Moriatsu Miyagi

Expression of ACE and ACE2 in Individuals With Diabetic Kidney Disease and Healthy Controls

BACKGROUND Angiotensin-converting enzyme (ACE) 2 (ACE2) is expressed mainly in the heart and kidney and forms angiotensin-1-7 from angiotensin II. ACE2 might act in a counterregulatory manner to ACE. There is little information about renal ACE and ACE2 expression in human diabetic nephropathy. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS Kidney tissue from 20 patients with type 2 diabetes and overt nephropathy and 20 healthy kidney donors. PREDICTOR Diabetes status. OUTCOMES & MEASUREMENTS Renal expression of ACE and ACE2 assessed by means of immunohistochemistry and in situ hybridization. Correlation between ACE and ACE2 expression and levels of various biochemical parameters. RESULTS Decreased ACE2 and increased ACE expression in both the tubulointerstitium and glomeruli resulted in a significant (P < 0.001) increase in ACE/ACE2 ratio in patients with diabetes with overt nephropathy compared with controls, although ACE messenger RNA in the tubulointerstitium did not significantly increase. ACE/ACE2 ratio correlated positively with values for mean blood pressure, fasting blood glucose, serum creatinine, proteinuria, and hemoglobin A(1c) and inversely with estimated glomerular filtration rate (P < 0.001). LIMITATIONS Inclusion of small number of human renal biopsy specimens with structural distortion of cortical tissue. CONCLUSIONS The high ACE/ACE2 ratio in kidneys of patients with type 2 diabetes with overt nephropathy may contribute to renal injury.

Significance of subclinical rejection in early renal allograft biopsies for chronic allograft dysfunction.

Abstract:  To determine the significance of early subclinical rejection of renal allografts, we reviewed 127 biopsy specimens obtained soon after transplantation. Histological finding was categorized according to a modification of the Banff scheme as: acute rejection (AR), borderline changes (BL); non‐specific inflammatory changes, (NI) and no rejection (NR). Subclinical rejection was defined as AR, BL or NI. Patients with BL or NI were divided into two groups; one was treated with high‐dose methylprednisolone (MP), the other remained untreated. Freedom from chronic allograft dysfunction (defined as non‐doubling of serum creatinine 5 yr after transplantation) was significantly more frequent in the NR group (89%) than in the BL (70%) and AR (64%) groups. At 1 yr after transplantation, mean serum creatinine had increased significantly only in the untreated group (p < 0.05), and re‐biopsy showed that interstitial fibrosis had developed to a significantly greater extent in the untreated group than in the treated group (p < 0.01). Subclinical rejection in the early protocol biopsies correlated closely with subsequent allograft dysfunction. High‐dose MP treatment for early subclinical rejection may be effective in suppressing the development of interstitial fibrosis at 1 yr after transplantation.

Estimation of damaged tubular epithelium in renal allografts by determination of vimentin expression

Background: Various invasive and non‐invasive methods have been investigated for their prognostic value in predicting the outcome of renal allografts. In the present study, vimentin expression in tubular epithelial cells (TEC) was determined by the immunohistochemical examination of biopsy specimens and the prognostic value of this method was assessed.

Increased ACE and decreased ACE2 expression in kidneys from patients with IgA nephropathy.

Background: Angiotensin-converting enzyme (ACE)2 forms angiotensin-1–7 which may protect kidney in a counterregulatory manner to angiotensin II. Recent studies revealed increased ACE and decreased ACE2 expression in kidneys of patients with diabetic nephropathy. However, these changes may not be specific for diabetic nephropathy. We studied ACE and ACE2 expression in patients with IgA nephropathy. Methods: Renal ACE and ACE2 expression was assessed by immunohistochemistry and in situ hybridization in 30 patients with IgA nephropathy and 21 healthy controls. Correlation between ACE and ACE2 expression and levels of various biochemical parameters was also assessed. Gene expression was also assessed in minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN) as disease controls. Results: Reduced ACE2 expression (p < 0.01) and increased ACE expression in glomeruli (p < 0.001), and reduced ACE2 expression in tubulointerstitium (p < 0.001) were observed in patients with IgA nephropathy compared to healthy controls, although the changes in ACE2 mRNA were not statistically significant. Reduced renal ACE2 expression was also found in MN but not in MCNS. Correlation between renal ACE and ACE2 expression and proteinuria was not observed in IgA nephropathy. Conclusion: IgA nephropathy is associated with increased ACE and decreased ACE2 expression in kidneys, as in diabetic nephropathy.

Post‐transplant early recurrent proteinuria in patients with focal glomerulosclerosis‐ Angiotensin II immunostaining and treatment outcome

Abstract:  We reviewed the transplantation data and results of histopathological studies with additional angiotensin II (AII) immunostaining of renal graft biopsies of nine cases (10 grafts) with recurrent proteinuria and three controls without recurrent proteinuria that received renal transplantation for primary focal segmental glomerulosclerosis (FSGS) between 1986 and 2002. Recurrent FSGS was confirmed in six grafts from nine cases by light microscopy. In cases with recurrent proteinuria, loss of graft function was noted in all six renal grafts received between 1986 and early 1992 but in none of four grafts received between late 1992 and 2002. Two of four patients of the late group but none of those of the early group received angiotensin converting enzyme (ACEI) or angiotensin II receptor blocker (ARB) with plasma exchange (PE). In control cases without proteinuria, AII immunostaining was detected in tubules but not in glomeruli in 1‐hour biopsies as well as later on. In cases with recurrent proteinuria, AII immunostaining was detected in both tubules and glomeruli, although glomerular AII staining was not observed in 1‐hour biopsies. Our results suggest that effective treatment of post‐transplantation recurrent FSGS requires ACEI or ARB with PE in the absence of another etiology.

Activation of nuclear factor-kappa B and macrophage invasion in cyclosporin A- and tacrolimus-treated renal transplants

Abstract:  This retrospective study was designed to compare the efficacy of cyclosporin A (CyA) and tacrolimus (FK506) on chronic rejection (CR) associated with nuclear factor‐kappa B (NF‐κB) activation and macrophage invasion. Non‐episodic day 50 protocol renal biopsy was performed in 63 consecutive patients with renal transplants from living donors, treated with either CyA or FK506. Southwestern histochemistry for NF‐κB, immunostaining for CD68, and Banff classification were performed, and these findings were compared with outcome over 34 ± 13 months. Compared with specimens from FK506‐treated patients (n = 20), specimens from CyA‐treated patients (n = 43) showed a significant increase in tubulointerstitial CD68‐positive cells (1.5 ± 0.9 vs. 0.9 ± 0.8, p < 0.01), although no significant differences were observed in NF‐κB activation. Specimens with Banff acute rejection (AR) grade ≥ 1A (n = 20) showed increased macrophages (p < 0.01) compared with specimens with AR < 1A (n = 43). Specimens from patients with clinical AR prior to day 50 biopsy (n = 23) also showed increased macrophage invasion (p < 0.01) compared with specimens from patients without prior clinical AR (n = 40). The cumulative well‐functioning (serum creatinine <1.5 mg/dL) graft survival rate was significantly lower in patients with increased tubulointerstitial CD68‐positive cells (n = 63, p < 0.05). Our findings suggest that tacrolimus is more effective than CyA against CR with respect to macrophage invasion and AR.

Effects of New Peritoneal Dialysis Solutions, Pyridoxamine and AT1 Receptor Blocker, on TGF-β1 and VEGF Expression in Rat Peritoneal Mesothelial Cells

Background: Transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF) are involved in peritoneal deterioration in continuous ambulatory peritoneal dialysis. The present study was designed to determine whether new peritoneal dialysis solutions (PDS), pyridoxamine (advanced glycation end products (AGE) inhibitor) or AT1 receptor blocker (ARB), affect the expression of VEGF and TGF-β1 in rat peritoneal mesothelial cells (RPMC). Methods: RPMC were stimulated by phosphate-buffered saline (PBS) as control, Dianeal 1.5% (D 1.5%), Dianeal 2.5% (D 2.5%), Dianeal 4.25% (D 4.25%), Dianeal N 1.5% (N 1.5%), Dianeal N 2.5% (N 2.5%) or Extraneal (Ex). In co-incubation experiments, RPMC were stimulated with N 2.5% including pyridoxamine or olmesartan (ARB). VEGF and TGF-β1 protein and mRNA expression in RPMC were analyzed by ELISA and RT-PCR. Results: Glucose-containing PDS, even N 2.5% diluted twofold with M199 (which contains 1.25% glucose), increased VEGF and TGF-β1 expression in RPMC (p < 0.05). Ex did not inhibit VEGF expression and did not inhibit TGF- β1 expression after 24 h in RPMC. Pyridoxamine and ARB significantly reduced N 2.5%-induced VEGF and TGF-β1 protein and mRNA expression in RPMC (p < 0.01). Conclusions: Neither new pH-neutral, lactate-buffered, low-GDP, two-chamber bag PDS, nor 7.5% icodextrin PDS alone satisfactorily inhibited VEGF and TGF-β1 overproduction in RPMC, but ARB or pyridoxamine effectively inhibited glucose-containing PDS (N 2.5%)-induced overproduction.

Comparing the efficacy of continuous erythropoietin receptor activator and darbepoetin Alfa treatments in Japanese patients with chronic kidney disease during the predialysis period: A propensity-matched analysis.

Erythropoiesis‐stimulating agent (ESA) treatment during the predialysis period can be a strategy to reduce cardiac mortality soon after initiation of dialysis. In this study, we compared the efficacy of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) in patients with chronic kidney disease (CKD) over 6 months prior to initiation of dialysis.

Renal Angiotensin-Converting Enzyme Localization in Diabetic Rats and the Effect of Low Protein Diet

Recent evidence suggests a role of angiotensin-converting enzyme (ACE) in diabetic nephropathy. The effect of diabetes and low protein diet on renal immunohistochemical ACE localization was studied in streptozotocin-induced DM rats. Immunohistochemical ACE localization was reduced in DM rats, and a low protein diet partially resolved this abnormality while inhibiting the progression of diabetic nephropathy.

Dietary treatment in hemodialysis patients, focused on dietary protein restriction.

血液透析患者における食事療法とくに低蛋白食の有用性について検討した. 対象は原則としてP吸着剤を投与されていない安定期血液透析患者17名とした. 入院前のfree dietと, 入院後2週間施行した低蛋白・高エネルギー・低P食 (蛋白質40g/日, エネルギー2,200kcal/日, NaCl 3g/日, P含有530mg/日) とを, 血液尿素窒素 (BUN), 血清P値, 血清Ca値, Ca×P積値, 血清総蛋白等の血液生化学データにより比較した. 食事療法後, BUNは75±17mg/dlから57±15mg/dlへ, 血清P値は7.5±2.1mg/dlから4.5±1.3mg/dlへ, Ca×P積値は69±22から44±12へいずれもP<0.01の有意な低下を認めた. 血清Ca値は食事療法後有意に (P<0.01) 上昇した. 血清総蛋白には有意な変化を認めなかった. 以上の結果から, 血液透析患者における低蛋白・高エネルギー・低P食は, BUNの改善のみならず, P吸着剤を投与せずにPコントロールを行い得ることが示された.