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Background Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. Methods Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. Results Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6–53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. Conclusions Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Serum uric acid (SUA) levels have a linear relationship with the estimated glomerular filtration rate (eGFR). It is unclear whether further changes, subsequent to normal level of SUA can attenuate eGFR decline in a healthy population, so we aimed to determine the normal level of SUA that can contribute to preventing kidney dysfunction. In this retrospective cohort study from Japan, annual health checkup data from 2009 to 2014 was collected. After propensity score matching (1:1), data from 2,634 individuals with basal SUA ≤7.0 mg/dL (normal; mean age, 39 y; mean eGFR, 80.8 mL/min/1.73 m2) and 1,642 individuals with basal SUA >7.0 mg/dL (elevated; mean age, 42 y; mean eGFR, 75.0 mL/min/1.73 m2) were collected to determine the relationship between followed-up SUA level and the rate of change in eGFR. In individuals with normal level SUA at baseline, the elevation of SUA (>7.0 mg/dL) accelerated eGFR decline compared to those with normal SUA levels at 5-year follow-up (−4.1 ± 9.6% vs −9.9 ± 9.0%, p < .0001). Digression of SUA level (≤7.0 mg/dL) reduced eGFR decline compared with persistent SUA level over 7.0 mg/dL (−1.5 ± 11.5% vs −7.0 ± 10.1, p < .0001). In multiple linear regression analysis, there was strong association between the rate of change in SUA and eGFR in individuals with basal SUA ≤7.0 and >7.0 mg/dL (standardized coefficient; −0.3348, p < .001 and −.2523, p < .001, respectively). Subsequent to normal level of SUA (under 7.0 mg/dL) may contribute to a decrease in eGFR decline in apparently healthy men.

Uremic cardiomyopathy, characterized by hypertension, cardiac hypertrophy, and fibrosis, is a complication of chronic kidney disease (CKD). Urea transporter (UT) inhibition increases the excretion of water and urea, but the effect on uremic cardiomyopathy has not been studied. We tested UT inhibition by dimethylthiourea (DMTU) in 5/6 nephrectomy mice. This treatment suppressed CKD-induced hypertension and cardiac hypertrophy. In CKD mice, cardiac fibrosis was associated with upregulation of UT and vimentin abundance. Inhibition of UT suppressed vimentin amount. Left ventricular mass index in DMTU-treated CKD was less compared with non-treated CKD mice as measured by echocardiography. Nephrectomy was performed in UT-A1/A3 knockout (UT-KO) to further confirm our finding. UT-A1/A3 deletion attenuates the CKD-induced increase in cardiac fibrosis and hypertension. The amount of α-smooth muscle actin and tgf-β were significantly less in UT-KO with CKD than WT/CKD mice. To study the possibility that UT inhibition could benefit heart, we measured the mRNA of renin and angiotensin-converting enzyme (ACE), and found both were sharply increased in CKD heart; DMTU treatment and UT-KO significantly abolished these increases. Conclusion: Inhibition of UT reduced hypertension, cardiac fibrosis, and improved heart function. These changes are accompanied by inhibition of renin and ACE.

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-β, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-β, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson’s trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

Obesity is a risk factor for the development of chronic kidney disease (CKD). However, it remains to be fully examined whether fatness is more useful in predicting incident CKD. We aimed this study to determine the association of body fat, body mass index and waist circumference (WC) with subsequent changes in estimated glomerular filtration rate (eGFR) and incident CKD in young- to middle-aged working men. We analyzed data from annual health check-up in male workers aged from 20 to 60 years with basal eGFR of 60–90 mL/min/1.73 m2. Cut-off values of parameters and odds ratio (OR) for the incident CKD were calculated by receiver operator characteristics analysis andχ2 test, respectively. We also tested trends of changes in eGFR according to changes in WC in each age decade. There were 8,015 men participants. During the 5-year follow-up, 11.0% of the participants (N = 878) had developed to incident CKD. When basal WC was greater than 80.0 cm, which was decided by Youden’s Index, there was a significantly higher risk of incident CKD [OR 1.57 (95% confident interval 1.35–1.84)]. Changes in WC over 5 years were significantly related to eGFR decline in young men ( 80.0 cm is a risk factor for incident CKD and strongly associated with a decline in eGFR in the young- to middle-aged working healthy men.

The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1–2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase. Electronic supplementary material The online version of this article (doi:10.1007/s13277-015-3928-7) contains supplementary material, which is available to authorized users.

It remains to be fully clarified whether there is a relationship between uncontrolled dyslipidemia and decline in estimated glomerular filtration rate (eGFR) in the general population. Therefore, this study’s aim was to test the association of dyslipidemia with changes in eGFR in apparently healthy working men. We retrospectively examined the annual medical check-up list of 14,510 male workers aged 20–60 years with eGFR ≥ 60 mL/min/1.73 m2 at baseline, and then evaluated the association of the changes in the check-up parameters with a decline in eGFR during the 5-year observation period. Mean age and eGFR were 38.5 years and 82.3 mL/min/1.73 m2 at baseline, respectively. Evaluated low-density lipoprotein cholesterol (LDL-C) (≥140 mg/dL) was a strong indicator of CKD development in participants (basal eGFR 60–90 mL/min/1.73 m2) without hypertension [odds ratio (95% confidence interval): 1.46 (1.12–1.90)] or diabetes mellitus (DM) [1.49 (1.23–1.82)]. When LDL-C normalized under 140 mg/dL during follow-up, the decline in eGFR was smaller in non-hypertensive participants [−5.9 (−14.4 to −0.9) vs −13.4 (−18.4 to −4.5) mL/min/1.73 m2, p

Background: The polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) family of enzymes regulates the initial steps of mucin-type O-glycosylation. N-acetylgalactosaminyltransferases might show novel patterns of GalNAc-T glycosylation on tumour-derived proteins, which could influence cancer biology, but its mechanisms are unclear. We investigated the association of GalNAc-T3 and -T6 expressions with clinicopathological features and prognoses of patients with renal cell carcinomas (RCCs). Methods: Expressions of GalNAc-T3/6 and cell-adhesion molecules were analysed immunohistochemically in 254 paraffin-embedded tumour samples of patients with RCC. Results: Of 138 GalNAc-T3+ cases, 46 revealed significant co-expression with GalNAc-T6. N-acetylgalactosaminyltransferases-3+ expression showed a close relationship to poor clinical performance and large tumour size, or pathologically high Fuhrman's grading, and presence of vascular invasion and necrosis. The GalNAc-T3-positivity potentially suppressed adhesive effects with a significantly low β-catenin expression. Univariate and multivariate analyses showed the GalNAc-T3+ group, but not the GalNAc-T6+ group, to have significantly worse survival rates. Conclusion: N-acetylgalactosaminyltransferases-3 expression independently predicts high-grade tumour and poor prognosis in patients with RCC, and may offer a therapeutic target against RCC.

Fibrosis occurs in systemic tissues other than the brain and finally induces dysfunction of the fibrotic organ. Kidney fibrosis is related to scarring after acute kidney injury and the progression of chronic kidney disease. Kidney function decreases with the progression of kidney fibrosis. As fibrotic tissue cannot return to its original status, advanced kidney fibrosis requires the administration of dialysis or kidney transplantation. Thus, elucidation the mechanism of kidney fibrosis is an important research theme. The proliferation and activation of (myo) fibroblasts and the excessive production of an extracellular matrix are common mechanisms in fibrosis in many organs, but it seems that kidney fibrosis has specific pathways. Tubular epithelial, mesangial cells, and erythropoietin producing cells, which exist only in the kidney, participate in forming kidney fibrosis. This review highlights an understanding of the cells and their underlying mechanisms, which are specific to kidney fibrosis process: transforming growth factor-β (TGF-β), epithelial-mesenchymal transition, wingless/int-1 (WNT) signaling, renal anemia, and uremia. Finally, we describe potential therapies that focus on the mechanisms of kidney fibrosis: anti-TGF-β antibody and mammalian target of rapamycin (mTOR).

WNT signaling mediates various physiological and pathological processes. We previously showed that WNT10A is a novel angio/stromagenic factor involved in such processes as tumor growth, wound healing and tissue fibrosis. In this study, we investigated the role of WNT10A in promoting the fibrosis that is central to the pathology of acute interstitial nephritis (AIN). We initially asked whether there is an association between kidney function (estimated glomerular filtration rate; eGFR) and WNT10A expression using kidney biopsies from 20 patients with AIN. Interestingly, patients with WNT10A expression had significantly lower eGFR than WNT10A-negative patients. However, changes in kidney function were not related to the level of expression of other WNT family members. Furthermore, there was positive correlation between WNT10A and α-SMA expression. We next investigated the involvement of WNT10A in kidney fibrosis processes using COS1 cells, a kidney fibroblast cell line. WNT10A overexpression increased the level of expression of fibronectin and peroxiredoxin 5. Furthermore, WNT10A overexpression renders cells resistant to apoptosis induced by hydrogen peroxide and high glucose. Collectively, WNT10A may induce kidney fibrosis and associate with kidney dysfunction in AIN.