Extent Of Glomerulosclerosis Research Articles

P0113STANDARDIZED GRADING OF CHRONIC CHANGES IN MINIMAL CHANGE DISEASE: A VALIDATION STUDY IN NATIVE KIDNEY BIOPSY SPECIMENS

Abstract Background and Aims Recently, a group of pathologists and nephrologists devised a simple scoring system for chronic changes based on the grading of glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF) and arteriosclerosis (AS). We aimed to validate for the first time this score in patients with minimal change disease. Method We included 79 adult patients (age 50.3 (46.3, 54.3) years, 57% male, eGFR 54.7 (44.2, 63.5) mL/min) with biopsy proven MCD between 2010-2015 who were followed up until January 1, 2017. The extent of GS, TA and AS was scored from 0 to 3, 0 to 3 and 0 to 1, respectively. The scores were then added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0–1 total score), mild (2–4 total score), moderate (5–7 total score) and severe (>8 total score). The outcomes were: patient survival; kidney survival defined as doubling of serum creatinine or ESRD; partial (proteinuria 0.3 to 3.5g/24h) or complete remission (proteinuria <0.3g/24h) - whichever came first. Variables related to renal outcome were further evaluated in a multivariate Cox proportional hazard (CPH) model. Results Minimal chronic lesions were found in 77%, mild in 18% and moderate in 5% of the studied patients. Fifty percent had a null score of chronicity; they were younger (44 (29-53) versus 62 (44-66) years, p<0.001), had higher eGFR (65.0 (42.1-83.2) versus 43.4 (25.8-63.9) mL/min, p<0.01) but similar proteinuria (4.8 (1.9-8.2) versus 4.5 (1.1-6.7) g/g, p=0.3). Patients with a score higher than one had higher mortality (18% versus 0%, p<0.001) and started RRT more often (15% versus 0%, p=0.01). There were no differences regarding the presentation as acute kidney injury, and in reaching complete or partial remission. Moreover, there were no clinical or pathology features that predicted remission. 17% of the patients reached the composite endpoint of kidney survival; mean kidney survival time was 5.7 (5.2, 6.3) years. In the CPH analysis the only independent predictors of decreased renal survival were elevated chronicity score (HR 1.56 (95%CI 1.14-2.14), p<0.01), lower serum albumin (HR 0.27 (95%CI 0.08-0.88), p=0.03) and the presence of hypertension (HR 0.18 (95%CI 0.03-0.93), p=0.04). Conclusion To the best of our knowledge, this is the first study to validate the standardized grading of chronic changes as an independent predictor of renal survival in patients with minimal change disease.

Reno-protection of Urine-derived Stem Cells in A Chronic Kidney Disease Rat Model Induced by Renal Ischemia and Nephrotoxicity.

Purpose: Drug-induced nephrotoxicity can occur in patients with pre-existing renal dysfunction or renal ischemia, potentially leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Prompt treatment of CKD and the related side effects is critical in preventing progression to ESRD. The goal of this study was to demonstrate the therapeutic potential of urine-derived stem cells (USC) to treat chronic kidney disease-induced by nephrotoxic drugs and renal ischemia.Materials and methods: Human USC were collected, expanded and characterized by flow cytometry. A CKD model was induced by creating an ischemia-reperfusion injury and gentamicin administration. Twenty-eight adult immunodeficient rats were divided into three groups: PBS-treated group (n=9), USC-treated group (n=9), and sham group with age-matched control animals (n=10). Cell suspension of USC (5 x 106 / 100µl / kidney) or PBS was injected bilaterally into the renal parenchyma 9 weeks after CKD model creation. Renal function was evaluated by collection blood and urine samples to measure serum creatinine and glomerulus filtration rate. The kidneys were harvested 12 weeks after cell injection. Histologically, the extent of glomerulosclerosis and tubular atrophy, the amount of collagen deposition, interstitial fibrosis, inflammatory monocyte infiltration, and expression of transforming growth factor beta 1 (TGF-ß1), and superoxide dismutase 1 (SOD-1) were examined.Results: USC expressed renal parietal epithelial cells (CD24, CD29 and CD44). Renal function, measured by GFR and serum Cr in USC-treated group were significantly improved compared to PBS-treated animals (p<0.05). The degree of glomerular sclerosis and atrophic renal tubules, the amount of fibrosis, and monocyte infiltration significantly decreased in USC-treated group compared to the PBS group (p<0.05). The level of TGF-ß1 expression in renal tissues was also significantly lower in the PBS group, while the level of SOD-1 expression was significantly elevated in the USC group, compared to PBS group (p<0.05).Conclusions: The present study demonstrates the nephron-protective effect of USC on renal function via anti-inflammatory, anti-oxidative stress, and anti-fibrotic activity in a dual-injury CKD rat model. This provides an alternative treatment for CKD in certain clinical situations, such as instances where CKD is due to drug-induced nephrotoxicity and renal ischemia.

Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCA-Salt Hypertensive Rats

The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson’s trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-β1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.

The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes.

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.

Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.

Background and ObjectiveWe have reported that toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), play an important role in the progression of diabetic nephropathy in mice. The aim of this study was to evaluate significance of kidney MRP8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.MethodsIn diabetic, obese or control subjects, MRP8 mRNA and protein expression levels in renal biopsy samples were determined by real-time RT-PCR and immunohistochemistry (n = 28 and 65, respectively), and their associations with baseline and prognostic parameters were analyzed. Effects of MRP8 upon pro-inflammatory gene expressions were examined using macrophages.ResultsKidney MRP8 gene and protein expression levels were elevated in obese or diabetic groups compared to control group. Among all subjects, by univariate linear regression analysis, glomerular MRP8-positive cell count and tubulointerstitial MRP8-positive area at baseline were both, respectively, correlated not only with various known risk factors for diabetic nephropathy (such as systolic blood pressure, proteinuria and serum creatinine) but also with extent of glomerulosclerosis and tubulointerstitial fibrosis. Independent factors predicting urinary protein levels a year later were examined by multivariate analysis, and they included glomerular MRP8-positive cell count (β = 0.59, P<0.001), proteinuria (β = 0.37, P = 0.002) and systolic blood pressure (β = 0.21, P = 0.04) at baseline, after adjustment for known risk factors. MRP8 protein expression was observed in CD68-positive macrophages and atrophic tubules. In cultured mouse macrophages, MRP8 protein induced proinflammatory cytokine expressions and also triggered auto-induction of MRP8 in a TLR4-dependent manner.ConclusionsGlomerular MRP8 expression appears to be associated with progression of proteinuria in obese or type 2 diabetic patients, possibly by inducing inflammatory changes in macrophages through TLR4 signaling.

Protective effects of angiotensin‐(1–7) administrated with an angiotensin‐receptor blocker in a rat model of chronic kidney disease

Angiotensin-(1-7) (Ang-(1-7)) opposes angiotensin-II-induced cell growth, matrix accumulation and fibrosis in cardiac tissue. However, the role of Ang-(1-7) in the pathogenesis of renal fibrosis is uncertain. This study observed the effects of Ang-(1-7), on its own or in combination with losartan, an angiotensin-receptor blocker, on five-sixths nephrectomized rats. Male Sprague-Dawley rats underwent five-sixths nephrectomy, and then were either untreated, treated with Ang-(1-7), treated with losartan, or treated with a combination therapy of Ang-(1-7) and losartan. After 8 weeks, renal function was assessed by measuring systolic blood pressure, serum creatinine and proteinuria. The effect of nephrectomy on the renin-angiotensin system was examined by measuring plasma levels of Ang-II and Ang-(1-7). The extent of glomerulosclerosis and tubulointerstitial fibrosis was assessed by periodic acid-Schiff staining and Masson-trichrome staining. The expression of plasminogen activator inhibitor-1, fibronectin and angiopoietins-Tie-2 was investigated by immunohistochemistry and western blot. In the groups of treated rats, serum creatinine, proteinuria and markers of glomerulosclerosis, such as fibronectin and plasminogen activator inhibitor-1, were ameliorated compared with the untreated, nephrectomized rats. Plasma Ang-(1-7) levels were elevated in all treatment groups, but the plasma Ang-II levels were reduced in the Ang-(1-7)-treated group and the combination therapy group. The ratio of Ang-1/Ang-2 was increased in the combination therapy group compared with two other treatment groups. Ang-(1-7) ameliorated the renal injury of nephrectomized rats. The combination of Ang-(1-7) treatment alongside losartan exerted a superior effect to that of Ang-(1-7) alone on regression of glomerulosclerosis.

Magnetic Resonance Diffusion Tensor Imaging for Evaluation of Histopathological Changes in a Rat Model of Diabetic Nephropathy

The aim of this study was to investigate whether magnetic resonance (MR) diffusion tensor imaging (DTI) allows assessment of renal pathologies in a rat model of diabetic nephropathy. Twenty-one male Sprague-Dawley rats were divided into 3 groups: (1) untreated controls, (2) diabetes (DM), (3) diabetes with uninephrectomy (DM UNX) to accelerate renal impairment. Eight weeks after diabetes induction with streptozotocin, MR imaging was performed in a 1.5-T scanner using an 8-channel wrist coil. Morphological proton density images and echoplanar DTI were obtained (b = 0 and 300 s/mm, 6 diffusion directions). Renal apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were calculated for each of the different anatomical layers of the kidney. Imaging results, laboratory parameters of diabetic state and kidney function, and renal histopathological changes (glomerulosclerosis, tubular dilatation, and renal fibrosis) were compared between groups. Correlations between FA and histopathological changes were evaluated. All diabetic animals developed hyperglycemia and hypoinsulinemia. Uremia, albuminuria, and histopathological changes were most pronounced in DM UNX animals. Fractional anisotropy was significantly reduced in DM UNX animals in the cortex (CO) (0.167; confidence interval [CI], 0.151-0.184; P < 0.001), outer stripe of the outer medulla (OS) (0.254; CI, 0.225-0.283; P = 0.038), and inner medulla (IM) (0.459; CI, 0.395-0.523; P = 0.008) compared with control animals (CO, 0.251; CI, 0.224-0.277; OS, 0.309; CI, 0.267-0.350; IM, 0.559; CI, 0.515-0.603). In DM-without-UNX animals, only cortical FA was significantly lower than in controls (P < 0.001). Between groups, ADC values were not different, except for cortical ADC, which was higher in DM UNX animals than in controls. Significant negative correlations were observed between the FA of different anatomical layers and the extent of glomerulosclerosis (CO, P = 0.003, r = -0.65; and OS, P = 0.022, r = -0.52), tubulointerstitial fibrosis (IM, P = 0.028, r = -0.50), and tubular dilatation (CO, P = 0.015, r = -0.55; and IM, P = 0.006, r = -0.61), respectively. Magnetic resonance DTI by reduction of FA identified renal pathologies of diabetic nephropathy such as glomerulosclerosis, interstitial fibrosis, and tubular damage. Representing different stages of disease, DM and DM UNX animals could be differentiated. Thus, MR DTI may be valuable for noninvasive detection and monitoring of renal pathology in patients with diabetes.

Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy

Ethnopharmacological relevanceSchisandra chinensis fruit is widely used in Chinese medicine for the treatment of hepatic, renal, heart, cerebrovascular and infectious diseases. Aim of the studyTo investigate the effects of Schisandra chinensis fruit extract (SE) on albuminuria and podocyte injury as well as the underlying mechanism in the mouse model of streptozotocin (STZ)-induced diabetic nephropathy and in cultured mouse podocyte cells. Materials and methodsSE was orally administrated in STZ-induced diabetic nephropathy mice for 7 weeks, at a daily dose of 5g/kg body weight. The urinary albumin/creatinine ratio and urine albumin excretion rate were measured at the 6th and 9th week of the experiment. The extent of glomerulosclerosis and extracellular matrix deposition were determined by periodic acid-silver methenamine and Masson's trichrome staining. The amount of podocytes and the integrity of the slit diaphragm were detected by immunohistological staining of podocyte markers, Wilms’ tumor 1 and nephrin. Alpha-smooth muscle actin, E-cadherin and plasminogen activator inhibitor-1 were measured by western blot and immunohistological staining to evaluate the level of epithelial-to-mesenchymal transition (EMT). Real-time reverse transcription PCR was used to detect the mRNA level of E-cadherin, alpha-SMA and snail in cultured podocyte cells. ResultsTreatment with SE significantly decreased the urine albumin excretion rate and urinary albumin/creatinine ratio. In addition, SE attenuated glomerulosclerosis and protected against podocyte loss and integrity of the slit diaphragm. Furthermore, SE effectively prevented the EMT of podocytes caused by diabetic nephropathy. ConclusionsOur studies suggest that SE might be beneficial for diabetic nephropathy. The effects of SE on attenuating albuminuria and glomerulosclerosis are possibly mediated by preserving podocyte integrity through suppressing EMT.

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

Background/Aims: Sildenafil, the first selective phosphodiesterase-5 (PDE5) inhibitor to be widely used for treating erectile dysfunction, has been investigated with regard to its cardioand renoprotective effects in animal models. This study further investigated the renoprotective effects of sildenafil and their molecular mechanisms in deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. Methods: DOCA strips (200 mg/kg) were implanted in rats 1 week after unilateral nephrectomy. These rats were fed on a control diet, with or without sildenafil (50 mg·kg^–1day^–1), for 2 weeks. Systolic blood pressure (SBP) was measured by the tail cuff method, and the urinary albumin-to-creatinine ratio (ACR) was calculated. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson’s trichrome stain. Renal expression of ED-1, transforming growth factor-β1 (TGF-β1), Bax, and Bcl-2 were determined by semiquantitative immunoblotting, polymerase chain reaction (PCR), and immunohistochemistry. TUNEL staining was used for detecting apoptotic cells. Results: The increased SBP in DSH rats was not attenuated by sildenafil treatment. The decreased creatinine clearance and increased ACR in DSH rats, compared with control animals, were attenuated by sildenafil treatment. Further, sildenafil treatment attenuated glomerulosclerosis and tubulointerstitial fibrosis in DSH rats and counteracted the increased expression of ED-1, TGF-β1, and Bax and the decreased expression of Bcl-2 in the kidneys of these rats. The increase in the number of apoptotic cells in DSH rats was attenuated by sildenafil treatment. Conclusion: Sildenafil effectively prevented the progression of renal injury in DSH rats via its anti-inflammatory, antifibrotic, and antiapoptotic effects.

Ischaemic nephropathy secondary to atherosclerotic renal artery stenosis: clinical and histopathological correlates

Advanced renal artery stenosis (RAS) may cause progressive deterioration in renal function. We correlated the histopathological findings and clinical characteristics in selected patients with atherosclerotic RAS who underwent nephrectomy of their small kidneys for resistant renovascular hypertension. We studied 62 patients who underwent nephrectomy of a small kidney for uncontrolled hypertension between 1990 and 2000. The mean patient age was 65.4 ± 9.6 years; 28 (45%) were men. Significant tubulointerstitial atrophy with relative glomerular sparing was the predominant pattern of injury in 44 (71%) patients. In 14 (23%) patients, diffuse global glomerulosclerosis was present. The severity of tubulointerstitial atrophy and the extent of glomerulosclerosis were both associated with smaller kidney size (P = 0.002). Three patterns of vascular involvement were present: atheroembolic, atherosclerotic and hypertensive vascular changes, which were documented in 39, 98 and 52% of subjects, respectively. The presence and severity of these vascular changes positively correlated with both atherosclerotic risk factors, such as hypertension, dyslipidaemia and renal insufficiency, and cardiovascular morbidity, including abdominal aortic aneurysm and myocardial infarction. Patients on statin therapy were noted to have less evidence of renal fibrosis as measured by transforming growth factor-beta staining (P = 0.003). The severity of renal histopathological findings in patients who underwent nephrectomy for resistant hypertension correlated with an increased prevalence of cardiovascular disease, a greater degree of renal dysfunction and more severe dyslipidaemia. Statin therapy may affect development of intra-renal injury by slowing the progression of fibrosis.

ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.

Renal mRNA levels as prognostic tools in kidney diseases.

Molecular biologic techniques are currently considered as new diagnostic and prognostic parameters with a sensitivity and specificity exceeding those of histologic and functional data currently used in clinical practice. The results in various clinical settings have been of limited value up to now. This study is an investigation of the use of tissue levels of RNA determined in routine clinical kidney biopsies as prognostic tools. The focus was on RNA encoding for molecules known to be involved in the pathogenesis of renal disorders. Fresh kidney biopsy tissue was obtained from 52 patients with various renal diseases. The GFR was followed for 12 mo. The extent of glomerulosclerosis and interstitial fibrosis in the biopsies was determined with quantitative digital image analysis. Glomerular and tubulointerstitial compartments from each biopsy specimen were separated, and mRNA levels of TGF-beta, collagen I, collagen IV, and fibronectin were quantitated by real-time PCR. Correlations, along with 95% confidence intervals (CI), between all variables tested at time biopsy were determined. To assess their prognostic value, these variables were correlated with the slope of GFR within several time intervals after biopsy. In addition, to evaluate the predictive value of the variables for outcome in individual patients, differences for each variable were tested between patients showing progressive decline in renal function (slope GFR < 0) and patients showing stable or improving renal function over time (slope GFR >or= 0). In chronic renal diseases, the extent of histologic damage correlated with the GFR at the time of biopsy (r = -0.44; CI -0.68 to -0.11), but it did not correlate with the slope expressing a change in GFR after the biopsy. Tubulointerstitial TGF-beta mRNA levels correlated with the rate of change in GFR between time of biopsy and 1 mo later (r = 0.41; CI, 0.07 to 0.67). The GFR at the time of biopsy correlated with the slope of change in GFR between time of biopsy and 12 mo later (r = -0.50; CI, -0.73 to -0.18). In chronic renal diseases, glomerular fibronectin mRNA levels, in comparison with the GFR at time of biopsy, correlated relatively strongly with the slope of change in GFR between 3 and 12 mo (r = 0.50; CI, 0.16 to 0.74). Patients with favorable renal outcome after 12 mo showed significantly higher TGF-beta mRNA levels and lower proteinuria levels at time of biopsy (P < 0.05) than patients with a progressive decline in renal function. This study shows that mRNA levels measured in kidney biopsies can function as prognostic tools in human renal diseases. In particular, relatively high levels of tubulointerstitial TGF-beta mRNA and glomerular fibronectin mRNA are associated with less deterioration in renal function.

Renal Pathology in Fabry Disease

Fabry disease is an X-linked recessive lysosomal storage disease that is caused by deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A), an enzyme that cleaves terminal α-galactosyl residues. This deficiency results in progressive lysosomal accumulation of glycosphingolipid with

Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes.

Previous studies demonstrated that 2 mo of dietary supplementation with alpha-lipoic acid (LA) prevented early glomerular injury in non-insulin-treated streptozotocin diabetic rats (D). The present study examined the effects of chronic LA supplementation (30 mg/kg body wt per d) on nephropathy in D after 7 mo of diabetes. Compared with control rats, D developed increased urinary excretion of albumin and transforming growth factor beta, renal insufficiency, glomerular mesangial matrix expansion, and glomerulosclerosis in association with depletion of glutathione and accumulation of malondialdehyde in renal cortex. LA prevented or ameliorated all of these changes in D. Because chronic LA supplementation also attenuated hyperglycemia in D after 3 mo, its effects on renal injury were compared with treatment of rats with sufficient insulin to maintain a level of glycemic control for the entire 7-mo period (D-INS) equivalent to that observed with LA during the final 4 mo. Despite superior longitudinal glycemic control in D-INS, urinary excretion of albumin and transforming growth factor beta, glomerular mesangial matrix expansion, the extent of glomerulosclerosis, and renal cortical malondialdehyde content were all significantly greater, whereas cortical glutathione content was lower than corresponding values in D given LA. Thus, the renoprotective effects of LA in D were not attributable to improved glycemic control alone but also likely reflected its antioxidant activity. The combined antioxidant and hypoglycemic actions of LA both may contribute to its utility in preventing renal injury and other complications of diabetes.

Combined Mycophenolate Mofetil and Losartan Therapy Arrests Established Injury in the Remnant Kidney

Previously it was shown that early treatment with mycophenolate mofetil (MMF) attenuated renal inflammation, glomerulosclerosis (GS), and interstitial expansion in the 5/6 ablation (NX) model. Angiotensin II antagonists also mitigate renal injury in NX, presumably by lowering glomerular pressure (P(GC)). This study investigated: (1) whether combined MMF/angiotensin II antagonists treatment affords superior protection compared with the respective monotherapies; and (2) whether this association is effective even when instituted late in the course of the disease. Adult male Munich-Wistar rats underwent NX, remaining untreated for 30 d. BP, albuminuria, and the extent of GS, interstitial expansion, and macrophage infiltration were then determined in 17 rats. The remaining 118 rats received either inert vehicle or one of the following: MMF, 10 mg/kg by gavage once daily; losartan potassium (L), 20 mg/dl in drinking water; or combined MMF/L treatment. Sixty days after ablation, untreated NX rats exhibited marked glomerular hypertension, which was attenuated by MMF and, more effectively, by either L or combined MMF/L treatment. At 120 d, hypertension and albuminuria were worsened in untreated NX rats, which exhibited intense macrophage infiltration and severe glomerular and interstitial disease. L and, to a lesser extent, MMF monotherapies attenuated these abnormalities, without preventing their progression. In rats given combined MMF/L therapy, macrophage infiltration, GS, and interstitial expansion remained at pretreatment levels. By acting on two distinct pathogenic mechanisms, combined MMF/L treatment arrested established renal injury in the NX model. Further investigation is needed to determine whether this association can prevent renal scarring in other models and in human disease.

Platelet-derived growth factor in experimental glomerulonephritis

Growth factors and in particular platelet-derived growth factor (PDGF) have been implicated in the pathogenesis of glomerulonephritis and glomerulosclerosis. We have studied the distribution of immunoreactive PDGF (iPDGF) within serial kidney biopsies (days 7, 15, 30, 90 and 120) of eight rats with an accelerated form of nephrotoxic serum nephritis (NTN). The course of NTN was mild in five rats and seere in three. Two patterns of immunostain for PDGF were noted. The first consisted of iPDGF-B chain in a glomerular segmental distribution similar to that of infiltrating monocytes (OX6+cells). At all stages of NTN the distribution of iPDGF-B chain correlated closely with the immunostain for monocytes. The second pattern of immunostain showed iPDGF-A chain in a diffuse distribution along the glomerular capillary lining and to a lesser extent in some mesangial cells. In severely affected rats the magnitude of the iPDGF-A increased along with glomerulosclerosis but disappeared later from areas of segmental and global glomerular obsolescence. By contrast, in rats with milder NTN glomerular iPDGF-A chain peaked early and decreased subsequently.(ABSTRACT TRUNCATED AT 250 WORDS)