Comparison of histopathological characteristics of allograft biopsy between responder and non-responder to antiproteinuric effect of angiotensin-converting enzyme inhibitor (ACEI)

Abstract:  Angiotensin-converting enzyme inhibitor (ACEI) has become recognized as agents that have renoprotective effects in the treatment of progressive renal diseases including post-transplant kidneys. Previously we demonstrated the safety and effectiveness of ACEI treatment on the hypertensive proteinuric post-transplant patients ( N  = 10) who had been followed up for 12 months. However, not all patients show good response in urinary protein reduction. We aimed to analyse the histopathological factor(s) affecting the responsiveness of proteinuria to ACEI treatment. Fourteen post-transplant patients with proteinuria who were treated with ACEI and underwent allograft biopsy were analysed. Eight patients showed 50% or more reduction in proteinuria (responder). The other 6 patients showed less (< 50%) reduction in proteinuria (non-responder). There was no difference in clinical characteristics (BP, renal function, donor age, recipient body mass index), dietary sodium or protein intake, and diuretic use between the two groups. As a histopathological characteristic, glomerular size in responder group was significantly larger than that in non-responder group. This suggests that the large glomerular size at least partly contributes to the responsiveness in urinary protein reduction to ACEI treatment in kidney allograft recipients with proteinuria.     

Correlation of histopathological features and renal impairment in autosomal dominant Alport syndrome in Bull terriers.

BACKGROUND: Bull terrier hereditary nephritis represents a model for autosomal dominant Alport syndrome, as affected dogs have the characteristically lamellated glomerular basement membrane and demonstrate vertical male-to-male disease transmission. METHODS: This study compared the histopathological features in kidneys from affected Bull terrier neonates, puppies, and adult dogs with normal or impaired renal function, with the histopathological appearance of kidneys from age- and size-matched normal dogs. RESULTS: There were fewer glomeruli per unit area of cortex in kidneys from affected neonatal kidneys (P<0.05), increased numbers of fetal glomeruli in affected puppy kidneys (P<0.05), and a separate population of glomeruli with larger renal corpuscles and glomerular tufts in kidneys from affected adult dogs with normal renal function (both P<0.0001) compared with normal dogs. Other histological features that are characteristic of human X-linked and autosomal recessive Alport syndrome and that were present included hypercellular glomeruli, occasional crescents, segmental and global glomerular sclerosis, periglomerular fibrosis, interstitial fibrosis without significant cellular infiltrates and cystic dilatation of Bowman's capsular space and tubules. In dogs with renal impairment, the tubular index was the best predictor of increased urinary protein:creatinine (r=0.92) compared with glomerular, interstitial and vascular indices (r=0.77, 0.88 and 0.81), and medullary fibrosis correlated best with serum creatinine (r=0.72, P=0.0002). CONCLUSIONS: The demonstration in Bull terrier kidneys of fewer nephrons in neonates increased fetal glomeruli, and a separate population of glomeruli with larger corpuscles and tufts reflects the effects of the underlying genetic mutation that are first manifest antenatally. The major determinant of renal impairment in adult affected Bull terriers is, however, progressive tubulointerstitial damage after birth.     

Predictors of poor outcomes in steroid therapy for immunoglobulin A nephropathy

Background: Steroid therapy appears to be beneficial in patients of immunoglobulin A nephropathy (IgAN), as it causes a reduction in the proteinuria and improves the renal survival. Methods: A retrospective review of the 5 year follow‐up data of 60 patients with IgAN who were treated with steroids was conducted. Steroid non‐responders were defined as patients in whom the primary end‐point of a 30% decrease of the estimated glomerular filtration rate from baseline was reached. The patients were divided into two groups, namely, the steroid responder group (n = 47) and the steroid non‐responder group (n = 13), and the clinicopathophysiological characteristics were compared between the two groups. Results: Significant decrease of the proteinuria was observed in the responder group over the 5 year follow‐up period, whereas no significant change of the urinary protein excretion was observed in the non‐responder group during the same period. In regard to the pathological findings, significantly higher ratios of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, and significantly higher severity of interstitial fibrosis at the time of diagnosis in the non‐responder group than in the responder group were found. The rates of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, the severity of interstitial fibrosis, serum albumin and urinary protein excretion were identified as independent risk factors influencing the rate of renal function deterioration. Conclusion: To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinicopathophysiological characteristics of IgAN patients showing poor treatment response to steroids (non‐responder group in this study).     

Glomerular crescents are associated with worse graft outcome in allograft IgA nephropathy

The prognosis of patients with allograft IgA nephropathy (IgAN) requires further investigation. We performed a bicenter retrospective cohort study on kidney transplant recipients diagnosed with IgAN in allograft biopsy. Recipients without allograft IgAN but with known IgAN before transplantation were included as the control group. We investigated the associations between clinicopathological characteristics, including allograft crescents, and the risk of death‐censored graft failure. In total, 1256 IgAN patients in both pre‐ and posttransplant stages were included. Among them, 559 were diagnosed with allograft IgAN, which was a time‐dependent risk factor for worse prognosis (adjusted hazard ratio = 5.009 [3.610‐6.951]; P < .001) during a median of 8.1 years of follow‐up. Of the patients with allograft IgAN, 88 (15.9%) had glomerular crescents, including 40 patients (7.2%) with >10% crescent formation in the total biopsied glomeruli. The presence of glomerular crescents in IgAN was associated with a worse graft prognosis, and the association was still valid with the C scores of the current Oxford classification. In conclusion, allograft IgAN is a time‐dependent event and is associated with worse graft outcomes. The pathological characteristics of allograft, particularly the degree of glomerular crescent formation, may represent important risk factors for a poor prognosis.     

The role of alpha-smooth muscle actin and platelet-derived growth factor-beta receptor in the progression of renal damage in human IgA nephropathy

BACKGROUND: The degree of tubulointerstitial damage can be considered a better indicator of renal function outcome in IgA nephropathy (N) than the extent of glomerular sclerosis. MATERIALS AND METHODS: To investigate the pathogenetic mechanisms of interstitial injury in IgAN, we used immunohistochemistry and in situ hybridization to evaluate the glomerular and tubolointerstitial expression of PDGF-beta receptor (R) and alpha-smooth muscle actin (SMA), two markers of mesenchymal cell activation, and correlated these findings with the histopathologic and clinical features of the disease. We studied 155 IgAN patients, divided into three groups based on the histological findings (mild, moderate and severe histological lesions). RESULTS: In normal kidneys and in patients with mild histological lesions, the interstitial areas showed scattered peritubular cells positive for PDGF-betaR and alpha-SMA, with a distribution resembling the capillary network. In the glomeruli several cells (mainly in the mesangial area) stained for PDGF-betaR, but only very few cells were positive for alpha-SMA. Alpha-SMA and PDGF-betaR staining, as expected, was also observed in vascular smooth muscle cells. Compared to patients with mild histological lesions, alpha-SMA expression was strikingly increased in patients with moderate to severe lesions, particularly in areas of tubulointerstitial fibrosis. In these patients, PDGF-betaR gene and protein expression, at the tubulointerstitial level, paralleled that in alpha-SMA. Both signals were significantly correlated with the interstitial damage (interstitial infiltrate and fibrosis). Interestingly, these patients showed a different pattern of distribution of alpha-SMA and PDGF-betaR in the glomeruli: PDGF-betaR expression was upregulated, whereas no changes were seen in alpha-SMA staining. In addition, glomerular PDGF-betaR staining was significantly correlated with mesangial cell proliferation, while alpha-SMA was not. Image analysis showed that 40.2+/-10.3/1,000 microm2 of interstitial cells were positive to both PDGF-betaR and alpha-SMA, but only 2.8+/-1.8/1,000 microm of glomerular cells expressed both signals. CONCLUSIONS: Our study supports the hypothesis that interstitial PDGF-betaR and alpha-SMA positive cells may play a key role in the pathogenesis of tubulointerstitial damage.     

Utility of Oxford Classification in Post-Transplant Immunoglobulin A Nephropathy

Background

With increasing graft survival, post-transplant immunoglobulin A nephropathy (IgAN) has emerged as an important cause of chronic graft dysfunction in renal allograft recipients. We studied the clinico-pathological features of post-transplant IgAN regardless of the primary disease. The aim was to study the usefulness of the Oxford classification in predicting survival.

Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants

The morphology of kidneys from heart (n = 55) and bone marrow (n = 112) transplant recipients treated either with cyclosporine (CSA) or conventional immunosuppression was investigated at autopsy. The major findings were: In the bone marrow transplant recipients glomerular collapse, tubular atrophy, interstitial fibrosis, striped form, CSA-associated arteriolopathy and thrombi in glomeruli and/or arterioles were more often found in the CSA group as compared to conventional immunosuppression. In the heart transplant recipients glomerular collapse and obsolescence, tubular atrophy and intimal fibrosis in arteries were more frequent in the CSA group. Vascular interstitial toxicity known to be associated with CSA treatment from renal transplant patients was found in 54% (25% severe) of the bone marrow and 19.5% (9.7% severe) of the the heart transplant recipients. The prevalence of vascular interstitial toxicity in bone marrow versus heart transplant recipients is possibly due to higher CSA dosage and pretreatment with cytostatic drugs and irradiation. Analyses of the lesions from early stages to the full picture of vascular interstitial toxicity suggests that CSA causes a form of thrombotic microangiopathy with focal glomerular and/or arteriolar thrombosis followed by typical CSA-associated arteriolopathy which results in interstitial fibrosis with tubular atrophy.     

Focal segmental sclerotic lesions of the glomerulus in transplanted kidneys assessed using computerized image analysis

Abstract:  Mechanisms responsible for the development of focal segmental sclerotic lesions of the glomerulus (FSGS lesions) in transplanted kidneys were investigated by morphometric analysis. The mean glomerular area and the interstitial area were measured using computerized image analysis to compare implantation biopsies (so-called 1-h biopsies; 1Bx) with later biopsies (episode Bx; EBx) that had been taken for diagnostic purposes to identify the cause of deteriorating renal function. Groups of patients with (group A, n  = 15) or without (group B, n  = 10) FSGS lesions were compared. Twelve of 15 in group A and all in group B had lost graft function due to chronic allograft nephropathy. It was found that neither the mean glomerular area nor the interstitial area differed significantly between the two groups in either 1Bx or EBx. The interstitial area was significantly increased ( P  = 0.007) and the mean glomerular area tended to be increased ( P  = 0.085) in EBx compared with 1Bx in group A but not in group B. The serum creatinine level at the time of EBx in group A correlated with the interstitial area ( P  = 0.031) but not the mean glomerular area. However, there was no similar correlation in group B. In conclusion, factors for the development of FSGS lesions in transplanted kidneys may be the increase in interstitial area and possible glomerular hypertrophy following transplantation, rather than pre-existing reduced renal mass of the donor kidneys.     

Tubular and interstitial expression of ICAM-1 as a marker of renal injury in IgA nephropathy

BACKGROUND: The upregulated renal expression of intercellular adhesion molecule 1 (ICAM-1) is associated with glomerular and interstitial infiltration of leukocytes. AIM: To test the hypothesis that renal expression of ICAM-1 may be predictive in the highly variable IgA nephropathy (IgAN). METHODS: ICAM-1 (CD54) in tubular epithelium and interstitial leukocytes, macrophages (CD14), and T cells (CD3) were assessed using avidin-biotin-peroxidase in renal biopsy specimens from 45 patients with IgAN and from 29 patients with no glomerulonephritis. RESULTS: In IgAN, tubular ICAM-1+ was seen in 25 of 45 (55%) biopsy specimens, associated with glomerular hypercellularity, glomerulosclerosis involving less than 50% of the glomerular area, interstitial cellular infiltration, tubular atrophy, and proteinuria (U = 44, p = 0.005). Interstitial ICAM-1+ leukocytes were correlated with glomerulosclerosis involving less and more than 50% of the glomerular area, tubular atrophy, interstitial fibrosis, and serum creatinine concentration (r = 0.6343, p < 0.001). In patients with an increase of 50% in the serum creatinine concentration, interstitial ICAM-1+ leukocytes and CD14+ and CD3+ cells were significantly more numerous than in patients with a stable creatinine concentration. In patients with no glomerulonephritis, tubular ICAM-1+ was seen in 7 of 29 (24%) biopsy specimens, inversely correlated with the number of normal glomeruli and associated with glomerulosclerosis covering more than 50% of the glomerular area, tubular atrophy, and creatinine. CONCLUSIONS: Tubular and interstitial expression of ICAM-1 can be a marker of tubulointerstitial disturbance in IgAN. Interstitial ICAM-1 may be an adverse predictor of disease progression.     

Immunoglobulin A nephropathy complicating ulcerative colitis

Ulcerative colitis is rarely associated with immunoglobulin A nephropathy (IgAN). The development of IgA nephropathy complicates further the clinical course of patients with ulcerative colitis. A 72-year old man with a 30-year history of ulcerative colitis requiring colectomy and modest renal insufficiency secondary to complications of nephrolithiasis and renal artery stenosis developed glomerular hematuria, proteinuria and progressive renal failure. Percutaneous kidney biopsy revealed IgAN with extensive glomerular and interstitial sclerotic changes. After resection of a chronically infected ileo-rectal pouch, renal function improved, while hematuria and proteinuria gradually disappeared without specific treatment of the IgAN. The manifestations of IgAN complicating ulcerative colitis can be improved with effective treatment of the bowel disease even when there are extensive sclerotic changes in the kidneys.     

Tissue-specific expression of renin-angiotensin system components in IgA nephropathy

BACKGROUND: The renin-angiotensin II system (RAS) has been implicated in the development of glomerulonephritis. The aims of this study were to determine (1) the expression of RAS components, angiotensin (Ang II)-forming enzymes [angiotensin-I-converting enzyme (ACE) and chymase], and Ang II receptors, and (2) the correlation between RAS expression and severity of tissue injury in IgA nephropathy (IgAN). METHODS: The expression levels of ACE, chymase, and Ang II type 1 and type 2 receptor (AT1R and AT2R) mRNAs were determined by in situ hybridization in renal specimens from 18 patients with IgAN, 5 patients with non-IgA mesangial proliferative glomerulonephritis (non-IgAN) and 10 patients with nonmesangial proliferative glomerulonephritis (minimal change nephrotic syndrome, n = 5, and membranous nephropathy, n = 5). Normal portions of surgically resected kidney served as control. RESULTS: In normal kidney, a few mesangial cells and glomerular and tubular epithelial cells weakly expressed ACE, chymase and AT1R mRNAs. In IgAN and non-IgAN samples, ACE, chymase, AT1R and AT2R mRNAs were expressed in resident glomerular cells, including mesangial cells, glomerular epithelial cells and cells of Bowman's capsule. The glomerular expressions in IgAN were stronger than in minimal change nephrotic syndrome and membranous nephropathy. In IgAN, the expressions in glomeruli correlated with the degree of mesangial hypercellularity, whereas the expression levels were weaker at the area of mesangial expansion. IgAN with severe tubulointerstitial injury showed expression of ACE, chymase, AT1R and AT2R mRNAs in atrophic tubules and infiltrating cells and such expression correlated with the degree of tubulointerstitial damage. CONCLUSION: Our results suggest that renal cells can produce RAS components and that locally synthesized Ang II may be involved in tissue injury in IgAN through Ang II receptors in the kidney.     

Relationship between renal function and morphometric assessment in chronic glomerulonephritis

In an attempt to reveal a correlation between the degree of glomerular hypertrophy, interstitial damage, and hemodynamic parameters in chronic nephritis, the glomerular area (GA) and proportion of interstitial area (IA%) were determined quantitatively with an image analyzer, and the effective renal plasma flow (ERPF) and filtration fraction (FF) were determined simultaneously. The subjects were 12 patients with focal glomerulosclerosis (FGS) and 12 patients with IgA nephropathy (IgAN), all of whom had a similar glomerular filtration rate (GFR). The GFR was 58.6 +/- 11.4 ml/min/1.48 m2 in the FGS group and 53.9 +/- 13.1 ml/min/1.48 m2 in the IgAN group, and the difference between the two groups was not significant. On the other hand, ERPF was significantly lower and FF was significantly higher in the FGS group than in the IgAN group. GA was significantly higher in the FGS group than in the control group (10 kidney donors), and GA in the IgAN group was equivalent to that in the control group. IA% was almost equal in the FGS and IgAN groups, and significantly higher in both groups than in the control group. Although GA was not correlated with GFR in the two groups, it tended to be positively correlated with FF in the FGS group, and the correlation between GA and FF reached statistical significance when the IgAN group was combined with the FGS group. The above findings suggest that the pattern of progression of the glomeruli and interstitial lesions and of the intrarenal hemodynamics involved in them may differ in the FGS and IgAN groups. However, since ERPF significantly decreased in the FGS group, even though IA% was the same in both groups, the possibility that ERPF was functionally decreased in the FGS group cannot be ruled out.     

Analysis of infiltrating cells in IgA nephropathy with acute clinical onset

Background. The prognosis of IgA nephropathy (IgAN) patients is worse than that of poststreptococcal acute glomerulonephritis (PSAGN) patients. Some IgAN patients with acute clinical onset exhibit severe glomerular inflammation similar to that seen in patients with PSAGN, although most IgAN has an insidious onset. The aim of this study was twofold: (1) to differentiate glomerular inflammatory responses between IgAN and PSAGN and (2) to differentiate IgAN by its clinical manifestations. Methods. We examined 31 IgAN patients; 10 with acute clinical onset (AIgAN), 6 with acute exacerbation associated with chronic IgAN (ACIgAN), 8 with insidious onset (IOIgAN), and 7 with acute clinical onset who were anti-streptolysin-O positive (ASLOIgAN). We also examined 11 patients with PSAGN. Conventional pathological examinations were done using immunohistopathologic evaluation of infiltrating cells. Results. (1) Injuries to the glomerular basement membrane (GBM) were common and more severe in AIgAN than in PSAGN. The number of activated monocytes/macrophages (BerMac-3) was significantly greater in the glomeruli of ASLOIgAN than in those of AIgAN (P < 0.05). The numbers of T cells (CD45RO), granulocytes (CD15), and myeloperoxidase (MPO)-positive cells were significantly greater in the glomeruli of PSAGN than those of AIgAN in the other two groups (P < 0.05). (2) In regard to clinical manifestations, injury to the glomerular basement membrane (GBM) was most severe in ACIgAN. The number of MPO-positive cells was significantly greater in the glomeruli of AIgAN than in those of ACIgAN or IOIgAN. Conclusion. In AIgAN, glomerular damage was accompanied by severe GBM injury, but this injury was unexplained by the analysis of cell subclasses, in contrast to findings in PSAGN. Regarding the clinical manifestations of IgANs, MPO-positive cells may play some role in the glomeruli of AIgAN. Received: July 27, 1998 / Accepted: October 13, 1998     

Glomerulonephritis is the major cause of proteinuria in renal transplant recipients: histopathologic findings of renal allografts with proteinuria

The proteinuria in renal allograft recipients has been regarded as a sign of poor prognosis. The causes of post-transplant proteinuria include chronic rejection, chronic transplant glomerulopathy, glomerulonephritis (GN), acute rejection, and cyclosporine nephrotoxicity. Among them, chronic rejection is known to be most frequent. We analyzed the histopathologic findings of renal allograft biopsies in 197 Korean recipients with proteinuria. Among them, 26 patients developed proteinuria over 500 mg/d. All patients received baseline immunosuppression with cyclosporine. From 26 patients with post-transplant proteinuria, 29 biopsies were performed and their histologic diagnoses were immunoglobulin A nephropathy (IgAN) in 17, IgAN combined with chronic allograft nephropathy in 1, focal segmental glomerulosclerosis in 2, crescentic GN in 1, membranous GN in 1, diabetic nephropathy in 1, acute tubulointerstitial nephritis in 1, and chronic rejection in 3 biopsies. The remaining two biopsies showed nonspecific findings. The most common cause of post-transplant proteinuria was IgAN (62% of biopsies). The incidence of chronic rejection was relatively low and predominant cyclosporine-associated changes were not observed. In conclusion, our data suggest that the main causes of post-transplant proteinuria in Korea are primary glomerulonephritides rather than chronic rejection or cyclosporine nephrotoxicity, and the kidney allograft biopsies from patients with proteinuria should be handled as native kidney.     

Unilateral ureteral obstruction in neonatal rats leads to renal insufficiency in adulthood

BACKGROUND: Although unilateral ureteropelvic junction obstruction is the most common cause of congenital obstructive nephropathy in infants and children, management remains controversial, and follow-up after pyeloplasty is generally limited to the pediatric ages. We have developed a model of temporary unilateral ureteral obstruction (UUO) in the neonatal rat: One month following the relief of five-day UUO, the glomerular filtration rate (GFR) of the postobstructed kidney was normal despite a 40% reduction in the number of glomeruli and residual vascular, glomerular, tubular, and interstitial injury. METHODS: To determine whether hyperfiltration and residual injury of remaining nephrons leads to progression of renal insufficiency in later life, 31 rats were sham operated or subjected to left UUO at one day of age, with relief of UUO five days later, and were studied at one year of age. GFR was measured by inulin clearance, and the number of glomeruli, tubular atrophy, glomerular sclerosis, and interstitial fibrosis were measured by histomorphometry in sham, obstructed (UUO), and intact opposite kidneys. Intrarenal macrophages and alpha-smooth muscle actin were identified by immunohistochemistry. RESULTS: Despite relief of UUO, ultimate growth of the postobstructed kidney was impaired. The number of glomeruli was reduced by 40%, and GFR was decreased by 80%. However, despite significant compensatory growth of the opposite kidney, there was no compensatory increase in GFR, and proteinuria was increased. Moreover, glomerular sclerosis, tubular atrophy, macrophage infiltration, and interstitial fibrosis were significantly increased not only in the postobstructed kidney, but also in the opposite kidney. CONCLUSIONS: Although GFR is initially maintained following relief of five-day UUO in the neonatal rat, there is eventual profound loss of function of the postobstructed and opposite kidneys because of progressive tubulointerstitial and glomerular damage. These findings suggest that despite normal postoperative GFR in infancy, children undergoing pyeloplasty for ureteropelvic junction obstruction should be followed into adulthood. Elucidation of the cellular response to temporary UUO may lead to improved methods to assess renal growth, injury, and functional reserve in patients with congenital obstructive nephropathy.     

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.     

Histological grading of IgA nephropathy predicting renal outcome: revisiting H. S. Lee's glomerular grading system.

BACKGROUND: The glomerular grading system is useful to compare biopsy specimens and to predict the natural course of disease in IgA nephropathy (IgAN), although no grading system can be perfect. METHODS: H. S. Lee's grading system for IgAN was refined as follows: grade I, normal or focal mesangial cell proliferation; grade II, diffuse mesangial cell proliferation, or <25% of glomeruli with crescent (Cr)/segmental sclerosis (SS)/global sclerosis (GS); grade III, 25-49% of glomeruli with Cr/SS/GS; grade IV, 50-75% of glomeruli with Cr/SS/GS; grade V, >75% of glomeruli with Cr/SS/GS. This refined H. S. Lee grading system was then tested for clinical relevance on 187 patients with IgAN followed up for an average of 6.5 years (minimum, 3 years). In the survival analysis, a modified primary end-point (progressive renal disease) was used. RESULTS: The glomerular grades were significantly related to hypertension, serum creatinine levels and the amounts of proteinuria at time of biopsy. By univariate analysis, glomerular grades, hypertension, renal insufficiency and significant proteinuria (> or =1 g/day) were significantly associated with progressive renal disease. By multivariate analysis using the Cox regression model, glomerular grades, renal insufficiency and significant proteinuria were independent prognostic factors for progressive renal disease. At the end of follow-up, glomerular grades were significantly related to serum creatinine levels, amounts of proteinuria, hypertension and progressive renal disease. CONCLUSIONS: These findings indicate that the refined H. S. Lee grading system for IgAN is useful in assessing the patients' clinical outcome and is sufficiently simple and easy to reproduce as to be universally applicable in prognostic work.     

Intraglomerular synthesis of complement C3 and its activation products in IgA nephropathy

BACKGROUND: Complement activation is thought to be pathologically important in IgA nephropathy (IgAN). Although C3 deposition in the mesangium is found in IgAN, the origin of C3 is not clear. We recently demonstrated intraglomerular C3 synthesis in the human kidney; however, the activation and pathological role of locally synthesized C3 remains unclear. Here we performed nonradioactive in situ hybridization for C3 mRNA and immunohistochemistry for C3 and its activation products, such as C3d and membrane attack complex (MAC), to determine whether locally produced C3 in glomeruli was activated in IgA nephropathy. METHODS: Renal samples from 14 patients with IgAN and 5 with minimal change nephrotic syndrome (MCNS) were examined. Uninvolved portions of surgically removed kidneys with tumors served as normal controls. RESULTS: C3 mRNA was not detected in glomeruli in control tissue and MCNS, but was strongly expressed in resident glomerular cells of IgAN, including mesangial cells, glomerular epithelial cells and the cells of Bowman's capsule. Examination of serial sections disclosed that more than 70% of cells positive for C3 mRNA were also stained for C3 protein, C3d, and MAC. Double staining for in situ hybridization and immunohistochemistry also revealed that those C3 mRNA signals were present in intraglomerular cells positive for C3. The expression of C3 mRNA and MAC in glomeruli correlated significantly with the degree of mesangial matrix expansion. CONCLUSIONS: Our results demonstrated that locally synthesized C3 is activated in the glomeruli of IgAN and that its expression correlated with the severity of mesangial matrix expansion. These findings suggest that activation of C3 may be involved in tissue injury in IgAN through the formation of membrane attack complex.     

Segmental glomerulosclerosis in IgA nephropathy after renal transplantation: relationship with proteinuria and therapeutic response to enalapril

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.     

Evolution and pathophysiology of renal-transplant glomerulosclerosis

BACKGROUND: Glomerulosclerosis (GS) is characteristic of chronic allograft nephropathy and graft failure; however, its natural history and pathophysiology are poorly defined. METHODS: We evaluated 959 prospective protocol kidney-transplant biopsies from 120 recipients taken regularly up to 10 years after transplantation for evidence of glomerular injury. RESULTS: GS exhibited a nonlinear triphasic time course. An intense but limited peak of damage in the first month was associated with cold ischemia (P<0.05) and calcineurin nephrotoxicity (P<0.001). GS then occurred as a late consequence of earlier immune-mediated tubular damage (9.3+/-6.6%, P<0.01 vs. no damage), suggesting delayed sclerosis of atubular glomeruli. Subsequent progressive GS occurred beyond 4 years, associated with increasing arteriolar hyalinosis from calcineurin inhibitor nephrotoxicity (r=0.33, P<0.001). From 5 years after transplantation, 32.4+/-22.2% of glomeruli were globally sclerosed, and segmental GS and periglomerular fibrosis increased by 4.0+/-9.3% and 8.4+/-14.2% per year, respectively. Severe arteriolar hyalinosis resulted in greater GS on sequential biopsies (P<0.001), consistent with vascular narrowing causing glomerular ischemia. Chronic glomerulopathy scores were relatively mild. Glomerular loss was patchy, with a high coefficient of variation of 633%. Isotopic glomerular filtration rate correlated best with Banff chronic interstitial fibrosis (r=-0.30, P<0.001) and chronic glomerulopathy scores (r=-0.23, P<0.001) rather than the percentage of sclerosed glomeruli (r=-0.12, P<0.05). Renal function gradually fell with time, and the hyperfiltration index increased from 1.14+/-0.42 at 3 months to 1.83+/-1.40 by 7 to 10 years after transplantation. CONCLUSIONS: In summary, GS is a time-dependent response to glomerular injury from early ischemia, immune-mediated tubular loss, and late calcineurin nephrotoxicity.