Nephrotic syndrome in the elderly: epidemiological aspects, clinical data, and renal biopsy findings.

Nephrotic syndrome is the most common clinical presentation of glomerular disease in elderly patients, and renal biopsy is an important diagnostic resource. The aim of this study was to describe nephrotic syndrome among elderly patients in Brazil, focusing on tubulointerstitial and vascular involvement. This was a retrospective study of patients over 65 years of age with nephrotic syndrome who underwent renal biopsy between January 2012 and December 2019. Of the 123 renal biopsies that occurred during the study period, 44 (35.8%) were performed for the investigation of nephrotic syndrome. Among those 44 cases, the main etiologies were membranous nephropathy in 13 cases (29.5%), amyloidosis in ten (22.7%), non-collapsing focal segmental glomerulosclerosis (FSGS) in four (9.1%), and collapsing FSGS in four (9.1%). Patients with minimal change disease (MCD) had the lowest degree of interstitial fibrosis compared with the other glomerulopathies, and histological signs of acute tubular necrosis (ATN) were less common among those with amyloidosis than among those with membranous nephropathy, FSGS, or MCD (P=0.0077). Of the patients with ATN, the frequency of acute kidney injury (AKI) was highest in those with MCD (P<0.001). All patients had some degree of vascular involvement, regardless of the type of glomerulopathy. In conclusion, the second most common cause of nephrotic syndrome in this population was amyloidosis, and acute interstitial tubule involvement was more marked in MCD. Vascular involvement is something that cannot be dissociated from the age of the patient and is not only due to the underlying glomerulopathy.

Nephrotic syndrome in the elderly: epidemiological aspects, clinical data, and renal biopsy findings

Nephrotic syndrome is the most common clinical presentation of glomerular disease in elderly patients, and renal biopsy is an important diagnostic resource. The aim of this study was to describe nephrotic syndrome among elderly patients in Brazil, focusing on tubulointerstitial and vascular involvement. This was a retrospective study of patients over 65 years of age with nephrotic syndrome who underwent renal biopsy between January 2012 and December 2019. Of the 123 renal biopsies that occurred during the study period, 44 (35.8%) were performed for the investigation of nephrotic syndrome. Among those 44 cases, the main etiologies were membranous nephropathy in 13 cases (29.5%), amyloidosis in ten (22.7%), non-collapsing focal segmental glomerulosclerosis (FSGS) in four (9.1%), and collapsing FSGS in four (9.1%). Patients with minimal change disease (MCD) had the lowest degree of interstitial fibrosis compared with the other glomerulopathies, and histological signs of acute tubular necrosis (ATN) were less common among those with amyloidosis than among those with membranous nephropathy, FSGS, or MCD (P=0.0077). Of the patients with ATN, the frequency of acute kidney injury (AKI) was highest in those with MCD (P<0.001). All patients had some degree of vascular involvement, regardless of the type of glomerulopathy. In conclusion, the second most common cause of nephrotic syndrome in this population was amyloidosis, and acute interstitial tubule involvement was more marked in MCD. Vascular involvement is something that cannot be dissociated from the age of the patient and is not only due to the underlying glomerulopathy.

Alpha-melanocyte stimulating hormone ameliorates disease activity in an induced murine lupus-like model.

Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α-MSH analogue [Nle4, DPhe7]-α-MSH (NDP-MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α-smooth muscle actin (α-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and α-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of α-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.

Podocyte injury in pure membranous and proliferative lupus nephritis: distinct underlying mechanisms of proteinuria?

Proteinuria is a major feature of lupus nephritis (LN) and reflects podocyte injury. Analysis of podocyte biomarkers was performed attempting to identify if podocyte phenotype is distinct in pure membranous and proliferative LN. Expression of synaptopodin, Wilms tumor protein 1 (WT1), glomerular epithelial protein 1 (GLEPP1) and nephrin was evaluated in 52 LN biopsies by immunohistochemistry. Preserved synaptopodin expression was observed in only 10 (19.2%) of all biopsies while 42 (80.8%) had reduced expression. Both groups had comparable proteinuria at the time of biopsy (p = 0.22); however, in the mean follow-up of four years there was a tendency toward lower mean levels of proteinuria in patients with preserved synaptopodin staining (0.26±0.23 vs. 0.84±0.90 g/24 h, p = 0.05) compared with those with diminished expression. Thirty-nine (75%) biopsies were classified as proliferative and 13 (25%) as pure membranous. Comparison of podocyte biomarkers demonstrated a predominance of preserved staining of synaptopodin (69.2%), WT1 (69.2%), GLEPP1 (53.9%) and nephrin (60%) in the pure membranous group whereas only <10% of the proliferative showed preserved expression. Our data suggest that in proliferative forms there seems to occur structural podocyte damage, whereas in the pure membranous the predominant preserved pattern suggests a dysfunctional podocyte lesion that may account for the better long-term prognosis of proteinuria outcome.

Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation.

We recently standardized a model (L(Lact)) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345-F1353, 2008). In this new study of the L(Lact) model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and L(Lact) groups, given losartan (L; 250 mg·kg(-1)·day(-1)) until weaning. The male L(Lact) offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (L(Lact)Pre), and followed no further. The remaining rats were then divided among groups L(Lact)+V, untreated; L(Lact)+L, given L (50 mg·kg(-1)·day(-1)) now as a therapy; L(Lact)+H, given H (6 mg·kg(-1)·day(-1)); and L(Lact)+LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, L(Lact) rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in L(Lact) rats.

Collapsing glomerulopathy associated with proliferative lupus nephritis: reversible acute kidney injury.

Collapsing glomerulopathy is a rare form of glomerular injury, characterized by segmental or global collapse of the glomerular capillaries, wrinkling and retraction of the glomerular basement membrane, and marked hypertrophy and hyperplasia of podocytes. Prognosis is usually poor, with most cases developing end-stage renal disease, in spite of treatment. The association of collapsing glomerulopathy and systemic lupus erythematosus is very unusual. In this report, we describe the first case of a simultaneous diagnosis of collapsing glomerulopathy and diffuse proliferative lupus nephritis. The case presented with acute kidney injury and nephrotic syndrome and evolved with partial remission of nephrotic syndrome and recovery of renal function after aggressive treatment with intravenous cyclophosphamide and methylprednisolone.

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA) on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 çg/mL); CsA (100 µg/mL); sirolimus (50 and 250 çg/mL) + CsA (100 µg/mL); control; vehicle (20 percent ethanol). For in vivo studies, 3-week-old Wistar rats (150-250 g) were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I) in five groups: sham, I, I + SRL (3 mg·kg-1·day-1, po), I + CsA (3 mg·kg-1·day-1, sc), I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR) at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 ± 0.1 mL/min) but not in rats receiving sirolimus + CsA (0.8 ± 0.1 mL/min) despite the reduction in renal blood flow (3.9 ± 0.5 mL/min). Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury.

Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA) on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 nanog/mL); CsA (100 microg/mL); sirolimus (50 and 250 nanog/mL) + CsA (100 microg/mL); control; vehicle (20% ethanol). For in vivo studies, 3-week-old Wistar rats (150-250 g) were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I) in five groups: sham, I, I + SRL (3 mg x kg(-1) x day(-1), po), I + CsA (3 mg x kg(-1) x day(-1), sc), I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR) at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 +/- 0.1 mL/min) but not in rats receiving sirolimus + CsA (0.8 +/- 0.1 mL/min) despite the reduction in renal blood flow (3.9 +/- 0.5 mL/min). Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

Percutaneous ultrasound-guided renal biopsy in children - safety, efficacy, indications and renal pathology findings: 14-year Brazilian university hospital experience.

INTRODUCTION: Pediatric percutaneous renal biopsy (Bx) is a routine procedure in pediatric nephrology to obtain renal tissues for histological study. We evaluated the safety, efficacy, indications and renal findings of this procedure at a tertiary care pediatric university hospital and compared our findings with the literature. METHODS: Retrospective study based on medical records from January 1993 to June 2006. RESULTS: In the study period, 305 Bx were performed in 262 patients, 127 (48.5%) male, aged 9.8 A+/- 4.2 years. A 16-gauge needle was utilized in 56/305 Bx, an 18-gauge needle in 252/305 Bx (82.6%). 56.1% Bx were performed under sedation plus local anesthesia, 43.9% under general anesthesia. The number of punctures per Bx was 3.1 A+/- 1.3. Minor complications occurred in 8.6% procedures. The 16-gauge needle caused a higher frequency of renal hematomas (p = 0.05). The number of glomeruli per puncture was >or= 5 in 96.7% and >or= 7 in 92%. Glomeruli number per puncture and frequency of complications were not different according to the type of anesthesia used. A renal pathology diagnosis was achieved in 93.1% Bx. The main indications of Bx were nephrotic syndrome (NS), lupus nephritis (LN) and hematuria (HE). The diagnosis of minimal change disease (MCD) (61.3%), class V (35.6%) and IgA nephropathy (26.3%) predominated in NS, LN and HE patients, respectively. CONCLUSION: Pediatric real-time ultrasound-guided percutaneous renal biopsy was safe and effective. The main clinical indications for Bx were NS and LN, the predominant renal pathology diagnoses were MCD and class V LN.

Statin monotherapy attenuates renal injury in a salt-sensitive hypertension model of renal disease.

BACKGROUND: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. METHODS: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). RESULTS: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. CONCLUSION: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.

Renin-angiotensin system function and blood pressure in adult rats after perinatal salt overload.

BACKGROUND AND AIM: To study the influence of high salt intake during pregnancy and lactation on body weight, blood pressure, and the function of the renin-angiotensin system in adult rats. METHODS AND RESULTS: Female Wistar rats received a low (0.15 NaCl), normal (1.30), or high (8% diet) salt diet. Mating occurred on the 12th week of age. From weaning, the offspring received normal salt diet. Weekly tail-cuff blood pressure and body weight measurements were performed during pregnancy and in the offspring (body weight since weaning and tail-cuff blood pressure between the 8th and the 12th week of age). Salt sensitivity of the blood pressure was evaluated and plasma renin activity determinations were performed in the 12-week-old offspring. Immunohistochemistry for renal angiotensin II was performed in the adult offspring. Renal mass and the number of glomeruli were determined. Tail-cuff blood pressure was higher in salt overloaded dams than in normal and low salt ones. In the adult offspring from the high salt dams, lower body weight, higher tail-cuff blood pressure, lower salt sensitivity in females, and increased kidney angiotensin II were observed. Plasma renin activity did not change with changes in salt intake in the adult offspring submitted to high salt environment during the perinatal period. In the offspring, renal mass and the number of glomeruli were not influenced by the dams' salt intake. CONCLUSIONS: Salt overload during pregnancy and/or lactation has long-term effects on offspring's body weight and blood pressure. In addition, high salt diet during the perinatal period induced renin-angiotensin system functional disturbances in the offspring.

Predominant IL-10 production in indirect alloreactivity is not associated with rejection.

In a prospective study of indirect alloresponse in renal transplantation, we detected proliferation and cytokine production to donor and third-party HLA-DR peptides unrelated to rejection. Twenty of 28 patients (71%) presented proliferation, 29% before and 71% after transplantation. Half of the patients also presented proliferation to third-party peptides. Indirect alloresponse was also detected in 75% of healthy individuals (HI). Variability of response was observed in patients and HI for both proliferation and cytokine production. IL-10 predominance was observed in indirect alloresponses to donor peptides pre- and post-Tx, in contrast with more IFN-gamma and TGF-beta being detected in HI. IL-10 production was frequently detected without proliferation, in contrast with more frequent proliferation being found with IFN-gamma and TGF-beta production. The lack of association of either cytokine or proliferation with rejection, together with the predominance of IL-10 unrelated to proliferation, suggests that regulatory cells may be part of the T cell repertoire involved in indirect alloreactivity.

Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy.

The biological functions of immunoglobulin (Ig)A antibodies depend primarily on their interaction with cell surface receptors. Four IgA receptors are presently characterized. The FcalphaRI (CD89) expressed by myeloid cells selectively binds IgA1 and IgA2 antibodies, whereas the poly-IgR, Fcalpha/muR, and asialoglycoprotein receptors bind other ligands in addition to IgA. IgA binding by mesangial cells, epithelial cells, and proliferating lymphocytes is also well documented, but the nature of the IgA receptors on these cells remains elusive. A monoclonal antibody (A24) is described here that specifically blocks IgA binding to epithelial and B lymphocyte cell lines. Both the A24 antibody and IgA1 myelomas bind a cell surface protein that is identified as the transferrin receptor (CD71). The transferrin receptor selectively binds IgA1 antibodies, monomeric better than polymeric forms, and the IgA1 binding is inhibitable by transferrin. Transferrin receptor expression is upregulated on cultured mesangial cells as well as on glomerular mesangial cells in patients with IgA nephropathy. The characterization of transferrin receptor as a novel IgA1 receptor on renal mesangial cells suggests its potential involvement in the pathogenesis of IgA nephropathy.

Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow.

BACKGROUND: Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by interstitial fibrosis and afferent arteriole hyalinosis. CsA lesion has been linked to maintained renal vasoconstriction and narrowing of the afferent arteriole lumen diameter, leading to preglomerular ischemia. We investigated the role of renal hemodynamics in CsA-induced transforming growth factor (TGF-beta) expression and interstitial fibrosis. METHODS: Groups of rats fed a low salt diet were given CsA 5 mg/kg/day (CsA) or the vehicle (olive oil, [VH]) s.c. and had the renal blood flow (RBF), glomerular filtration rate (GFR), mean arterial pressure, renal vascular resistance, renal histologic changes, and immunohistochemical features for macrophages and TGF-beta evaluated after 1, 2, and 8 weeks of treatment. RESULTS: At week 1, despite normal renal hemodynamics and MAP, there was a significant macrophage interstitial influx in CsA-treated rats (70+/-16 vs. 29+/-4 cells+/0.5 mm2, in CsA vs. VH, P=0.02) that was progressive with treatment (80+/-13 vs. 32+/-8 cells+/0.5 mm2, P=0.016 and 197+/-36 vs. 23+/-3 cells+/0.5 mm2, P=0.0002, CsA vs. VH at 2 and 8 weeks, respectively). After 2 weeks of treatment, CsA animals developed a significant interstitial fibrosis, with preserved RBF, even when it was assessed 2 hr after CsA injection. There was a significant increase in the immunostaining for TGF-beta in the juxtaglomerular arterioles in CsA-treated rats (48.6+/-3.8 vs. 35.1+/-1.1%, CsA vs. VH at 2 weeks, P<0.05 and 59.0+/-3.2 vs. 37.0+/-2.1%, CsA vs. VH at 8 weeks, P=0.0001). A significant and progressive GFR decrease followed the renal structural injury of CsA treatment. Arteriolar and glomerular anatomic injury were not found throughout the study. CONCLUSIONS: Low CsA doses might generate interstitial fibrosis without any decrease in RBF or structural arteriolar lesion evidence, possibly through early macrophage influx and increased TGF-beta expression. It clearly seems that CsA-induced ischemia and tubulointerstitial injury may occur independently, suggesting that chronic CsA nephrotoxicity may be very hard to prevent or even not be preventable at all.

Mycophenolate mofetil attenuates renal injury in the rat remnant kidney.

BACKGROUND: Mycophenolate mofetil (MMF), an inhibitor of lymphocyte proliferation, has been used to prevent allograft rejection. We investigated whether MMF also limits progressive renal injury in rats with 5/6 renal ablation, a model not primarily related to immunologic mechanisms. METHODS: Eighty-eight adult male Munich-Wistar rats underwent ablation and received either vehicle (N = 42) or oral MMF (N = 46), 10 mg/kg/day. Forty-seven sham-operated rats were also studied. RESULTS: Thirty days after surgery, remnant kidneys exhibited glomerular hypertension and hypertrophy. MMF treatment did not correct these abnormalities. Immunohistochemistry revealed interstitial lymphocyte infiltration 7 and 30 days after ablation. Proliferating cells abounded seven days after ablation, especially in tubules, declining in number along the following weeks. By contrast, the number of macrophages was moderately increased in the first weeks, attaining values eightfold as high as control 60 days after ablation. MMF attenuated these cellular events at all phases of the study. Sixty days after ablation, marked albuminuria, glomerulosclerosis and interstitial expansion were prominent in untreated rats. MMF treatment largely attenuated glomerular and interstitial injury without changing proteinuria. CONCLUSION: This is the first evidence that MMF may impact favorably on progressive renal diseases of "nonimmunologic" origin.

Nitroflurbiprofen, a new nonsteroidal anti-inflammatory, ameliorates structural injury in the remnant kidney.

Cyclooxygenase derivatives and nitric oxide (NO) may influence the pathogenesis of progressive nephropathies. We investigated the effect of nitroflurbiprofen (NOF), a NO-releasing nonsteroidal anti-inflammatory drug (NSAID) without gastrointestinal toxicity, in rats with 5/6 ablation (NX). The following four groups were studied: Sham, sham-operated rats; Sham + NOF, Sham receiving oral NOF two times daily; NX, rats subjected to NX; and NX + NOF, NX receiving NOF. NOF was barely detected in plasma but released the parent compound flurbiprofen. At 30 days, glomerular hydraulic pressure (PGC) was 76 +/- 3 mmHg in NX (52 +/- 1 in Sham, P < 0.05). NOF slightly reduced PGC to 69 +/- 2 mmHg in NX + NOF (P > 0.05 vs. NX). Glomerular volumes behaved similarly. At 60 days, tail cuff pressure was 152 +/- 6 mmHg, glomerulosclerosis index was 22.1 +/- 9.5, and interstitial fractional area was 9.9 +/- 1.2% in NX. NOF reduced these parameters to 137 +/- 4 mmHg, 3.5 +/- 0.7, and 6.4 +/- 0.8%, respectively (P < 0.05), without causing growth stunting or anemia. These beneficial effects could not be ascribed to NO donation and may reflect cyclooxygenase inhibition. This is the first evidence that chronic NSAID treatment may ameliorate progressive nephropathies.

Acute renal failure due to hemolytic uremic syndrome in adult patients.

Hemolytic uremic syndrome is characterized by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and renal failure. Clinical/ pathologic data, along with the treatment and outcome of 8 adult patients with HUS, are described. There were 7 females and 1 male, age 30.7 +/- 12 years; 7 were White and 1 Black. Three patients were kidney graft recipients, 2 of whom were receiving cyclosporine; 2 patients were postpartum; 1 case followed an abortion; 1 occurred with prodromic infection; and 1 case was without a causal factor. All patients presented with hematuria and 6 with oligoanuria. Laboratory data showed hemolytic anemia with schistocytes, LDH values were 2584 +/- 2191 U/L, platelets were 79,000 +/- 40,000/mL, creatinine concentrations were 5.9 +/- 2.5 mg/dL. Renal biopsy showed thrombotic microangiopathy. Two had predominant glomerular involvement. 2 showed renal cortical necrosis, 4 were marked by predominant arteriolar involvement. In 5 patients dialytic therapy was performed. All were treated with fresh-frozen plasma infusion and 6 with plasmapheresis. Three patients died, 2 without recovery of renal function. In conclusion, the trigger events were related to renal transplant in 3.2 of them taking cyclosporine; 3 with pregnancy; 1 to precedent infection; and 1 with no causal factor. There was no correlation between histological form and outcome in this group of patients. The benefit of plasmapheresis was evident in the recovery of the extrarenal manifestations, although it did not change the renal outcome. The prognosis is poor, with a high mortality (37.5%) and/or end-stage renal failure (37.5%). Complete recovery of renal function was obtained in 25%.

Effect of salt intake and inhibitor dose on arterial hypertension and renal injury induced by chronic nitric oxide blockade.

Long-term nitric oxide blockade by N omega -nitro-L-arginine methyl ester (L-NAME) leads to severe and progressive hypertension. The role of salt intake in this model is unclear. To verify whether salt dependence in this model is related to the extent of nitric oxide inhibition, we gave adult male Munich-Wistar rats a low salt, standard salt, or high salt diet and oral L-NAME treatment at either 3 or 25 mg/kg per day. At 10 to 15 days of treatment, the slope of the pressure-natriuresis line was decreased in rats receiving low-dose L-NAME compared with untreated controls. In rats treated with the higher dose, the line was shifted to the right but remained parallel to that obtained in untreated controls. Renal vascular resistance was moderately increased in rats receiving low-dose L-NAME, whereas high-dose L-NAME induced a marked vasoconstriction that was aggravated by salt overload. Low-dose L-NAME treatment induced hypertension only when associated with sodium overload. In rats receiving high-dose L-NAME, hypertension was aggravated by sodium excess but was not ameliorated by sodium restriction. Long-term (6 weeks) L-NAME treatment was associated with progressive hypertension, which was aggravated by salt overload, and with the development of albuminuria, focal glomerular collapse, glomerulosclerosis, and renal interstitial expansion. These abnormalities were worsened by salt overload and largely prevented by salt restriction. In the model of chronic nitric oxide blockade, salt dependence is a function of the inhibitor dose, and renal injury varies directly with the level of salt intake.