Search

Epidemiological studies suggest the existence of a genetic susceptibility to the development of diabetic nephropathy. The apolipoprotein E gene (APOE), which is well known to have a polymorphism (ε2, ε3, and ε4) in exon 4, has been considered a candidate gene susceptible to this complication, because this variation was reportedly involved in lipid metabolism. To date, numerous case-control studies in patients with type 1 and type 2 diabetes have been reported. Although the ε2 allele of the APOE polymorphism tends to be associated with an increased risk for diabetic nephropathy, the results of these case-control comparisons are conflicting. However, a family-based study (the transmission/disequilibrium test) provided strong evidence that the ε2 allele was preferentially transmitted to patients with diabetic nephropathy but not transmitted to those without it. Several prospective follow-up studies also reported an increased risk for progression to higher stages of diabetic nephropathy for the ε2 carriers. Furthermore, two recent meta-analyses reported that the ε2 allele is associated with a risk for diabetic nephropathy. Based on the results of these studies, the ε2 allele of the APOE polymorphism seems to be a genetic risk factor for diabetic nephropathy susceptibility. However, this genetic effect only accounts for a small proportion of this complication, and the mechanism remains unclear at present. Further studies are needed to explore whether genotyping of the APOE polymorphism in patients with diabetes is of value for better management in clinical practice.

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. An early clinical sign of this complication is an increase of urinary albumin excretion, called microalbuminuria, which is not only a predictor of the progression of nephropathy, but also an independent risk factor for cardiovascular disease. Although microalbuminuria is clinically important to assess the prognosis of diabetic patients, it may be insufficient as an early and specific biomarker of diabetic nephropathy because of a large day-to-day variation and lack of a good correlation of microalbuminuria with renal dysfunction and pathohistological changes. Thus, more sensitive and specific biomarkers are needed to improve the diagnostic capability of identifying patients at high risk. The factors involved in renal tubulo-interstitial damage, the production and degradation of extracellular matrix, microinflammation, etc., are investigated as candidate molecules. Despite numerous efforts so far, the assessment of these biomarkers is still a subject of ongoing investigations. Recently, a variety of omics and quantitative techniques in systems biology are rapidly emerging in the field of biomarker discovery, including proteomics, transcriptomics, and metabolomics, and they have been applied to search for novel putative biomarkers of diabetic nephropathy. Novel biomarkers or their combination with microalbuminuria provide a better diagnostic accuracy than microalbuminuria alone, and may be useful for establishing personal medicine. Furthermore, the identification of novel biomarkers may provide insight into the mechanisms underlying diabetic nephropathy.

The number of elderly diabetic patients who require chronic hemodialysis is progressively increasing in Japan. Thus, halting the progression of diabetic nephropathy in elderly diabetic patients is a clinically important issue. However, there is little information or evidence of this complication. Understanding the change of the kidney function with aging, the clinical characteristics and factors associated with the progression of diabetic nephropathy in this population should be useful for establishing effective therapeutic strategies to prevent this life threatening complication.

Objective: Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking., Research Design and Methods: A total of 211 T2DM patients with albuminuria≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated., Results: During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12-0.76])., Conclusions: Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.

Aging is a dominant risk factor for end-stage renal disease. We analyzed the mechanism involved in age-related exacerbation of proteinuria-induced proximal tubular cell (PTC) damage by focusing on endoplasmic reticulum-related unfolded protein response (UPR). After equal-degree induction of proteinuria in 24-month-old (aged) and 3-month-old (young) mice by intraperitoneal free fatty acid-bound albumin overload, tubulointerstitial lesions were more severe in aged than in young mice. In aged PTCs, proteinuria-induced cell-adaptive UPR resulting from induction of the molecular chaperone BiP was significantly suppressed, whereas proapoptotic UPR with CHOP overexpression was enhanced. Treatment with the exogenous molecular chaperone tauroursodeoxycholic acid (TUDCA) ameliorated proteinuria-induced tubulointerstitial lesions and PTC apoptosis in aged mice. Among the three UPR branches, alterations in the inositol-requiring 1α (IRE1α) pathway, but not the activating transcription factor 6 or PERK pathway, were associated with impaired BiP induction in aged kidneys. Moreover, siRNA-mediated suppression of BiP and IRE1α exacerbated free fatty acid-bound albumin-induced apoptosis in cultured PTCs, whereas siRNA-mediated CHOP suppression ameliorated apoptosis. Finally, proteinuria-induced BiP induction in PTCs was diminished in kidney specimens from elderly patients. These results indicate that maladaptive UPRs are involved in proteinuria-induced tubulointerstitial lesions exacerbation in aged kidneys, and that supplementation of chaperones may be used to treat elderly patients with persistent proteinuria. These results should improve understanding of cell vulnerability in aged kidneys., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

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 <30 mL/min/1.73 m(2), and the annual decline rate in 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.

AIMS/INTRODUCTION: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. MATERIALS AND METHODS: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. RESULTS: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β(2)-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR (r = -0.51, P < 0.001).When patients were divided into four subgroups according to albuminuria and urinary angiotensinogen levels, patients with albuminuria and high urinary angiotensinogen levels showed a progressive decline of eGFR and a higher incidence of renal and cardiovascular composite endpoints. CONCLUSIONS: These results suggest that the higher level of urinary angiotensinogen in type 2 diabetic patients with albuminuria is a high risk factor for worsening renal and cardiovascular complications.

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., (© 2012 Japan Geriatrics Society.)

Background: There is little evidence regarding the target blood pressure level in patients with type 2 diabetes mellitus without overt proteinuria., Methods and Results: We followed 608 Japanese patients with type 2 diabetes without apparent cardiovascular disease and overt proteinuria who underwent cerebral magnetic resonance imaging for a mean of 7.5 years. The patients were categorized according to their mean systolic blood pressure during the follow-up period (strict: <130 mm Hg, moderate: ≥130 and <140 mm Hg, poor: ≥ 140 mm Hg). The risks for the primary composite outcome of death or end-stage renal disease were not different among the three groups. The renal risk of the doubling of serum creatinine for the poor group was significantly higher than those in other groups. In addition, among the patients without silent cerebral infarction (SCI), the renal risk was significantly lower in the strict group than in the moderate group. Further, in both the SCI and non-SCI groups, strict blood pressure control slowed the progression of albuminuria., Conclusions: In nonproteinuric diabetic patients without SCI, strict blood pressure control was associated with improved renal outcomes. There may be different effects of intensive blood pressure control on the renoprotection of diabetic patients according to their complications., (Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Aims/Introduction:  Although increases in urinary protein excretion generally precede a decline in the glomerular filtration rate, non-proteinuric renal impairment is common in patients with diabetes. In the present study, we examined the relationship between indices of arterial stiffness and renal function in type 2 diabetic patients without proteinuria., Methods:   Blood sampling, 24-h urine collection, brachial-ankle pulse wave velocity, and 24-h ambulatory blood pressure monitoring were performed in type 2 diabetic patients without overt proteinuria. The ambulatory arterial stiffness index was calculated as (1 - the regression slope of diastolic/systolic ambulatory blood pressure). Estimated glomerular filtration rate (eGFR)was calculated using the simplified prediction equation proposed by the Japanese Society of Nephrology., Results:   Of 213 non-proteinuric patients with type 2 diabetes, 60 (28.2%) had a reduced eGFR (<60 mL/min per 1.73 m(2)). Although the urinary albumin excretion rate was significantly correlated with the eGFR, 34 of 152 patients with normoalbuminuria (22.4%) had a reduced eGFR. The eGFR was significantly and negatively correlated with the ambulatory arterial stiffness index and brachial-ankle pulse wave velocity, but not with 24-h pulse pressure. Multivariate analysis revealed that increased age and increased urinary albumin excretion were independently associated with decreased eGFR. In addition, the ambulatory arterial stiffness index, but not brachial-ankle pulse wave velocity, were found to be independently and significantly associated with eGFR., Conclusions:   Ambulatory arterial stiffness index is a marker for increased risk of renal failure in non-proteinuric patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00146.x, 2012).

During the past 10 years, a global pandemic of end-stage renal disease (ESRD) attributed to diabetes mellitus has changed the therapeutic strategies based on landmark trials that have shown that diabetic micro- and macrovascular complications might be preventable. However, the remaining risk of the progression of diabetic kidney disease to ESRD is still high, despite newly introduced anti-diabetic, antihypertensive and dyslipidemic drugs in the 21st century. Here, we show the importance of targeting remission and regression of microalbuminuria in type 2 diabetic patients. To achieve the remission and regression of microalbuminuria, physicians have revised the management strategy of diabetic patients and have to act immediately. Early detection of microalbuminuria with continuous screening, the use of renin-angiotensin system blockades, and targets for HbA1c of <7.35% and systolic blood pressure of <130 mmHg are closely associated with the remission and regression of microalbuminuria, resulting in protection against the progression of diabetic kidney disease, as well as cardiovascular events. Our concept of the natural history of diabetic kidney disease has to be modified by our results and others. Reducing microalbuminuria is therefore considered to be an important therapeutic target and could be a pivotal biomarker of therapeutic success in diabetic patients. (J Diabetes Invest, doi:10.1111/j.2040-1124.2011.00112.x, 2011).

Aim: The aim of our study was to investigate whether serum levels of soluble tumor necrosis factor α receptor (sTNFR) 1 and 2 are markers for renal dysfunction in type 2 diabetic patients without overt proteinuria., Methods: Japanese type 2 diabetic patients without overt proteinuria (n = 168) enrolled in the prospective observational follow-up study in 2001 were retrospectively analyzed. At baseline, the serum levels of sTNFR1 and sTNFR2 were measured by sandwich ELISA. The associations between these markers and change in estimated glomerular filtration rate (eGFR) after 5 years were evaluated., Results: The levels of sTNFR1 and sTNFR2 closely correlated. At baseline, sTNFR1 and sTNFR2 associated inversely with eGFR. After 5 years, patients with high level of both sTNFR1 and sTNFR2 showed a greater decline in eGFR (-13.8 ± 15.5% versus -8.5 ± 11.8%, P = 0.027) and a 4-fold higher risk for a GFR decline of ≥ 25% than those with high level of only one receptor or low level of both receptors. These associations were enhanced in diabetic women., Conclusions: The higher levels of sTNFR1 and sTNFR2 were associated with a greater decline in eGFR in type 2 diabetic patients without proteinuria, especially in diabetic women., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Aims/Introduction:  Platelet-derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high-dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes., Materials and Methods:   The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks., Results:   Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups., Conclusions:   Patients with morning hypertension might be at risk for cardiovascular diseases. High-dose renin-angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00048.x, 2010).

Objective: Genetic factors are believed to contribute to the development and progression of diabetic nephropathy. Recently, a genome-wide association study for diabetic nephropathy revealed four novel candidate loci in European American subjects with type 1 diabetes. In this study, we determined the association of the four loci with diabetic nephropathy in Japanese subjects with type 2 diabetes., Research Design and Methods: We genotyped 11 singlenucleotide polymorphisms (SNPs) in four distinct loci (rs39059 and rs39075 in the CPVL/CHN2, rs1888747 and rs10868025 in FRMD3, rs739401 and rs451041 in CARS, and rs1041466, rs1411766, rs6492208, rs7989848, and rs9521445 in a chromosome 13q locus) in four independent Japanese populations., Results: Six SNPs were nominally associated with diabetic nephropathy in one of the four Japanese populations (P < 0.05; rs451041 in study 1; rs39059 and rs1888747 in study 3; rs1411766 in studies 1 and 4; and rs7989848 and rs9521445 in study 4); however, no significant association was observed for any SNP after correction for multiple testing errors in the individual populations. Nevertheless, a meta-analysis performed for the data obtained from all four populations revealed that one SNP (rs1411766) in chromosome 13q was significantly associated with diabetic nephropathy in the Japanese populations (nominal P = 0.004, corrected P = 0.04, odds ratio 1.26 [95% CI = 1.07-1.47])., Conclusions: Our results suggest that the rs1411766 locus may be commonly involved in conferring susceptibility to diabetic nephropathy among subjects with type 1 or type 2 diabetes across different ethnic groups.

Objective: Cross-sectional studies have reported increased levels of urinary type IV collagen in diabetic patients with progression of diabetic nephropathy. The aim of this study was to determine the role of urinary type IV collagen in predicting development and progression of early diabetic nephropathy and deterioration of renal function in a longitudinal study., Research Design and Methods: Japanese patients with type 2 diabetes (n = 254, 185 with normoalbuminuria and 69 with microalbuminuria) were enrolled in an observational follow-up study. The associations of urinary type IV collagen with progression of nephropathy and annual decline in estimated glomerular filtration rate (eGFR) were evaluated., Results: At baseline, urinary type IV collagen levels were higher in patients with microalbuminuria than in those with normoalbuminuria and correlated with urinary beta(2)-microglobulin (beta = 0.57, P < 0.001), diastolic blood pressure (beta = 0.15, P < 0.01), eGFR (beta = 0.15, P < 0.01), and urinary albumin excretion rate (beta = 0.13, P = 0.01) as determined by multivariate regression analysis. In the follow-up study (median duration 8 years), urinary type IV collagen level at baseline was not associated with progression to a higher stage of diabetic nephropathy. However, the level of urinary type IV collagen inversely correlated with the annual decline in eGFR (gamma = -0.34, P < 0.001). Multivariate regression analysis identified urinary type IV collagen, eGFR at baseline, and hypertension as factors associated with the annual decline in eGFR., Conclusions: Our results indicate that high urinary excretion of type IV collagen is associated with deterioration of renal function in type 2 diabetic patients without overt proteinuria.

Objective: Albuminuria in type 2 diabetic patients is a risk factor for cardiovascular disease. We investigated the correlation between albuminuria and spontaneous microaggregation of platelets (SMAP) formed under shear stress., Research Design and Methods: The study subjects were 401 type 2 diabetic individuals (252 with normoalbuminuria and 149 with albuminuria) who were examined for SMAP under conditions of shear stress only (no agonist stimulation) and the reversibility of platelet microaggregation after stimulation with 1 mumol/l ADP, measured by a laser light-cattering method. Active glycoprotein IIb/IIIa (GPIIb/IIIa) and P-selectin expression levels on platelets as an index of platelet activation were measured by whole-blood flow cytometry., Results: SMAP formation was noted in 53% of diabetic patients. All patients with SMAP showed an irreversible pattern of platelet microaggregates by a low dose of ADP. SMAP was observed in 75% of diabetic subjects with albuminuria and in 39% of those with normoalbuminuria. Multivariate logistic regression analysis identified urinary albumin excretion rate and brachial-ankle pulse-wave velocity as independent factors associated with SMAP. The degree of SMAP correlated with active GPIIb/IIIa (gamma = 0.59, P < 0.001) and P-selectin (gamma = 0.55, P < 0.001) expression levels. These early-activated platelet profiles were significantly inhibited in albuminuric patients with aspirin intake, although the effect was incomplete., Conclusions: Our study demonstrated an independent association between albuminuria and early changes in activated platelet profiles of type 2 diabetic patients. Further follow-up and intervention studies are needed to establish whether the inhibition of SMAP affects the course of cardiovascular disease in type 2 diabetic patients.

Diabetic nephropathy in type 2 diabetes is a leading cause of end-stage renal disease worldwide. Its early clinical sign is microalbuminuria, which is not only a predictor for progression of nephropathy but also an independent risk factor for cardiovascular disease. A few decades ago, diabetic nephropathy was believed to be progressive and irreversible. Thus, the main therapeutic objective for type 2 diabetic patients with microalbuminuria was to prevent progression to overt proteinuria. However, there is now growing evidence regarding remission/regression of diabetic nephropathy. In recent clinical trials using the renin-angiotensin system blockade drugs, a reduction in microalbuminuria by the use of these drugs has been noted. We also reported that a reduction in microalbuminuria was more frequent than progression to overt proteinuria and that multifactorial control approach was important to the reduction of microalbuminuria. These results for type 2 diabetes are similar to those previously reported for type 1 diabetes. Furthermore, our recent study showed that the 8-year cumulative incidence rate of renal and cardiovascular events was significantly lower in patients with remission than in those without it. The annual decline rate of estimated glomerular filtration rate in patients with remission was also significantly slower. These studies provide clinical evidence implying that the reduction of microalbuminuria in type 2 diabetic patients occurs frequently and brings about renal and cardiovascular risk reduction. Reducing microalbuminuria is therefore considered to be an important therapeutic objective and may be a biomeasure of therapeutic success in type 2 diabetic patients.

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferator-activated receptor gamma-deficient (PPARgamma(+/-)) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase (ACC) and by increased ACC activity. In addition, renal lipolysis was suppressed, determined by reduced mRNA expression of the lipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1 and by reduced activity of AMP-activated protein kinase. In PPARgamma(+/-) mice, renal injury, systemic metabolic abnormalities, renal accumulation of lipids, and the changes in renal lipid metabolism were attenuated. Thus, a high-fat diet leads to an altered balance between renal lipogenesis and lipolysis, subsequent renal accumulation of lipid, and renal injury. We suggest that renal lipid metabolism could serve as a new therapeutic target to prevent chronic kidney disease in patients with metabolic syndrome.

Objective: Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study., Research Design and Methods: We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction <50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated., Results: Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred., Conclusions: The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction.

To estimate the frequency of remission/regression of microalbuminuria and to identify factors affecting such outcomes in Japanese patients with type 2 diabetes, we observed 216 patients with type 2 diabetes and microalbuminuria enrolled during an initial 2-year evaluation period for the next 6 years. Remission was defined as shift to normoalbuminuria and regression as a 50% reduction in urinary albumin excretion rate (AER) from one 2-year period to the next. Reduction of urinary AER was frequent, with a 6-year cumulative incidence of 51% (95% CI 42-60) for remission and 54% (45-63) for regression, whereas the frequency of progression to overt proteinuria was 28% (19-37). Microalbuminuria of short duration, the use of renin-angiotensin system-blocking drugs, and lower tertiles for HbA(1c) (<6.95%) and systolic blood pressure (<129 mmHg) were independently associated with remission or regression in the pooled logistic regression analysis. The results indicate that reduction in urinary AER occurs frequently in Japanese patients with type 2 diabetes. Early detection of microalbuminuria and a multifactorial control may result in improved outcomes for diabetic nephropathy and cardiovascular events.

A 31-year-old man was admitted to the hospital because of a low-grade fever, general malaise, nausea, vomiting, and a poor appetite. On admission his renal function was severely deteriorated (serum creatinine 16.12 mg/dl, BUN 163 mg/dl), and he had severe anemia (Hb 7.5 g/dl) and thrombocytopenia (67,000/microl). A radiological examination revealed the presence of multiple cysts in his kidneys bilaterally. The patient was diagnosed as having end-stage renal disease due to polycystic kidney disease, and hemodialysis was started on the day of admission. After the initiation of hemodialysis, his symptoms and laboratory tests improved, except for anemia and thrombocytopenia. He was noted to have marked splenomegaly and dilation of the portal vein, raising the suspicion of portal hypertension as the cause of the splenomegaly and pancytopenia. To treat his pancytopenia (anemia and thrombocytopenia) and to determine the reason for his portal hypertension, a splenectomy and open-wedge biopsy of the liver were performed. Histological findings in the liver included extensive fibrosis of the portal areas with an excess of moderately dilated bile ducts, compatible with a diagnosis of congenital hepatic fibrosis. After splenectomy, his red blood cell and platelet counts returned to normal, and he was discharged on maintenance dialysis. Congenital hepatic fibrosis is often associated with autosomal recessive polycystic kidney disease (ARPKD), but not with autosomal dominant polycystic kidney disease (ADPKD). However, both his mother and older brother had multiple renal cysts, indicating that this was an unusual case of ADPKD complicated by congenital hepatic fibrosis.

Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both betaI and betaII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (--1504C/T and --546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the --1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the --546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of >/==" BORDER="0">24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus.

There is a unique relationship between the kidney and blood pressure. The importance of the kidney on the pathogenesis of hypertension was clearly demonstrated in renal transplantation studies both in genetic hypertensive rats and humans with hypertension. Also, hypertension accelerates loss of function of the diseased kidney and the antihypertensive treatment attenuates the progression of various renal diseases. A lot of mechanisms to explain this relationship are considered: salt retention, abnormalities of renal hemodynamics, inappropriate activation of the renin-angiotensin system etc. This review is an attempt to highlight a renal role on the development of hypertension, especially in diabetic nephropathy.