Decrease In Urinary Protein Excretion Research Articles

Resolution of typical lipoprotein glomerulopathy by intensive lipid-lowering therapy

Lipoprotein glomerulopathy (LPG), characterized by glomerular lipoprotein thrombi, presumably composed of abnormal apolipoprotein E (apoE), leads to a progressive decline in renal function and eventually results in end-stage renal failure. A successful treatment for LPG has not yet been established. The authors treated a 36-year-old woman with LPG and exhibiting a nephrotic syndrome using an intensive lipid-lowering therapy consisting of fenofibrate (300 mg), niceritrol (750 mg), ethyl-icosapentate (1,800 mg), and probucol (500 mg). After the start of treatment, a remarkable decrease in urinary protein excretion and improvement in the hyperlipidemia were obtained; proteinuria was no longer detected 11 months after the initiation of treatment. A second biopsy performed 11 months after the initiation of treatment showed the complete disappearance of the lipoprotein thrombi that had been observed in a diffuse and global manner in the first renal biopsy. These findings suggest that typical LPG could be regressed if the abnormal lipoproteinemia is controlled sufficiently. Am J Kidney Dis 41:244-249. © 2003 by the National Kidney Foundation, Inc.

Differential evolution of blood pressure and renal lesions after RAS blockade in Lyon hypertensive rats.

The present work aimed to assess, in Lyon hypertensive (LH) rats, whether an early and prolonged inhibition of the renin-angiotensin system (RAS) could result in a blood pressure (BP) lowering and nephroprotection that persist after its withdrawal. Male LH rats received orally from 3 to 12 wk of age either an angiotensin-converting enzyme inhibitor perindopril at the doses of 0.4 and 3 mg x kg(-1) x day(-1) or an AT(1) receptor antagonist losartan at the dose of 10 mg x kg(-1) x day(-1). BP, histological changes in the kidney, and urinary protein excretion were examined during and 10 wk after cessation of the treatments. Both perindopril and losartan decreased BP, prevented renal lesions, and limited urinary protein excretion. After cessation of the treatment, BP returned to the level of never-treated LH rats in rats having received 3 mg x kg(-1) x day(-1) of perindopril while it remained slightly lower in those treated with 0.4 mg x kg(-1) x day(-1) of perindopril or with losartan. This lack of marked persistent antihypertensive effect contrasted with a durable decrease in urinary protein excretion and improvement of the renal histological lesions. In conclusion, it is possible to separate the BP-lowering effects of RAS blockade from those on glomerulosclerosis and urinary protein excretion.

In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.

Effect of Camostat Mesilate on Urinary Protein Excretion in Three Patients with Advanced Diabetic Nephropathy

Effective treatment has not yet been established for patients with persistent proteinuria and hypoproteinemia related to advanced diabetic nephropathy. We report three patients with diabetic nephropathy presented with the nephrotic syndrome who showed a marked decrease in proteinuria following the administration of camostat mesilate, a protease inhibitor. Each patient was resistant to treatment with an angiotensin-converting enzyme (ACE) inhibitor and a platelet-aggregation inhibitor. Camostat mesilate, 600 mg/day, orally, caused a marked decrease in urinary protein excretion after the 7th consecutive day of drug administration. There were no serious adverse effects. Its mechanism of action in this respect is not known. Camostat mesilate thus merits clinical trials in the treatment of nephrotic syndrome related to diabetic nephropathy.

Age-related increase in expression of TGF-beta1 in the rat kidney: relationship to morphologic changes.

In the kidney, aging is characterized by the development of structural changes, including glomerulosclerosis and interstitial fibrosis. Transforming growth factor-beta1 (TGF-beta1) is known to play a critical role in the genesis of these alterations in pathologic conditions. The present experiments were designed to test the hypothesis that TGF-beta1 may be involved in the development of age-related histopathologic changes in rat kidney, and that captopril, an angiotensin-converting enzyme inhibitor, may influence the progression of glomerular and interstitial lesions. In this study, 3-, 18-, 24-, and 30-mo-old rats were examined, and an age-related increase in urinary protein excretion was found; plasma creatinine and systolic BP did not change. Significant structural changes, including glomerular sclerosis and interstitial fibrosis, were found in the group of aged rats (24- and 30-mo-old). Immunostaining for TGF-beta in the renal cortex interstitium was increased in the group of 24-mo-old rats, with a parallel increase in TGF-beta1 mRNA expression, measured with reverse-transcription PCR. Captopril-treated animals showed a statistically significant decrease in urinary protein excretion but no significant changes in BP. Moreover, captopril reduced the extent of interstitial fibrosis, but did not affect the degree of glomerulosclerosis. A significant inhibition of TGF-beta1 mRNA expression was observed in the captopril-treated animals. These findings suggest that TGF-beta1 may act as a fibrogenic growth factor that could be responsible, at least partially, for the renal interstitial fibrosis associated with aging. Treatment with captopril might delay the progression of these lesions.

Role of Neutrophils and Macrophages in Experimental Nephrosis of the Rat

The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxlline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p <. 01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/ cytotoxic T-cells (0×8+), in kidneys of rats given either treatment compared with PAN control rats. In summary, both pentoxflline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role ofpentoxlline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.

Association of angiotensin I-converting enzyme gene polymorphism with susceptibility to antiproteinuric effect of angiotensin I-converting enzyme inhibitors in patients with proteinuria.

The antiproteinuric effect of angiotensin I-converting enzyme (ACE) inhibitors in patients with renal diseases of various origins has been well recognized. However, individual responses regarding the degree of decrease in urinary protein excretion appear to vary considerably. The mechanism underlying this variable response to ACE inhibitors has not been clarified yet. A possible role of ACE gene insertion/deletion (I/D) polymorphism in the responsiveness to antiproteinuric effect of ACE inhibitors is examined. Thirty-six patients with proteinuria (23 men and 13 woman; mean age, 47 +/- 13 yr) were studied. These patients were classified into two groups on the basis of the percent decrease in their urinary protein excretion: the effective group, those with a decrease in proteinuria (18 patients, -64 +/- 19%) and the noneffective group (18 patients, +13 +/- 40%). A 287-base pair (bp) I/D polymorphism in the ACE gene was examined by polymerase chain reaction. The allelic frequencies of the ACE gene were I/D = 0.53/0.47 in the effective group and I/D = 0.81/0.19 in the noneffective group. The difference in the allelic frequencies between the two groups was significant (chi 2 = 6.25, P = 0.0114 < 0.05). Furthermore, the difference in the responsiveness of proteinuria to ACE inhibition between genotype II versus genotype ID + DD was statistically significant (chi 2 = 4.05, P = 0.0442 < 0.05). There was no significant difference between the two groups with regard to initial urinary protein level, blood pressure, renal function, and daily sodium intake. The genetic susceptibility to the antihypertensive effect of ACE inhibitors was also studied, but no significant relation was observed. This study suggests the association of ACE gene I/D polymorphism with the antiproteinuric efficacy of ACE inhibitors in patients with proteinuria.

Effects of polysaccharides purified from Salviae miltiorrhizae radix on experimental nephrosis in rats

AbstractA polysaccharide active fraction (AF) obtained from a hot‐water extract of Salviae miltiorrhizae radix was found to reduce urinary protein excretion in rats with aminonucleoside‐induced experimental nephrosis. Its composition was determined as 20% neutral sugars and 80% uronic acids. Oral or intramuscular administration of AF to the rats with aminonucleoside‐induced nephrosis resulted in a significant decrease of urinary protein excretion and an improvement in the levels of serum albumin, cholesterol and lipid peroxide. Further, electron microscopical analysis revealed that the extent and the severity of lesions of the epithelial cells in glomerulus were significantly less in the rats treated with AF.

Effects of glycyrrhetinic acid on aminonucleoside nephrosis in rats

The effects of glycyrrhetinic acid (GA), an aglycon of glycyrrhizin extracted from the roots of Glycyrrhizae radix, on puromycin aminonucleoside (PA) nephrosis were studied in rats. Urine protein excretion in female rats (130 g-150 g) receiving PA (50 mg/kg) alone was significantly elevated on the 2nd day after injection of PA and reached a peak on the 14th day. Urinary protein on the 14th day was reduced to 74% in animals treated with GA (20 mg/kg) starting on the 2nd day after injection of PA. The increase in serum cholesterol and the decrease in serum protein were also suppressed by GA. Observation by electron microscopy revealed that the degree of abnormality in glomerular epithelial cells, i.e. loss or fusion of foot processes, was lower in the rats treated with GA after PA injection than in the rat treated with PA alone. Moreover, pretreatment with GA did not suppress urinary protein excretion but when it was given at the same time as PA and after PA a significant decrease in urinary protein excretion was observed.

Intraglomerular Immune Cell Infiltration and Complement 3 Deposits in Membranoproliferative Glomerulonephritis Type I: A Serial-Biopsy Study of 25 Cases

We examined chronological changes in intraglomerular immune cell infiltration in comparison to the changes in glomerular complement 3 (C3) deposits (C3-D) and serum complement levels in 25 patients with membranoproliferative glomerulonephritis (MPGN) type I. These patients were divided into the following two groups: group A (n = 13), cases in which there were fewer intraglomerular C3-D at the second biopsy (2nd-Bx) than at the first biopsy (1st-Bx); and group B (n = 12), those in which the amount of C3-D at the 2nd-Bx was greater than or equal to that at the 1st-Bx. At the 1st-Bx, monocytes (Mo)/macrophages (M phi) and total leukocytes (TLC) were the predominant cell types in both groups, whereas T cells were less marked. At the 2nd-Bx, only group A showed a significant decrease in the number of either Mo/M phi (P < 0.01), TLC (P < 0.01), pan-T cells (P < 0.01), or intraglomerular nuclei per glomerular cross-section ([NIN] P < 0.01). In group B, there was a positive correlation between the number of intraglomerular pan-T cells (CD3-positive cells) and M phi (CD68-positive cells, P < 0.05 at the 1st-Bx and P < 0.01 at the 2nd-Bx), but not in group A. An improvement in light-microscopic findings and a significant decrease of urinary protein excretion (P < 0.05) at the 2nd-Bx was observed only in group A. Hypocomplementemia (hypo-C) was found in 12 of 13 cases of group A and in eight of 12 cases of group B at the 1st-Bx. Hypo-C in group A was not found at the 2nd-Bx. On the other hand, in group B, hypo-C was still observed in the eight cases and was found in one additional case at the 2nd-Bx.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effects of CS-045 treatment in obese Zucker rats

The association of hypertension with obesity has been well recognized, but the etiology remains poorly understood. Obesity is characterized by hyperinsulinemia, which reflects peripheral insulin resistance. Insulin resistance may participate in the development of hypertension with obesity. CS-045 [(I)-5-[4-(5-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-thiazolidiendion] is a new orally effective antidiabetic agent that potentiates insulin action and reduces insulin resistance in obese Zucker rats and other obese diabetic animals. In this study, we examined the antihypertensive effect of CS-045 in obese male and female Zucker rats as a model of hypertension associated with obesity. CS-045 was administered as a food admixture (∼16 and ∼70 mg/kg/d) for 4 weeks (female) and (∼15 and ∼67 mg/kg/d) 8 weeks (male) in obese Zucker rats at 5 to 7 months of age. CS-045 slightly but significantly decreased plasma glucose levels. Plasma insulin levels were significantly decreased in obese male rats, but were not significantly decreased in obese female rats. Drug administration led to significant decreases in plasma triglyceride and cholesterol levels and systolic blood pressure (SBP) in a dose-dependent manner from 1 week after administration in obese Zucker rats. CS-045 increased urinary sodium excretion, sodium/potassium ratio, and creatinine clearance in a dose-dependent manner, and also led to a remarkable decrease in urinary protein excretion. However, CS-045 did not reduce urinary catecholamine excretion. These data indicate that CS-045 may promote renal sodium excretion and improve decreased glomerular filtration rates, which may reflect the amelioration of insulin resistance. Since the obese Zucker rat may be a useful animal model for hypertension associated with obesity, CS-045 may provide a new pharmacologic approach to the management of hypertension in obesity and/or non-insulin-dependent diabetes mellitus.

Clinical Studies in the Use of BCG and Levamisole in the Treatment of Glomerulonephritis

Sixty patients with primary glomerulonephritis and nephrotic range proteinuria (most resistant to corticosteroid therapy) were given killed BCG inoculations as a major part of combined therapy with levamisole, 3 of every 7 days, and corticosteroids in 53 patients. Following treatment 80% of patients showed complete or partial remission of proteinuria with significant improvement in urinary protein excretion, serum albumin, blood urea, and serum creatinine. Thirteen of 15 patients followed up for 1-2 years and more had complete remission at the latest review, as did five of six patients followed for less than 1 year. The longer the course of the combined immunostimulant treatment, the lower the recurrence rate. The beneficial effects of retreatment in recurrent cases were much more rapid in onset than on initial treatment. The phagocytic function of monocytes was examined in a separate group of 24 patients with primary glomerulonephritis. Function was found to be significantly depressed but could be returned to normal following BCG inoculation. Associated with the improved monocyte phagocytic function there was a significant decrease in urinary protein excretion.

Serum lipoprotein abnormalities in patients with nephrotic syndrome and effects of steroid therapy

With polyacrylamide gel electrophoresis (PAGE), we studied serum lipoprotein (Lp) abnormalities in patients with nephrotic syndrome (NS) caused by primary glomerulonephritis. Nineteen untreated nephrotic patients were studied. Seven patients of them were followed up with PAGE in the remitting course. Serum total cholesterol, triglycerides and beta-Lp concentrations were higher in untreated patients than those in normal control. Serum HDL-cholesterol concentration was lower in untreated patients than those in normal control. PAGE showed broad midband-Lp and increased pre-beta-Lp in 16 of 19 untreated patients. Those findings suggested that untreated nephrotic patients had impaired catabolism of VLDL to LDL in peripheral tissue or impaired hepatic catabolism of IDL and LDL. Furthermore, PAGE showed decreased alpha-Lp in all patients with untreated NS. Correlation was not found between histological classification of glomerulonephritis and broad midband or hyperlipidemia. After administration of prednisolone, PAGE revealed the appearance of chylomicron, and increased pre-beta-LP and alpha-Lp. After remission, broad midband-Lp and pre-beta-Lp were markedly decreased or dis appeared in all 6 patients with broad midband-Lp in untreated phase, and serum total cholesterol and beta-Lp concentrations were markedly decreased, and HDL- cholestrol was markedly increased. In the course of remission, serum total cholesterol, triglycerides and beta-Lp concentrations had negative correlation with serum albumin concentration. Furthermore, serum total cholesterol and beta-Lp concentrations were decreased along with decrease of urinary protein excretion. The results of the present study suggest that the loss of serum albumin and/or some other substances to the urine cause broad midband.

Analysis of proteins in unconcentrated urine.

SummaryWe investigated methods for measurement of β2‐microglobulin, lysozyme, IgG and other globulin fragments such as Fc, F(ab')2, K‐and Δ‐chains in unconcentrated urine. A log‐log correlation was observed between the percent transferrin clearances and the molecular weights of β2‐microglobulin, lysozyme, transferrin and IgG in normal children by quantitative analysis. Glomerular damage was suggested in patients who excreted urinary protein in excess of 1 g/m2/ day. The selectivity patterns showed persistence of glomerular disorders in patients with membranoproliferative glomerulonephritis, crescentric glomerulonephritis, glomerulonephritis due to Henoch‐Schonlein purpura and lupus nephritis, in spite of decrease in urinary protein excretion after treatment.Scanty globulin fragments were found in urine. The ratio of dimer‐ and monomer‐light chains found varied depending on the pathogenesis.Electrophoretic figures seen by the Western blot method were able to differentiate urinary proteins using unconcentrated urine.A combination of the procedures in this report could be useful to evaluate the severity and to monitor the progress of nephropathy.

Renal effects of angiotensin converting enzyme inhibitors in hypertension

This review focuses on the renal effects of the angiotensin converting enzyme inhibitors, captopril and enalapril. Emphasis is placed on the renal response to these drugs in patients with primary essential hypertension, and in hypertension accompanying renal parenchymal disease. Specifically reviewed are the renal function and hemodynamic, salt and water, body fluid composition, and urinary protein excretion responses. The interruption of the renin-angiotensin-aldosterone axis has the potential to produce a variety of favorable renal responses, including reduction of renal vascular resistance, enhancement of renal blood flow, enhancement of glomerular filtration rate, acute natriuresis, sustained diuresis, and a decrease in urinary protein excretion. Data in support of these potential renal perturbations are presented and discussed. The results suggest that the angiotensin converting enzyme inhibitors are important therapeutic agents in the treatment of hypertensive disease, in that they may modify pathophysiologic renal abnormalities encountered in this disease state.

Proteinuria and Nephrotic Syndrome Induced by Renin in Patients With Renal Artery Stenosis

Exacerbation of hypertension and a marked excretion of protein in the urine were observed in three patients in the absence of underlying renal parenchymal disease or other causes of proteinuria. Stenosis of a renal artery and hyperreninemia were present in all three patients. Correction of the stenosis by arterial bypass or nephrectomy resulted in a rapid decrease in urinary protein excretion. The relationship between the levels of renin activity and the proteinuria in one patient and long-term follow-up in the other two patients are reported, and the mechanisms of this proteinuria are reviewed. Renal artery stenosis may be the underlying cause in some cases of idiopathic nephrotic syndrome.

Potassium hydrogen phosphate induced nephropathy in the dog. II. Glomerular alterations (author's transl)

A disseminated atrophy of the proximal tubule accompanies K2HPO4-induced nephropathy in dogs. These pathologic processes cause glomerular changes that pass through different inflammatory stages and terminate in glomerular sclerosis. Experimental animals, design of the experiment and methods have been described [15]. During the 14-week study we determined the amount of urine (24 hours), protein (mg/dl), protein excretion (mg protein/24 hr) and the macro- and microprotein fraction in the urine by SDS-polyacrylamide gel electrophoresis. Clinical examinations were at 15, 66, and 85 days. Beagle dogs treated with 0.8 g K2HPO4/kg body weight developed significant glomerular selective and unselective protienuria. During the experiment the macroproteins in the urine decreased markedly, and at the last examination (day 85) glomerular proteinuria was no longer detectable by electrophoresis. Morphologically, there were only slight glomerular changes in the biopsy material taken at four weeks. Widespread lesions at 14 and 38 weeks were dilatation of Bowman's space, thickening of the basement membrane, increase in mesangial matrix, interposition of non-argentophilic mesangial matrix into the glomerular basement membrane, protein deposits in the mesangium and parietal basement membrane, formation of crescents, shrinkage of the glomeruli with collapse of glomerular tufts, and finally glomerular sclerosis. The parietal epithelial cells contained cytoplasmic areas that were free of organelles and contained microfilamentous and fine-granular material. These areas were close to the capsular basement membrane. Bundles of filaments within parietal epithelial cells had contact with the basement membrane, thus resembling hemidesmosomes. The sequelae of tubular atrophy are retention of glomerular filtrate and dilatation of Bowman's space, followed by compression and shrinkage of the glomerular tufts, and inflammatory processes within the glomerulus. The latter may be characterized as mesangio-sclerosing, mesangio-proliferative, membrano-proliferative, and extra-capillary glomerulonephritis. The decrease of urinary protein excretion towards the end of the experiment may be related to intratubular lysosomal digestion of cellular and amorphous components.