Lupus nephritis is more severe in children and adolescents than in older adults.

OBJECTIVE: To evaluate clinicopathological features and treatment response in patients with lupus nephritis (LN), comparing the childhood- and late-onset forms of the disease. METHODS: We retrospectively analyzed clinical presentation, treatment and evolution in patients diagnosed with LN by renal biopsy between 1999 and 2008. Patients were grouped by age-≤18 years (n = 23); and ≥50 years (n = 13)-and were followed for the first year of treatment. RESULTS: The baseline features of the childhood- and late-onset groups, respectively, were as follows: mean age, 15 ± 2 and 54 ± 5 years; female gender, 87% and 92%; hypertension, 87% and 77%; Systemic Lupus Erythematosus Disease Activity Index, 29 ± 9 and 17 ± 7 (p = 0.002); estimated glomerular filtration rate (eGFR), 86 ± 66 and 70 ± 18 ml/min; concurrent SLE/LN diagnosis, 90% and 15% (p < 0.001); crescents on biopsy, 74% and 30% (p = 0.02); activity index on biopsy, 4.8 ± 2.6 and 3.3 ± 1.9 (p = 0.10); and interstitial fibrosis (>10%), 39% and 61% (p = 0.08). Treatment consisted mainly of methylprednisolone, prednisone and intravenous cyclophosphamide, average cumulative doses being similar between the groups. After 12 months of treatment, the eGFR in the younger and older patients was 116 ± 62 and 78 ± 20 ml/min, respectively (p = 0.005). Three of the younger patients progressed to dialysis at 12 months, compared with none of the older patients. CONCLUSION: Childhood-onset LN seems to be more severe than is late-onset LN.

Worse renal outcome of lupus nephritis in male patients: a case-control study.

BACKGROUND: Progression and long-term renal outcome of lupus nephritis (LN) in male patients is a controversial subject in the literature. The aim of this study was to evaluate the influence of male gender on the renal outcome of LN. METHODS: All male (M) LN patients who fulfilled American College of Rheumatology lupus criteria and who were referred for a kidney biopsy from 1999 to 2009 were enrolled in the study. Subjects with end-stage renal disease at baseline, or follow-up time below 6 months, were excluded. Cases were randomly matched to female (F) patients according to the class of LN, baseline estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease simplified formula) and follow-up time. Treatment was decided by the clinical staff based on usual literature protocols. The primary endpoint was doubling of serum creatinine and/or end-stage renal disease. The secondary endpoint was defined as a variation of glomerular filtration rate (GFR) per year (ΔGFR/y index), calculated as the difference between final and initial eGFR adjusted by follow-up time for each patient. RESULTS: We included 93 patients (31 M : 62 F). At baseline, M and F patients were not statistically different regarding WHO LN class (II 9.7%, IV 71%, V 19.3%), eGFR (M 62.4 ± 36.4 ml/min/1.73 m2 versus F 59.9 ± 32.7 ml/min/1.73 m2), follow-up time (M 44.2 ± 27.3 months versus F 39.9 ± 27.9 months), and 24-hour proteinuria (M 5.3 ± 4.6 g/day versus F 5.2 ± 3.0 g/day), as well as age, albumin, C3, antinuclear antibody, anti-DNA antibody and haematuria. There was no difference in the primary outcome (M 19% versus F 13%, log-rank p = 0.62). However, male gender was significantly associated with a worse renal function progression, as measured by ΔGFR/y index (ß coefficient for male gender -12.4, 95% confidence interval -22.8 to -2.1, p = 0.02). The multivariate linear regression model showed that male gender remained statistically associated with a worse renal outcome even after adjustment for eGFR, proteinuria, albumin and C3 complement at baseline. CONCLUSION: In our study, male gender presented a worse evolution of LN (measured by an under GFR recovering) when compared with female patients with similar baseline features and treatment. Factors that influence the progression of LN in men and sex-specific treatment protocols should be further addressed in new studies.

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.

ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: a double-blind randomized clinical trial.

OBJECTIVE: The combination of an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for the treatment of diabetic nephropathy (DN), but doubts remain about its efficacy and safety. We compared the effects of combination therapy and ACEI monotherapy on proteinuria and on three urinary inflammatory cytokines (MCP-1, TGF-beta and VEGF). DESIGN AND PATIENTS: 56 patients with macroalbuminuric DN received 40 mg/d enalapril for 4 months, followed by add-on 100 mg/day losartan or placebo for another 4 months. The primary and secondary endpoints were reduction of proteinuria and cytokine levels, respectively. RESULTS: Proteinuria did not fall in either group. Repeated measures ANOVA revealed no difference between groups. A high side effect rate was observed (28.5%). Finally, unadjusted logistic regression showed no difference between groups, but after adjustments the risk of worsening proteinuria was higher in the combination therapy group (p = 0.04). The same pattern was observed for urinary MCP- 1. CONCLUSION: These results suggest that 1) in advanced DN with severe proteinuria and poor metabolic control, angiotensin II blockade may be less effective than in other groups of CKD patients. 2) In such patients, combination therapy may not afford superior renoprotection compared to enalapril. 3) Urinary MCP-1 is a promising biomarker for the response to ACEI and/or ARB treatment and for the risk of associated unwanted effects.

Genetic potential for an acute inflammatory response in IgA glomerulonephritis in mice.

Mice selected on the basis of an acute inflammatory response (AIR) can provide information about the immunopathological mechanisms of glomerulonephritis. We studied the differences between mice selected for a maximal AIR (AIRmax that attract more polymorphonuclear cells to the site of injury) or a minimal AIR (AIRmin that attract more mononuclear cells) in an experimental model of IgA nephropathy in order to investigate the effect of genetic background on glomerular disease progression and the participation of the monocyte chemoattractant protein-1 (MCP-1) chemokine. IgA nephropathy was induced by intraperitoneal ovalbumin injection and bile duct ligation in AIRmax and AIRmin mice. Histological changes, urinary protein/creatinine ratio, serum IgA levels, immunofluorescence for IgA, IgG and complement C3 fraction, immunohistochemistry for macrophages and MCP-1, and MCP-1 levels in macerated kidney were determined. Mesangial IgA deposition was seen only in AIRmin mice, which presented more renal lesions. Increased serum IgA levels (1.5 +/- 0.4 vs 0.3 +/- 0.1 mg/mL, P < 0.001), high glomerular MCP-1 expression and decreased monocyte/macrophage infiltration in the interstitial area (0.3 +/- 0.3 vs 1.1 +/- 0.9 macrophages/field, P < 0.05) were detected in AIRmin mice compared to AIRmax mice. No glomerular monocyte/macrophage infiltration was detected in either strain. In spite of the absence of IgA deposition, AIRmax mice presented discrete or absent mesangial proliferation. The study showed that there are differences between mice selected for AIRmax and AIRmin with respect to serum IgA levels, histological damage and MCP-1 chemokine production after ovalbumin injection in combination with bile duct ligation.

Comparative study of IgA nephropathy with and without crescents.

Glomerular crescents were analyzed as a prognostic factor in retrospectively reviewed data from 144 patients with biopsy-proven IgA nephropathy. Crescents were found in 26 (18%) patients, and detected in 2 to 100% of glomeruli in each specimen. In 5% of the patients more than 50% of the glomeruli were affected. Thirty patients with IgA nephropathy without crescents were studied as a control group. Mean age was 30.3 +/- 9.4 and 30.2 +/- 12.0 years for the patients with and without crescents, respectively, and males prevailed in both groups. The length of follow-up was 23.2 +/- 41.6 months for patients with crescents and 29.3 +/- 35.3 months for patients without crescents. Eighty percent of the patients with crescents were hypertensive, compared to 27% of the non-crescent control group (P < 0.05). Mean serum creatinine at the time of diagnosis was 3.9 +/- 2.9 and 1.9 +/- 2.1 mg/dl for the patients with and without crescents, respectively. Initial urinary protein excretion was higher in patients with crescents (4.6 +/- 3.5 vs 1.2 +/- 0.9 g/day; P < 0.05). At the end of follow-up 17 patients (77.3%) from the crescent group and 3 (11.1%) from the non-crescent group had end-stage renal disease (P < 0.0001). The presence of crescents was associated with higher levels of initial serum creatinine and urinary protein excretion, and a higher frequency of hypertension and progression to end-stage renal disease.

The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats.

The aim of the present study was to evaluate renal and liver distribution of two monoclonal immunoglobulin light chains. The chains were purified individually from the urine of patients with multiple myeloma and characterized as lambda light chains with a molecular mass of 28 kDa. They were named BJg (high amount of galactose residues exposed) and BJs (sialic acid residues exposed) on the basis of carbohydrate content. A scintigraphic study was performed on male Wistar rats weighing 250 g for 60 min after i.v. administration of 1 mg of each protein (7.4 MBq), as the intact proteins and also after carbohydrate oxidation. Images were obtained with a Siemens gamma camera with a high-resolution collimator and processed with a MicroDelta system. Hepatic and renal distribution were established and are reported as percent of injected dose. Liver uptake of BJg was significantly higher than liver uptake of BJs (94.3 vs 81.4%) (P < 0.05). This contributed to its greater removal from the intravascular compartment, and consequently lower kidney accumulation of BJg in comparison to BJs (5.7 vs 18.6%) (P < 0.05). After carbohydrate oxidation, there was a decrease in hepatic accumulation of both proteins and consequently a higher renal overload. The tissue distribution of periodate-treated BJg was similar to that of native BJs: 82.7 vs 81.4% in the liver and 17.3 vs 18.6% in the kidneys. These observations indicate the important role of sugar residues of Bence Jones proteins for their recognition by specific membrane receptors, which leads to differential tissue accumulation and possible toxicity.

Nephrotic syndrome associated with hepatointestinal schistosomiasis.

Schistosomal nephropathy has long been related to the hepatosplenic form of schistosomiasis. In the last few years, 24 patients with hepatointestinal schistosomiasis and the nephrotic syndrome were studied. Aiming at evaluating a possible etiologic participation of schistosomiasis in the development of the nephropathy, this group was comparatively studied with a group of 37 patients with idiopathic nephrotic syndrome. Both groups had a different distribution of the histologic lesions. In the group with schistosomiasis there was a statistically significant prevalence of proliferative mesangial glomerulonephritis (33.3%), whereas in the control group there was prevalence of membranous glomerulonephritis (32.4%). On immunofluorescence, IgM was positive in 94.4% of the patients with schistosomiasis versus 55.0% in the control group (P < 0.01). In the group with schistosomiasis, 8 patients evidenced mesangial proliferative glomerulonephritis and 5, membranoproliferative glomerulonephritis. In both histological types immunofluorescence showed IgM and C3 granular deposits in the glomeruli. The data in this study suggests that mesangial proliferative and membranoproliferative glomerulonephritis, with glomerular granular IgM and C3 deposits, represent the renal lesions of the schistosomiasis associated nephropathy.

Urinary MCP-1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy.

BACKGROUND: Albuminuria has been considered a sine qua non condition for the diagnosis of diabetic nephropathy (DN) and has been widely used as a surrogate outcome of chronic kidney disease (CKD). However, recent data suggest that albuminuria may fail as a biomarker in a subset of patients, and the search for novel markers is intense. METHODS: We analyzed the role of urinary RBP and of serum and urinary cytokines (TGF-beta, MCP-1 and VEGF) as predictors of the risk of dialysis, doubling of serum creatinine or death (primary outcome, PO) in 56 type 2 diabetic patients with macroalbuminuric DN. RESULTS: Mean follow-up time was 30.7±10 months. Urinary RBP and MCP-1 were significantly higher in patients presenting the PO, whereas no difference was shown for TGF-ß or VEGF. In the Cox regression, urinary RBP, MCP-1 and VEGF were positively associated and serum VEGF was inversely related to the risk of the PO. However, after adjustments for creatinine clearance, proteinuria, and blood pressure only urinary RBP (OR 11.6; 95% CI 2.7-49.2, p=0.001 for log RBP) and urinary MCP-1 (OR 11.0; 95% CI 1.6-76.4, p=0.02 for log MCP-1) remained as significant independent predictors of the PO. CONCLUSION: Urinary RBP and MCP-1 are independently related to the risk of CKD progression in patients with macroalbuminuric DN. Whether these biomarkers have a role in the setting of normoalbuminuria and microalbuminuria in DN should be further investigated.

High-titer antichromatin antibody is associated with proliferative class IV of lupus nephritis.

The antichromatin antibody (aCT) has been described as a useful marker for lupus nephropathy. The relevance of its nephritogenic potential may be appropriately evaluated in the context of renal histopathology. Therefore, the present study investigated the relationship of aCT with a particular histopathologic class of lupus nephritis (LN). Seventy-eight consecutive patients with systemic lupus erythematosus (ACR criteria) and active nephritis who underwent renal biopsy from 1999 to 2004 and with available frozen serum sample obtained at the time of biopsy were selected. aCT was measured by ELISA, and anti-dsDNA was measured by indirect immunofluorescence (IIF) and by ELISA. All renal biopsies were revised in a blinded manner by the same expert renal pathologist. Charts were extensively reviewed for demographic and renal features obtained at the time of biopsy. The prevalence of aCT (>or=20 U) was 59% with a mean titer of 74.3 +/- 38.7 U. Both aCT-positive and aCT-negative groups of patients had similar age, gender distribution, duration of lupus, and duration of renal disease. Anti-dsDNA was detected by IIF in 29.5% and by ELISA in 42.3% of the patients. Concomitant presence of both antibodies was observed in 63% (29/46) [anti-dsDNA by ELISA] and 45.6% (21/46) [anti-dsDNA by IIF] of the patients. Lower serum levels of C3 (73% vs. 40%, P = 0.0058) and C4 (82% vs. 46.7%, P = 0.0021) were more commonly observed in aCT >or= 20 U patients compared to the aCT-negative group. It is important to note that the use of a higher cut-off value (>or=40 U) for aCT test revealed a predominance of class IV LN (58% vs. 33%, P = 0.039) in aCT >or= 40 U compared to aCT < 40 U group. The mean levels of proteinuria, serum albumin, and creatinine were markedly altered but were comparable in both groups (P >or= 0.05). One fourth (26.3%) of the 19 patients with class IV LN and aCT >or= 40 U had no detectable anti-dsDNA (ELISA). These data suggest that high-titer aCT seems to be a valuable biomarker for proliferative class IV of LN.

Decreased in vitro osteoblast proliferation and low turnover bone disease in nonuremic proteinuric patients.

Patients with proteinuria, even those with normal glomerular filtration rate, often present abnormal bone histology. We evaluated bone histology and the in vitro proliferation of osteoblasts in samples obtained from 17 proteinuric patients with primary glomerulopathies. Histomorphometric analysis of bone biopsies was performed, and bone fragments were obtained for osteoblast culture, in which we evaluated cell proliferation. In comparison to controls, patients presented lower trabecular bone volume (20.9+/-14.5% vs 26.8+/-5.9%; P=0.0008); lower trabecular number (1.7+/-0.2/mm vs 2.0+/-0.3/mm; P=0.004); and greater trabecular separation (475.5+/-96.4 microm vs 368.3+/-86.2 microm, P=0.0002). We also found alterations in bone formation and resorption: lower osteoid volume (0.9+/-0.7% vs 2.0+/-1.4%; P=0.0022); lower osteoid thickness (6.4+/-2.8 microm vs 11.5+/-3.2 microm; P<0.0001); less mineralizing surface (4.6+/-3.1% vs 13.5+/-6.0%; P<0.0001); lower bone formation rate (0.03+/-0.04 microm(3)/microm(2)/day vs 0.09+/-0.05 microm(3)/microm(2)/day; P<0.0001); and greater osteoclast surface (0.35+/-0.6 vs 0.05+/-0.1%, P=0.0016). Mean in vitro osteoblast proliferation was lower in patients than in controls (910.2+/-437.1 vs 2261.0+/-1121.0 d.p.m./well, P=0.0016). Serum concentrations of 25-hydroxyvitamin-D(3) correlated negatively with proteinuria and positively with in vitro osteoblast proliferation. Our results demonstrate that nonuremic proteinuric glomerulonephritic patients present bone structure disorder, low bone formation and high bone resorption, as well as low osteoblast proliferation.

[Protein/creatinine index in isolated samples of urine for evaluation of 24-hour proteinuria]. / Indice proteína/creatinina em amostra isolada de urina para avaliação da proteinúria de 24 horas.

The correct determination of the 24 hours proteinuria (PU24) in the non-hospitalized patients is frequently subject to collection errors. To overcome this problem it has been proposed the use of the proteinuria ratio (PR), obtained by dividing the concentrations of protein/creatinine in random urine samples. In the present investigation PR and PU24 were correlated in 42 patients (22 male and 20 female), aged between 14 and 63 years. Each patient was submitted to a 2 hours creatinine clearance (Ccr), to determination of PU24 and to evaluation of PR in the urine samples. The measures of PU24 were correlated with the values of PR. On linear regression analysis the equation y = 0,517 + 0,759x was obtained, with r = 0,914, suggesting good correlation between PU24 and PR. Values of r greater than 0,9 were always obtained, independently of the values of Ccr and PU24. The results indicate that PR in random urine samples may be practical and reliable in the follow-up of nephrological patients.

Nodular diabetic glomerulosclerosis without diabetes mellitus.

A 66-year-old white man presented with severe chronic renal failure. He had no past or present symptomatic glucose intolerance nor a family history of diabetes mellitus. Several fasting plasma glucose determinations, hemoglobin Alc and an oral glucose tolerance test were normal. Funduscopic ophthalmoscopy and retinal fluorescein angiography did not demonstrate diabetic retinopathy. The kidney biopsy showed nodular diabetic nephropathy, with increased mesangial matrix, thickened glomerular basement membrane, and afferent and efferent glomerular arteriolar hyalinization. The diagnosis of nodular diabetic nephropathy was made in this patient in the absence of past or present or familial evidence of diabetes mellitus.

Genetic potential for an acute inflammatory response in IgA glomerulonephritis in mice

Mice selected on the basis of an acute inflammatory response (AIR) can provide information about the immunopathological mechanisms of glomerulonephritis. We studied the differences between mice selected for a maximal AIR (AIRmax that attract more polymorphonuclear cells to the site of injury) or a minimal AIR (AIRmin that attract more mononuclear cells) in an experimental model of IgA nephropathy in order to investigate the effect of genetic background on glomerular disease progression and the participation of the monocyte chemoattractant protein-1 (MCP-1) chemokine. IgA nephropathy was induced by intraperitoneal ovalbumin injection and bile duct ligation in AIRmax and AIRmin mice. Histological changes, urinary protein/creatinine ratio, serum IgA levels, immunofluorescence for IgA, IgG and complement C3 fraction, immunohistochemistry for macrophages and MCP-1, and MCP-1 levels in macerated kidney were determined. Mesangial IgA deposition was seen only in AIRmin mice, which presented more renal lesions. Increased serum IgA levels (1.5 ± 0.4 vs 0.3 ± 0.1 mg/mL, P < 0.001), high glomerular MCP-1 expression and decreased monocyte/macrophage infiltration in the interstitial area (0.3 ± 0.3 vs 1.1 ± 0.9 macrophages/field, P < 0.05) were detected in AIRmin mice compared to AIRmax mice. No glomerular monocyte/macrophage infiltration was detected in either strain. In spite of the absence of IgA deposition, AIRmax mice presented discrete or absent mesangial proliferation. The study showed that there are differences between mice selected for AIRmax and AIRmin with respect to serum IgA levels, histological damage and MCP-1 chemokine production after ovalbumin injection in combination with bile duct ligation.

Comparative study of IgA nephropathy with and without crescents

Glomerular crescents were analyzed as a prognostic factor in retrospectively reviewed data from 144 patients with biopsy-proven IgA nephropathy. Crescents were found in 26 (18 percent) patients, and detected in 2 to 100 percent of glomeruli in each specimen. In 5 percent of the patients more than 50 percent of the glomeruli were affected. Thirty patients with IgA nephropathy without crescents were studied as a control group. Mean age was 30.3 ± 9.4 and 30.2 ± 12.0 years for the patients with and without crescents, respectively, and males prevailed in both groups. The length of follow-up was 23.2 ± 41.6 months for patients with crescents and 29.3 ± 35.3 months for patients without crescents. Eighty percent of the patients with crescents were hypertensive, compared to 27 percent of the non-crescent control group (P < 0.05). Mean serum creatinine at the time of diagnosis was 3.9 ± 2.9 and 1.9 ± 2.1 mg/dl for the patients with and without crescents, respectively. Initial urinary protein excretion was higher in patients with crescents (4.6 ± 3.5 vs 1.2 ± 0.9 g/day; P < 0.05). At the end of follow-up 17 patients (77.3 percent) from the crescent group and 3 (11.1 percent) from the non-crescent group had end-stage renal disease (P < 0.0001). The presence of crescents was associated with higher levels of initial serum creatinine and urinary protein excretion, and a higher frequency of hypertension and progression to end-stage renal disease.

Nephrotic syndrome associated with hepatointestinal schistosomiasis

Schistosomal nephropathy has long been related to the hepatosplenic form of schistosomiasis. In the last few years, 24 patients with hepatointestinal schistosomiasis and the nephrotic syndrome were studied. Aiming at evaluating a possible etiologic participation of schistosomiasis in the development of the nephropathy, this group was comparatively studied with a group of 37 patients with idiopathic nephrotic syndrome. Both groups had a different distribution of the histologic lesions. In the group with schistosomiasis there was a statistically significant prevalence of proliferative mesangial glomerulonephritis (33.3%), whereas in the control group there was prevalence of membranous glomerulonephritis (32.4%). On immunofluorescence, IgM was positive in 94.4% of the patients with schistosomiasis versus 55.0% in the control group (P < 0.01). In the group with schistosomiasis, 8 patients evidenced mesangial proliferative glomerulonephritis and 5, membranoproliferative glomerulonephritis. In both histological types immunofluorescence showed IgM and C3 granular deposits in the glomeruli. The data in this study suggests that mesangial proliferative and membranoproliferative glomerulonephritis, with glomerular granular IgM and C3 deposits, represent the renal lesions of the schistosomiasis associated nephropathy