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L-carnitine is an important factor in fatty acid metabolism, and carnitine deficiency is common in dialysis patients. This study evaluated whether L-carnitine supplementation improved muscle spasm, cardiac function, and renal anemia in dialysis patients. Eighty Japanese outpatients (62 hemodialysis (HD) patients and 18 peritoneal dialysis (PD) patients) received oral L-carnitine (600 mg/day) for 12 months; the HD patients further received intravenous L-carnitine injections (1000 mg three times/week) for 12 months, amounting to 24 months of treatment. Muscle spasm incidence was assessed using a questionnaire, and cardiac function was assessed using echocardiography. Baseline free carnitine concentrations were relatively low in patients who underwent dialysis for >4 years. Total carnitine serum concentration, free carnitine, and acylcarnitine significantly increased after oral L-carnitine treatment for 12 months, and after intravenous L-carnitine injection. There was no significant improvement in muscle spasms, although decreased muscle cramping after L-carnitine treatment was reported by 31% of patients who had undergone HD for >4 years. Hemoglobin concentrations increased significantly at 12 and 24 months in the HD group. Therefore, L-carnitine may be effective for reducing muscle cramping and improving hemoglobin levels in dialysis patients, especially those who have been undergoing dialysis for >4 years.

Background: Blockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has not been well established whether this therapy provides additional effects when combined with vitamin D or its analog in a model of adriamycin (ADR)-induced nephropathy., Methods: We evaluated the effect of an angiotensin II subtype 1 receptor blocker (telmisartan) combined with a vitamin D analog (oxacalcitriol) on mice ADR-induced nephropathy (9.5 mg/kg single intravenous injection). We also tested immortalized murine podocytes to examine the effects on podocyte apoptosis., Results: Mice with ADR-induced nephropathy developed progressive albuminuria and glomerulosclerosis within 30 days accompanied by decreased expression of slit diaphragm (SD)-associated proteins (nephrin and podocin), reduced numbers of podocytes, and increased systolic blood pressure. Treatment with telmisartan or oxacalcitriol alone moderately ameliorated kidney injury. The combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by the restoration of SD-associated proteins, reduction of podocyte apoptosis, and prevention of podocyte depletion in the glomeruli. Treatment with telmisartan, oxacalcitriol, and the combination therapy resulted in similar reductions in systolic blood pressure. In cultured murine podocytes, ADR stimulated the expression of Bax/Bcl-2 and apoptosis as determined by Hoechst 33342 staining. These changes were effectively inhibited by telmisartan or oxacalcitriol, but the combination treatment most effectively reduced these effects., Conclusions: These data demonstrated that application of a renin-angiotensin system blocker plus a vitamin D analog effectively prevented renal injury in ADR-induced nephropathy. The observed amelioration of renal injury may be partly attributable to antiapoptotic effects in podocytes., (© 2015 S. Karger AG, Basel.)

Background: Urinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH)., Methods: In the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay., Results: The U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes., Conclusions: In the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.

Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis. In vitro, the specific knockdown of Notch2 increases apoptosis in damaged podocytes, while Notch2 agonistic antibodies enhance activation of Akt and protect damaged podocytes from apoptosis. Treatment with triciribine, an inhibitor of Akt pathway, abolishes the protective effect of the Notch2 agonistic antibody. We find a positive linear correlation between the number of podocytes expressing activated Notch2 and the number of residual podocytes in human nephrotic specimens. Hence, specific activation of Notch2 rescues damaged podocytes and activating Notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis.

The renoprotective effects of benidipine, a calcium channel blocker (CCB) developed in Japan, are reviewed herein. Benidipine has a sustained antihypertensive effect independent of its blood concentration since it binds to dihydropyridine (DHP) receptors via a "membrane approach" (approach to the cell membrane followed by long retention at the DHP binding site). Benidipine dilates glomerular afferent and efferent arterioles equally through inhibition of Ttype Ca channels. Thus, it may cause a decrease of intraglomerular pressure and is superior to CCBs (capable of inhibiting only L-type Ca channels) in terms of suppression of proteinuria. Additionally, benidipine suppresses worsening of renal function more powerfully than CCBs (suppressing only L-type Ca channels), allowing better prognosis as to renal function. The inhibitory effect of benidipine on T-type calcium channels results in the suppression of aldosterone formation in the adrenal glands and of oxidative stress induced by aldosterone. Thus, the aldosterone-inhibitory and antioxidant activities of benidipine mediated by inhibition of T-type calcium channels would result in renoprotection and suppression of disease progression in hypertensive patients with chronic kidney disease (CKD). If such patients have proteinuria, renin-angiotensin system (RAS) inhibitors are used as first-line drugs, but benidipine, as an L-/T-type CCB, is recommended when they require some concomitant drugs. Moreover, the superiority of RAS inhibitors has not been demonstrated in hypertensive patients with CKD and without proteinuria. Thus, in such patients, benidipine should be considered as a first-line antihypertensive drug.

Background: The long-term antiproteinuric effects of benidipine, a calcium channel blocker (CCB), have not been evaluated in detail in hypertensive patients with chronic kidney disease (CKD)., Methods: Benidipine (4 mg/day) was administered to previously untreated hypertensive patients with CKD, or hypertensive patients with CKD not achieving target blood pressure (BP) despite taking an angiotensin II receptor blocker (ARB). The patients were followed up for 1 year. If target BP was not achieved by 2 weeks after the start of benidipine treatment, the dosage was increased to 8 mg/day. The urinary protein to creatinine (UP/cre) ratio was evaluated before and after benidipine treatment., Results: This study evaluated 65 hypertensive patients with CKD. BP (systolic/diastolic) decreased from 154 ± 19 / 91 ± 12 mm Hg before treatment to 134 ± 16 / 78 ± 10 mm Hg at 1 year after treatment (p<0.001). The UP/cre ratio decreased significantly from 2.21 ± 2.47 g/g creatinine (g/g cre) before treatment to 1.43 ± 2.21 g/g cre after treatment (p<0.001). In both the untreated and ARB-treated groups, the BP and UP/cre ratio decreased significantly at 1 year after treatment. The percentage change in the UP/cre ratio was significantly greater in patients aged 65 years or older than in those less than 65 years (79.1% vs. 48.7%, p=0.038)., Conclusions: Benidipine treatment reduced the UP/cre ratio in hypertensive patients with CKD, and the percentage decrease of the UP/cre ratio was greater in elderly patients, suggesting that benidipine may have more potent antiproteinuric effects in elderly hypertensive patients with CKD.

Obesity is a risk factor for development of kidney disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the pathogenesis of renal disorders that are not associated with diabetes. Harcourt et al. provide evidence to support the mechanism responsible for AGE-RAGE interaction and the downstream oxidative stress and inflammation in obesity-related dysfunction. These findings might provide a new strategy for kidney disease in obesity.

Background: Liver-type fatty acid-binding protein (L-FABP) in proximal tubules was reported to have renoprotective roles in experimental tubulointerstitial diseases via its anti-oxidative properties. Since tubuloglomerular cross-talk was recently discussed in the progression of renal diseases, to investigate whether tubular L-FABP may have an impact on the progression of glomerular damage, we induced IgA nephropathy (IgAN) in mice (Tg) transgenically tubular overexpressing human L-FABP (hL-FABP)., Methods: We reconstituted IgAN by bone marrow transplantation (BMT) from IgAN-prone mice into Tg and wild-type (WT) mice. Renal damage was evaluated at 6 and 12 weeks after BMT. During in vitro experiments, mesangial cells (MC) were stimulated by aggragated IgA (AIgA), and their supernatants (AIgA-MC medium) were collected. Stable cell line of mouse proximal tubular cell (mProx) transfected with or without hL-FABP gene was cultured with the AIgA-MC medium., Results: Although mesangial IgA deposition and serum IgA level were not different between WT (WT/ddY) and Tg (Tg/ddY) recipients, WT/ddY mice showed a significantly higher urinary albumin level and mesangial matrix expansion with a significantly higher glomerular damage score. Furthermore, CD68 + macrophage infiltration was also significantly attenuated in Tg/ddY mice. Up-regulation of renal hL-FABP was associated with significant suppression of renal heme oxygenase-1 (HO-1) expression and accumulation of 4-hydroxy-2-nonenal (4-HNE) and MCP-1 expression in Tg/ddY mice. In vitro experiments showed that AIgA-MC medium and recombinant TNF-α significantly up-regulated hL-FABP expression, which was partially blocked by anti-TNF-α antibody, and major mediators of oxidative stress (HO-1 and 4-HNE) and inflammation (MCP-1). Importantly, such up-regulation of the mediators in mProx with hL-FABP was significantly suppressed much more than that in mProx., Conclusions: Tubular L-FABP activated by MC-origin humoral factors may lessen progression of glomerular damage at early stages of IgAN by reducing oxidative stress and inflammatory mediators.

Background: Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories., Study Design: Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory., Setting & Participants: Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study., Reference Test: Measured GFR (mGFR) computed from inulin clearance., Index Test: Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4)., Measurements: Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient., Results: In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively., Limitation: Most study participants had chronic kidney disease, and some may have had changing GFRs., Conclusion: The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

Extracellular fluid expansion states are characterized by increase total body water. These disorders are usually associated with avid renal sodium and water retention. Some examples of such abnormal sodium retention in renal diseases are acute glomerulonephritis and nephrotic syndrome. Edema formation in case of acute glomerulonephritis is primarily responsible for salt retention. On the other hand, the pathogenesis of edema in nephrotic syndrome involves two different mechanisms those are underfill and overfill hypothesis. According to the underfill hypothesis, nephrotic syndrome results in increase of urinary loss of albumin, which subsequently leads to hypoalbuminemia and decreased plasma osmotic pressure. Overfill theory explains that renal salt and water retention is primary phenomenon that leads to plasma volume expansion and subsequent exudation of fluid to the interstitium.

A preliminary study of the intact-parathyroid hormone (i-PTH) measurements from haemodialysis patients was conducted to determine the prevalence of renal bone diseases at the Dr Soetomo Hospital. The objective of this study is to evaluate the osteodystrophy renal pattern in haemodialysis patients using i-PTH and radiological parameters. The selected populations of 48 (32 males and 16 females), the mean age 48 +/- 10.3 years, was evaluated to conduct a cross-sectional study. The calorimetric method was applied to measure serum P and Ca, while a radioimmunoassay was used to assay the i-PTH level. Of those 48 patients receiving haemodialysis, with a duration ranging from 4 to 432 weeks, 61% had hypocalcaemia and 10% had hypercalcaemia. The i-PTH levels below 100 pg/mL (normal, 10-65 pg/mL) suggested 'aplastic' bone, and values of 100-200 pg/mL most commonly indicated 'normal' bone turnover. The i-PTH levels over 200 pg/mL suggested hyperparathyroidism. The results of this study demonstrated that 42% of those patients had <100 pg/mL (low turnover bone presumed, no biopsy), 23% had 100 - <200 pg/mL ('normal' bone turnover) and 35% of them had >200 pg/mL ('hyperparathyroidism'). In addition, the radiological study showed that 10% of those patients were positive for renal bone diseases. In conclusion, this study shows that the common type of renal osteodystrophy was of a low turnover type, which was different from the findings in other previous studies. It is postulated that this difference is likely to be caused by some factors such as the general health condition of the population those patients belong to and, in particular, the nutritional status of those patients.

Lipoprotein glomerulopathy (LPG) is a unique renal disease characterized by intraglomerular lipoprotein thrombi associated with severe proteinuria and frequent progression to renal failure. The histologic hallmark of LPG is the presence of laminated thrombi, consisting of lipid droplet, within the lumina of dilated glomerular capillaries. The findings of thrombi consisting of lipoproteins raised the possibilities that LPG might be related to a primary abnormality in lipid metabolism. However, the precise pathogenic basis of LPG remains unresolved. It was herein found that chronic graft-versus-host disease (GVHD) induced by the transfer of Ia-incompatible spleen cells from B6.C-H2(bm12) into coisogenic C57BL/6 mice with deficiency of Fc receptor gamma chain (FcRgamma) resulted in glomerulopathy that resembled LPG. The uptake of acetylated LDL was partially decreased in peritoneal macrophages isolated from FcRgamma-deficient mice compared with wild-type mice, suggesting that partial impairment of modified LDL uptake might contribute to the development of LPG associated with chronic GVHD in FcRgamma-deficient mice. LPG has been suggested to be a disorder of primary abnormality in lipid metabolism; these findings would therefore provide novel insight into the disease process.

When Berger et al. first reported IgA nephropathy in 1968, the prognosis was generally thought to be benign. However, as more case data were accumulated, it became evident that not all patients with IgA nephropathy necessarily had a good prognosis. IgA nephropathy has a significant morbidity, culminating in end‐stage kidney disease (ESKD) in about 40% of patients without treatment within 20 years of the diagnosis. Although almost 20% of patients remain stable in their renal function, 30%–40% of patients develop ESKD from its onset. The important factors of renal outcome in patients with IgA nephropathy is the severity of histopathological findings, heavy proteinuria, long duration of proteinuria, haematuria and hypertension. [ABSTRACT FROM AUTHOR]

Recently, as the number of case reports of IgG4-related kidney disease (IgG4-RKD) has increased, the histopathological features and clinical approach have been clarified. IgG4-RKD generally has a benign prognosis due to the efficacy of steroid therapy and rarely requires dialysis. Herein, we report a case of IgG4-RKD that presented with a subacute onset, advanced to end-stage kidney disease, and finally required maintenance hemodialysis despite steroid therapy. A 75-year-old man was admitted to our hospital for further evaluation of subacute renal failure. Diffuse enlargement of the kidney on computed tomography and increased urinary N-acetyl-β-D-glucosaminidase and α1-microglobulin levels led us to suspect IgG4-RKD. Upon admission, the laboratory serological findings were as follows: creatinine 3.3 mg/dL, urea nitrogen 46.9 mg/dL, and IgG4 235 mg/dL. Urinalysis showed slight proteinuria without hematuria. Percutaneous renal needle biopsy showed diffuse infiltration of abundant lymphocytes and IgG4-positive plasma cells and storiform fibrosis, which is specific to IgG4-RKD, in the interstitium on light microscopy. Slight linear deposition of C3 was also observed in the tubules on immunofluorescence microscopy, with no electron-dense deposits. He was definitively diagnosed as having IgG4-RKD and started on prednisolone 0.6 mg/kg/day. However, the renal insufficiency continued to progress and hemodialysis was necessary. As the prednisolone was tapered, renal function did not improve and maintenance hemodialysis was started. In conclusion, this case indicates that the prognosis of IgG4-RKD is not necessarily benign and that further studies involving more patients are needed. [ABSTRACT FROM AUTHOR]

Chronic kidney disease has become a worldwide problem. Among chronic kidney disease patients, IgA nephropathy is common in the world. Serum levels of galactose deficient (Gd)‐IgA1 and Gd‐IgA1‐specific antibodies are elevated in most IgA nephropathy patients. Glomerular Gd‐IgA1 deposition has been observed by immunofluorescence. There are many reports that the anti‐proteinuric effect is significantly greater in groups who receive tonsillectomy with steroid pulse therapy in IgA nephropathy patients. Furthermore, patients with tonsillectomy with steroid pulse therapy have shown a strong down‐regulation of delta serum IgA/C3 per year and have conserved their renal function. New treatments, that is, Atacicept and glucocorticoid budesonide, have been developed for this disease. Summary at a Glance: IgA nephropathy is a major cause of CKD in the world. Using of new biomarkers, we should select the treatment for the patients with IgA nephropathy. [ABSTRACT FROM AUTHOR]

Podocytes serve as the final barrier to urinary protein loss through a highly specialized structure called a slit membrane and maintain foot process and glomerular basement membranes. Podocyte injury results in progressive glomerular damage and accelerates sclerotic changes, although the exact mechanism of podocyte injury is still obscure. We focus on the staining gap (podocin gap) defined as the staining difference between podocin and synaptopodin, which are normally located in the foot process. In puromycin aminonucleoside nephrosis rats, the podocin gap is significantly increased ( p < 0.05) and podocin is translocated to the cytoplasm on days 7 and 14 but not on day 28. Surprisingly, the gap is also significantly increased ( p < 0.05) in human kidney biopsy specimens of poor-prognosis IgA nephropathy patients. This suggests that the podocin gap could be a useful marker for classifying the prognosis of IgA nephropathy and indicating the translocation of podocin to the cytoplasm. Next, we find more evidence of podocin trafficking in podocytes where podocin merges with Rab5 in puromycin aminonucleoside nephrosis rats at day 14. In immunoelectron microscopy, the podocin positive area was significantly translocated from the foot process areas to the cytoplasm ( p< 0.05) on days 7 and 14 in puromycin aminonucleoside nephrosis rats. Interestingly, podocin is also translocated to the cytoplasm in poor-prognosis human IgA nephropathy. In this paper, we demonstrate that the translocation of podocin by endocytosis could be a key traffic event of critical podocyte injury and that the podocin gap could indicate the prognosis of IgA nephropathy. [ABSTRACT FROM AUTHOR]

Background and Objectives: There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN. Materials and Methods: We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients. Results: Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria. Conclusions: Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases. [ABSTRACT FROM AUTHOR]

Background: A wide variety of treatments, including tonsillectomy and steroid pulse therapy (TSP), are performed for the various stages of IgA nephropathy (IgAN) in Japan. However, the current status of treatments for IgAN patients in Japan is still unclear. The objective of the present study was to investigate the current status of treatments for IgAN patients. Methods: A nationwide survey was conducted in 2008 by sending questionnaires to the 1,194 teaching hospitals of the Japanese Society of Nephrology (JSN) via Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan. Results: Among the total 376 hospitals (31.4 %) that responded, 188 hospitals (66.2 % in the internal medicine departments) performed TSP, out of which 137 hospitals (61.4 %) had begun to perform TSP in the period from 2004 to 2008. The following two major steroid pulse protocols in TSP were used: (1) three cycles over 3 consecutive weeks and (2) three cycles every 2 months. Approximately 68 % of pediatric hospitals (68 hospitals) performed combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The clinical remission rates for hematuria and proteinuria after TSP tended to be higher than those following other corticosteroid therapies. Almost all hospitals prescribed antiplatelet agents and renin angiotensin system inhibitor (RAS-I). Conclusion: In addition to popular treatments such as antiplatelet agents and RAS-I, TSP is becoming a standard treatment for adult IgAN patients in Japan. [ABSTRACT FROM AUTHOR]

Summary: Purpose: It has been reported that acceleration plethysmography (APG) that is a noninvasive and very simple method for the assessment of arterial stiffness. The objectives of the present study were to evaluate usefulness of APG and to compare the data on blood pressure (BP), serum biochemistry, and aortic calcification index (ACI) in chronic kidney disease (CKD) patients. Methods: ACI, systolic BP, diastolic BP, and serum biochemistry values were obtained from 35 hemodialysis (HD group) patients, 15 peritoneal dialysis (PD group) patients and 20 nondialysis patients (CKD Stages 1–5; nondialysis group). After APG, the acceleration plethysmogram aging index (APG-AI) was calculated. Aortic calcification was measured semiquantitatively using computed tomography (CT) images of the abdominal aorta, and then ACI was calculated. Results: Phosphate (PO4) and calcium×phosphate product (Ca×PO4) in the HD or PD groups were significantly higher than those in the nondialysis group. APG-AI and ACI, which are used for evaluation of arteriosclerosis, in HD or PD groups were higher compared with the nondialysis group. APG-AI and ACI increased with aging. APG-AI was significantly correlated with ACI. Conclusion: APG-AI and ACI in the HD and PD groups were more advanced than in the nondialysis group. Aortic calcification in the HD and PD groups was affected by high levels of P and Ca×PO4. There was a significant correlation between APG, a functional evaluation of arteriosclerosis, and ACI, a morphological evaluation. Therefore, it appears that APG might provide valuable information on arteriosclerosis in CKD patients. [Copyright &y& Elsevier]

Patients with end-stage kidney disease on peritoneal dialysis often develop progressive scarring of the peritoneal tissues. This manifests as submesothelial thickening and is associated with increased vascularization that leads to ultrafiltration dysfunction. Hypoxia induces a characteristic series of responses including angiogenesis and fibrosis. We investigated the role of hypoxia in peritoneal membrane damage. An adenovirus expressing transforming growth factor (TGF) β was used to induce peritoneal fibrosis. We evaluated the effect of the mTOR inhibitor rapamycin, which has been previously shown to block hypoxia-inducible factor (HIF) 1α. We also assessed the effect of HIF1α independently using an adenovirus expressing active HIF1α. To identify the TGFβ1-independent effects of HIF1α, we expressed HIF1α in the peritoneum of mice lacking the TGFβ signalling molecule Smad3. We demonstrate that TGFβ-induced fibroproliferative tissue is hypoxic. Rapamycin did not affect the early angiogenic response, but inhibited angiogenesis and submesothelial thickening 21 days after induction of fibrosis. In primary mesothelial cell culture, rapamycin had no effect on TGFβ-induced vascular endothelial growth factor (VEGF) but did suppress hypoxia-induced VEGF. HIF1α induced submesothelial thickening and angiogenesis in peritoneal tissue. The fibrogenic effects of HIF1α were Smad3 dependent. In summary, submesothelial hypoxia may be an important secondary factor, which augments TGFβ-induced peritoneal injury. The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic-induced angiogenic effects but does not affect the direct TGFβ-mediated fibrosis and angiogenesis. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Megalin, an endocytic receptor in proximal tubule cells, is involved in the mechanisms of albuminuria in diabetic nephropathy (DN). To develop efficient novel biomarkers associated with the pathogenesis of DN, we investigated urinary megalin excretion in type 2 diabetes. RESEARCH DESIGN AND METHODS--Sandwich enzyme-linked immunosorbent assay systems were established with monoclonal antibodies against the NH2 (amino [A]-megalin assay) and COOH (C-megalin assay) termini of megalin to analyze urinary forms of megalin in 68 patients with type 2 diabetes. RESULTS--The A-megalin assay mainly detected a megalin ectodomain form in the soluble urinary fraction, whereas the C-megalin assay identified a full-length form in both soluble and insoluble fractions. Urinary C-megalin levels were significantly high in patients with normoalbuminuria, were elevated in line with increased albuminuria, and showed a better association with estimated glomerular filtration rate (eGFR) (,60 mL/min/1.73 m²) than did urinary albumin. In contrast, urinary A-megalin levels were increased in patients with normo- and microalbuminuria but not in those with macroalbuminuria. Urinary C-megalin levels were also positively associated with plasma inorganic phosphate and negatively with hemoglobin levels in those showing no features of bleeding and not taking vitamin D analogs, phosphate binders, or erythropoiesis-stimulating agents. CONCLUSIONS--Urinary full-length megalin excretion as measured by the C-megalin assay is well associated with reduced eGFR and linked to the severity of DN, phosphate dysregulation, and anemia, whereas urinary excretion of megalin ectodomain as measured by the A-megalin assay may be associated with distinctive mechanisms of earlier DN in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Summary: Background/Purpose: Several types of herbal preparations have been used as supplementary therapies for the treatment of progressive chronic kidney disease (CKD), but the scientific evidence for their use is scarce. The aim of the present study was to determine the effects of Astragalus membranaceus on renal outcome in patients with progressive CKD. Methods and Results: The study population consisted of 35 patients with CKD stages 4 and 5 whose estimated glomerular filtration rate (eGFR) decreased over a 3-month period before the start of A membranaceus treatment despite the use of conventional therapy (from 14.6±6.28mL/min/1.73m2 to 11.6±5.24; mean±SD, p <0.05). Similarly, the eGFR of 15 patients with CKD stage 4 decreased over the same period despite conventional therapy (from 20.8±4.59 to 16.7±4.17; r =−1.298; p <0.05), but increased after the initial period of 3 months of supplementary treatment with A membranaceus (to 18.6±5.67; r =0.973; p <0.05) and remained at that level at 6 months (17.8±5.60) and 12 months (16.3±5.89). However, in 20 patients with CKD stage 5, the beneficial effect of A membranaceus was limited to the first 3 months only (−3 months: 10.5±2.7, baseline: 8.0±2.75, 3 months: 8.4±2.96, 6 months: 6.8±2.45). A membranaceus had no significant effects on other laboratory parameters. Only seven patients (1 in stage 4 and 6 in stage 5) required dialysis within 12 months of A membranaceus treatment, whose eGFR at baseline was relatively low (7.4±1.06). Conclusion: The results suggest that A membranaceus can maintain stable levels of eGFR and delay the initiation of renal replacement therapy in patients with progressive CKD stage 4. 至今已有數種草藥製劑被應用於進行性慢性腎病(CKD)的補充療法，然而此用途仍缺乏相關的科學理據。本研究旨在探討膜莢黃耆(Astragalus membranaceus)對進行性CKD患者的腎臟效應。研究對象為35位第4或5期CKD患者，即使在常規治療下(不包括A membranaceus)，其腎絲球過濾率估算值(eGFR)仍在3個月內明顯下降(從14.6±6.28mL/min/1.73m2至11.6±5.24; mean±SD, p <0.05)。其中15人為第4期CKD患者，eGFR於該段期間明顯下降(從20.8±4.59至16.7±4.17; r =−1.298; p <0.05)，但在膜莢黃耆補充療法開始後3個月回升(至18.6±5.67; r =0.973; p <0.05)，並維持穩定於6個月(17.8±5.60)及12個月(16.3±5.89)。另外20位為第5期CKD患者，膜莢黃耆對其效益僅可見於首3個月(−3個月: 10.5±2.7, 基線: 8.0±2.75, 3個月: 8.4±2.96, 6個月: 6.8±2.45)。至於其他實驗室項目，膜莢黃耆並不具明顯效應。在膜莢黃耆的12個月治療期間，僅7人(第4期：1人；第5期：6人)需接受透析治療，其基線eGFR均偏低(7.4±1.06)。因此，對於第4期進行性CKD患者，膜莢黃耆有助維持eGFR於穩定水平，並延遲腎臟替代療法的開始時間. [Copyright &y& Elsevier]

Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK-Ay mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK-Ay mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK-Ay mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK-Ay mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background. GeneChip Expression Analysis was employed to survey the glomerular gene expression profile in a type 2 diabetes (T2D) model of KK/Ta mice fed with a high-calorie diet (HC), and we focused on the role of mindin (also called spondin 2), whose expression is upregulated by HC.Methods. Isolated glomeruli from three 20-week-old KK/Ta mice fed with HC or a standard diet (SD) were dissected. Total RNA was extracted and labelled for hybridization using the Affymetrix GeneChip Mouse Genome 430 2.0 Array. The gene expression profile was compared between the HC and SD groups using GeneSpring 7.3.1 software. Mindin expression was examined using real-time PCR, western blot analysis and immunohistochemical staining in the glomeruli, cultured podocytes and urine samples of both mice and humans.Results. Podocyte foot process effacement was observed in mice fed with HC. The mindin protein expression levels in mice were localized in the podocytes, and their levels in the glomeruli were increased in the HC group compared with the SD group. The levels of urinary mindin in the HC group at 16 weeks of age were also significantly higher than those in the SD group although albumin/creatinine ratio (ACR) did not differ between the groups. Furthermore, the levels in patients with T2D were higher than those in healthy individuals and increased gradually with increases in ACR.Conclusions. Mindin could be related to podocyte injury and appears to be an early biomarker of the progression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: A majority of patients with chronic kidney disease (CKD) have cardiovascular disease at the initiation of dialysis therapy, suggesting that periodic echocardiographic examinations are important in such patients. The purpose of the present study was to evaluate the correlation between echocardiographic parameters and period of time before initiation of hemodialysis (iHD) in patients with CKD. Methods: 140 patients with CKD stages 4 and 5 were enrolled. They were divided into diabetes and nondiabetes groups. Cardiac predictive parameters for the period of time before iHD were investigated in the patients using univariate and multivariate regression analyses. Results: In the nondiabetes group, systolic blood pressure (SBP) and left atrial volume index (LAVi) were identified as independent risk factors for the period of time before iHD by multivariate regression analysis. Serum albumin level was identified as an independent risk factor in the diabetes group. SBP, LAVi and serum albumin level were identified as independent risk factors in the combined diabetes and nondiabetes groups. Conclusion: LAVi measurements during echocardiography, together with SBP and serum albumin levels, may be useful predictive factors for the period of time before iHD in patients with CKD stages 4 and 5. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Immunoglobulin (Ig)A nephropathy is one of the major causes of chronic kidney disease (CKD) in Japan. Despite statutory urinalysis of industrial workers and school children, Japan unfortunately still ranks among the countries with the highest CKD-5D prevalence in the world. Topics of this review are as follow: (i) early diagnosis and treatment; (ii) influence of the period from onset to medical intervention on renal prognosis; and (iii) epidemiology of IgA nephropathy patients in Japan. Some investigators have discussed the possibility of predicting the diagnosis and prognosis of this disease. We indicated that the frequency of various casts in urinary sediments and total numbers of each type of urinary cast should provide highly convincing data for prediction of the prognosis in IgA nephropathy patients prior to renal biopsy. Furthermore, early medical intervention (anti-platelet agents, anticoagulants, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, corticosteroids and/or tonsillectomy) may lead to better renal prognosis in patients with IgA nephropathy. In a nationwide survey on IgA nephropathy in Japan, predictive factors after 10 years were as follows: (i) male sex; (ii) under 30 years old; (iii) diastolic hypertension; (iv) heavy proteinuria; (v) mild haematuria; (vi) low serum albumin; and (vii) elevated serum creatinine and impaired renal pathology. It appears that substantial renal deterioration can be validly estimated using these predictive factors in patients with IgA nephropathy. In conclusion, early diagnosis, treatment and improvement of predictive factors for a long duration may lead to better renal prognosis in patients with IgA nephropathy. [ABSTRACT FROM AUTHOR]

A 49-year-old man with pulmonary sarcoidosis was admitted to our hospital because of nephrotic syndrome. Renal biopsy revealed membranous nephropathy and granulomatous interstitial nephritis. DNA and cell membrane constituents of Propionibacterium acnes were detected in the patient’s glomeruli and tubular epithelial cells. Treatment with corticosteroids and an antimicrobial agent resulted in remission of the nephrotic syndrome. This is the second case in which components of P. acnes were found in renal tissue, suggesting latent pathogenesis of P. acnes infection in renal sarcoidosis. [ABSTRACT FROM PUBLISHER]

A major limitation in the study of immunoglobulin (Ig)A nephropathy is the lack of suitable animal models. This review describes ddY mice which spontaneously develop mild to moderate IgA nephropathy. This model provides opportunities for genetic analysis of the disease and for testing established and novel therapies for IgA nephropathy. Immunoglobulin (Ig)A nephropathy has the highest incidence among the various forms glomerulonephritis in the world. The initiating and progressive factors in patients with IgA nephropathy are still obscure. Although there is no specific treatment for patients with IgA nephropathy at present, more clinical trials of new treatments are warranted for such patients. Therefore, it is necessary to clarify those factors and to develop more effective drugs using a spontaneous animal model, the ddY mouse, in the future. [ABSTRACT FROM AUTHOR]

The etiology, prevalence, and prognosis of rapidly progressive glomerulonephritis (RPGN) including renal vasculitis vary among races and periods. To improve the prognosis of Japanese RPGN patients, we conducted a nationwide survey of RPGN in the nephrology departments of 351 tertiary hospitals, and found 1772 patients with RPGN (Group A: diagnosed between 1989 and 1998, 884 cases; Group B: diagnosed between 1999 and 2001, 321 cases; and Group C: diagnosed between 2002 and 2007, 567 cases). ANCA subclasses, renal biopsy findings, treatment, outcome and cause of death were recorded. The most frequent primary disease was renal-limited vasculitis (RLV) (42.1%); the second was microscopic polyangiitis (MPA) (19.4%); the third was anti-GBM-associated RPGN (6.1%). MPO-ANCA was positive in 88.1% of RLV patients and 91.8% of MPA patients. The proportion of primary renal diseases of RPGN was constant during those periods. The most frequent cause of death was infectious complications. The serum creatinine at presentation and the initial dose of oral prednisolone decreased significantly in Groups B and C compared to Group A. However, both patient and renal survival rates improved significantly in Groups B and C (survival rate after six months in Group A: 79.2%, Group B: 80.1%, and Group C: 86.1%. Six-month renal survival in Group A: 73.3%, Group B: 81.3%, and Group C: 81.8%). Early diagnosis was the most important factor for improving the prognosis of RPGN patients. To avoid early death due to opportunistic infection in older patients, a milder immunosuppressive treatment such as an initial oral prednisolone dose reduction with or without immunosuppressant is recommended. [ABSTRACT FROM AUTHOR]

Background. Whereas visceral fat accumulation (VFA) is related to insulin resistance and atherosclerosis in both haemodialysis (HD) patients and the general population, little is known about the role of subcutaneous fat accumulation (SFA). The purpose of the present study was to examine and confirm the relationship between abdominal fat accumulation (AFA) and various clinical parameters in HD patients. [ABSTRACT FROM PUBLISHER]

The Japanese Society of Nephrology (JSN) sponsored the Asian Forum of CKD Initiative (AFCKDI) 2007 with the support of the International Society of Nephrology-Commission for Global Advancement in Nephrology (ISN-COMGAN), Asian Pacific Society of Nephrology (APSN), the Kidney Disease: Improving Global Outcome (KDIGO) and other national societies of nephrology in the Asian Pacific region on 27–28 May 2007 in Hamamatsu City, Japan. An international organising committee was established by leading experts of the CKD initiative. The main objective of this forum was to clarify the current status and perspectives of CKD and to promote coordination, collaboration and integration of initiatives in the Asian Pacific region. The forum received 56 papers from 16 countries; it began with the symposium “A Challenge to CKD in the world” and was followed by the ISN-COMGAN affiliated workshop “Current status and perspective of CKD in Asia”. The second day was dedicated to discussion on the evaluation, surveillance and intervention in CKD in this area. At the end of the forum, we decided on the future plan as follows: (1) The AFCKDI will provide opportunities annually or biannually for every person who promotes CKD initiatives in the Asian Pacific region to join together and build consensus for action; (2) the second forum will be held in Kuala Lumpur on 4 May 2008 at the time of the 11th Asian Pacific Congress of Nephrology (APCN). Zaki Morad, President of the 11th APCN, will host the second forum; (3) the International Organising Committee (IOC) of the 1st AFCKDI will continue its function by adding other experts, including the organisers of the APCN; (4) the AFCKDI is not an organisation by itself, nor does it belong to any society, but is organised by each host national society of nephrology. The IOC will assist the domestic committee for the success of the forum and will assure the continuation of the mission; (5) in order to organise the forum and promote CKD initiatives in the Asia Pacific region, the AFCKDI will look for support by both national and international societies. The AFCKDI will keep an intimate and mutual relation with the ISN, APSN and KDIGO. [ABSTRACT FROM AUTHOR]

Abstract: It is generally considered that 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) have renoprotective effects via a pathway independent of their cholesterol-lowering cascade. In the kidneys of diabetic nephropathy, monomeric endothelial nitric oxide synthase (eNOS) is thought to be overexpressed; and its dimerization is suppressed. In the present study, we investigated the expression of eNOS and oxidative stress in type 2 diabetes mellitus KK-Ay/Ta mice treated with pitavastatin, one of the statins. The KK-Ay/Ta mice were divided into 3 groups and given pitavastatin intraperitoneally starting at 8 weeks of age for 8 weeks: pitavastatin 3 mg/(kg d) (n = 5), pitavastatin 10 mg/(kg d) (n = 5), and a control group (n = 10). The urinary albumin-creatinine ratio (ACR), urinary 8-hydroxy-2''-deoxyguanosine, body weight, fasting blood glucose, hemoglobin A1c, total cholesterol, and triglyceride were measured; and the intraperitoneal glucose tolerance test was performed. The eNOS, nitrotyrosine, and p47 phox were evaluated by immunohistochemical analyses and/or Western blot analyses. Guanosine triphosphate cyclohydrolase 1 messenger RNA expression in the kidneys was evaluated using a real-time polymerase chain reaction assay. Pitavastatin improved the levels of urinary ACR and 8-hydroxy-2''-deoxyguanosine, intraperitoneal glucose tolerance test, and hemoglobin A1c. Protein levels of monomeric eNOS, nitrotyrosine, and p47 phox in the kidneys were decreased in the pitavastatin-treated groups. Guanosine triphosphate cyclohydrolase 1 messenger RNA expression was significantly increased in the pitavastatin groups. There were no significant changes in body weight, levels of fasting blood glucose, serum total cholesterol, triglyceride, and blood pressure among all groups. Pitavastatin improved urinary ACR apparently because of suppression of eNOS uncoupling and its antioxidant effect in the kidneys of KK-Ay/Ta mice. [Copyright &y& Elsevier]

Abstract: Eicosapentaenoic acid (EPA) has been reported to have beneficial effects on the progression of various renal diseases including diabetic nephropathy; however, the precise mechanisms are not completely understood. We examined the effects of EPA on the early stage of type 2 diabetic nephropathy in KKAy/Ta mice and the possible role of inflammation, oxidative stress, and growth factor in this process. KKAy/Ta mice were divided into 2 groups. The treatment group was injected with EPA ethyl ester at 1 g/kg per day intraperitoneally from 12 to 20 weeks of age and the control group was injected with saline. Renal morphologic examinations were performed after 8 weeks of treatment. Glomerular macrophage infiltration and expression of monocyte chemoattractant protein 1, malondialdehyde (MDA), nitrotyrosine, transforming growth factor β1 (TGF-β1), and type I collagen were evaluated. Eicosapentaenoic acid decreased the levels of urinary albumin, serum triglyceride and MDA, and improved glucose intolerance in KKAy/Ta mice. Morphometric analysis showed that accumulation of extracellular matrix and the tubulointerstitial fibrosis area were significantly decreased after treatment. Immunohistochemistry revealed that glomerular macrophage infiltration and the expression of MDA and nitrotyrosine in KKAy/Ta mice were increased and were inhibited by EPA treatment. Protein and gene expression levels of monocyte chemoattractant protein 1, TGF-β1, and type I collagen, which were evaluated by immunohistochemistry and real-time reverse transcriptase–polymerase chain reaction, were down-regulated in the EPA treatment group. In conclusion, EPA improves type 2 diabetic nephropathy in KKAy/Ta mice. This beneficial effect might be mediated by attenuation of metabolic abnormalities and inhibition of renal inflammation, oxidative stress, and TGF-β expression. [Copyright &y& Elsevier]

Background: Complement receptor type 1 on erythrocytes (E-CR1) plays important roles not only in the regulation of complement activation, but also the clearance of immune complexes. Reduced E-CR1 was previously found in patients undergoing hemodialysis (HD). We investigated whether the E-CR1level in HD patients with diabetic nephropathy (DMN) is decreased. The levels of decay accelerating factor (DAF) and CD59 on erythrocytes (E) were also determined to ascertain whether the loss of CR1 is a specific phenomenon or other complement regulatory proteins are also affected. Methods: The levels of CR1, DAF, and CD59 on E were analyzed in 176 HD patients with DMN, 101 HD patients with non-diabetes mellitus renal diseases (non-DMN), and 108 healthy individuals. Hind III restriction fragment length polymorphism of intron 27 of the CR1 gene was analyzed. The serum-soluble CR1 levelwas measured by ELISA. Results: The E-CR1 level was significantly lower in the DMN group than the non-DMN group (p < 0.0001) and healthy individuals (p < 0.05). The E-CR1 level was significantly higher in the non-DMN group than in healthy individuals (p < 0.01). The levels of E-DAF and E-CD59 were significantly lower in the DMN group than non-DMN group (DAF, p < 0.01; CD59, p < 0.0001). Within each genotype of the CR1 gene, the E-CR1 level was significantly lower in the DMN group than in the non-DMN group and healthy individuals (non-DMN, p < 0.01; healthy individuals, p < 0.05). The serum-soluble CR1 level was significantly higher in the DMN group than non-DMN group and control group (p < 0.01 each). However, soluble CR1 did not correlate with E-CR1. Conclusion: Acquired loss of E-CR1 was found among HD patients with DMN. From the viewpoint of host defense, it may be a prognostic factor. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

BACKGROUND: Hyperhomocysteinaemia is an independent cardiovascular risk factor in patients with renal disease. The current study aimed to determine the effect of intravenous N-acetylcysteine on plasma homocysteine levels when administered during haemodialysis in patients with end-stage renal failure. PATIENTS AND METHODS: Sixty patients with end-stage renal failure were randomised to receive a 4-hour intravenous infusion of N-acetylcysteine or placebo during a 4-hour haemodialysis session. Plasma homocysteine levels were measured before and after haemodialysis. Haemodynamic parameters, including pulse pressure, were also measured. RESULTS: After haemodialysis in the placebo treatment group, plasma homocysteine was reduced by 23.7% from the pre-dialysis level, whereas patients treated with N-acetylcysteine exhibited an 88.3% decrease (p < 0.001). Reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure (p = 0.001). A 10% decrease in plasma homocysteine concentration was associated with a 1.45mm Hg decrease in pulse pressure. CONCLUSIONS: Intravenous administration of N-acetylcysteine during haemodialysis normalises plasma homocysteine concentration, and this is associated with improved pulse pressure in patients with end-stage renal failure. Intravenous administration of N-acetylcysteine during haemodialysis may be a promising approach to help reduce cardiovascular risk in this vulnerable group of patients. [ABSTRACT FROM AUTHOR]

The article examines the role of fibrosing factors in immunoglobulin A (IGA) nephropathy and diabetic nephropathy. Topics discussed include urinary levels of monocyte chemoattractant protein-1 (MCP-1) or interleukin-8 (IL-8) and renal injuries in patients with IGA nephropathy and diabetic nephropathy and MCP-1 production on glomerular mesangial cells and podocytes.

Although calcium antagonists, derived from dihydropyridine (DHP), are important agents in achieving control in a majority of patients with high blood pressure and renal disease, there are no comparative data regarding their inhibitory effects on the progression of renal dysfunction in Japan.Benidipine and nifedipine retard both calcium antagonists derived from DHP and were compared in terms of their inhibitory effect on the progression of renal dysfunction in hypertensive patients. The primary end-points were defined as 1.5 times the serum creatinine value at baseline, progression to end-stage renal failure (ESRF) necessitating dialysis or renal transplantation, and death.During the study period, a significant decline in blood pressure was observed in the two groups, with no significant difference between them. The worsening of nephropathy was significantly inhibited in the benidipine group as compared with the nifedipine retard group (log-rank test:P = 0.014, Wilcoxon's test:P = 0.022). Among the subjects who reached a primary end-point, one (33%) in the benidipine group and five (50%) in the nifedipine retard group were placed on haemodialysis within 1 year.It appears that benidipine inhibits the progression of hypertensive renal diseases more effectively than nifedipine retard. [ABSTRACT FROM AUTHOR]

Background. Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. Methods. We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] ≧ 140 mmHg or diastolic blood pressure [DBP] ≧ 90 mmHg) and CKD (male, body weight [BW] ≧ 60 kg: 1.5 ≦ SCr < 3.0 mg/dl; female or male BW < 60 kg: 1.3 ≦ SCr < 3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. Results. A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group (n = 43), but there was no change in the amlodipine group (n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. Conclusions. Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action. [ABSTRACT FROM AUTHOR]

The KK/Ta strain serves as a suitable polygenic mouse model for the common form of type 2 diabetes associated with obesity in humans. Recently, we reported the susceptibility loci contributing to type 2 diabetes and related phenotypes in KK/Ta mice. In this study, we focused on expression in the kidneys and liver of KK/Ta and BALB/c mice using differential display (DD) PCR. Zn-alpha(2) glycoprotein-1 (Azgp1) mRNA levels were increased in the kidneys and liver in KK/Ta mice, and sequence analysis revealed a missense mutation. We analyzed the relationship between this polymorphism and various phenotypes in 208 KK/Ta x (BALB/c x KK/Ta) F1 backcross mice. Statistical analysis revealed that Azgp1 and D17Mit218 exhibit a suggestive linkage to body weight (8 weeks) (logarithm of odds 2.3 and 2.9, respectively). Moderate gene-gene interactions were observed at these loci. Adiponectin mRNA levels in 3T3-L1 cells transfected with the expression pcDNA 3.1 vector containing Azgp1 coding sequence of KK/Ta mice were significantly higher than those of BALB/c mice. These results suggest that Azgp1 is a possible candidate gene for regulation of body weight, elucidation of polygenic inheritance, and age-dependent changes in the genetic control of obesity. [ABSTRACT FROM AUTHOR]

In 1995, clinical guidelines for the diagnosis and treatment of patients with immunoglobulin A (IgA) nephropathy in Japan were published by a joint committee of the Special Study Group on Progressive Glomerular Disease, Ministry of Health and Welfare of Japan (Chairman, Kiyoshi Kurokawa, MD), and the Japanese Society of Nephrology (President, Toshihiko Nagasawa, MD).1 The purpose of this new committee of the Special Study Group on Progressive Glomerular Disease, Ministry of Health and Welfare of Japan (Chairman, Hideto Sakai, MD), is to provide new clinical guidelines for the diagnosis and treatment of patients with IgA nephropathy in Japan. Although this document addresses current clinical practice in Japan, it is hoped that this English version will be helpful to the international community and will facilitate further discussion on this increasingly important disease. [ABSTRACT FROM AUTHOR]

SUMMARY: Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy (ROD), may occur in patients in the comparatively early stage of chronic renal failure (CRF). Secondary hyperparathyroidism patients with parathyroid hyperplasia showed resistance to vitamin D3 treatment during long-term dialysis. At present, evaluation by ultrasonography is considered to be useful for confirming parathyroid hyperplasia. There are no clinical data associated with imaging evaluation of 2HPT in CRF patients. In the present study, the relationship among clinical and biochemical data, and parathyroid hyperplasia by ultrasonography, was evaluated in 12 patients (six males and six females) with end-stage renal failure (ESRF) before and at initiation of dialysis. Five patients showed an enlargement of parathyroid glands in ultrasonography. Levels of serum-intact parathyroid hormone (PTH) in patients with parathyroid hyperplasia (positive group) were significantly higher than in those without hyperplasia (negative group; 97.6 ± 36.65 vs 17.4 ± 4.45 pmol/L; P < 0.05). The levels of intact PTH were above 35.0 pmol/L in all five patients with hyperplasia. All patients in the positive group had never taken vitamin D3 supplements. Calcium-containing phosphate binders were not prescribed before the present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was recognized in patients before and at initiation of dialysis in this study. It appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF before and/or after the early stage of dialysis. The levels of serum intact PTH are useful in predicting parathyroid hyperplasia. [ABSTRACT FROM AUTHOR]

We have recently identified two novel polymorphisms (–114T/C and +56T/C relative to the major transcription start site) in the functional promoter region of the Fcα receptor (FcαR) gene. Since altered FcαR expression may be associated with IgA nephropathy, we examined these promoter polymorphisms in this disease. Patients with IgA nephropathy (n=90), patients with other primary glomerulonephritis (n=50), and healthy adults (n=83) were studied. Genotyping was performed by the polymerase chain reaction (PCR) followed by direct sequence analysis and was subsequently confirmed by PCR with mismatched primers followed by restriction fragment length polymorphism analysis. The study demonstrated that the frequency of the +56C allele in patients with IgA nephropathy (0.511) was significantly (P<0.01) higher than that in patients with other primary glomerulonephritis (0.350) and healthy adults (0.337). In addition, a significant increase in the frequency of the +56CC genotype was observed in patients with IgA nephropathy (27.8% vs 10.0% in other GN and vs 9.6% in healthy adults). In contrast, no significant difference in the frequencies of the +56CC genotype and +56C allele was observed between other primary glomerulonephritis patients and healthy adults. The frequency of the –114CC genotype in patients with IgA nephropathy was significantly increased compared with those in both control groups (15.6% vs 4.0% in other GN and vs 2.4% in healthy adults). Polymorphisms of the FcαR promoter region therefore appear to be associated with susceptibility to IgA nephropathy, suggesting the importance of the FcαR gene and its expression in this disease. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents. [ABSTRACT FROM AUTHOR]

The article discusses papers on experimental models of type-2 diabetic nephropathy published in the January 2012 issue of "Experimental Diabetes Research," including a paper which examined the renoprotective effects of dietary restriction (DR) in Wistar fatty rats, a paper on the role of T cells in type 2 diabetic nephropathy and a paper on the role of mindin in diabetic nephropathy.

Glomerular visceral epithelial cells, also known as podocytes, are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane. Podocytes consist of cell bodies, major processes and foot processes (FP) of neighbouring cells, with the filtration slits bridged by the slit membrane between them. The function of podocytes is largely based on their specialized cell architecture and functions such as stabilization of glomerular capillaries and participation in the barrier function of the glomerular filter. Therefore, they form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Under pathological conditions, podocytes exhibit various changes. Among these changes, FP effacement represents the most characteristic change in cell shape of podocytes. FP effacement is dependent on disruption of the actin cytoskeletal network in the podocytes, The mechanisms of organization and re-organization of actin in the FP of podocytes are discussed in this review. [ABSTRACT FROM AUTHOR]

Background. It is generally considered that 3-hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have renoprotective effects via a pathway independent of their cholesterol lowering cascade. In the kidneys of diabetic nephropathy patients, monomeric endothelial nitric oxide synthase (eNOS) is thought to be overexpressed and its dimerization is suppressed. In this study, we investigated the expression of eNOS and oxidative stress in type 2 diabetic KK-A[sup y]/Ta mice treated with pitavastatin, one of the statins. Methods. KK-A[sup y]/Ta mice were given pitavastatin (3mg/kg/day or 10mg/kg/day) intraperitoneously starting at 8 weeks of age for 8 weeks. They were divided into 3 groups as follows: pitavastatin 3 mg/kg/day treatment group (n=5), pitavastatin 10 mg/kg/day treatment group (n=5) and a control group (n=10). The urinary albumin/creatinine ratio (ACR), body weight (BW), fasting blood glucose, hemoglobin A[sub 1c] (HbA[sub 1c]), fasting serum insulin, fasting serum total cholesterol and fasting serum triglyceride were measured and the intraperitoneal glucose tolerance test (IPGTT) was performed as biochemical parameters. eNOS, nitrotyrosine and p47 phox were evaluated by immunohistochemical analyses and/or Western blot analyses. GTPCH-1 mRNA expression in the kidneys was evaluated using a real-time PCR assay. Results. Pitavastatin, especially in the 10mg/kg/day group, improved the levels of urinary ACR and 8-OHdG. Protein levels of monomeric eNOS, nitrotyrosine and p47 phox in the kidneys were decreased in the pitavastatin treated groups according to immunohistochemical and/or Western blot analyses. Furthermore, pitavastatin prevented not only urinary ACR but also vincreases of glucose tolerance and HbA[sub 1c]. Protein levels of monomeric eNOS, nitrotyrosine and p47 phox in kidneys were significantly lower than those in the controls. GTPCH-l mRNA expression in the kidneys was significantly increased compared with those in the controls. There were no significant changes in the levels of fasting blood glucose and systemic blood pressure among all groups. Conclusions. Pitavastatin improved urinary ACR apparently due to suppression of eNOS uncoupling and its anti-oxidant effects in the kidneys of KK-A[sup y]/Ta mice. [ABSTRACT FROM AUTHOR]

The article focuses on the analysis of Immunoglobulin A (IgA) nephropathy by serial renal biopsies. IgA nephropathy is the most common type of primary glomerulonephritis worldwide. The onset and degree of IgA nephropathy were highly variable. Serum IgA levels and the levels of urinary albumin were also highly variable. Levels of albuminuria and intensity of glomerular IgA deposition were significantly correlated with the degree of glomerulonephritis. Serum IgA concentration did not correlate with histological findings and proteinuria.