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Little information is available regarding renal histology in cases of chronic allograft dysfunction and graft failure in patients with recurrent immunoglobulin A nephropathy. We compared 57 renal allograft biopsies of 44 patients with recurrent immunoglobulin A nephropathy to 43 biopsies of 33 patients without immunoglobulin A nephropathy recurrence. Clinical parameters such as patient demography and biopsy indications did not differ between the 2 groups, with the exception of time to biopsy. Renal allograft injury, which was assessed by semiquantitative scoring of glomerular, tubulointerstitial, and arteriolar changes, increased linearly over time after transplantation in both recurrent and nonrecurrent samples. Glomerular injuries were significantly correlated with tubulointerstitial injuries in both groups, but the correlation graph reflected an increasing gap in the degrees of tubulointerstitial injury between the 2 groups over time. The levels of glomerulosclerosis, mesangial proliferation, and crescent formation were significantly higher in recurrent samples, whereas the prevalence of chronic rejection was significantly higher in nonrecurrent samples. The presence of segmental sclerosis was associated with significant proteinuria in recurrent samples. Graft survival was better in recurrent immunoglobulin A nephropathy patients than in nonrecurrent patients (74.4% versus 51%) at 10 years after transplantation. In conclusion, slow and progressive glomerular injury is the major cause of long-term graft failure in patients with recurrent immunoglobulin A nephropathy. In contrast, rapidly increasing tubulointerstitial injury is responsible for graft failure in nonrecurrent patients.

Background: Polyomavirus (PV) nephropathy may coexist with or follow acute renal transplant rejection. The aim of this study was to evaluate whether HLA-DR and CD54 are useful cellular markers for surveillance of acute rejection in PV-infected patients., Methods: A prospective study was conducted using 205 renal transplant patients. Urine samples were collected at a regular interval post-transplantation for routine cytology and immunocytochemistry. Urinary levels of tumour necrosis factor alpha, soluble interleukin-2 receptor and interleukin-6 were used as adjunctive markers for acute rejection., Results: Of the 699 total samples, decoy cells were identified in 100 samples of 50 patients. Patients with decoy cell-positive (DCP) samples had higher serum creatinine levels than decoy cell-negative (DCN) samples (1.55 vs 1.41 mg/dl, respectively; P = 0.006). DCP samples were also more likely to be HLA-DR positive (50.0 vs 32.4%; P = 0.029), as well as CD54 positive (17.4 vs 6.9%; P = 0.038). However, serum creatinine levels did not correlate with HLA-DR or CD54 positivity among DCP samples. Instead, CD54 positivity correlated with decoy cell grades. Immunosuppression decreased in 11 DCP patients, and HLA-DR was negatively converted in three of them. None of the patients developed acute clinical rejection. Urinary cytokine levels did not correlate with serum creatinine levels, nor did they correlate with HLA-DR or CD54 status among DCP patients., Conclusions: Urinary tubular HLA-DR and CD54 expression increased in decoy cell shedding patients but did not indicate a concomitant acute rejection. These markers may instead indicate renal inflammatory activity associated with viral reactivation, which has the potential to progress to PV interstitial nephritis.

To identify the factors affecting histological regression of crescentic Henoch-Schönlein nephritis (HSN), we retrospectively analyzed serially biopsied 20 children with crescentic HSN treated with immunosuppressants. They were classified into two groups according to the histological changes between the first and second biopsy: group I (n=10) with histological regression and group II (n=10) with no change or histological progression. Of the 20 patients, 19 showed a favorable outcome at the end of follow-up. Initial laboratory and histological findings did not differ between the two groups. Histological regression was associated with a younger age at onset (P=0.003), early treatment with immunosuppressants (P=0.044) and absent or decreased fibrinogen deposits at the second biopsy (P<0.0001) in a univariate analysis. Mesangial IgA and fibrinogen depositions at the second biopsy were reduced significantly in group I (P<0.05). In the multivariate analysis, a younger age was an independent determinant of histological regression (OR 1.44; 95% CI 1.03-2.02). The intensity of fibrinogen deposits at the second biopsy correlated positively with the age at onset (r=0.503, P=0.024), and the chronicity index at the second biopsy correlated positively with the time that immunosuppressive therapy was started (r=0.619, P=0.004).

To evaluate the effect of azathioprine with steroids on the clinical course and histologic parameters of severe Henoch-Schönlein nephritis (HSN), 20 patients with a median age of 9.3 years (range 4.4-17 years) and a follow-up period of 4.8 years (range 1-14 years) were included in this study. The patients were divided into two groups. Ten patients received azathioprine with steroids for 8 months (group A), and the other ten received steroids alone (group B). All patients underwent renal biopsy at presentation, and ten of them who were treated with azathioprine underwent follow-up biopsy after therapy. Six patients in group A achieved clinical remission, and the remaining four showed minor urinary abnormalities at the latest observation. The histological grades of the International Study of Kidney Disease in Children (ISKDC) improved in four of the ten patients, and the activity index decreased significantly from 6.8+/-2.0 to 4.3+/-2.3 (p=0.016). In group B, however, four patients had normal urine and renal function; two had minor urinary abnormalities; one had active renal disease, and three had chronic renal insufficiency, at the latest observation. The combination treatment of azathioprine and steroids may be beneficial in ameliorating histopathological features and improving the clinical course of severe HSN.

To evaluate the efficacy of cyclosporin A (CyA) for treating severe Henoch-Schönlein nephritis (HSN), seven patients with nephrotic syndrome, aged 3.9-13.8 years (mean 6.5 years), were analyzed retrospectively. Mean follow-up times were 5.5 years (range 2-9 years). All underwent renal biopsy before treatment, and follow-up renal biopsy was performed in six of the seven patients. All patients improved, with 24-h protein declining from a mean of 9.2 g/m(2)/day (range 1.5-16 g/m(2)/day) to 0.3 g/m(2)/day (range 0.03-1.2 g/m(2)/day) (p=0.016) and serum albumin increasing from a mean of 2.1 g/dl (range 1.5-2.4 g/dl) to 4.6 g/dl (range 3.5-5.3 g/dl) (p=0.016) after CyA therapy. The activity index decreased significantly at the second renal biopsies obtained at a mean interval of 11.7 months after the first (6.4+/-3.3 vs 3.5+/-1.2, p=0.042, respectively), while the chronicity index and the tubulointerstitial scores did not change. On the immunofluorescent findings at the second biopsies, the degree of deposits of immunoglobulins such as IgA, IgM, C3, and fibrinogen decreased in five of the six patients. Although this case series is without controls, our study suggests that CyA may be beneficial to a subset of HSN patients with nephrotic syndrome.

Purpose: We evaluated the collagen-to-smooth muscle tissue matrix ratio and percentage of elastin in the renal pelvis, ureteropelvic junction (UPJ) and ureter, and compared these findings with the degree of obstruction, patient age and post-pyeloplasty renal recovery., Materials and Methods: We analyzed histological sections from 75 patients with UPJ obstruction. Nine patients were excluded owing to bilateral UPJ obstruction and an improper specimen. We divided the specimen obtained from pyeloplasty into 3 parts, namely the renal pelvis above the obstruction, the obstructed UPJ portion and the ureter below the obstruction. To examine the collagen and smooth muscle, sections were stained using Masson's trichrome, and elastic van Giesson stain was used for elastin, smooth muscle and collagen. Collagen, smooth muscle and elastin populations were identified, and the tissue matrix ratio and percentage of elastin were calculated by color image analysis., Results: In patients with lower ratios of collagen-to-smooth muscle in the UPJ proper hydronephrosis was more improved postoperatively (p = 0.049). In patients with a lower percentage of elastin in the renal pelvis, UPJ and ureter hydronephrosis was more improved postoperatively (p <0.0001)., Conclusions: Because the UPJ portion was resected during pyeloplasty, the renal pelvis and the ureter remaining after pyeloplasty are likely to be related to improved hydronephrosis. A higher percentage of elastin in the renal pelvis and ureter contributes to inelasticity and low compliance, and results in a slower recovery from hydronephrosis after pyeloplasty.

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.

Purpose: Increasing clinical importance is being placed on the role of differential renal function (DRF) in the management of congenital ureteropelvic junction obstruction. Supranormal DRF of the hydronephrotic kidney on renal scan is a puzzling phenomenon and is hypothesized to be due to an increase in single nephron filtration or nephron volume without sound evidence. We studied the histopathological changes of hydronephrotic kidneys to determine whether glomerular hypertrophy underlies supranormal DRF., Materials and Methods: We retrospectively evaluated the records of 3 females and 32 males with unilateral congenital hydronephrosis who underwent pyeloplasty. Mean patient age at operation was 12.6 months (range 0.1 to 144). Needle biopsies from 3 different sites at the lower pole of the kidney were performed during surgery. To evaluate the presence of glomerular hypertrophy, the maximal planar area of glomeruli was measured under light microscopy using an image analyzer. Tissue samples obtained from kidneys without a history of urinary tract disease at autopsy were used as controls. The mean glomerular areas of the patient and control groups were evaluated according to DRF and age., Results: The mean glomerular area values of the patient group were smaller than those of the control group, except for 4 patients. The glomerular areas of the hydronephrotic kidneys with supranormal DRF were not significantly different from those of the control group. Instead, the probability of larger renal glomeruli increased with decreasing DRF (p = 0.1155)., Conclusions: Increased nephron volume can be discounted as a cause of supranormal DRF.

The aim of this study was to evaluate the role of osteopontin (OPN) in cyclosporine (CsA) nephrotoxicity of the human kidney. Renal biopsy samples obtained before and after 1-2 years of CsA treatment were evaluated in 18 children (2.2-13.0 years, 14 males, 4 females) diagnosed with minimal change nephrotic syndrome. The changes in tubular OPN expression between pre- and post-treatment samples were correlated with interstitial macrophage infiltration, transforming growth factor-beta (TGF-beta) expression, interstitial fibrosis, and microvascular density. OPN, TGF-beta, CD68, and CD34 positivity were quantitatively assessed by immunohistochemical staining. Light microscopy showed that interstitial fibrosis developed in two-thirds of patients after CsA treatment. However, CD68-positive macrophages infiltrated minimally in fibrotic areas and were found in only one-third of patients. OPN expression was significantly increased in the glomerular mesangium (P=0.001) and tubules (P=0.025) after CsA treatment, whereas the number of CD34-positive peritubular capillaries decreased (P=0.022). An inverse relationship was observed between tubular OPN expression and microvascular density (r=-0.644). However, tubular OPN expression was not related to proteinuria, interstitial fibrosis, or interstitial or tubular TGF-beta expression. This study indicates that increased OPN expression may be related to microvascular injury in human CsA nephrotoxicity. It also shows that OPN expression may be used as an early but non-specific marker of CsA toxicity before the manifestation of interstitial fibrosis.

Polyomavirus (PV) nephropathy is a rare cause of graft dysfunction, but it may accompany acute rejection (AR), resulting in complications with respect to its diagnosis and treatment. To examine the validity of tubulitis and inflammatory phenotype in the diagnosis of concurrent AR, we reviewed the renal histology of ten biopsy samples from nine patients with PV nephropathy, and the immunohistochemistry from eight samples. Tubulitis was present in seven patients and was associated with AR in six. The degrees of tubulitis and interstitial inflammation were higher in biopsy samples with AR than in those without, but the degree of tubulitis was not related to the degree of interstitial inflammation. Virally infected cells were rare in the samples with no, or mild, tubulitis, but did not increase with the degree of interstitial inflammation. Immuno-phenotyping of inflammatory cells did not show any T-cell dominance in AR: T cells were dominant over B cells in three of six samples with AR and both samples without AR. Although the degrees of tubulitis and interstitial inflammation were higher in the AR subjects, the presence of tubulitis or inflammatory phenotype was not helpful in the diagnosis of concurrent AR. Further studies will be required to find a better marker for coexisting AR in patients with PV nephropathy and to establish strategies for treatment.

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.

Background: The remnant kidney model, usually involving sudden removal or ablation of 1- 1 / (2) to 1-5 / (6) of renal mass, results in compensatory hypertrophy followed by hypertension, proteinuria and declining glomerular filtration rate (GFR) associated with focal (FSG) and then global glomerulosclerosis (GS) and tubulointerstitial injury (TI). Since most renal diseases involve much more gradual injury, we asked whether slow ablation (SA) produced a different natural history than fast ablation (FA)., Methods: Male Münich-Wistar rats underwent heminephrectomy, 3 weeks later a second, and 3 weeks later a third heminephrectomy (SA). They were compared to littermates undergoing simultaneous removal of 1- 1 / (2) kidneys (FA) and sham operated controls (C)., Results: Three weeks after the second heminephrectomy, the SA rats had no FSG and glomerular volume (GV) was similar to that of FA rat renal tissue removed at that time. Eight weeks following the final surgical procedure (FSP), the SA and FA groups had similar blood pressures (BP) but higher than C. Albumin excretion rates (AER) were higher in SA and FA vs. C at 1 month after the FSP and, throughout most of the subsequent 5 months, greater in the SA vs. FA groups. At 24 weeks, cortical interstitial fractional volume was double C values in both the SA and FA groups. Percentage of glomeruli with FSG and size (score) of FSG lesions was much higher in SA and FA than C. Moreover, the percentage of FSG in SA (61.2+/-16%) and FSG score (1.7+/-0.7) was greater than in FA animals (35.6+/-11.9% and 0.9+/-0.4, p<0.01 for each comparison). Mean GV, increased at 24 weeks in both groups over C (1.4+/-0.2 X 10(6) micro m(3)) was greater in SA (3.4+/-0.7 X 10(6) micro m(3)) than FA rats (2.1+/-0.4 X 10(6) micro m(3); p<0.005)., Conclusions: The gradual uninephrectomy in the SA group, insufficient per se to produce significant renal damage, preconditioned the residual kidney, upon further removal of another 1 / (2) kidney, to more albuminuria and FSG lesions than occurred following sudden 1- 1 / (2) nephrectomy, despite similarly elevated BP. Perhaps more time for glomerular enlargement in the SA group preconditioned the remnant kidney to accelerated injury.