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Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and renal involvement (HSP nephritis, HSPN) is a severe manifestation. HSPN is histologically classified by the International Study of Kidney Disease in Children (ISKDC) based on mesangial hypercellularity and the extent of glomerular crescents. Macrophages, categorized as M1 or M2, frequently infiltrate in various glomerular and tubulointerstitial diseases and infiltration of specific subtypes is associated with disease progression. Therefore, to identify whether infiltration of M1 or M2 macrophages has clinical significance, we quantified the subtypes of macrophages in 49 HSPN specimens and correlated the counts with histologic features and clinical parameters. Higher tubulointerstitial M2 counts were associated with chronic renal failure (CRF), ISKDC classes III-IV, and crescents ( P <0.001, 0.002, 0.001). Glomerular M2 counts were significantly related to ISKDC classes III-IV and crescents (area under curve, AUC 0.804, 0.833). Tubulointerstitial M2 counts were associated with CRF, ISKDC classes III-IV, and crescents (AUC 0.872, 0.778, 0.830). Tubulointerstitial M2 counts also revealed higher AUC than tubulointerstitial M1 counts for CRF ( P =0.036) and ISKDC classes III-IV ( P =0.047). Glomerular M2 counts revealed higher AUC than glomerular M1 counts for ISKDC classes III-IV ( P =0.024). Tubulointerstitial M2 counts were the most powerful parameter for CRF (AUC 0.872) and revealed even higher AUC than ISKDC classification (AUC 0.716) with borderline significance ( P =0.086) for CRF. In summary, tubulointerstitial M2 counts were a superior parameter to tubulointerstitial M1 counts and even to ISKDC classification indicating the presence of CRF.

Background: CD44 is a marker of activated parietal epithelial cells (PECs), and is expressed in glomerular visceral epithelial cells (VECs) during development of segmental sclerosis. We explored the significance of glomerular epithelial CD44 expression in relation to segmental sclerosis in patients with mild IgA nephropathy (IgAN)., Methods: A total of 126 cases of IgAN were divided into three groups based on glomerular morphology: normal (group A, n = 30), mild mesangial proliferation without segmental sclerosis or synechia (SS) (group B, n = 31), or mild mesangial proliferation with SS (group C, n = 65). The number of CD44-expressing PECs and VECs was counted in each glomerulus and expressed as the mean number per case., Results: CD44 staining was positive in VECs in 59.5 %, in PECs in 79.4 % and in both cell types in 56.3 % of cases. The number of CD44 + PECs or VECs was significantly higher in group C than in groups A or B. Cases with >1 CD44 + cell (PECs and VECs) per glomerulus were associated with increased urine protein/creatinine ratio (UPCr) at last follow-up. The presence of >1 CD44 + VEC/glomerulus was associated with increased UPCr and serum creatinine levels, and decreased estimated glomerular filtration rate (eGFR) even in the absence of SS at the time of biopsy., Conclusion: CD44 was expressed in PECs and VECs in association with SS in IgAN. Increased CD44 expression in VECs is a sign of active glomerular injury and dysfunction in these patients.

The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7 weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction.

Purpose: Smoking reportedly exerts deleterious effects on renal function; however, its effects on histology have not been clarified in patients with IgA nephropathy (IgAN)., Materials and Methods: Renal histology was evaluated in a cohort of 397 patients diagnosed with IgAN according to smoking status and dose in relation to renal function., Results: Among the study cohort, which was predominantly male (88.5%), 52 patients (13%) were current smokers. These current smokers demonstrated more frequent hypertension and higher serum creatinine levels than non/ex-smokers at the time of diagnosis, which was apparent with increased smoking dose. The percentages of global glomerulosclerosis and arteriolar hyalinosis increased with increased smoking dose, whereas tubulointerstitial fibrosis or arterial intimal thickening did not. Glomerular mesangial alpha-smooth muscle actin expression were similar between current and non/ex-smokers matched for age, gender, hypertension, and histologic severity, although the number of glomerular CD68+ cells was significantly fewer in smokers. Initial serum creatinine level, estimated glomerular filtration rate (eGFR), and global glomerulosclerosis were found to be risk factors of serum creatinine doubling in both smokers and non/ex-smokers by univariate analysis during a mean follow-up of 3.8 years., Conclusion: In addition to dose dependent renal functional decline and hypertension, smoking contributes to renal disease progression by eliciting microvascular injury in IgAN patients.

C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti-rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident.

Information is limited regarding the histological features related to chronic graft dysfunction and failure in patients with IgA nephropathy developing after renal transplantation. The prevalence and significance of glomerular crescents in post-transplant IgAN including recurrent, de novo and transmitted forms (TxIgAN), were studied. Renal morphology was evaluated in 71 patients of TxIgAN, obtained at more than 6 months post-transplant, and compared with regard to the presence (C-TxIgAN) or absence (N-TxIgAN) of glomerular crescents. Crescents were demonstrated in 12 samples of 10 patients (14.1%). The percentages of crescents were from 4.8% to 83.3% (median, 28.6%) in each sample. Ten samples of C-TxIgAN had cellular to fibrocellular crescents, and four of these were associated with diffuse mesangial proliferation. Serum creatinine levels and the frequency of nephrotic range proteinuria at the time of biopsy and the degree of interstitial inflammation were significantly different in the two groups. Graft survival after allograft biopsies was significantly lower in C-TxIgAN (P = 0.0017). Chronic rejection was a major cause of graft loss in N-TxIgAN (31.8%), whereas TxIgAN was the major cause in C-TxIgAN (66.7%). In conclusion, the current study suggests that glomerular crescents are not rare and that they are responsible for chronic graft dysfunction in TxIgAN patients.

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

This study was designed to evaluate whether glomerular C4d deposition may be a useful marker of lupus nephritis activity. Twenty-one patients diagnosed as having lupus nephritis (WHO class III: 4 cases; IV: 12 cases; V: 5 cases) were included. Mean patient age was 29.3 +/- 13.5 years (range: 7-55 years). The presence and intensity of glomerular C4d deposition were compared with the corresponding histologic activity index for each case. Immunofluorescence for C4d showed diffusely granular staining along glomerular capillary loops, in all cases examined (1+, in 8 cases; 2+, in 7 cases; 3+, in 6 cases). In eight cases, C4d deposition was found in the absence of capillary or mesangial C4 deposits. Moreover, the intensity of C4d deposits correlated with those of capillary IgG, IgA, C4, C1q, and fibrinogen deposits. However, C4d staining intensity did not correlate with the lupus nephritis activity index. Although glomerular capillary C4d deposition is a sensitive marker of classic complement pathway activation, it is not a sensitive marker for active lupus nephritis.

Diffuse glomerular basement membrane (GBM) lamellation, reminiscent of Alport's syndrome, has rarely, and exclusively, been reported in renal allografts from pediatric donors to adult recipients. We report on a similar lesion, identified in a 42-year-old male, who received a kidney from an unrelated 21-year-old living male donor. The disease of the recipient was unknown. Renal allograft biopsies were performed 3.5 and 4.8 years after the renal transplantation, due to massive proteinuria and serum creatinine elevation. The histological features of both biopsies were similar, but more advanced in the second biopsy. Glomerular mesangium was widened and had an IgA deposit in the first biopsy. In addition to the presence of mesangial electron dense deposits, the GBM showed diffuse lamellation and splintering on the subepithelial side, but no definite deposits. In the second biopsy, IgA deposits were extended to the peripheral capillary walls, but electron microscopic examination was not available. Two months after the second biopsy, the patient returned for hemodialysis.

Previously, we reported that high glucose enhanced cytokine-induced nitric oxide (NO) production by rat mesangial cells (MCs), and that the enhanced expression of the iNOS pathway may promote extracellular matrix accumulation by MCs. The present study was designed to examine whether the iNOS pathway is pathologically altered in experimental diabetic nephropathy, and whether therapy with angiotensin converting enzyme (ACE) inhibitor (imidapril: I) or angiotensin II type I receptor (AT1) blocker (L-158,809: L), ameliorates these changes. Male Sprague-Dawley rats were injected with diluent (control: C) or streptozotocin. At sacrifice after 4, 8 and 12 weeks, rats underwent either a 4 hour placebo or an intraperitoneal lipopolysaccharide (LPS, 2 mg/kg) challenge. Systolic blood pressure (SBP) and urinary protein excretion (UPE) increased significantly in diabetic (D) rats compared with C. The basal expression of glomerular iNOS mRNA was increased in D rats compared with that of C rats, by reverse- transcription (RT)-polymerase chain reaction (PCR), whereas there was no significant difference in the level of protein by Western blot analysis. Upon LPS stimulation, the iNOS mRNA and protein expression was significantly elevated in D rats. In D rats, this up-regulation, of LPS-stimulated iNOS expression, was equally ameliorated both by I and L in mRNA and protein levels. From immunohistochemistry (IHC), there was a negative staining for the iNOS within the glomeruli of five C rats without LPS treatment, but one of four rats, with LPS treatment, showed minimal iNOS staining in the glomeruli. In D rats, the glomerular mesangium and podocytes were positive for iNOS in each of three out of five rats with, and without, LPS treatment. In conclusion, LPS-stimulated glomerular iNOS expression was enhanced in diabetic pnephropathy, and the activation of angiotensin II may play a role in this enhancement.