Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Proteinuria”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed1990

Decreases of proteinuria during alternate-day prednisone therapy in nephrotic syndrome.

Treatment of patients with membranous glomerulonephritis with prednisone on alternate days results in a decreased proteinuria on non-prednisone days. We have studied this phenomenon in more detail in 14 patients (11 M, 3 F) with membranous glomerulonephritis. Mean age +/- SD of the patients was 47 +/- 14 years, mean endogenous creatinine clearance 94 +/- 35 ml/min, and median proteinuria 8.8 g/24 h (range 5.0-30.0 g/24 h). Glomerular filtration rate (GFR, inulin clearance), effective renal plasma flow ERPF, PAH clearance), and proteinuria were measured on a control day (C), and six days after the start of alternate-day prednisone treatment, on the third non-prednisone day (NP3, 24-28 h after the last dose of prednisone). Proteinuria decreased from 6.1 mg/min (3.2-9.8 mg/min) (C) to 2.5 mg/min (1.0-7.7 mg/min) at NP3 (median, interquartile range; P less than 0.01), the percentage decrease averaged 45 +/- 8%. The decrease of proteinuria was correlated with baseline GFR (r = 0.75; P less than 0.01). GFR and ERPF did not change significantly, but filtration fraction decreased significantly from 14.5 +/- 0.8% (C) to 13.5 +/- 0.9% (NP3; P less than 0.05). Fractional excretion of albumin, IgG, and transferrin decreased significantly, by -40 +/- 8%, -52 +/- 6%, and -52 +/- 7% respectively. Fractional excretion of beta 2-microglobulin decreased significantly less by -12 +/- 10%. We conclude that proteinuria is decreased on non-prednisone days in patients with membranous glomerulonephritis treated with alternate-day steroids. The observed decrease of filtration fraction suggests that a reduction of glomerular pressure is involved. In addition, the magnitude of the decrease of proteinuria might indicate a change in glomerular permselectivity characteristics.

Adult↗
PubMed1994

Relationship between interstitial infiltrates and steroid responsiveness of proteinuria in membranous nephropathy.

Mononuclear inflammatory cells were retrospectively analysed using monoclonal antibodies in the interstitium and glomeruli of 16 renal biopsy specimens from patients with nephrotic syndrome due to idiopathic membranous nephropathy (IMN). The aim of the study was to determine the composition of the infiltrate and to assess the ability to predict the response of proteinuria to corticosteroids. All patients had received prednisolone as a sole treatment. Nine patients had shown a complete or partial remission of proteinuria (group A) and seven did not respond at all (group B). Both groups were matched for age and degree of proteinuria; also both groups had normal renal function at the time of biopsy. Very few intraglomerular leukocytes, mostly monocytes/macrophages (MM) were found. The majority of interstitial T cell population and B cells were a minor component. No significant differences were found between the two groups regarding the types of the intraglomerular cells. However, interstitial T-cells, CD4+ve T helper/inducer cells, CD8+ve T cytotoxic/suppressor cells and MM were significantly higher in group A than in group B. Also HLA-DR expressing interstitial cells were much in excess in group A. In addition patients with complete remission of proteinuria had higher numbers of interstitial cells compared to those with partial response. There was no correlation between the numbers of types of intraglomerular and interstitial cells and the degree of proteinuria at presentation. Also no association was found between intraglomerular or interstitial cell population and subsequent relapse of proteinuria. In conclusion, interstitial but not intraglomerular mononuclear cells seem to determine the initial response of proteinuria to corticosteroids in patients with IMN.

Adult↗
PubMed2005

In mice, proteinuria and renal inflammatory responses to albumin overload are strain-dependent.

BACKGROUND: The availability of genetically modified mice has increased the need for relevant mouse models of renal disease, but widely used C57BL/6 mice often show resistance to proteinuria. 129/Sv mice are considered more sensitive to certain renal models. Albumin overload, an important model of proteinuric disease, induces marked proteinuria in rats but barely in C57BL/6 mice. We hypothesized that albumin overload would induce more proteinuria in 129S2/Sv than C57BL/6J mice. METHODS: Male and female C57BL/6J and 129S2/Sv mice received bovine serum albumin (BSA) for 11 days. Control groups received saline injections. Injected BSA was immunohistochemically localized to study intrarenal handling of overloaded protein. Renal macrophage infiltration (F4/80 immuno-staining) and glomerular ultrastructure (electron microscopy) were assessed. RESULTS: The BSA-treated groups were similarly hyperproteinemic at Day 11 (D11). Proteinuria differed widely. In C57BL/6J mice, it remained unchanged in females but significantly, though mildly, increased in males (from 3+/-1 to 8+/-2 mg/day, P < 0.05). In 129S2/Sv, proteinuria was marked in both males and females (4+/-1 to 59+/-14, and 0.6+/-0.2 to 29+/-9 mg/day, respectively, both P < 0.01). Proteinuria was accompanied by tubulo-interstitial macrophage infiltration in 129S2/Sv mice. Injected BSA was visualized within glomeruli in both strains and in the urinary space and tubules of 129S2/Sv but not C57BL/6J mice, indicating much greater glomerular leakage in the former. No glomerular macrophages or ultra-structural differences were detected. CONCLUSION: There are major strain differences in the proteinuria and renal inflammatory response of mice to albumin overload, which are not due to structural variation in the filtration barrier but possibly to functional differences in glomerular protein permeability.

Animals↗
PubMed2002

Dissociation between blood pressure reduction and fall in proteinuria in primary renal disease: a randomized double-blind trial.

OBJECTIVE: Guidelines recommend lower threshold and goal blood pressure (BP) for patients with proteinuria. BP reduction could be accompanied by a different fall in proteinuria depending of the antihypertensive drug. The objective was to compare proteinuria reduction when BP is lowered to the same level with different drugs. DESIGN: Prospective, randomized, double-blind, controlled trial. SETTING: 12 Spanish centres. PATIENTS: A total of 119 patients with primary renal disease, blood pressure > 130/85 mmHg, proteinuria > 1 g/day, and creatinine clearance > or = 50 ml/min. INTERVENTION: After a 4-week run-in placebo period, patients were randomized to: atenolol 50 mg/day; trandolapril 2 mg/day; verapamil 240 mg/day or verapamil 180 + trandolapril 2 mg/day combination; forced double-dose titration was carried out at the 4th week. Treatment duration was 6 months. OUTCOME MEASURES: Changes in BP, 24 h proteinuria, serum albumin and calcium. RESULTS: BP was significantly reduced with the four treatments [SBP/DBP (mmHg]: atenolol 12.2/9.9; trandolapril 12.9/9.3; verapamil 8.2/7.9 and verapamil + trandolapril 13.6/11.3) without differences between them. A significant fall in proteinuria was seen in the trandolapril, 40.2% [95% confidence interval (CI) 24.3-56.2%], and verapamil + trandolapril groups, 48.5% (95% CI, 31.7-64.3%) accompanied with increases in serum albumin (trandolapril: from 3.86 +/- 0.64 to 4.03 +/- 0.67 g/dl; verapamil + trandolapril: from 4.15 +/- 0.58 to 4.40 +/- 0.51 g/dl). CONCLUSIONS: In patients with proteinuric primary renal disease, adequate dose titration of antihypertensive drugs may provide a substantial BP reduction. Only angiotensin-converting enzyme inhibitor (trandolapril) treatment, alone or better combined with verapamil, reduces proteinuria and increases serum albumin.

Adult↗
PubMed2002

The risk of cardiovascular disease associated with proteinuria in renal transplant patients.

Proteinuria in the general population has been shown to be associated with cardiovascular disease, which is the main cause of death in renal transplantation. We investigated the effect of proteinuria on cardiovascular disease after renal transplantation in 532 renal transplant patients with functioning grafts for more than 1 year. Patients were classified into two groups depending on the presence of persistent proteinuria. We analyzed graft and patient survival, posttransplantation cardiovascular disease, and main causes of graft loss and death. Five- and 10-year graft and patient survival rates were lower in the group with proteinuria. The main cause of death was vascular disease in both groups. The presence of posttransplantation cardiovascular disease was higher in the group with proteinuria. Persistent proteinuria was associated with graft loss (RR=4.18), patient death (RR=1.92), and cardiovascular disease (RR=2.45). In conclusion, persistent proteinuria was an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant patients.

Adult↗
PubMed2004

Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue.

BACKGROUND: Little is known about the incidence and evolution of proteinuria as a complication of sirolimus rescue in children. This study describes pediatric renal transplant (Tx) recipients who were treated with sirolimus and who developed heavy proteinuria. Risk factors for the development of proteinuria and its time course are explored. METHODS: Data at various time points after sirolimus introduction were abstracted from the records of children treated at the author's center. The repeated measures general linear model and the Student's paired t test were used to analyze changes in laboratory values over time. RESULTS: Of the 13 children on sirolimus, 12 developed heavy proteinuria after a mean interval of 1 month. The mean urine protein (Up)-to-creatinine (c) ratio increased from 1.1 to a peak value of 3.9 (P=0.003) at 4.6 months after the start of sirolimus. Although not statistically significant, children on no calcineurin inhibitor (CNI) had a greater increase in the Up/c than those on low-dose CNI. At last follow-up, with the use of angiotensin receptor blockers (ARB), the Up/c declined to 2.2. No predictors could be identified for the development of proteinuria. CONCLUSIONS: Heavy proteinuria is common after the use of sirolimus as rescue therapy in children with renal Tx. Whether this is attributable to a toxic effect of the sirolimus itself or to lower CNI exposure is uncertain. Early detection of proteinuria is important to enable prompt intervention. Most children have a reduction in their Up/c with the use of ARB and can therefore be continued on sirolimus.

Adolescent↗
PubMed2005

Proteinuria following a switch from calcineurin inhibitors to sirolimus.

BACKGROUND: Sirolimus is an alternative option for kidney transplant patients treated with calcineurin inhibitors (CNI) when renal function is deteriorating. However, the incidence of proteinuria following a switch from CNI to sirolimus has caused concern, and was therefore investigated here. METHODS: In a retrospective study, 68 renal transplant recipients were switched from CNI to sirolimus. Proteinuria was measured using 24-hour urine collection before the switch and collections 3, 6, 12, and 24 months thereafter. In addition, proteinuria was measured in patients who had to be switched back to CNI due to side effects. Survival analyses were performed. RESULTS: Baseline proteinuria was 0.39+/-0.69 g/day in all 68 patients. It increased to a mean 1.44+/-1.90 g/day at 3 months (P<0.001) and remained elevated at 6, 12 and 24 months. When sirolimus was withdrawn after the CNI-sirolimus switch for 19 patients, proteinuria decreased from 1.95+/-2.06 g/day to 0.9+/-1.4 g/day (P<0.05). Proteinuria above 0.3 g/day before the CNI-sirolimus switch correlated significantly with the decrease of renal function thereafter. CONCLUSION: CNI-treated kidney transplant recipients may develop reversible proteinuria when switched to sirolimus.

Adult↗
PubMed2006

Hyperlipidaemia, lack of sleep and smoking as risk factors for proteinuria among high altitude mountain trekkers.

AIM: The number of alpine accidents has been increasing among trekkers in Japan. Some of the alpine accidents have been related to acute mountain sickness (AMS). At present, the mechanism of AMS is poorly clarified, however, it is well known that hypoxia at high altitudes plays an important role. A good relation exists between proteinuria, altitude and hypoxia. However, no reports are available concerned with the risk factors of proteinuria for trekkers at high altitudes. METHODS: The authors evaluated 41 trekkers and 13 highlanders (cabin employees) through physical examinations and interviews held in a mountain cabin (2300 m above sea level) located in a mountain (2926 m above sea level) in the Japanese Alps. First, urine samples were collected and urinalysis was performed. Second, non-invasive blood pressure, heart rate, and arterial oxygen saturation (SpO2) were measured using a portable life monitor. RESULTS: Proteinuria was present in 20 (49%) participants. Past history of hyperlipidaemia, amount of sleep, and smoking history are independently associated with proteinuria. Among the physiological examinations conducted at the cabin, only systolic blood pressure demonstrated strong association with proteinuria. Receiver operating characteristic curve analysis using a score combining past history of hyperlipidaemia, amount of sleep and smoking history revealed that the diagnostic accuracy of proteinuria at the cut-off score of 2 was 80%. CONCLUSIONS: This study indicated that these three variables were significantly and independently correlated with proteinuria: hyperlipidaemia, amount of sleep (night before) and smoking history. Improvement of these three variables might decrease the risk of alpine accidents including AMS.

Accident Prevention↗
PubMed2004

Clinical study of bladder cancer: Proteinuria as a predictor of recurrence and efficacy of intravesical bacille Calmette-Guerin therapy.

AIM: We studied the clinical characteristics of bladder cancer, with special attention to the clinical and pathological variables that affect tumor stage, relapse and efficacy of intravesical therapy. METHODS: We reviewed the medical records of 152 patients of the Saiseikai Central Hospital who had been diagnosed as having bladder cancer between 1981 and 2001. RESULTS: The age of the patients ranged from 24 to 88 years, with a median of 63.5 years. The median follow up was 52.4 months (range, 0.5-259.5 months). There was no difference in the incidence of gross hematuria as a presenting symptom among the patients with invasive cancer, superficial cancer and carcinoma in situ (CIS). However, the incidence of urinary frequency and painful urination did differ significantly between patients. Although patients with invasive cancer had a longer time to hospital visit than those with superficial cancer, this time difference was not statistically significant. Presence of proteinuria, multifocality and intravesical bacille Calmette-Guerin (BCG) therapy were the significant predictors of relapse after transurethral resection (TUR). Presence of proteinuria was shown to adversely affect the efficacy of intravesical BCG therapy. In the BCG-treated group, 3-year relapse-free survival was 78.4% for patients without proteinuria and 40.0% for those with proteinuria; this difference was statistically significant (P = 0.0277). CONCLUSIONS: Time to hospital visit did not influence the pathological stage of cancer in patients included in the present study. Presence of proteinuria, multifocality and BCG therapy were the significant predictors of relapse after TUR. Presence of proteinuria was shown to adversely affect the efficacy of intravesical BCG therapy. Proteinuria might be helpful in predicting tumor relapse and efficacy of intravesical BCG therapy in clinical settings, along with other markers.

Adjuvants, Immunologic↗
PubMed1995

Inadequacy of dipstick proteinuria in hypertensive pregnancy.

The objective of this study was to determine the accuracy of ward urinalysis and the sensitivity of dipstick testing in the assessment of proteinuria in hypertensive pregnant women. Subjects were 230 consecutive hypertensive pregnant women who were admitted to hospital over a 2-year period. Routine ward urinalyses for protein, obtained on a mid-stream sample before and after a 24-hour urine collection for quantitating proteinuria, were compared with the 24-hour urine protein excretion. As a control for dipstick accuracy, urinalysis was also performed on a mixed aliquot of each of the 24-hour samples by a single observer experienced in urinalysis. True proteinuria was considered as > 300 mg/day. The positive predictive value for urinalysis ranged from 38% (for the precollection test) to 60% (for tests on the aliquot). Negative predictive values were 86-88%. The false negative rates at 'nil' or 'trace' proteinuria ranged from 8-18%. The false positive rates at '3+' (3 g/L) or '4+' (> or = 20 g/L) ranged from 0-17%, at '2+' (1 g/L) from 18-50% and at '1+' (0.3 g/L) from 67-83%. Best results for urinalysis were obtained on the aliquot testing but even under these ideal circumstances there was a high false positive rate (67%) at '1+' (0.3 g/L) urinalysis level. These studies show that in routine clinical practice 'nil' or 'trace' proteinuria will miss significant proteinuria in approximately 1 out of 8 hypertensive pregnant women while '3+' (3 g/L) or '4+' ( > or = 20 g/L) will rarely be a false positive. At urinalysis of '1+' or '2+' a 24-hour urine collection is required to be certain about the presence or absence of proteinuria. Research studies should demand 24-hour urine protein quantitation and not rely solely upon urinalysis results.

Female↗
PubMed2006

Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial.

OBJECTIVES: To determine whether data on proteinuria are useful for refining estimates of risk based on kidney function alone, and whether the results of kidney function tests can be a useful adjunct to data on proteinuria. DESIGN: Analysis of data from a randomised trial. Impaired kidney function was defined as low glomerular filtration rate (< 60 ml/min/1.73 m2) and proteinuria (> or = 1+ protein) on dipstick urinalysis. SETTING: Study of cholesterol and recurrent events: a randomised trial of pravastatin 40 mg daily versus placebo. PARTICIPANTS: 4098 men and women with previous myocardial infarction. MAIN OUTCOME MEASURES: All cause mortality and cardiovascular events. RESULTS: 371 participants died in nearly 60 months of follow-up. Compared with participants without proteinuria or impaired kidney function, patients with both characteristics were at high risk (hazard ratio 2.39, 95% confidence interval 1.72 to 3.30), and those with only proteinuria or only impaired kidney function were at intermediate risk (1.69, 1.32 to 2.16; 1.41, 1.12 to 1.79, respectively) of dying from any cause. The results were similar for cardiovascular outcomes, including new cases of heart failure, stroke, and coronary death or non-fatal myocardial infarction. A graded increase in the risk of all cause mortality was seen for severity of renal impairment and degree of proteinuria by dipstick. CONCLUSIONS: The presence or absence of proteinuria on dipstick urinalysis may be used to refine estimates of risk based on kidney function alone.

Female↗
PubMed1992

Indomethacin attenuates exercise-induced proteinuria in hypertensive miniature swine.

Exercise-induced proteinuria may be increased in hypertensives. The mechanisms underlying the increased proteinuria are not known, and it has not been determined whether animal models of hypertension exhibit a similar response. We investigated whether indomethacin (Indo) altered exercise-induced proteinuria in normal and hypertensive deoxycorticosterone acetate (DOCA) Yucatan miniature swine (YMS). Five normal and four DOCA YMS underwent 30 min of treadmill exercise at 80% of maximal heart rate. Cumulative (exercise + recovery) albumin excretion in the DOCA YMS was 25-fold (P < 0.01) greater than observed in the normal YMS. Indo had no effect on resting or exercise-induced proteinuria in the normal YMS. However, Indo decreased the slightly elevated proteinuria at rest, and normalized the exaggerated exercise-induced proteinuria in the DOCA YMS. The antiproteinuric effect of Indo in the DOCA YMS was not associated with altered exercise, recovery blood pressure, or glomerular filtration rate. Thus hypertensive DOCA YMS exhibit an exaggerated exercise-induced proteinuria. It is suggested that eicosanoids are involved in this abnormal renal proteinuric response to exercise.

Animals↗
PubMed2006

Clinicopathological characteristics and outcome of adult patients with hematuria and/or proteinuria found during routine examination.

BACKGROUND: Patients with hematuria and/or proteinuria found during routine examination are commonly encountered. To define the clinicopathological characteristics and outcome of these patients, 142 patients with definite pathological diagnosis were studied retrospectively. METHODS: All the 142 patients were divided into three groups: pure hematuria (HU, n = 13), concomitant hematuria and proteinuria (HUPU, n = 79), and proteinuria alone (PU, n = 50). RESULTS: At the time of renal biopsy, 26% of the patients had renal insufficiency and 48% of the patients had hypertension. Pathologically, IgA nephropathy (n = 67) was the most common. A total of 51 patients were enrolled into the follow-up group. Finally, urinary abnormalities disappeared in 18% of the patients, 22% of HU developed proteinuria, 21% of HUPU and 23% of PU appeared to have a distinct increase of proteinuria, and 15% of PU developed hematuria. Seven patients with normal blood pressure before became hypertensive and 6% of the patients with normal renal function initially developed renal insufficiency. The renal outcome was associated with proteinuria and tubulointerstitial lesions. CONCLUSION: Because renal pathologic change does not always coincide with clinical manifestations, patients with hematuria and/or proteinuria found during routine examination do not necessarily imply a favorable outcome, so renal biopsy is quite important. Besides, early treatment and careful follow-up are helpful in these patients.

Adolescent↗
PubMedDate not supplied

Proteinuria in congestive heart failure.

To clarify the association between proteinuria and congestive heart failure (CHF), 24-hour urinary protein determinations were obtained from 27 patients with objectively documented CHF, before and after therapy of the CHF. The results demonstrate that modest proteinuria is a frequent feature of CHF and that this proteinuria reverses promptly with successful CHF therapy. Proteinuria exceeding 500 mg/day occurred only in patients with acute pulmonary edema. However, there was no other correlation between severity of proteinuria and type or chronicity of CHF. When proteinuria exceeds 1 g/24 h or when proteinuria does not reverse within 2 weeks of successful CHF therapy, intrinsic renal disease should be suspected.

Albuminuria↗
PubMed1999

Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria.

Persistent proteinuria is considered a deleterious prognostic factor in most progressive renal diseases. However, the mechanisms by which proteinuria induces renal damage remain undetermined. Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II), we approached the hypothesis that proteinuria could elicit the renal activation of the renin-angiotensin system in a model of intense proteinuria and interstitial nephritis induced by protein overload. After uninephrectomy (UNX), Wistar-Kyoto rats received daily injections of 1 g BSA or saline for 8 days. The mean peak of proteinuria was observed at the fourth day (538+/-89 versus 3+/-1 mg/24 h in UNX controls; n=12; P<0.05) and was increased during the whole study period (at the eighth day: 438+/-49 mg/24 h; n=12; P=NS). Morphological examination of the kidneys at the end of the study showed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion. In relation to UNX control rats, renal cortex of BSA-overloaded rats showed an increment in the gene expression of angiotensinogen (2.4-fold) and angiotensin-converting enzyme (ACE) (2.1-fold), as well as a diminution in renin gene expression. No changes were observed in angiotensin type 1 (AT1) receptor mRNA expression in both groups of rats. By in situ reverse transcription-polymerase chain reaction and immunohistochemistry, ACE expression (gene and protein) was mainly localized in proximal and distal tubules and in the glomeruli. By immunohistochemistry, angiotensinogen was localized only in proximal tubules, and AT1 receptor was localized mainly in proximal and distal tubules. In the tubular brush border, an increase in ACE activity was also seen (5. 5+/-0.5 versus 3.1+/-0.7 U/mg protein x10(-4) in UNX control; n=7; P<0.05). Our results show that in the kidney of rats with intense proteinuria, ACE and angiotensinogen were upregulated, while gene expression of renin was inhibited and AT1 was unmodified. On the whole, these data suggest an increase in Ang II intrarenal generation. Since Ang II can elicit renal cell growth and matrix production through the activation of AT1 receptor, this peptide may be responsible for the tubulointerstitial lesions occurring in this model. These results suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.

Animals↗
PubMed2001

Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1.

The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-kappaB (NF-kappaB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-kappaB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-kappaB at all time periods studied. By in situ Southwestern histochemistry, NF-kappaB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET(A)/ET(B) receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-kappaB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-kappaB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT(1): losartan and AT(2): PD-123,319) or ET-1 (ET(A): BQ123 and ET(B): IRL1038) inhibited significantly the BSA-induced NF-kappaB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-kappaB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.

Analysis of Variance↗
PubMed1994

Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.

Passive Heymann nephritis (PHN) is a model of human membranous nephropathy that is characterized by formation of granular subepithelial immune deposits in the glomerular capillary wall which results in complement activation. This is causally related to damage of the filtration barrier and subsequent proteinuria. The local accumulation of injurious reactive oxygen species (ROS) is a major effector mechanism in PHN. ROS may induce tissue damage by initiating lipid peroxidation (LPO). In turn, this leads to adduct formation between breakdown products of LPO with structural proteins, such as formation of malondialdehyde (MDA) or 4-hydroxynonenal-lysine adducts. To examine the role of LPO in the development of proteinuria we have localized MDA and 4-hydroxynonenal-lysine adducts in glomeruli of PHN rats by immunofluorescence microscopy, using specific monoclonal antibodies. By immunogold electron microscopy, MDA adducts were localized to cytoplasmic vesicles and cell membranes of glomerular epithelial cells, to the glomerular basement membrane (GBM), and also to immune deposits. Type IV collagen was specifically identified as being modified by MDA adducts, using a variety of techniques. Collagenase pretreatment of GBM extracts indicated that the NC-1 domain of type IV collagen was a site of adduct formation. When LPO was inhibited by pretreatment of PHN rats with the antioxidant probucol, proteinuria was reduced by approximately 85%, and glomerular immunostaining for dialdehyde adducts was markedly reduced, even though the formation of immune deposits was not affected. By contrast, lowering of the serum cholesterol levels had no influence on the development of proteinuria. These findings are consistent with the premise that ROS-induced glomerular injury in PHN involves LPO and that this results not only in damage of cell membranes but in modification of type IV collagen in the GBM as well. The close temporal correlation of the occurrence of LPO with proteinuria and the ability of probucol to inhibit proteinuria support a causal role for LPO in the the alteration of the glomerular permselectivity which results in proteinuria.

Aldehydes↗
PubMed2005

Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy.

Proteinuria is a risk factor for progression of chronic renal failure. A model of proteinuria-associated tubulointerstitial injury was developed and was used to examine the therapeutic effect of rapamycin. Two studies were performed. In study A, proteinuric rats were given sheep anti-Fx1A to induce experimental membranous nephropathy; control rats received normal sheep serum. Four weeks later, groups were subdivided and underwent laparotomy alone (two kidneys), nephrectomy alone (one kidney), or nephrectomy with polectomy (0.6 kidney). Renal function and morphology were evaluated 4 wk later. Whereas control rats never developed proteinuria, anti-Fx1A induced severe proteinuria. Proteinuria was unaffected by renal mass reduction. Proteinuric rats developed tubulointerstitial disease that was most severe in rats with 0.6 kidneys. Renal function (GFR) was reduced by loss of renal mass and was reduced further in proteinuric rats with 0.6 kidneys. In study B, the effect of rapamycin on the expression of candidate proinflammatory and profibrotic genes and the progression of proteinuria-associated renal disease were examined. All rats received an injection of anti-Fx1A and were nephrectomized and then divided into groups to receive rapamycin or vehicle. Gene expression, renal morphology, and GFR were evaluated after 4, 8, and 12 wk. Rapamycin reduced expression of the proinflammatory and profibrotic genes (monocyte chemotactic protein-1, vascular endothelial growth factor, PDGF, TGF-beta(1), and type 1 collagen). Tubulointerstitial inflammation and progression of interstitial fibrosis that were present in vehicle-treated rats were ameliorated by rapamycin. Rapamycin also completely inhibited compensatory renal hypertrophy. In summary, rapamycin ameliorates the tubulointerstitial disease associated with chronic proteinuria and loss of renal mass.

Animals↗