Proximal Tubule Cell Hypothesis for Cardiorenal Syndrome in Diabetes

Incidence of cardiovascular disease (CVD) is remarkably high among patients with chronic kidney disease (CKD), even in the early microalbuminuric stages with normal glomerular filtration rates. Proximal tubule cells (PTCs) mediate metabolism and urinary excretion of vasculotoxic substances via apical and basolateral receptors and transporters. These cells also retrieve vasculoprotective substances from circulation or synthesize them for release into the circulation. PTCs are also involved in the uptake of sodium and phosphate, which are critical for hemodynamic regulation and maintaining the mineral balance, respectively. Dysregulation of PTC functions in CKD is likely to be associated with the development of CVD and is linked to the progression to end-stage renal disease. In particular, PTC dysfunction occurs early in diabetic nephropathy, a leading cause of CKD. It is therefore important to elucidate the mechanisms of PTC dysfunction to develop therapeutic strategies for treating cardiorenal syndrome in diabetes

PROTECTIVE EFFECTS OF ISOLATED SOY PROTEINFEEDING ON RENAL TUBULES IN THE EARLY STAGEOF DIABETIC NEPHROPATHY.

Progression of diabetic nephropathy (DN) is strongly related to the severity of tubulointerstitial damage. Isolated soy protein (ISP) feeding has shown beneficial effects in animal DN models. However, the mechanisms underlying the renal effects of ISP feeding in early disease stages have not been clarified. In this study, 6-week-old obese Zucker (fa/fa) rats and lean control rats were fed 20% casein or 20% ISP diet for either 2 or 24 weeks. In casein-fed fa/fa rats, the levels of urinary markers of tubular injury started to increase 2 weeks after the commencement of experimental feeding, and the increase continued over time. The levels of these markers were significantly lower in ISP-fed fa/fa rats than in casein-fed fa/fa rats. Renal MCP-1, IL-1β, and TNF- α mRNA levels and urinary MCP-1 levels were also lower in ISP-fed fa/fa rats than in casein-fed fa/fa rats after 2 weeks. IL- 1β-induced upregulation of MCP-1 expression in cultured tubular NRK-52E cells was suppressed by ISP peptides produced by digestion with pepsin and trypsin, but not by casein peptides. In conclusion, casein feeding induces tubular damage at the early stage of DN, whereas ISP feeding alleviates it. The renoprotective effects of ISP may be associated with the downregulation of renal inflammatory cytokines

Pathogenic variants of Alport syndrome and monogenic diabetes identified by exome sequencing in a family

Abstract We present a family of two female Alport syndrome patients with a family history of impaired glucose tolerance. Whole exome sequencing identified a novel heterozygous variant of COL4A5 NM_033380.3: c.2636 C > A (p.S879*) and a rare variant of GCK NM_001354800.1: c.1135 G > A (p.A379T) as the causes of Alport syndrome and monogenic diabetes, respectively. Two independent pathogenic variants affected the clinical phenotypes. Clinical next-generation sequencing is helpful for identifying the causes of patients’ manifestations

Beneficial effects of rice endosperm protein intake in Japanese men with risk factors for metabolic syndrome: a randomized, crossover clinical trial

BACKGROUND: Rice protein is proved to have hypocholesterolemic and anti-atherosclerotic effects, and a few experimental studies showed its renoprotective effects, using animal diabetic models. However, no clinical studies have investigated its benefits for human health. We aimed to clarify how the intake of rice endosperm protein affects markers correlating to lipid dysfunction in human. METHODS: We recruited 18 male volunteers, 26–64 years of age, with risk factors for metabolic syndrome and allocated randomly into two groups. Half of them were administered test food containing rice endosperm protein and other half were administered control food containing sodium caseinate for 4 weeks. The dose of supplemental protein was 10 g/day. After medical examinations, the study foods were switched and the intervention was continued for another 4 weeks. Lipid metabolism markers were evaluated as primary outcome measures. Cross-over analysis was performed for 18 subjects using physical and clinical values measured before and after each intervention period. RESULTS: The serum high-density lipoprotein cholesterol (HDL-C) level was increased at 0.08 mmol/L [interquartile range (IQR) from −0.05 to 0.19 mmol/L] during the period when rice endosperm protein was administered (the rice endosperm protein period), whereas it was decreased at −0.04 mmol/L [IQR from −0.13 to 0.05 mmol/L] during the period when casein was administered (the casein period). Treatment effect was significant with P = 0.047. Changes in total cholesterol, low-density lipoprotein cholesterol and triglycerides were not different between treatments. Among the secondary outcome measures, decrease in serum uric acid (UA) during the rice endosperm protein period [−24 μmol/L (IQR from −39 to −6 μmol/L)] was greater than that during the casein period [0 (IQR from −6 to 13 μmol/L)] with a significant treatment effect (P = 0.030). CONCLUSION: Supplemental intake of rice endosperm protein may elevate serum HDL-C level and lower serum UA level in male subjects with risk factors for metabolic syndrome. TRIAL REGISTRATION: Clinical Trials Registry: UMIN000008923

Successful treatment of gamma 1 heavy chain deposition disease with bortezomib and dexamethasone

Heavy chain deposition disease (HCDD) is a rare complication of plasma cell dyscrasias, characterized by nonamyloid tissue deposits of incomplete monoclonal heavy chains in renal tissues. We report the case of a 78-year-old female with HCDD who was successfully treated with bortezomib and dexamethasone (BD); histopathological improvements were confirmed by kidney biopsy after 2 years of chemotherapy. She presented with renal insufficiency, proteinuria, hematuria, hypogammaglobulinemia, and hypocomplementemia. Renal biopsy showed diffuse global nodular glomerulopathy with the deposition of IgG1 and C3 in the glomeruli and on the tubular basement membrane. Kappa and lambda light chains were not detected. Staining for the constant regions of the gamma heavy chain revealed the absence of the CH1 domain. These findings are consistent with those of gamma 1 HCDD. Results of liquid chromatography-tandem mass spectrometric analysis were consistent with the immunohistochemical results. Two years after weekly BD therapy, normalization of the kappa/lambda ratio and reduction of urinary protein excretion were achieved. A follow-up biopsy showed remarkable diminution of nodular lesions of glomeruli and deposits of IgG and C3. Keywords: Heavy chain deposition disease, Bortezomib, Liquid chromatography-tandem mass spectrometr

Cryofibrinogen-associated glomerulonephritis diagnosed by mass spectrometry and immunoelectron microscopy

A 60-year-old male presented with accelerated hypertension, renal insufficiency, proteinuria, and hematuria. Percutaneous kidney biopsy revealed membranoproliferative glomerulonephritis (MPGN) without any immunoglobulin and complement deposition. On performing electron microscopy, deposits with a tubular, organized structure and approximately 60 nm in diameter were detected in the glomerular subendothelial spaces and mesangial areas. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated the significantly increased deposition of fibrinogen and fibronectin in glomeruli. Immunohistochemistry and immunoelectron microscopy demonstrated that the deposits were composed of fibrinogen. Here we report a case of cryofibrinogen -associated GN in which LC-MS/MS and immunoelectron microscopy were useful for diagnosis. When MPGN with organized deposits without the deposition of immunoglobulins and complements is diagnosed, we considered the cryofibrinogen-associated GN in one of the differential diagnosis, and even skin symptoms cannot be detected. Keywords: Cryofibrinogen-related kidney disease, Liquid chromatography-tandem mass spectrometry, Immunoelectron microscop