explored this using immunohistochemical techniques. METHOD: OU was created in fetal lambs at 60-day gestation, ligating the urethra and urachus. The kidneys of MCDK lambs, 60-day gestation fetal lambs, full-term lamb (145 days), term sham-operated lambs, and adult ewes were evaluated by HE staining, and immunohistochemistry with paired box genes 2 (PAX2) and CD10. RESULTS: Multiple cysts were found in the MCDK model. CD10 was expressed in proximal tubular epithelial cells, glomerular epithelial cells, and medullary stromal cells in the kidneys of 60-day gestation fetal lambs and full-term lambs and adult ewes. PAX2 expression was found in ureteric buds, C- and S-shaped bodies, epithelial cells of collecting ducts, and Bowman's capsule of fetal kidneys at 60-day gestation, but only in the collecting ducts of full-term fetal lambs and adult ewes. Both CD10 and PAX2 were expressed in the cystic epithelial cells of the MCDK model. DISCUSSION: PAX2 expression in cystic epithelial cells suggests that cyst formation is associated with disturbed down-regulation of PAX2 in the nephrogenic zone epithelial cells during the renal development in the OU model.

The triangular cord ratio and the presence of a cystic lesion in the triangular cord. Suggested new ultrasound findings in the early diagnosis of Biliary Atresia.

BACKGROUND: In biliary atresia (BA), the ultrasonic triangular cord (TC) sign is positive at ≥ 3 mm, but sometimes there is BA even if it is ≤ 3 mm. For improving the ultrasonographic diagnosis, we have established a new evaluation, adding the ratio of the anterior/posterior thickness (TC ratio) in the hyperechoic area and the presence of a cystic lesion in the triangular cord (TCC). METHODS: We examined 24 cases of suspected BA who demonstrated acholic stools from 2006 to 2020. We retrospectively reviewed the timing of ultrasonographic diagnosis, the gallbladder diameter, gallbladder mucosal irregularity, the TC sign, TCC, and the TC ratio. RESULTS: In the BA group (n = 10) vs the Non-BA group (n = 14), the age at ultrasonography was 75 ± 41.7 vs. 81 ± 39.1 days (p = 0.72), the gallbladder diameter was 12.1 ± 9.7 vs. 24.2 ± 6.96 mm (p = 0.02), irregularity of gallbladder mucosa was 7 cases vs. 1 case (p < 0.01), and TC sign was 3.9 ± 1.3 vs. 2.0 ± 0.49 mm (p = 0.01), respectively. TCC was observed in 8/10 cases in the BA group and none in the Non-BA group (p < 0.01). TC ratio was 3.40 ± 0.68 (BA group) and 1.59 ± 0.41 (Non-BA group) (p < 0.01). CONCLUSION: The ultrasonic TC ratio improves the diagnostic accuracy of BA. TCC is a specific finding in the BA group.

Urinary and plasma proteomics to discover biomarkers for diagnosing between diabetic nephropathy and minimal change nephrotic syndrome or membranous nephropathy.

The choice of treatment for primary nephrotic syndrome depends on the pathologic type of the disorder. Renal biopsy is necessary for a definitive diagnosis, but it is burdensome for the patients, and can be avoided if tests could be performed using urine or plasma. In this study, we analyzed 100 urinary proteins, 141 plasma proteins, and 57 urine/plasma ratios in cases of diabetic nephropathy (DN; n = 11), minimal change nephrotic syndrome (MCNS; n = 14), and membranous nephropathy (MN; n = 23). We found that the combination of urinary retinol-binding protein 4 and SH3 domain-binding glutamic acid-rich-like protein 3 could distinguish between MCNS and DN, with an area under the curve (AUC) of 0.9740. On the other hand, a selectivity index (SI) based on serotransferrin and immunoglobulin G, which is often used in clinical practice, distinguished them with an AUC of 0.9091. Similarly, the combination of urinary afamin and complement C3 urine/plasma ratio could distinguish between MN and DN with an AUC of 0.9842, while SI distinguished them with an AUC of 0.8538. Evidently, the candidates identified in this study were superior to the SI method. Thus, the aim was to test these biomarkers for accurate diagnosis and to greatly reduce the burden on patients.

The Expression of Transcription Factors in Fetal Lamb Kidney.

(1) Background: Renal development involves frequent expression and loss of transcription factors, resulting in the activation of genes. Wilms' tumor 1 (WT1), hepatocyte nuclear factor-1-beta (HNF1ß), and paired box genes 2 and 8 (Pax2 and Pax8) play an important role in renal development. With this in vivo study, we examined the period and location of expression of these factors in renal development. (2) Methods: Fetal lamb kidneys (50 days from gestation to term) and adult ewe kidneys were evaluated by hematoxylin and eosin staining. Serial sections were subjected to immunohistochemistry for WT1, HNF1ß, Pax2, and Pax8. (3) Results: Pax2, Pax8, and HNF1ß expression was observed in the ureteric bud and collecting duct epithelial cells. We observed expression of WT1 alone in metanephric mesenchymal cells, glomerular epithelial cells, and interstitial cells in the medullary rays and Pax8 and HNF1ß expression in tubular epithelial cells. WT1 was highly expressed in cells more proximal to the medulla in renal vesicles and in C- and S-shaped bodies. Pax2 was expressed in the middle and peripheral regions, and HNF1ß in cells in the region in the middle of these. (4) Conclusions: WT1 is involved in nephron development. Pax2, Pax8, and HNF1ß are involved in nephron maturation and the formation of peripheral collecting ducts from the Wolffian duct.

Adjuvant heparinization before manipulation of artery reduces early failure in primary arteriovenous fistula for end-stage renal disease patients.

BACKGROUND: Arteriovenous fistula (AVF) is the most preferred vascular access for hemodialysis patients, and early failure of AVF is one of the most avoidable complications of this procedure. We retrospectively evaluated whether adjuvant systemic heparinization just before arterial manipulation could reduce early failure of primary AVF. METHODS: Three hundred and fifty-six patients with end-stage renal failure who underwent primary AVF surgery from April 2009 to September 2020 were enrolled in this study. The patients were divided into two groups based on whether they received adjuvant heparinization or not. Patient backgrounds, frequency of early AVF failure, and bleeding events were compared between the two groups. Multivariate Cox regression analysis identified risk factors for early AVF failure. RESULTS: Early failure of AVF was observed in only 2 of 157 patients (1.2%) in the adjuvant group, and the incident was significantly lower than observed in the non-adjuvant group, i.e., 17 of 199 patients (8.5%) (p = 0.002). Bleeding events were not significantly different between the two groups. Seven of 157 patients (4.5%) in the adjuvant group and 7 of 199 patients (3.5%) in the non-adjuvant group experienced bleeding events (p = 0.785). Female sex, use of steroids, hypoalbuminemia, venous stenosis in pre-surgical evaluation, arterial spasm in the perioperative period, new-onset venous stenosis after AVF anastomosis, technical failure of surgery, no early cannulation after surgery, and non-adjuvant heparinization were related to early AVF failure in the multivariate regression analysis. CONCLUSION: Adjuvant systemic heparinization therapy just before arterial manipulation reduced early failure of primary AVF without increasing bleeding events.

Association among chronic kidney disease, airflow limitation, and mortality in a community-based population: The Yamagata (Takahata) study.

Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) are known risk factors for mortality. In this study, we examined the overlap of CKD and airflow limitation (AFL) that characterises COPD and its effect on 10-year mortality in a community-based population. This study included 1,233 health check-up participants (mean age, 63.7 years; 46.7% men). We defined serum creatinine-based CKD (CKDcr) and serum cystatin C-based CKD (CKDcys) as glomerular filtration rate <60 mL/min/1.73 m2, estimated using serum creatinine or cystatin C, and/or dipstick proteinuria ≥1+. AFL was defined as forced expiratory volume in 1 s to forced vital capacity ratio <70% on spirometry. Compared with subjects without AFL, those with AFL showed a significantly higher prevalence of CKDcys but not of CKDcr. Cox proportional hazard analysis adjusted for confounders showed that the hazard ratio (95% confidence interval) for all-cause mortality was 1.45 (0.77-2.63) in subjects with CKDcys alone, 1.29 (0.60-2.54) in those with AFL alone, and 2.94 (1.33-6.12) in those with both CKDcys and AFL, with subjects without both AFL and CKD as the reference. This study showed that AFL and CKDcys are strongly associated and that their overlap is a significant risk factor for mortality in community-based populations.

A microarray analysis of urinary microRNAs in renal diseases.

BACKGROUND: MicroRNAs (miRNAs), a family of endogenous small non-coding RNAs, are associated with the development of renal diseases. To clarify whether urinary miRNAs (UmiRNAs) can be used for the evaluation of renal disease, we examined the profiles of UmiRNAs in various renal diseases. METHODS: We extracted miRNAs from urine specimens of 5 healthy controls and 71 patients with renal diseases, and we examined the correlation between clinical and histological parameters and the profile of UmiRNAs by microarray analysis. RESULTS: The urinary concentration of miRNAs increased in patients with renal disease compared with healthy controls, and the levels correlated with urinary protein and the degree of glomerular sclerosis. The microarray analysis detected 83-137 distinct UmiRNAs. We observed 80-99 % of the miRNAs in both the healthy controls and the renal disease patients. The majority of UmiRNAs displayed higher signal intensity in renal disease patients than in healthy controls, including 39 miRNAs exhibiting signal intensities 100 times greater than in healthy controls. A different pattern of UmiRNAs was observed in each type of renal disease. A comparison of renal tissue and UmiRNAs revealed that the sample profiles were similar and that their signal intensity was significantly correlated. CONCLUSION: This study demonstrated that UmiRNAs are correlated with renal pathological changes and that the profile of UmiRNAs presented different patterns corresponding to the type of renal disease. These results suggest that UmiRNAs can potentially be used as novel biomarkers for renal diseases.

Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study.

BACKGROUND: Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study. METHODS: This study included 3,445 registered Japanese subjects (mean age 62.6 years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR) ≥30 mg/g in the morning spot urine. RESULTS: Subjects with albuminuria (n = 514, 14.9 %) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n = 2931, 85.1 %). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P < 0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4 %; log-rank test, P < 0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95 % confidence interval [CI] 1.12-2.56 and HR 2.27, 95 % CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (≥300 mg/g). CONCLUSIONS: Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful.

The association between serum uric acid and renal damage in a community-based population: the Takahata study.

BACKGROUND: Hyperuricemia is a risk factor for end-stage renal disease. This study examined the association between serum uric acid and renal damage in a community-based population. METHODS: In this study 3126 subjects without renal insufficiency were recruited at baseline and were followed for one year. The urinary albumin-creatinine ratio (UACR) and ß2-microglobulin-creatinine ratio (UBCR) in morning spot urine samples were used as indices of either glomerular (UACR) or tubular (UBCR) damage. RESULTS: The mean value of serum uric acid (mg/dL) was 5.8 ± 1.3 (SD) in men and 4.5 ± 1.1 in women. In cross-sectional analysis the increased serum uric acid levels were accompanied by higher UACR values in both men and women (P < 0.01). In contrast, UBCR values were reduced when uric acid levels increased in both men and women (P < 0.01). Multivariate analysis revealed that albuminuria (UACR ≥ 30 mg/g) was significantly associated with increased uric acid (≥7 mg/dL for men, ≥6 mg/dL for women). High UBCR (≥300 µg/g) was negatively associated with uric acid in men, but not in women, after adjustment for possible confounders. In longitudinal analysis in 1388 subjects multiple linear regression analysis showed that uric acid at baseline was an independent factor for one-year increase of UACR [coefficient 4.80 (95 % confidence interval 0.40-9.33) (mg/g) per 1 mg/dL increase in uric acid, P = 0.033]. CONCLUSION: This study showed that serum uric acid concentration was positively associated with UACR, suggesting that uric acid may be related to glomerular damage in a community-based population.

Comparison of Mortality between Japanese Peritoneal Dialysis and Hemodialysis Patients: A 5-Year Multicenter Follow-Up Study.

To examine the relationship between dialysis modality and prognosis in Japanese patients, we conducted a prospective multicenter observational study. We recruited 83 background-matched peritoneal dialysis (PD) and 83 hemodialysis (HD) patients (average age, 64.9 years; men, 53.6%; diabetic patients, 22.9%; median duration of dialysis, 48 months in all patients) and followed them for 5 years. During the follow-up period, 27 PD patients (16 cardiovascular and 11 non-cardiovascular deaths) and 27 HD patients died (14 cardiovascular and 13 non-cardiovascular deaths). There were 8 PD patients switched to HD, and 6 PD patients received renal transplantation. Kaplan-Meier analysis revealed that the crude survival rate was not significantly different at the end of 5 years (PD 67.5% versus 67.5%, log-rank P = 0.719). The difference in cardiovascular and non-cardiovascular mortalities between PD and HD was not statistically significant. Multivariate Cox analysis showed that the independent predictors for death were age and serum albumin levels, but not the dialysis modality. This study showed that the overall mortality was not significantly different between PD and HD patients, which suggests that dialysis modality might not be an independent factor for survival in Japanese patients.

Relationship between kidney damage and stroke types in Japanese patients.

BACKGROUND: Kidney disease is a known risk factor for stroke. This study investigated the relationship between kidney damage and stroke types. METHODS: A total of 525 incident stroke patients were registered and followed for 1 year. The prevalence of kidney damage [proteinuria and/or renal insufficiency (estimated glomerular filtration rate<60 ml/min/1.73 m(2))] in incident stroke and its effects on 1-year prognosis were examined. RESULTS: Among all stroke patients, kidney damage and its component (proteinuria and renal insufficiency) were commonly observed (48.2, 25.5, and 33.9%, respectively). The prevalence of ischemic stroke was significantly higher in patients with kidney damage (75.9%) than in those without (58.9%). The most frequent type of stroke among all patients with kidney damage and renal insufficiency only was cardioembolic infarction. In contrast, in patients with proteinuria only and patients without kidney damage, the most frequent type was subcortical and subarachnoid hemorrhage, respectively. Multiple logistic regression analysis showed that kidney damage or the combination of its components were independently associated with 1-year death [odds ratio (OR) 3.04, 95% confidence interval (CI) 1.40­6.59, P = 0.005 for kidney damage, OR 2.82, 95% CI 1.05­7.58, P = 0.040 for proteinuria only, and OR 5.77, 95% CI 2.23­15.0, P<0.001 for both proteinuria and renal insufficiency]. In addition, for 1-year outcomes, there were selective associations between ischemic stroke and proteinuria and between hemorrhagic stroke and renal insufficiency. CONCLUSIONS: This study shows that kidney damage is common in Japanese stroke patients, and proteinuria and renal insufficiency are differentially related to development and prognosis, depending stroke types.

Increases in urinary albumin and beta2-microglobulin are independently associated with blood pressure in the Japanese general population: the Takahata Study.

Essential hypertension is a multifactorial disorder and a risk factor for renal failure and cardiovascular disease. Recently it was hypothesized that subtle acquired renal injury such as renal microvascular and tubulointerstitial damage induces salt-sensitive hypertension. The objective of this study was to examine the relationship between blood pressure and renal abnormalities in the Japanese general population. The participants in this community-based, cross-sectional study were 1,965 subjects over 40 years old, without renal insufficiency and antihypertensive medication. Urine albumin-creatinine ratio (UACR) and beta2-microglobulin-creatinine ratio (UBCR) were measured in single spot urine samples, as markers of renal microvascular and tubulointerstitial damage, respectively. Multiple linear regression analysis showed a significant positive correlation of blood pressure with UACR and UBCR, but not with estimated glomerular filtration rate. In multiple logistic regression analysis, the increases in UACR and UBCR were independently associated with hypertension, after adjustment for possible confounders. Higher levels of UACR (≥ 5.9 mg g(-1)) and UBCR (≥ 145 µg g(-1)) were associated with a significantly higher risk of hypertension, compared with UACR ≤ 5.8 mg g(-1) and UBCR ≤ 84.5 µg g(-1), respectively. Furthermore, there was a positive relationship between urinary sodium excretion and blood pressure in subjects with high UBCR tertile. This study showed that the increases in urinary albumin and beta2-microglobulin were independently associated with blood pressure in a general population. These renal abnormalities may be differentially related to the development of hypertension.

Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study.

BACKGROUND: A cluster of proinflammatory cytokines plays an important role in the development of various renal diseases, and the expression of these cytokines is genetically modified. To examine the association between polymorphisms of proinflammatory cytokine genes and albuminuria, a cross-sectional study was conducted in the general population. METHODS: Single nucleotide polymorphisms (SNPs) in six proinflammatory cytokine genes, including interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, CC chemokine ligand 1 (CCL1) and monocyte chemoattractant protein-1 (MCP-1), were genotyped in 2927 Japanese subjects. Urine albumin-creatinine ratio (UACR) was measured in morning spot urine samples. RESULTS: Albuminuria (UACR ≥ 30 mg/g) was significantly associated with the A/A + A/G genotype at rs2069852 in the IL-6 gene (P = 0.01) and the A/A genotype at rs228269 in the CCL1 gene (P = 0.002). Multivariate analysis with adjustment for traditional risk factors showed that these genotypes independently predicted albuminuria [odds ratio (OR) 1.782, 95% confidence interval (CI) 1.171-2.712, P = 0.007 for the A/A + A/G genotype at rs2069852 in IL-6, and OR 1.432, 95% CI 1.128-1.770, P = 0.003 for the A/A genotype at rs228269 in CCL1]. The prevalence of albuminuria and the UACR were increased along with the increase of risk genotypes. CONCLUSIONS: This study revealed that SNPs in the IL-6 and CCL1 genes were associated with albuminuria, and the combination of these genotypes had an additive effect on the prevalence and severity of albuminuria. This indicates that genetic factors influencing inflammatory responses may affect the development of renal injury in the Japanese general population.

The association between renal tubular damage and rapid renal deterioration in the Japanese population: the Takahata study.

BACKGROUND: Injury to renal tubules plays an important role in the development of various renal diseases; however, the prevalence and significance of renal tubular damage in the general population are unclear. To clarify this point, we conducted a community-based study, using urinary ß(2)-microglobulin as a marker of tubular damage. METHODS: The subjects studied were 3,444 Japanese over the age of 40 years. The urinary ß(2)-microglobulin-creatinine ratio (UBCR) was assessed in morning spot urine samples. RESULTS: In this population, the distribution of the UBCR among these subjects was skewed towards higher values and a high UBCR (≥300 µg/g) was identified in 438 (12.7%) subjects. However, overlap with macroalbuminuria and renal insufficiency [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2)] was observed in only 25 (5.7%) and 58 (13.2%) of these subjects, respectively. Multivariate analysis indicated that a high UBCR was positively associated with aging, hypertension, macroalbuminuria and increased urinary sodium excretion. A 5-year longitudinal analysis in 899 subjects indicated a greater decline in eGFR in parallel with the increase in baseline UBCR. After adjustment for possible confounders, a high UBCR was an independent risk factor for rapid decline in eGFR [<-10 mL/min/1.73 m(2); odds ratio 1.79 (95% confidence interval 1.07-2.99), P = 0.026]. CONCLUSION: This study showed that renal tubular damage was common and was an independent risk factor for renal deterioration in the Japanese population. More attention should be paid to occult renal tubular damage in order to prevent end-stage renal disease.

New technique for visualizing cerebral vessels in MR angiographic images using three-dimensional discrete wavelet transform.

Visualization techniques for magnetic resonance (MR) angiographic images are generally based on the projection ray concept; for example, maximum intensity projection (MIP) and volume rendering (VR). A new technique based on a different concept from projection rays is explored in this study: three-dimensional (3-D) discrete wavelet transforms are used for visualizing cerebral vessels in the MR angiographic image. This technique successfully visualizes cerebral vessels and represents the spatial relationship between the cerebral vessels, as in the case of VR. The proposed technique is, thus, indicated to be promising for visualizing cerebral vessels in 3-D MR angiographic images.