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The accumulation of advanced glycation end products (AGE) is a key factor in diabetic nephropathy (DN). Pyridoxamine inhibits AGE formation and protects against type I DN. Herein we tested: (1) whether C57BL6 db/db mice as a model of established type II DN resembled patients treated with drugs which inhibit angiotensin II action; (2) whether pyridoxamine was effective as a single therapy; and (3) whether pyridoxamine would add to the benefit of angiotensin-converting enzyme inhibition (ACEi) by enalapril. In first set of experiments mice were treated with ACEi (benazepril) and an angiotensin II receptor blocker (valsartan) combination for 16 weeks after the onset of diabetes. In second group, mice with established DN were treated with pyridoxamine for 8 weeks. In a third set, mice with established DN were treated with pyridoxamine and enalapril combination for 16 weeks. Benazepril and valsartan combination partially prevented the development and progression of DN. Pyridoxamine treatment, as single therapy, decreased the progression of albuminuria and glomerular lesions. The combination of pyridoxamine with enalapril reduced both mortality and the progression of DN. In conclusion, (1) C57 BL6 db/db mice are a model of progressive type II DN; (2) The combination of pyridoxamine with enalapril decreased progression of type 2 DN and overall mortality. Thus, pyridoxamine could be a valuable adjunct to the current treatment of established type II DN.Kidney International (2006) 70, 507–514. doi:10.1038/sj.ki.5001578; published online 14 June 2006 [ABSTRACT FROM AUTHOR]

Although recurrent diabetic nephropathy is common in patients with type I diabetes after kidney transplantation, the development of focal segmental glomerulosclerosis (FGS) is rare, and its development generally takes several years. We report here a case of type I diabetes mellitus with secondary FGS accompanied by proteinuria 10 months following kidney transplantation. Episode biopsy showed secondary FGS, evidenced by glomerular capillary collapse and large epithelial cells with ballooning degeneration. Exudative dense deposition of IgM in a diffuse global mesangial pattern and enlarged glomerular diameters were observed, suggestive of glomerular hyperfiltration which can lead to secondary FGS. An imbalance in body size between donor and recipient and/or uncontrolled diabetes are potential causes of glomerular hyperfiltration. We administered angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker to reduce hyperfiltration-induced renal damage; the combination therapy reduced proteinuria from 2346 to 258 mg/d. Secondary FGS should be a consideration after kidney transplantation in patients with type I diabetes mellitus. [ABSTRACT FROM AUTHOR]

OBJECTIVE To monitor the decrease in the number of glomeruli in reflux nephropathy (RN) and to investigate its association with glomerular hypertrophy or clinical data, as some cases of RN progress to end-stage renal failure, although the mechanism of progression remains unknown and is generally thought to depend on remnant normal renal tissue mass, i.e. the number of remnant renal glomeruli (functional nephrons). PATIENTS AND METHODS From 1987 onward, a renal biopsy was taken in 71 patients (mean age 8.08 years) in two institutions to estimate the prognosis of patients with RN. The number of glomeruli per unit area and glomerular size in grossly normal renal tissue specimens were determined to explore the potential association between these variables and the total renal scars, renal function (glomerular filtration rate, GFR), or daily urinary protein excretion. RESULTS The number of glomeruli was closely correlated with the actual size of glomeruli ( y = 14.783 − 0.052 x, R = 0.782). To a lesser extent, the number of glomeruli was also closely correlated with the size of glomeruli expressed insds ( y = 6.264 − 0.832 x, R = 0.630). There was a good correlation between the number of glomeruli and the extent of renal scarring, renal function, or daily urinary protein excretion, although its association with renal function (GFR) was least evident. CONCLUSION There was an association between the decrease in the number of glomeruli and glomerular hypertrophy, decreased renal function, or increased proteinuria. A renal biopsy taken from radiographically and macroscopically normal regions can be useful for assessing RN, and the size and number of glomeruli in the specimens might provide an important measure for estimating the prognosis of RN. [ABSTRACT FROM AUTHOR]

Rat male hypogonadism ( hgn/hgn) is accompanied by oligomeganephronic hypoplastic kidney (HPK), in which each kidney contains one quarter the number of nephrons present in a normal kidney. The nephrons of the HPK are extremely hypertrophied. These characters were apparently common to human oligomeganephronia (OMN). To determine the age-related changes in renal pathophysiology in HPK rats, we measured several parameters of renal function at 70 days, 140 days, 210 days, and 280 days of age. At all time points, relative kidney weight was significantly smaller in HPK rats than in their normal litter mates. In HPK rats, both polyuria and polydipsia became more severe with advancing age. Although creatinine clearance (Ccr) and urinary nitrogen clearance (Cun) were significantly lower in HPK than in normal rats, the values did not decrease with age. A severe form of glomerulosclerosis, as well as interstitial infiltration and cystic dilation of tubules with proteinaceous luminal casts, was observed in the inner cortex and medulla of HPK rats at advanced age. In these animals the surface glomeruli retained their functional architecture but were hypertrophied. Both mean blood pressure (MBP) and proteinuria became more elevated with age in HPK rats, and their urine samples included considerable amounts of high molecular weight protein. These results suggest that the HPK rat is a suitable model of human OMN. [ABSTRACT FROM AUTHOR]

In diabetic nephropathy, glomerular hypertrophy is evident early in response to hyperglycaemia. Alterations of capillary length and vascular remodelling that may contribute to glomerular hypertrophy and the subsequent development of glomerulosclerosis remain unclear. The present study used the db/db mouse model of Type 2 diabetes to examine the glomerular microvascular changes apparent with long-term diabetic complications. Unbiased stereological methods and high-resolution light microscopy were used to estimate glomerular volume, and glomerular capillary dimensions including length and surface area in 7-month-old db/db diabetic mice and age-matched db/m control mice. The db/db diabetic mice showed significant glomerular hypertrophy, corresponding with elevated blood glucose levels, and increased body weight and kidney weight, compared with db/m control mice. Glomerular enlargement in db/db mice was associated with increases in the surface area (5.387 ± 0.466 × 104 µm2 vs. 2.610 ± 0.287 × 104 µm2; P < 0.0005) and length (0.3343 ± 0.022 × 104 µm vs. 0.1549 ± 0.017 × 104 µm; P < 0.0001) of capillaries per glomerulus, compared with non-diabetic mice. Stereological assessment at the electron microscopic level revealed increased glomerular volume density of mesangial cells and mesangial matrix, and thickening of the glomerular basement membrane in db/db mice. These results demonstrate that glomerular hypertrophy evident in advanced diabetic nephropathy in this model is associated with increased length and surface area of glomerular capillaries. The contribution of angiogenesis and vasculogenesis to the glomerular microvascular alterations in response to hyperglycaemia remain to be determined. [ABSTRACT FROM AUTHOR]

Nishi S, Imai N, Alchi B, Iguchi S, Ueno M, Fukase S, Mori H, Arakawa M, Saito K, Takahashi K, Gejyo F. The morphological compensatory change of peritubular capillary network in chronic allograft rejection. Clin Transplant 2005: 19 (Suppl. 14): 7–11.© Blackwell Munksgaard, 2005 To clarify the compensatory hemodynamic alterations in the interstitium of renal allograft biopsies with chronic rejection, we evaluated the morphological changes in the peritubular capillary (PTC) network. Seven renal biopsy specimens from recipients with chronic rejection presenting with elevation of serum creatinine of 1.9 ± 0.5 mg/dL were examined. Renal biopsy specimens from their counterpart donors were used as normal controls. In each specimen, non-pathological interstitial areas without fibrosis, tubular atrophy or cell infiltration were compared with pathological areas (PA) showing fibrosis and/or tubular atrophy using a computer image analysis. Morphological measurements revealed that the mean cut surface area of the PTC in the non-pathological and pathological interstitial areas in the recipient biopsies were significantly larger than that of the normal controls (p < 0.001 and 0.001, respectively). In the recipient biopsies, both of the mean cut surface areas of the tubules and PTC in the non-pathological areas were significantly higher than those in the PA (p < 0.001). The mean glomerular diameter in the recipient biopsies was also significantly higher than that of the donors (p < 0.01). In this study, we provided pathological evidence for the compensatory interstitial and glomerular hemodynamic alterations in kidney graft with chronic rejection and the condition as single kidney. [ABSTRACT FROM AUTHOR]

Background: We have already reported Gas6 is involved in glomerular hypertrophy observed in diabetic nephropathy. However, the molecular mechanisms involved in glomerular hypertrophy are still unknown, especially in vivo.Methods: In vivo, diabetes was induced in rats and mice by streptozotocin (STZ) and the activation of the Akt/mTOR pathway in glomeruli was examined. In vitro, mesangial hypertrophy was assessed by [(3)H]leucine incorporation and measuring cell areas.Results: Akt, p70 S6 kinase, and 4E-BP-1 were induced and phosphorylated in rat glomerular lysates after 12 weeks of STZ injection when mesangial and glomerular hypertrophy was observed. We then examined the role of Gas6 by treating STZ-rats with warfarin, and found that warfarin treatment inhibited the phosphorylation of these molecules as well as the hypertrophy. We next examined whether high glucose stimulation can induce the expression of Gas6/Axl in mesangial cells. Stimulation of the cells with 25 mmol/L of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/L of glucose. This hypertrophic effect was abolished in mesangial cells derived from Gas6 knockout mice. We also found that LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Furthermore, less phosphorylated Akt-positive or 4E-BP-1-positive areas were found in STZ-treated Gas6 knockout mice than in STZ-treated wild-type mice.Conclusion: Our study indicates that the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy and revealed a crucial role of Gas6/Axl and the Akt/mTOR pathway in the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: AST-120, an oral adsorbent, inhibits progression of diabetic nephropathy by reducing albuminuria. The purpose of the present study was to explore the mechanism underlying the protective effect of AST-120 against albuminuria. Methods: Twenty-four male Sprague-Dawley rats underwent intravenous injection of streptozotocin and subsequent uninephrectomy. Half of the rats were fed standard rat chow, and the other half were fed rat chow containing AST-120. All rats were killed at week 6 after a clearance study. Results: There were no significant differences in body weight, kidney weight, urinary volume, blood pressure, blood glucose or inulin clearance between the two groups at week 6. However, urinary albumin excretion at week 6 was significantly lower in the AST-120 group than in the control group (p < 0.05). Light microscopic observation showed that the planar area of glomeruli was significantly smaller in the AST-120 group than in the control group (p < 0.01), and the shortest diameter of proximal tubules was less in the AST-120 group than in the control group (p < 0.01). Electron microscopic observation showed a significantly greater number of anionic sites on the lamina rara externa of the glomerular basement membrane in the AST-120 group than in the control group (p < 0.01). Conclusion: We conclude that AST-120 reduces albuminuria by preventing the decrease in the number of anionic sites in the glomerular basement membrane in rats with diabetic nephropathy. In addition, AST-120 inhibits the appearance of glomerular and tubular hypertrophy. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Rats submitted to chronic hypoxia develop hypertension that persists despite cessation of the hypoxia or correction of the hematocrit. We examined whether chronic hypoxia might induce subtle renal injury since studies in other animal models of hypertension suggest this may cause persistent hypertension. Methods: Chronic hypoxia was induced in rats by placement in a hypobaric chamber for up to 24 days. Blood pressure and kidney biopsies were performed at baseline, 6 hours, 24 hours, and 24 days of hypoxia. Results: Chronic hypoxia induced hypertension and erythrocytosis at 24 days. Acute hypoxia was associated with endothelial cell swelling in arterioles (6 and 24 hours), followed by thickening of the arterioles at 24 days. Subtle tubulointerstitial injury and inflammation occurred and was progressive. The influx of macrophages increased steadily over the 24 days and was associated with a progressive increase in interstitial collagen III deposition. Hypoxia was associated with increased tubular expression of osteopontin as early as 6 hours, the same period when an increase of proximal tubular cell proliferation occurred. Interstitial cell proliferation peaked twice, at 6 hours and at 24 days. Glomerular hypertrophy was manifest at 24 days. Conclusion: Both afferent arteriolar disease and subtle tubulointerstitial inflammation and injury occur early in hypoxic rats. These changes may predispose these animals to persistent hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Although graft dysfunction has been increasingly reported in post-transplant IgA nephropathy (Tx-IgAN), intragraft morphological changes have been largely overlooked. We evaluated glomerular changes in Tx-IgAN to identify the histological features pertaining to significant proteinuria and therapeutic response to enalapril. Materials and methods: Fifty-four renal allograft biopsies, diagnosed as Tx-IgAN at a median of 46 months after transplantation, were the subject of the study. In 10 patients, glomerular morphometry was performed. In 14 patients who have been treated with enalapril for more than 12 months, we correlated the therapeutic response to enalapril with allograft histology. Results: No uniform pattern was found in the glomeruli of Tx-IgAN. The glomerular mesangium was mostly indistinct. Interstitial fibrosis was negative or mild in 88.9%. By morphometry, the glomerular tuft areas and mesangial areas were significantly larger in Tx-IgAN than those of the normal native kidney (p < 0.05), but were not different from transplant cases without glomerulonephritis. Proteinuria of ≥1 g/24 h was correlated with glomerulosclerosis, interstitial fibrosis and interstitial inflammation at time of biopsy (p < 0.005). The presence of segmental sclerosis (SS) correlated well with the amount of 24-h proteinuria (p < 0.001). After treatment with enalapril, the amount of proteinuria reduced in 64.3%. Therapeutic response to enalapril tended to be less effective in patients having SS (28.6 versus 71.4%), but this finding did not reach a statistical significance. Conclusions: Significant proteinuria was associated with advanced chronic injury, especially with the presence of SS in Tx-IgAN, but anti-proteinuric effect of enalapril was not affected by graft histology. It remains to be clarified whether glomerular mesangial expansion plays a role in graft dysfunction in a subset of Tx-IgAN showing prominent mesangial changes. [ABSTRACT FROM AUTHOR]

Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Background. Strict glycemic control and antihypertensive treatment may decrease but not eliminate the risk of progressive nephropathy in diabetic patients. C-peptide has been shown to exert beneficial effects on complications, including incipient nephropathy, in type 1 diabetes. Methods. Renal effects of 14 days of intravenous infusion of C-peptide or NaCl (placebo) were studied in three groups of rats: one nondiabetic NaCl-treated (normal, N = 7), one streptozotocin diabetic NaCl-treated (D-placebo, N = 7), and one streptozotocin diabetic C-peptide-treated group (D-C-p, N = 7). Metabolic data and albuminuria were measured in metabolic cages every fourth day. After 14 days, the glomerular filtration rate (GFR) was measured by inulin clearance and available renal functional reserve (RFR) by glycine infusion, whereupon one kidney was perfusion fixed for morphological studies. Results. Glucose levels were 36.7 ± 1.3 and 34.0 ± 1.7 mmol/L in the D-placebo and D-C-p groups, respectively. The D-placebo group presented a 32% (P < 0.001) larger glomerular volume than the D-C-p group. The D-placebo group also presented a significantly larger renal weight than the normal group in contrast to the D-C-p group. Urinary albumin excretion increased in the D-placebo group in contrast to the other groups. GFR was 1.72 ± 0.12 mL/min (normal), 3.73 ± 0.19 mL/min (D-placebo, P < 0.001 vs. normal) and 2.16 ± 0.16 mL/min (D-C-p, nonsignificant vs. normal). Available RFR was 93 ± 25% (normal), 10 ± 4% (D-placebo, P < 0.05 vs. normal) and 57 ± 13% (D-C-p, nonsignificant vs. normal) of basal GFR. Conclusions. Physiological doses of homologous C-peptide prevent the development of glomerular hypertrophy, albuminuria, and glomerular hyperfiltration in rats with experimentally induced diabetes. [ABSTRACT FROM AUTHOR]

Details of renal structural changes and structural-functional relationships at the early stage of diabetic nephropathy (DN) in type 2 diabetes are not well known. The present review focuses on these topics from previous studies using light and electron microscopic morphometric analysis. Glomerular hypertrophy, one of the histological changes in DN, is present in type 2 as well as in type 1 diabetic patients. However, mechanisms of increased glomerular size might be different from those in type 1 diabetes. Other typical glomerular changes, glomerular basement membrane thickening and mesangial expansion, are present in normoalbuminuric type 2 diabetic patients as a group. However, these parameters are similar between normo- and microalbuminuric patients. Renal structural-functional relationships cannot be seen in type 2 diabetic patients and therefore urinary albumin might not be a reliable indicator for glomerular structural changes in type 2 diabetic patients. Although previous reports showed reversibility of advanced diabetic glomerulosclerosis in type 1 diabetes by 10 years of strict glycemic control, there is no report regarding histological reversibility by therapeutic interventions in type 2 diabetic patients. In addition, it is unclear whether DN lesions are concordant or discordant with diabetic retinopathy grade in type 2 diabetes. From this information, renal structural changes or structural-functional relationships in type 2 diabetic patients might be heterogeneous and different from those in type 1 diabetic patients. Careful longitudinal study of renal structure and function including serial renal biopsy at the early stage of DN in type 2 diabetes is necessary. [ABSTRACT FROM AUTHOR]

Aims/ hypothesis. Renal hypertrophy occurs early in diabetes mellitus and precedes the development of glomerulosclerosis and tubulointerstitial fibrosis. We have previously shown that cultured mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and undergo cellular hypertrophy. High glucose-mediated induction of p27Kip1, an inhibitor of cyclin-dependent kinases, is essential in this process. Further investigations have also shown that p27Kip1 and p21Cip1, other cyclin-dependent kinase inhibitors, are up regulated in the kidneys of mice with Type I (insulin-dependent) as well as Type II (non-insulin-dependent) diabetes mellitus. Our study was undertaken to test a potential effect of short-term treatment with the angiotensin-converting enzyme inhibitor enalapril on the glomerular expression of the cyclin-dependent kinase inhibitors p16INK4, p21Cip1, and p27Kip1 in BBdp rats, an autoimmune model of Type I diabetes.¶ Methods. We evaluated p16INK4, p21Cip1, and p27Kip1 protein expression in isolated glomeruli by western blots. We also assessed p27Kip1 positive glomerular cells by immunohistochemistry.¶ Results. Glomerular expression of all three cyclin-dependent kinase inhibitors were stimulated in BBdp rats compared with non-diabetic BBdr animals. Enalapril treatment for 3 weeks, started after the onset of diabetes, reduced the glomerular expression of p16INK4 and p27Kip1 but not of p21Cip1. Enalapril also prevented the increase in kidney weights observed in BBdp rats but had no effect on systolic blood pressure or glucose concentrations.¶ Conclusion/ interpretation. Our data show that enalapril attenuates the glomerular expression of cyclin-dependent kinase inhibitors in diabetes and suggest a molecular mechanism of how angiotensin-converting enzyme inhibitors prevent renal hypertrophy in diabetes. [Diabetologia (1999) 42: 1425–1432] [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a peptide growth factor, and its activity is modulated by interaction with the family of IGF binding proteins (IGFBP-1 to 6). IGF-1 is detected in rat kidney and has metabolic and growth effects. To explore the possible involvement of IGFBPs in glomerular hypertrophy in streptozotocin (STZ)-induced diabetic rat, the immunolocalization of IGF-1 and IGFBPs were investigated. IGF-1 was gradually increased in the glomeruli of diabetic rats and correlated with glomerular hypertrophy. IGFBP-1 was transiently increased at 1 week after the STZ injection and declined to control level during the following period. In contrast, IGFBP-4 was increased in the diabetic glomeruli throughout the observation period. With insulin treatment, the levels of IGF-1, IGFBP-1 and 4 were normalized and glomerular hypertrophy was prevented. Initial glomerular hypertrophy of diabetic nephropathy is a related IGF-1 action, which may be modulated by IGFBP-1 and 4. [ABSTRACT FROM AUTHOR]

Differential response of glomerular epithelial and mesangial cells after subtotal nephrectomy. Recent studies in both human and experimental chronic renal disease suggest that there is a linkage between glomerular hypertrophy and glomerulosclerosis. To further define these relationships, we studied the changes in glomerular hypertrophy, procollagen α1(IV) mRNA levels and glomerulosclerosis in rats undergoing 12/3 nephrectomy (Nx) or sham nephrectomy (SNx). Glomerular hypertrophy, measured biochemically by RNA/DNA and protein/DNA ratios, was significantly increased in Nx compared to SNx two days after subtotal renal ablation (RNA/DNA: Nx = 133 ± 8%, SNx = 100 ± 3% of the mean control value, P < 0.01; protein/DNA: Nx = 164 ± 22%, SNx = 100 ± 10%, P < 0.05) and remained elevated after 7 and 15 days (RNA/DNA: seven days Nx = 155 ± 3%, SNx = 100 ± 13%, P < 0.01; 15 days Nx = 303 ± 21%, SNx = 100 ± 24%, P < 0.001; protein/DNA: seven days Nx = 228 ± 57%, SNx = 100 ± 18%, P < 0.05; 15 days Nx = 341 ± 23%, SNx = 100 ± 18%, P < 0.01). Light microscopic measures of glomerular tuft volume (GTV) were too insensitive to detect glomerular enlargement until 15 days postoperatively, but GTV measured ultrastructurally demonstrated a 20% increment in Nx compared to SNx as early as two days postoperatively (P < 0.01). The latter increment in GTV was due exclusively to glomerular visceral epithelial cell (GVEC) expansion. Glomerular procollagen α1(IV) mRNA levels were significantly elevated only 15 days after nephrectomy (Nx = 265 ± 58% of the mean control value, SNx = 100 ± 12%, P < 0.05; corrected for β-actin mRNA levels). At this time, exuberant mesangial expansion measured ultrastructurally contributed to a 1.6 ± 0.1-fold increase in GTV (P < 10-5 ), and to a relative decrement in the GVEC contribution to glomerular cells plus matrix (P < 0.01). Segmental sclerosis was observed... [ABSTRACT FROM AUTHOR]

Quantitative analysis of the glomerular area, mesangial matrix and mesangial cells was performed using renal biopsy specimens from 22 children with focal segmental glomerulosclerosis (FSGS) and 20 with minimal change nephrotic syndrome (MCNS). Non-sclerotic glomeruli were examined. All children in both groups showed nephrotic syndrome at the time of biopsy. Children with benign haematuria were examined as controls. Glomerular area increased with age in the FSGS, MCNS and control groups. The glomerular area was significantly greater in FSGS (1.5±0.4×10 μm) than in MCNS (1.2±0.2×10 μm) or in controls (1.2±0.3×10 μm) ( P<0.05). Mesangial matrix was increased with age in the three groups. The mesangial matrix was significantly increased in FSGS (28.3±4.0%; mesangial matrix area/glomerular area) compared with MCNS (24.9±4.1%) and controls (23.0±3.0%) ( P<0.01). These findings suggest that both glomerular hypertrophy and mesangial matrix increase in non-sclerotic glomeruli in FSGS may lead to glomerular sclerosis. [ABSTRACT FROM AUTHOR]

Effects of growth hormone (GH) overproduction were studied in transgenic mice expressing murine metallothionein I-GH fusion genes. The most obvious consequence was the acceleration of growth, which led to substantial increases in body weight of up to more than twice that seen in controls. Growth of the internal organs was stimulated, with hepatomegaly and nephromegaly as the most prominent features. GH transgene expression was also reflected in increased skeletal growth which affected various bones to different extents. The mean life-span of human GH transgenic mice with serum levels of hGH ranging from 3×10 to 9×10 ng/ml was drastically reduced at 160 days in both sexes. Severe renal lesions were the primary cause of the decrease in life expectancy and were characterized by marked nephron atrophy, obsolescence of numerous glomeruli, and a massive cystic dilation of the tubules. Initial changes involved the glomeruli, which showed significant enlargement and sclerotic lesions. The liver exhibited a pronounced hepatocellularmegaly and progressive degenerative as well as hyperplastic changes. One-third of the hGH transgenic animals displayed myocardial fibrosis. Hepatocellylar carcinoma was found in bovine GH transgenic mice older than 12 months. Our observations are compared with results of other investigators. [ABSTRACT FROM AUTHOR]

The effects of growth hormone (GH) on renal structure and function were investigated in rats aged 10-16 weeks bearing a tumour secreting GH. Body weight gain, food intake, urine volume, and urinary excretion of cretinine and urea nitrogen were significantly greater in tumour-bearing rats than in controls. The tumour-bearing rats presented progressive proteinuria, hyperproteinaemia, and hyperlipidaemia. Creatinine clearance was significantly higher in experimental animals during the early experimental stage, but decreased as the glomerular lesions progressed, associated with a rise in serum creatinine levels. The glomeruli became progressively enlarged with degenerative changes of the visceral epithelial cells and capsular adhesions. In advanced stages proteinaceous material invaded the subcapsular space and the capillary lumen collapsed finally leading to glomerulosclerosis. Except for the presence of proteinaceous material and damaged epithelial cells the glomerular lesions resemble those observed experimentally after reduction of renal mass, and in diabetes mellitus. We speculate that the pathological features described are due to effects of persistently high levels of circulating GH on the glomerular cells. [ABSTRACT FROM AUTHOR]

The vascular pole area (VPA) and glomerular volume were measured in renal biopsies from 9 insulin-dependent diabetes mellitus (IDDM) patients with normal albumin excretion rate (IDDM group 1), 38 IDDM patients with albumin excretion rate >15 μg/min (IDDM group 2) and 10 living kidney donors (ND). The volume of individual glomeruli was estimated as the sum of profile areas factored by the measured distance between levels, t∼ 10 μm, and VPA as the sum of chords multiplied by t. Mean glomerular volume was increased in IDDM patients but reached statistical significance only in IDDM group 2 ( P = 0.002 vs ND). VPA was significantly different among the groups, mean (CV%) was 2036 (29) μm2 in ND, 3555 (34) μm2 in IDDM group 1, and 3528 (48) μm2 in IDDM group 2, p = 0.004 and 0.001, IDDM versus ND. VPA calculated as a percentage of the surface area of the corresponding glomerulus was 2.4 (23)% in ND, 3.4 (27)% in IDDM group 1, and 3.3 (42)% in IDDM group 2; P = 0.007 and 0.01, IDDM versus ND. The intra-biopsy coefficient of variation was high (20–35%) and of the same order in all groups for all three measurements. Glomerular volume and absolute as well as relative size of VPA showed a positive correlation with estimates of mesangial expansion in IDDM group 2 and the VPA showed a negative correlation with GFR. Thus, part of the enlargement may represent a compensatory phenomenon triggered by the development of structural and functional abnormalities in the diabetic kidney. [ABSTRACT FROM AUTHOR]

Background. Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists. Study design. 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague—Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks. Methods. Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR. Results. SNX caused a significant (P<0.01) increase of systolic blood pressure (170±8.6 mmHg) compared to sham operated controls (131±5.3 mmHg). Blood pressure was significantly (P<0.001) lower with Trandolapril (128±5.3 mmHg), but not with BMS 182874 (153±5.9 mmHg) or Ro 46-2005 (167±7.6 mmHg). Compared to sham operated rats (0.03±0.01) glomerulosclerosis index (GSI) was significantly (P<0.01) higher in the untreated SNX group (0.9±0.15). Significantly lower GSI was found in Trandolapril treated (0.29±0.04), BMS 182874 treated (0.36±0.05), and Ro 46-2005 treated animals (0.45±0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P<0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P<0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower. Conclusion. Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomeruloscierosis by mechanisms which are, at least in part, independent of systemic blood pressure. [ABSTRACT FROM PUBLISHER]

In order to examine the mechanism by which the oral carbonaceous adsorbent, AST-120 delays the appearance of glomerular sclerosis, experiments were carried out in 120 male Sprague-Dawley rats weighing 285–320 g. The rats were first subjected to 2/3, 3/4, and 4/5 nephrectomy (=40). The experiments were begun at 2 weeks after the surgery, and were performed over an 8-week period. Half of each group (=20) was administered 1 g/day of liquid AST-120, and the other half received liquid vehicle solution with pair feeding in each group. In the 2/3 nephrectomized group the administration of AST-120 delayed the occurrence of glomerular hypertrophy and prevented the appearance of glomerular sclerosis without any significant differences in renal function, systemic blood pressure (SBP), and urinary protein excretion (U-P). In the 3/4 nephrectomized group the administration of AST-120 delayed the appearance of glomerular hypertrophy and sclerosis with significant decreases in SBP and U-P. In the 4/5 nephrectomized group the administration of AST-120 delayed the appearance of glomerular sclerosis and prevented a decrease in renal function. It is concluded that administration of the oral adsorbent AST-120 delays the occurrence of glomerular sclerosis by delaying the appearance of glomerular hypertrophy, systemic hypertension, and the increase in proteinuria. It can be therefore mentioned that the accumulating substances in the digestive tract worsen the abnormal milieu of chronic renal failure. [ABSTRACT FROM PUBLISHER]

Aluminium hydroxide, a phosphate binder, is regarded as a strong candidate to halt the progression of chronic renal disease. In order to determine the most effective time to start treatment, aluminium hydroxide was administered either immediately (ADR-0w), or at 8 weeks (ADR-8w) or 16 weeks (ADR-16w) after repeated injection of Adriamycin (ADR) inducing glomerular sclerosis. In the aluminium hydroxideuntreated group the survival rate at the end of the experiment was 50%, while the early initiation of aluminium hydroxide (ADR-0w) resulted in a greater survival rate of 90%. Serum phosphate concentration and serum calcium-phosphate product were significantly less in the aluminium hydroxide groups (ADR-0w, 8w, 16w) than in the untreated group after week 20. Urinary protein excretion was significantly less in the ADR-0w and ADR-8w groups at week 12 or 16 compared to the aluminium hydroxide-untreated group. Blood urea nitrogen in the aluminium hydroxide groups was significantly less than that in the untreated group at week 34. Histological examination revealed that glomerular sclerosis was less severe in the ADR-Ow and ADR-8w groups than in the aluminium hydroxideuntreated group, and glomerular hypertrophy was significantly decreased in the ADR-Ow group. We conclude that early treatment with aluminium hydroxide was effective in preventing renal deterioration in focal glomerular sclerosis induced by Adriamycin. [ABSTRACT FROM PUBLISHER]

Chronic renal failure (CRF) is characterized histologically by progressive glomerulos-clerosis (GS) and tubulo-interstitial scarring (TIS). Recently, research has focused on the study of the pathophysiology of GS. Most advances in this field have been derived from the study of various experimental models of CRF and GS in the rat. In this paper, I will review some of the concepts and hypotheses put forward to explain progressive GS and examine their relevance to glomerular scarring and CRF in humans. [ABSTRACT FROM AUTHOR]

Glomerular ultrastructure was examined in a series of 20 Type 2 (non-insulin-dependent) diabetic patients with proteinuria. Reference was made to data previously obtained in non-diabetic kidney donors and in Type 1 (insulindependent) diabetic patients with similar degrees of proteinuria. The Type 2 diabetic patients demonstrated the changes which characterize the diabetic glomerulopathy seen in Type 1 diabetic patients: basement membrane thickening, and increase in the mesangium and mesangial matrix expressed as fraction of the glomerular volume. Among the Type 2 diabetic patients there was more variation then among the Type 1 diabetic patients, as this group included subjects with normal parameters. The group means and coefficients of variation (=SD/mean) of the glomerulopathy parameters combined in the glomerulopathy index=basement membrane thickness/10+V(matrix/glom)·100 were 81 (0.30) and 92 (0.15) in the two diabetic groups, clearly different from the non-diabetic index, 42 (0.16). All Type 2 diabetic patients who also had retinopathy had a glomerulopathy index above the normal range. Similar changes in glomerular composition were seen in the two diabetic groups: with increasing glomerulopathy the volume of matrix dominated over the peripheral basement membrane, and a shift in the ratio of interfaces was seen: mesangial surface towards capillary lumen increased relative to the urinary surface, and peripheral capillary surface comprised less of the total capillary surface. Data indicated marked glomerular hypertrophy, which correlated with the mesangial volume fraction, thus encompassing preserved filtration surface per glomerulus. An inverse correlation obtained between the index of glomerulopathy and current glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate: (index (glomerulopathy) vs rate of decline in glomerular filtration rate r=0.84, p<0.0001). No correlation was found between glomerular volume and the ensuing rate of decline in glomerular filtration rate. [ABSTRACT FROM AUTHOR]

A clinicopathological and morphometric analysis of glomerular hypertrophy (GH) was conducted using biopsies obtained from 52 selected pediatric patients with IgA nephropathy (IgAN). Of the 52 patients, consisting of 12 with chronic renal failure (CRF) and 40 without CRF, various clinical and morphometric parameters were compared to 10 controls with benign hematuria. The mean glomerular tuft size, mesangial area, and interstitial area all significantly increased in patients with poor prognosis when compared to the non-CRF-IgAN cases and the control cases. The glomerular capillary loop size was also significantly greater in CRF-IgAN than in non-CRF-IgAn patients (1.37 times) and the controls (1.55 times). The 10-year renal survival rates of patients with ‘large’ loop size (>1.55-fold) were significantly lower (p < 0.001) than those of patients with a smaller capillary loop size. The size of the capillary loops was directly related to the relative interstitial area (A[sub int] ) (r[sup 2] = 0.43, p < 0.001), to the degree of glomerulosclerosis (GS; r[sup 2] = 0.348, p < 0.001) and the mesangial area (r[sup 2] = 0.326, p < 0.001). Proteinuria tightly correlated with the capillary loop size (r[sup 2] = 0.374, p < 0.001). It was not unexpected that a strong relationship was detected between the serum creatinine level and A[sub int] (r[sup 2] = 0.452, p < 0.001) and the percentage of GS (r[sup 2] = 0.342, p < 0.001). In IgAN the percentage of GS correlated significantly with A[sub int] (r[sup 2] = 0.484, p < 0.001). GH, which was manifested by glomerular capillary loop dilatation, shows a close correlation with the interstitial expansion, degree of GS and mesangial enlargement. These data suggest that both extra- and intraglomerular hemodynamic changes followed by primary glomerular damage thus lead to capillary dilatation of the intact glomeruli as a morphological manifestation of GH and therefore such changes play a key role in the progression of IgAN. [ABSTRACT FROM AUTHOR]

Although Østerby and coworkers have shown that the onset of diabetes is associated with glomerular hypertrophy and enlargement of the filtration surface, the pathogenesis of this lesion and the behaviour of the glomerular tuft cells during the increase in glomerular filtration surface area remain unclear. Autoradiography and electron microscopic morphometry in kidneys of male Sprague-Dawley rats with streptozotocin-induced diabetes indicate that glomerular enlargement is combined with glomerular cell hyperplasia. 6 days after continuousH-thymidine infusion there is a significant increase in DNA-synthesis in tuft cells indicating cell proliferation. Since podocyte volume only increases in acute diabetes (as shown by Østerby and Gundersen in 1980), and the mean podocyte nuclear area remains unchanged, we conclude that the increased DNA-synthesis results in podocyte hypercellularity so that an increased glomerular filtration surface area can be covered by a greater number of cells. [ABSTRACT FROM AUTHOR]

Renal glomerular structures have been studied during the initial phases of renal and glomerular hypertrophy in streptozotocin diabetic rats. - After four days of diabetes significant increases were found in the following absolute structural quantities: the tuft volume (25%), the surface area (42%) and volume (46%) of peripheral basement membrane, and capillary luminal volume (29%). No further changes in these quantities took place over the succeeding 47 days. The geometry of the capillaries, however, changed over this period: at 4 days the total capillary length had increased significantly (32%) with an unchanged average cross sectional area, whereas at 47 days the length had reverted to normal, but average cross sectional area had increased (30%). The increased surface of filtering area may be the morphological counterpart of increased glomerular filtration rate. The changes in glomerular volume were thus accompanied by changes in glomerular structural composition which after a few weeks returned to normal, in balance with the increased volume. [ABSTRACT FROM AUTHOR]