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Intravenous bisphosphonate therapy is used to prevent fractures in the management of bone metastasis. However, it may induce renal damage. We herein report an 81-year-old woman with Fanconi syndrome and osteomalacia who had been diagnosed with metastatic breast cancer and received treatment with zolendronate for over 5 years. Her bone markers normalized after switching zolendronate to denosmab and starting vitamin D and mineral supplementation. This case shows that chronic renal damage induced by zolendronate can cause osteomalacia. In patients with intravenous zolendronate therapy, close monitoring of renal and bone markers is needed, even under long-term therapy.

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Aims Consensus‐derived guidelines recommend renal stenting for patients with atherosclerotic renal artery disease (ARAD) and heart failure (HF). The aim of this prospective multi‐centre observational study was to verify our hypothesis that changes in E/e′, an echocardiographic correlate of left ventricular (LV) filling pressure, following renal stenting may differ between ARAD patients with and without HF. Methods and results This study enrolled de novo ARAD patients undergoing renal stenting at 14 institutions. The primary endpoint was the difference in E/e′ change between ARAD patients with and without HF. Clinical and echocardiographic data were prospectively collected at baseline, the day following renal stenting, and 1 month and 6 months afterwards. ARAD patients with HF were defined as patients with New York Heart Association (NYHA) Class 2 and more, or a history of HF hospitalization. A total of 76 patients were included, and 39% were ARAD patients with HF. ARAD patients with HF had significantly lower estimated glomerular filtration rate (P = 0.028) and higher NYHA functional class (P

Background Pleuroperitoneal leak is an uncommon but significant complication of peritoneal dialysis. Although the exact pathogenesis of pleuroperitoneal communication remains unclear, the pressure gradient between the thorax and abdominal cavity has been thought to play a major role. Case presentation A 48-year-old man with diabetes mellitus and hypertension who had been treated with continuous ambulatory peritoneal dialysis (1.5 L dwells four times a day) for 3 months was admitted because of massive right-sided pleural effusion. He underwent video-assisted thoracoscopic surgery for blebs on the diaphragm. Six weeks after diaphragmatic repair, he resumed peritoneal dialysis (1.5 L dwells four times a day) with once-a-week hemodialysis. Thereafter, pleural effusion was not significant on a chest radiogram. Six months after surgery, his dwell volume increased from 1500 to 2000 ml, and significant right-sided pleural effusion also developed. Conclusion Pleuroperitoneal leak caused by blebs can recur even after surgical treatment, and reducing the dwell volume may be effective for patients with pleuroperitoneal communication.

A 27-year-old man who developed heavy proteinuria with hematuria and acute kidney injury 2 weeks after a fever was referred to our hospital. Because he had low complements without autoantibodies, we clinically diagnosed him with infection-related glomerulonephritis. The proliferation of mesangial cells and endothelial cells with glomerular deposits of immunoglobulin A and complement 3 was found. Deposition of glomerular nephritis-associated plasmin receptor, a marker of infection-related glomerulonephritis, was also found. In addition, the distribution of nephritis-associated plasmin receptor deposition almost perfectly matched the plasmin activity-positive region. Over 3 months later, his symptoms were resolved, although moderate proteinuria and active urine sediment were persistent. He underwent a second renal biopsy, and the histological findings revealed that he had immunoglobulin A nephropathy. Therefore, we diagnosed him with infection-related glomerulonephritis superimposed on immunoglobulin A nephropathy at the first renal biopsy. The glomerular deposition of nephritis-associated plasmin receptor is a useful marker and may cause worsening urinalysis findings after bacterial infection in cases of chronic glomerulonephritis.

A 31-year-old woman with retinitis pigmentosa who had been diagnosed with renal failure due to nephrosclerosis related to hypertensive disorders of pregnancy was referred to our hospital to prepare for renal replacement therapy. Ultrasonography and MRI of the kidneys revealed multiple corticomedullary cysts. A renal biopsy showed that the tubules were tortuous and atrophic with segmented tubular basement membrane thickening. These findings indicated that she had Senior-Løken syndrome. A molecular genetic analysis was performed, and homozygous deletion of the gene encoding nephronophthisis-1 was found. Thus, the clinical diagnosis of Senior-Løken syndrome was genetically confirmed. Because her renal function was gradually worsening, she was scheduled to undergo living donor kidney transplantation. Senior-Løken syndrome, which is recognised as a very rare paediatric inherited disease characterised by nephronophthisis and eye problems, can cause adult-onset end-stage renal failure.

The patient was a 75-year-old man who was admitted to our hospital because of fatigue, leg edema and heavy proteinuria. Due to his cloudy urine and elevated triglyceride level in his urine, he was diagnosed with chyluria. Tests for infectious disease were negative, and lymphoscintigraphy showed no blockage in the lymphatic system. He was therefore diagnosed with idiopathic chyluria. Hypothyroidism was also found and his cloudy urine and heavy proteinuria disappeared without dietary modifications after starting levothyroxine treatment for hypothyroidism. The patient is currently being followed up in an outpatient clinic and is doing well, with no recurrence of chyluria.

Background O-linked β- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes. Results Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment. Conclusions O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.

Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

Hypoxia causes proximal tubular cell damage in diabetes, even though proximal tubular cells have an adaptive system to combat hypoxia involving induction of hypoxia factor-1 (HIF-1) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). Here, we examined the interference effect of altered glucose and lipid metabolism on the hypoxia responses in proximal tubular cells. In culture, hypoxia alone induced HIF-1 and inhibited mTORC1, preventing death in proximal tubular cells. However, hypoxia with high glucose and palmitate increased mTORC1 activity and promoted apoptosis in proximal tubular cells, which was inhibited by pharmacological and genetic inactivation of mTORC1. Since inhibition of all mTORC1's physiological functions regulated by growth factors including insulin causes various adverse effects, we screened for a microRNA that can inhibit only pro-apoptotic effects of mTORC1 to discover a safe therapeutic target. This screen found microRNA-148b-3p was able to specifically inhibit mTORC1-dependent apoptosis in hypoxic proximal tubular cells exposed to high glucose and palmitate, without affecting insulin-dependent mTORC1 activation. Furthermore, tumor necrosis factor receptor (TNFR) 2 was the target of microRNA-148b-3p and its suppression inhibited apoptosis. Finally, enhanced apoptosis with TNFR2 overexpression was found in hypoxic and mTORC1-activated proximal tubular cells in diabetic rats. Thus, diabetes activated mTORC1 even in hypoxic proximal tubular cells, leading to apoptosis by reducing microRNA-148b-3p expression. Modulating this pathogenic pathway may be a novel therapy for proximal tubular cell damage in diabetes.

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes., Highlights • Fasting-induced hypothalamic AMPK activation inhibited first-phase GSIS by stimulating the α-adrenergic nerve. • The brain-pancreas neural axis was involved in β cell dysfunction and glucose intolerance in diabetes. • Pancreatic denervation improved first-phase GSIS, glucose tolerance and β cell survival in type 2 diabetic animals. Glucose-stimulated insulin secretion (GSIS) from pancreatic β cells is biphasic. Furthermore, first-phase GSIS is inhibited in type 2 diabetes. This study revealed that fasting reduced first-phase GSIS by signaling via the brain-pancreatic β cell neural axis, which is essential for maintaining glucose supply to the brain at re-feeding after fasting. Abnormal excitability of this neural axis was also associated with impaired first-phase GSIS in type 2 diabetes. Surgical pancreatic denervation improved diabetes in an animal study. The present data reveal that diabetic β cells exist under conditions that mimic starvation and provide a therapeutic potency of pancreatic denervation against diabetes., Graphical Abstract Image 2

Anticoagulants have recently been recognised as a cause of acute kidney injury (AKI). We describe the case of a 75-year-old man with IgA vasculitis and atrial fibrillation treated with rivaroxaban, who presented with macroscopic haematuria and an acute decline in renal function. Two months before referral, he noted palpable purpuric lesions and was diagnosed with IgA vasculitis based on skin biopsy findings; the skin lesion disappeared following treatment with a steroid external preparation. Renal biopsy revealed glomerular haemorrhage and red blood cell casts. Although rivaroxaban was withdrawn, his kidney function worsened and he was started on haemodialysis. His renal function did not recover. To the best of our knowledge, this is the first case of direct oral anticoagulant (DOAC)-related AKI in systemic vasculitis. During DOAC therapy, close monitoring of a patient’s urinalysis results and their renal function may be required for patients with systemic vasculitis to avoid AKI.

Dipeptidyl peptidase (DPP)-4 inhibitors, a new class of antidiabetic agent, have recently been suggested to exert pleiotropic effects beyond glucose lowering. Renal prognosis in patients with diabetic nephropathy depends on the severity of tubulointerstitial injury induced by massive proteinuria. We thus examined the renoprotective effect of DPP-4 inhibitors on inflammation in cultured mouse proximal tubular cells stimulated with free fatty acid (FFA)-bound albumin. Linagliptin and higher concentrations of sitagliptin, vildagliptin, and alogliptin all inhibited FFA-bound albumin-induced increases in mRNA expression of MCP-1 in cultured mouse proximal tubular cells. Furthermore, linagliptin significantly inhibited tubulointerstitial injury induced by peritoneal injection of FFA-bound albumin, such as inflammation, fibrosis, and apoptosis, in mice without altering systemic characteristics including body weight, fasting blood glucose, and food intake. These results indicate that DPP-4 inhibitors pleiotropically exert a direct renoprotective effect, and may serve as an additional therapeutic strategy to protect proximal tubular cells against proteinuria in patients with diabetic nephropathy.

Free fatty acid-bound albumin (FFA-albumin)-related oxidative stress is involved in the pathogenesis of proximal tubular cell (PTC) damage and subsequent renal dysfunction in patients with refractory proteinuria. Nicotinamide adenine dinucleotide (NAD) metabolism has recently been focused on as a novel therapeutic target for several modern diseases, including diabetes. This study was designed to identify a novel molecule in NAD metabolism to protect PTCs from lipotoxicity-related oxidative stress. Among 19 candidate enzymes involved in mammalian NAD metabolism, the mRNA expression level of nicotinamide n-methyltransferase (NNMT) was significantly increased in both the kidneys of FFA-albumin-overloaded mice and cultured PTCs stimulated with palmitate-albumin. Knockdown of NNMT exacerbated palmitate-albumin-induced cell death in cultured PTCs, whereas overexpression of NNMT inhibited it. Intracellular concentration of 1-Methylnicotinamide (1-MNA), a metabolite of NNMT, increased and decreased in cultured NNMT-overexpressing and -knockdown PTCs, respectively. Treatment with 1-MNA inhibited palmitate-albumin-induced mitochondrial reactive oxygen species generation and cell death in cultured PTCs. Furthermore, oral administration of 1-MNA ameliorated oxidative stress, apoptosis, necrosis, inflammation, and fibrosis in the kidneys of FFA-albumin-overloaded mice. In conclusion, NNMT-derived 1-MNA can reduce lipotoxicity-mediated oxidative stress and cell damage in PTCs. Supplementation of 1-MNA may have potential as a new therapy in patients with refractory proteinuria.

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in patients and rats with diabetes and massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)–induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed, podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from patients and rats with diabetes and massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss, leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of a new therapeutic strategy for advanced diabetic nephropathy.

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes.

We report a case involving a 43-year-old Japanese woman with steroid-resistant focal segmental glomerular sclerosis (FSGS) and severe renal dysfunction, which was ameliorated by low-density lipoprotein apheresis (LDL-A). She had been treated with steroid therapy, but had experienced anuria for over 10 weeks and required hemodialysis. She was then treated with LDL-A, which resulted in improved urinary protein excretion and renal function. Her renal function recovered after 97 days of hemodialysis therapy. This case suggests that LDL-A may represent an effective rescue treatment in patients with FSGS and long-term anuria.

Worldwide, the number of patients with diabetes is increasing. Adults with diabetes have a two- to threefold increased risk of heart attack and stroke, and diabetic nephropathy is a leading cause of end-stage renal failure. Salt sensitivity of blood pressure is reported to be elevated in patients with diabetes. Hyperinsulinemia, hyperglycemia, and an activated sympathetic nervous system play key roles in the genesis of salt-sensitive blood pressure in individuals who are obese and/or have type 2 diabetes. In this review, I summarize previous research performed to improve our understanding of the relationship between salt and hypertension in diabetic patients.

Glycated albumin (GA) is considered a more reliable marker than glycated hemoglobin (HbA1c) for monitoring glycemic control, particularly in diabetic hemodialysis patients. We investigated the associations of GA, HbA1c, and random serum glucose levels with survival, and evaluated possible targets for improving survival in diabetic hemodialysis patients. In this prospective, longitudinal, observational study, we enrolled 90 diabetic hemodialysis patients across six dialysis centers in Japan. The median duration of follow-up was 36.0 months (mean follow-up, 29.8 months; range, 3-36 months). There were 11 deaths during the observation period. GA was a significant predictor for mortality (hazard ratio, 1.143 per 1% increase in GA; 95% confidence interval, 1.011-1.292; P = 0.033), whereas HbA1c and random glucose levels were not predictors for mortality. Receiver operating characteristics curve analysis showed that the cutoff value of GA for predicting the risk of mortality was 25%. In the Kaplan-Meier analysis, the cumulative survival rate was significantly greater in patients with GA ≤ 25% than in patients with GA >25%. GA predicted the risk of all-cause and cardiovascular mortality in diabetic hemodialysis patients. Our results suggest that GA ≤ 25% is an appropriate target for improving survival in diabetic hemodialysis patients.

Aims/Introduction In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching. Materials and Methods We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates

OBJECTIVE To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid–binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis. RESEARCH DESIGN AND METHODS Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR RESULTS During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13–3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes. CONCLUSIONS Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.

A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.

Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissue-specific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.

Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG-CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals.

Autophagy meaning 'self-eating' in Greek, is a large-scale mechanism of intracellular degradation that seeks to maintain homeostasis in cells of all eukaryotes, from yeast to humans. Over the past several decades, autophagy research has actively proceeded both at home and abroad. As a result, studies have reported the physiological role of autophagy in different organs of mammals and of the role that impairment of its activation plays in the development of age-related diseases, abnormal glucose-lipid metabolism, and neurodegenerative disorders. Currently, new therapies targeting the regulation of activation of autophagy are anticipated, and research is continuing. In recent years, the role of autophagy in the kidneys has gradually been elucidated, and reports are indicating an association between autophagy and the development of various kidney diseases. This paper reviews the molecular mechanisms regulating autophagy and discusses new findings from autophagy research on the kidney and issues that have yet to be resolved.

Aim: Diabetic nephropathy is a serious complication in patients with type 2 diabetes. The aim of this study was to explore the factors associated with the progression of this complication in elderly patients with type 2 diabetes. Methods: This retrospective study of a subgroup of patients registered with the Japanese Elderly Diabetes Intervention Trial included 621 Japanese patients with type 2 diabetes mellitus (age ≥65 years, 346 with normoalbuminuria, 190 with microalbuminuria and 85 with overt proteinuria). Multivariate Cox proportional hazard regression model with a backward stepwise procedure was applied to select factors with significant effects on worsening of nephropathy stage and the doubling of serum creatinine. Results: During the follow up (median 52 months), 21% of patients progressed from normoalbuminuria and microalbuminuria to a worse nephropathy stage. Aging, female sex and high-density lipoprotein cholesterol were identified as independent and significant factors that worsen nephropathy stage. Also, 6.1% of patients showed doubling of serum creatinine during follow up. A positive history of cardiovascular disease, hyperuricemia and conventional therapy were identified as significant factors involved in the doubling of serum creatinine. The cumulative incidence of the doubling of serum creatinine was significantly lower in the intensive therapy group than the conventional therapy group (P = 0.016), although that of progression of nephropathy stage was similar in the two groups. Conclusions: We identified several factors associated with the progression of diabetic nephropathy in elderly patients with type 2 diabetes. The results suggest that multiple risk factor intervention seems important in preventing deterioration of renal dysfunction. Geriatr Gerontol Int 2012; 12 (Suppl. 1): 127–133.