Percentage Of Sclerotic Glomeruli Research Articles

MO259LYMPHOPENIA AT ANCA-GLOMERULONEPHRITIS DIAGNOSIS IS CORRELATED WITH SEVERITY AND RENAL PROGNOSIS

Abstract Background and Aims Lymphopenia is commonly observed in various autoimmune diseases, such as systemic lupus erythematosus, where it has been associated with disease activity or prognosis. However, in ANCA-associated vasculitis (AAV) only few, small-scale studies have been targeted to this issue. Research has not yet focused on ANCA-glomerulonephritis (ANCA-GN) patients. Thus, the aim of this study was to analyze the association between lymphocyte counts and outcomes in a large cohort of ANCA-GN patients. Method We used the Maine-Anjou AAV registry that retrospectively gathers data on consecutive patients affected by AAV in four French Nephrology Centers, recorded since January 2000. We analyzed clinical, biological, and histological data at diagnosis of ANCA-GN. Biological data, including lymphocyte counts, were collected before the administration of any immunosuppressive treatment. Risk factors for end-stage kidney disease (ESKD) were analyzed. Event-free survival was also assessed. Results Among the 145 patients included in the study, 53 (37%) patients presented with lymphopenia at ANCA-GN diagnosis. Lymphopenic patients were older (72 [63–79] vs 66 [56–73] years old, p = 0.010), had a lower renal function at baseline (eGFR 13 mL/min vs 26 mL/min, p = 0.002), and a higher proteinuria (1.86 [1.21–3.52] g/g vs 1.30 [0.75–2.65] g/g, p = 0.042). There was a trend for a higher BVAS (18 [14–22] vs 15 [12–20], p = 0.076) in lymphopenic patients. Therapeutic management between the two groups was similar. There was no difference in relapse rate between the two groups but lymphopenic patients were more likely to require kidney replacement therapy (51% vs 25%, p = 0.003) and were more likely to die (34% vs 17%, p = 0.039). Lymphopenia was correlated with histological lesions and especially with the percentage of sclerotic glomeruli (p = 0.0027). ESKD-free survival and overall survival were lower in lymphopenic patients (p < 0.0001 and 0.0051 respectively). In multivariate Cox analysis, lymphopenia, but not death, was an independent risk factor for ESKD (HR 4.47 (95% confidence interval: [2.06–9.72], p < 0.001). Conclusion Lymphopenia correlates with severity of ANCA-GN at diagnosis and predicts poor renal outcome. In this view, lymphopenia could be used as a simple and cost-effective biomarker to assess renal prognosis at ANCA-GN diagnosis.

Lymphopaenia at diagnosis of anti-neutrophil cytoplasmic antibody-vasculitis with renal involvement is correlated with severity and renal prognosis.

Lymphopaenia is commonly observed in autoimmune diseases, where it has been associated with disease activity or prognosis. However, in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) only a few small-scale studies have been targeted towards this issue. Research has not yet focused on AAV with renal involvement (AAV-RI). Thus the aim of this study was to analyse the association between lymphocyte counts and outcomes in a large cohort of AAV-RI patients. We used the Maine-Anjou AAV registry that retrospectively gathers data on consecutive patients affected by AAV in four French nephrology centres, recorded since January 2000. We analysed clinical, biological and histological data at diagnosis of AAV-RI. Risk factors for end-stage kidney disease (ESKD) were analysed. Event-free survival was also assessed. Among the 145 patients included in the study, those with lymphopaenia at diagnosis had a lower renal function at baseline [estimated glomerular filtration rate (eGFR) 13 versus 26 mL/min; P = 0.002] and were more likely to require kidney replacement therapy (51% versus 25%; P = 0.003). Lymphopaenia was correlated with histological lesions and especially with the percentage of sclerotic glomeruli (P = 0.0027). ESKD-free survival was lower in lymphopaenic patients (P < 0.0001). In multivariate Cox analysis, lymphopaenia was an independent risk factor for ESKD [hazard ratio 4.47 (95% confidence interval 2.06-9.72), P < 0.001]. Lymphopaenia correlates with the severity of AAV glomerulonephritis at diagnosis and predicts poor renal outcome. In this view, lymphopaenia could be used as a simple and cost-effective biomarker to assess renal prognosis at AAV-RI diagnosis.

P0388ABC-R ANCA STUDY ESTABLISHMENT OF AN ANATOMOPATHOLOGICAL BIOLOGICAL AND CLINICAL PROGNOSTIC SCORE IN THE MANAGEMENT OF ANCA VASCULITIS WITH RENAL IMPAIRMENT

Abstract Background and Aims Glomerulonephritis is common in ANCA associated vasculitis (GN-AAV). There is extensive published data on the renal prognosis of these conditions. However, few authors have described predictive factors for end-stage renal disease (ESRD) in patients with GN-AAV. Many authors suggest that renal biopsy should be abandoned in patients whose diagnosis would be established by antibody positivity alone. The aim of the study was to establish a prognostic score for renal damage during ANCA vasculitis and demonstrate need for prognostic renal biopsy. Method One Hundred and eighteen patients referred to 2 french nephrology departments in Lyon between January 2003 and January 2019 were retrospectively analysed. Patients were randomly divided in 2 cohorts at a ratio of 70/30: training and validation cohorts. ESRD was defined as glomerular filtration rate (eGFR) ≤ 15mL/min/1.73m2,need of chronic dialysis or renal transplantation. Results Of the 118 patients, 38 (32.20%) developed ESRD. We identified 3 criteria associated with development of ESRD in patients with GN-AAV. One point was assigned to each criterion according to a threshold value: eGFR at the time of renal biopsy ≤ 15 mL/min; percentage of sclerotic glomeruli ≥ 11% and percentage of normal glomeruli &amp;lt; 20%. A new prognostic renal score was established in patients with GN-AAV. It classifies patients into 3 categories at risk of developing ESRD: low (≤ 1 point), moderate (2 points) and high (3 points). Conclusion Two of the three criteria of our score are histological. Biopsy remains, when possible, an essential tool for diagnosis and especially to predict renal prognosis of ANCA vasculitis with renal impairment.

P0678RENAL SUBCAPSULAR ADMINISTRATION OF ADIPOSE DERIVED MESENCHYMAL STEM CELLS PREVENTED THE PROGRESSION OF RENAL DAMAGE IN AN EXPERIMENTAL MODEL OF CKD

Abstract INTRODUCTION / AIMS Chronic kidney disease (CKD) is a progressive, debilitating condition of high lethality, which prevalence have been increasing considerably in recent decades. CKD can be triggered by many different factors, such as genetic predisposition, systemic hypertension, diabetes mellitus and autoimmune diseases. It is characterized by the gradual loss of renal function, leading to kidney failure and the need for renal replacement therapy for the maintenance of life. Regardless of the etiology of CKD, the establishment of local renal inflammation, with leucocyte recruitment, cell proliferation, extracellular matrix accumulation, glomerular and tubulointerstitial fibrosis, contribute significantly to its establishment and evolution. Due to its known pathophysiology, the primary aim when clinically treating CKD is to slow the progression of renal function loss and the advance of inflammation. However, until the present moment, there is no efficient pharmacological treatment to completely arrest the aggravation of renal inflammation and, specially, renal fibrosis. This motivates the scientific community to develop experimental research in order to test new therapeutic approaches to stunt renal fibrosis. In this context, experimental application of mesenchymal stem cells (mSC) as a treatment to control renal inflammation have been showing promising results in studies with animal models of CKD. The aim of the present study was to analyze the renoprotective effects of subcapsular application of Adipose Tissue-derived mSC (ASC), in rats submitted to 5/6 nephrectomy, after the establishment of the disease (15 days after CKD induction), in order to more closely resemble the clinical settings in humans. METHODS ASC were obtained from gonadal adipose tissue from healthy male Wistar rats. These cells were cultured until P4 when characterization by flow cytometry and in vitro differentiation were performed. Male Wistar rats underwent 5/6 nephrectomy and were followed for 15 days until the complete establishment of CKD (group CKD 15d). At this time, animals underwent a new surgery in which they received a subcapsular injection of 2x106 ASC diluted in 10 μL of sterile PBS (group CKD + ASC 30d), or only 10 μL of sterile PBS (group CKD 30d). Sham-operated rats, euthanized at day 15 (Sham 15d) and 30 (Sham 30d) were used as controls. Survival rate, body weight (BW), 24h urinary protein (24h UPE) and albumin (24h UAE) excretion serum creatinine (SCr) and blood urea nitrogen (BUN) concentration, percentage (GS%) and index (GSI) of glomerulosclerosis, tubulointerstitial fibrosis (INT%) and renal infiltration by macrophages (CD68) were studied at 15 and 30 days after 5/6 nephrectomy. Our results are presented as Mean ± SE. Differences among groups were analyzed by one-way ANOVA. RESULTS ASC injection significantly improved the survival rate of CKD + ASC 30d animals, compared to the observed in the untreated group. Moreover, ASC treatment markedly reduced protein and albumin urinary excretion, prevented the development of glomerulosclerosis, both the percentage of sclerotic glomeruli and the index of glomerular damage, numerically reduced interstitial fibrosis and significantly avoided renal inflammation by halting the progression of renal cortical macrophage infiltration. CONCLUSIONS According to our results, subcapsular ASC application promoted considerable renoprotection in the 5/6 renal ablation model, even after the complete establishment of severe CKD, suggesting that experimental therapy with these cells could be associated to the current pharmacological treatments employed to detain the progression of CKD. Figure

Retrospective clinical and morphological analysis of patients with AL amyloidosis (the 2008 to 2015 nephrobiopsies)

To study correlations between the clinical signs of dysfunction and pathological structural changes in the renal parenchyma in a group of Russian patients with AL amyloidosis in 2008-2015. A total group (At) including Group 1 with AL (kappa + lambda light chains) (n=46) was divided into subgroups: 2λ) 40 patients with AL-lambda (AL-λ); 3κ) 6 patients with AL-kappa (AL-κ). All the patients underwent standard laboratory and instrumental studies: determinations of the peak systolic and diastolic blood pressures (SBP and DBP, respectively, mm Hg), glomerular filtration rate (GFR) (ml/min/1.73 m2) by the EPI equation, daily protein loss (g/day). Polyclonal antibodies against kappa and lambda light chains, AA component, and transthyretin (DAKO, Denmark) were used as immunomorphological markers. Light optical structural changes were semiquantitatively assessed, by ranking the following analyzed sign: interstitial focal sclerosis (FS), tubular atrophy (TA), interstitial inflammatory infiltration (II) semi-quantitatively (0 - no; 1 - < 25%; 2 - <50%, 3 - >50% of the volume of a histological compartment). Glomerulosclerosis (GS) was defined as the percentage of sclerotic glomeruli. The extent of amyloid depositions in the renal parenchyma structures was estimated according to the procedure proposed by Ying Yao et al., 2013. The AL group showed a female preponderance (65.21%). The patients' mean age was 62±11 years. There were no significant differences in daily proteinuria and the levels of serum creatinine, GFR, SBP, and DBP between the groups. The predominant clinical manifestation in the patients was nephrotic syndrome. A comparative analysis of the pathomorphological criteria for the spread of amyloid masses and the markers of fibroplastic processes revealed no statistically significant differences in the studied groups. Correlation analysis of the spread of AL deposits in the renal parenchyma in the patients of Group 1 and Subgroup 2λ, as well as laboratory data showed that there were significant (p<0.05) correlations with GFR, serum creatinine, unlike in Subgroup 3κ. At the same time, the analysis demonstrated that daily proteinuria had a significant positive correlation with VA, IA, GA, and TA values in Subgroup 3κ, unlike in Group 1 and Subgroup 2λ. Positive correlations were found between glomerulosclerosis and VA in Subgroup 2 λ and IA in Group 1. Sclerotic (FS and TA) changes in the tubular interstitium (TIN) were significantly positively correlated with all the indicators of AL (GA, VA, IA, TA) in the examinees in Group 1 and Subgroup 2λ, but not in Subgroup 3κ. Inflammatory TIN infiltration showed statistically significant (p<0.05) positive correlations with IA and VA in Group 1 and Subgroup 2λ and their absence in subgroup 3κ. : The retrospective analysis of nephrobiopsy specimens from of patients with AL amyloidosis revealed that kidney damage was mainly associated with the development of λ-associated AL amyloidosis. The clinical and laboratory parameters were correlated with the pathomorphological criteria for loading the renal parenchyma with amyloid masses. The findings suggest that there are clinical and morphological features of the subclasses of AL amyloidosis, which may be of value for predicting the course and progression of the disease.

Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders

The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment.

Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

ABSTRACTDistinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.

Does Histopathology of Implanted Kidney According to Banff 07 Help Predict Long-term Transplantation Outcome?

Analyses of peritransplant biopsies of deceased-donor kidneys show high incidence of chronic abnormalities. The question arises whether chronic abnormalities present at implantation determine engrafted kidney fate regardless of other concomitant variables.The aim of this study was to identify risk factors of graft loss considering histopathological changes present at implantation scored according to Banff 07 criteria. Patients and methodsInclusion criteria (n = 300) was engraftment between years 2000 and 2008 and availability of implantation biopsy. Analyzed abnormalities present in donor biopsy were arteriolar hyalinization, interstitial fibrosis, intimal sclerotization, tubular atrophy, total inflammation, and percentage of sclerotic glomeruli (Banff classification).Allograft function was estimated by abbreviated Modification of Diet in Renal Disease formula and proteinuria semi-quantitatively by standard dip-stick test. Kaplan-Meier estimate was used to assess graft survival. Searching for independent risk factors of graft survival was performed by means of Cox proportional hazards models (SAS System, SAS Institute Inc, Cary, NC, United States). ResultsIn one-factor analyses, predictors of kidney allograft loss were donor age, donor history of diabetes, kidney allograft dysfunction within first posttransplant year, and recipient chronic hepatitis C. In terms of chronic abnormalities, arteriolar hyalinization of any intensity nearly doubled the risk of allograft loss.Independent risk factors of kidney allograft loss in multivariate analysis were donor age, posttransplant diabetes mellitus, proteinuria after engraftment, and recipient hepatitis C. ConclusionThe effect of arteriolar hyalinization on renal transplant survival is probably interwoven with other predictors of graft loss. Recognizing the negative impact of recipient chronic hepatitis C on graft survival, hepatitis C virus treatment should be provided to patients with advanced chronic kidney disease, patients on wait lists, or patients already transplanted.

The effect of hypercalcemia on allograft calcification after kidney transplantation.

Persistent hypercalcemia after kidney transplantation (KTx) may cause nephrocalcinosis and graft dysfunction. The aim of this study was to evaluate patients with hypercalcemia and assess its effect on tubulointerstitial calcification. A total of 247 recipients were enrolled. Transient and persistent hypercalcemia was defined as hypercalcemia (corrected serum calcium >10.2mg/dL) persisting for 6 and 12months after KTx, respectively. The severity of calcification in the 0-h, 6- and 12-month protocol biopsies of patients with transient (n=8) and persistent hypercalcemia (n=20) was compared with a matched control group (n=28). Twenty-eight patients were hypercalcemic at 6months posttransplantation. Serum calcium levels were normalized in eight of them at the end of the first year. Dialysis duration was a positive predictor of persistent hypercalcemia. Tubulointerstitial calcification was detected in 70.6 and 90% of patients with persistent hypercalcemia at 6 and 12months posttransplantation, respectively. In 20% of patients with transient hypercalcemia, severity of calcification regressed at 12months posttransplantation along with normalization of serum calcium levels. Graft functions and histopathological findings (ci, ct, ci+ct, cv, ah, percentage of sclerotic glomeruli) were not different at 6 and 12months posttransplantation. Hypercalcemia and persistent hyperparathyroidism are not rare after KTx. Tubulointerstitial calcification is more common and progressive among patients with persistent hypercalcemia. Normalization of calcium levels may contribute to regression of calcification in some patients.

Angiotensin II Contributes to Diabetic Renal Dysfunction in Rodents and Humans via Notch1/Snail Pathway

In nondiabetic rat models of renal disease, angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. Herein, we wanted to explore the role of Ang II in diabetic nephropathy by a translational approach spanning from in vitro to in vivo rat and human studies, and to dissect the intracellular pathways involved. In isolated perfused rat kidneys and in cultured human podocytes, Ang II down-regulated nephrin expression via Notch1 activation and nuclear translocation of Snail. Hairy enhancer of split-1 was a Notch1-downstream gene effector that activated Snail in cultured podocytes. In vitro changes of the Snail/nephrin axis were similar to those in renal biopsy specimens of Zucker diabetic fatty rats and patients with advanced diabetic nephropathy, and were normalized by pharmacological inhibition of the renin-angiotensin system. Collectively, the present studies provide evidence that Ang II plays a relevant role in perpetuating glomerular injury in experimental and human diabetic nephropathy via persistent activation of Notch1 and Snail signaling in podocytes, eventually resulting in down-regulation of nephrin expression, the integrity of which is crucial for the glomerular filtration barrier.

Presentation of HIV-associated nephropathy and outcome in HAART-treated patients

Among the numerous renal diseases observed in human immunodeficiency virus (HIV) patients, HIV-associated nephropathy (HIVAN) is a major cause of end-stage renal disease (ESRD). The purpose of our study was to describe the presentation and outcome of HIVAN in the era of highly active antiretroviral therapy (HAART). We analysed clinical features and outcome of 57 patients with histologically proven HIVAN diagnosed between 2000 and 2009 in four teaching hospitals in Paris, France. This series was characterized by median age of 41 years (18-58), frequent African origin (87%), severe renal dysfunction [estimated glomerular filtration rate (eGFR) 20 mL/min/1.73m(2) (1-68)], high-grade proteinuria [4.1 g/day (0.6-16.8)], high proportion of sclerotic glomeruli [31.5% (0-95)], high HIV load [4.5 log copies/mL (0-6.7)] and low CD4+ count [127/mm(3) (3-713)]. Nevertheless, a non-negligible proportion of patients did not present with these typical features. Follow-up data were available for 51 patients. ESRD occurred in 30 patients (58.8%). Median renal survival was 40 months. Baseline characteristics significantly associated with ESRD were as follows: severity of renal dysfunction, percentage of sclerotic glomeruli, time from HIV infection to HIVAN diagnosis longer than 1 year and prior exposure to antiretroviral drugs. There was an insignificant trend towards better renal outcome being associated with viral suppression during follow-up. Use of renin-angiotensin system (RAS) blockers was associated with higher renal survival (P < 0.05). Despite HAART, HIVAN led to ESRD in more than half of the cases. Early recognition of the disease is crucial to start HAART and RAS blockers before irreversible renal injury.

The Relevance of Periglomerular Fibrosis in the Evaluation of Routine Needle Core Renal Biopsies

Renal interstitial fibrosis and, to a lesser extent, sclerotic glomeruli correlate with poor renal function. However, not all nonfunctional glomeruli are sclerotic. Many or most glomeruli with periglomerular fibrosis, while retaining blood flow, probably do not filter; therefore, they may not contribute to renal function. To examine the relationship of periglomerular fibrosis and the sum of globally sclerotic glomeruli and glomeruli with periglomerular fibrosis (GSG+PF) with interstitial fibrosis and renal function. Native kidney biopsies from 177 patients with chronic renal injury were assessed for interstitial fibrosis, glomerular sclerosis, and GSG+PF. Renal biopsies with active or acute lesions were not included. The percentage of globally sclerotic glomeruli and GSG+PF was correlated with the degree of interstitial fibrosis and serum creatinine levels. The percentage of GSG+PF correlates better with the degree of interstitial fibrosis and renal function than does the percentage of globally sclerotic glomeruli alone. This appears particularly true in chronic renal diseases of patients without diabetes. The number of globally sclerotic glomeruli correlates better with interstitial fibrosis and renal function than does the sum of globally and segmentally sclerotic glomeruli. The percentage of GSG+PF in a renal biopsy specimen provides a better estimate of chronic renal injury than does the percentage of sclerotic glomeruli alone, probably because many or most glomeruli with periglomerular fibrosis are nonfunctional. Therefore, we recommend that the number of glomeruli with periglomerular fibrosis also be provided in the renal biopsy report.

The reliability of pre-transplant donor renal biopsies (PTDB) in predicting the kidney state. A comparative single-centre study on 154 untransplanted kidneys

Pre-transplant donor biopsy (PTDB) is a common practice in marginal donors, taking for granted that it represents the whole kidney state, but its reliability has not yet been thoroughly investigated. This prompted us to carry out a comparative study on a needle biopsy group (NBG) and a wedge biopsy group (WBG) and their corresponding untransplanted kidneys. One hundred and fifty-four biopsies and matched kidneys were scored for four morphologic indexes, i.e. tubular atrophy, interstitial fibrosis, vascular damage and global glomerulosclerosis. Categorical indexes were statistically evaluated for concordance with the k index, and the percentage of sclerotic glomeruli with correlation and linear regression analysis. Agreement between biopsies and kidneys was similar in both NBG and WBG with high scores for vascular damage (k 0.74 and 0.75) and intermediate ones for tubular atrophy (k 0.54 and 0.50). Agreement as to fibrosis and glomerular sclerosis was intermediate in the WBG (k 0.56 and 0.55) and poor in the NBG (k 0. 34 and 0.18). Vascular damage was underscored and glomerulosclerosis overscored in both groups, whereas interstitial fibrosis was underscored in the NBG and overscored in WBG. The agreement for the total score, i.e. the sum of the single indexes, was high in the NBG (k 0.73) and intermediate in WBG (k 0.57). Agreement for glomerulosclerosis and total score rose consistently in both groups along with the increasing number of biopsy glomeruli. There was an agreement as to biopsy and kidney evaluation for fitness for transplantation in 85% of NBG and 81% of WBG. PTDB supplies reliable data on the actual kidney state, with better results for needle biopsy. Although the biopsy size plays a role, samples with over 10 glomeruli suffice for clinical purposes. Vascular damage is the most faithful single parameter, whereas global glomerulosclerosis estimation requires some caution.

Estimation of age from sclerotic glomeruli

Glomerular sclerosis is one of the age-related causes of nephron damage. Histological studies of cadaver kidneys in several ethnic groups have shown that there is a consistent relationship between the percentage of sclerotic glomeruli (PSG) and age. However, no study regarding this relationship in the Japanese population has been reported to date. Here, we investigated such relationship in 150 Japanese cadavers that were selected regardless of clinical history. The straight line regression was estimated as follows: Age = 23.3 + 1.36 × APSG (APSG: arcsine-transformed PSG). The R 2 value of the regression line was 0.598. The diagnostic test with the PSG value (cutoff = 0.6%) for the age stratum (cutoff = 33 years old) showed very high sensitivity (100%) and specificity (97.6%). From the results, PSG appears to be useful for the estimation of a cadaver's age in the Japanese population.

An evaluation of renal biopsy in type-II diabetic patients.

To determine the renal damage in type-II diabetic patients, who underwent renal biopsy for impaired renal functions and its role in overall patient management. Descriptive, cross-sectional study. The Kidney Postgraduate Centre, Karachi, Pakistan from January 2000 to May 2005. Histopathological evaluation of 73 patients of type-II Diabetes mellitus were included who underwent renal biopsy. Renal biopsy was performed when a renal disease other than diabetic nephropathy was suspected because of the presence of haematuria, nephrotic syndrome, non-nephrotic proteinuria < 3 gms/day in the absence of retinopathy, rapidly progressive glomerulonephritis and renal insufficiency of unknown origin. On the basis of light microscopy and immunofluorescence, three groups of patients were defined. Group I was characterized by diabetic glomerulosclerosis (DGS) only, group II by the prevalence of vascular changes, while group III had sub-groups IIIa (DGS co-existing with nondiabetic renal diseases) and IIIb (non-diabetic renal diseases without DGS). Among the 73 patients studied, 20 (27.3%) had diabetic glomerulosclerosis alone (group I), 17 (23.3%) showed occurrence of vascular changes (group II), and 36 (49.3%) had non-diabetic renal diseases (group III). Mean serum creatinine level was significantly greater in group II than in group I and III (p < 0.001). Amount of proteinuria and the presence of haematuria did not show a statistically significant difference in groups I, II and III. The systolic and diastolic blood pressure was higher in groups II as compared to group I and III (p < 0.001). The percentage of sclerotic glomeruli, tubular injury and interstitial inflammation in group II were significantly greater than group I and III (p < 0.001). Type-II diabetic patients undergoing renal biopsy for impaired renal functions constituted a heterogeneous group of renal damage. This study emphasized the usefulness of renal biopsy for determining the pattern of renal damage that would aid in the overall management of the patients.

An introduction to biomarkers: applications to chronic kidney disease

Diagnosis and management of chronic kidney disease (CKD) will be characterized in the future by an increasing use of biomarkers—quantitative indicators of biologic or pathologic processes that vary continuously with progression of the process. “Classical” biomarkers of CKD progression include quantitative proteinuria, the percentage of sclerotic glomeruli or fractional interstitial fibrosis. New candidate biomarkers (e.g., urinary proteomic patterns) are being developed based on both mechanistic and “shotgun” approaches. Validation of potential biomarkers in prospective studies as surrogate endpoints for hard clinical outcomes is often complicated by the long lag time to the ultimate clinical outcome (e.g., end-stage renal disease). The very dense data sets that result from shotgun approaches on small numbers of patients carry a significant risk of model overfitting, leading to spurious associations. New analytic methods can help to decrease this risk. It is likely that clinical practice will come to depend increasingly on multiplex (vector) biomarkers used in conjunction with risk markers in early diagnosis as well as to guide therapy.

Oxidative stress in Dahl salt-sensitive hypertension.

The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 micromol x kg(-1) x h(-1) plus low Na or high Na. After 21 days, mean arterial pressure was 140+/-3 mm Hg in the high-Na group, 118+/-1 mm Hg (P<0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O2*- release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O2*- release in the high- and low-Na rats, but the decrease in O2*- release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage.

Henoch-Schönlein Purpura in adults: outcome and prognostic factors.

Henoch-Schönlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] <50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl <30 ml/min), and 14% moderate renal insufficiency (CrCl <50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.

Long-term renal injury in ANCA-associated vasculitis: an analysis of 31 patients with follow-up biopsies.

We reported previously that in renal disease in relation to antineutrophil cytoplasm auto-antibodies (ANCA)-associated vasculitis, renal outcome correlates better with the percentage of normal glomeruli than with separate active lesions. This may imply that glomeruli, once affected by necrotizing and crescentic lesions, are irreversibly damaged. We quantified and evaluated the course of renal lesions in the present study. We retrospectively analysed 31 patients with renal disease in relation to ANCA-associated vasculitis, all treated with immunosuppressive drugs. In all patients, a renal biopsy was performed at diagnosis. A follow-up biopsy was performed in all patients on the indication of a suspected renal relapse, after a mean interval of 31 months. The mean percentage of normal glomeruli in the renal biopsy did not change over time (29% in the initial and 30% in the follow-up biopsy). The mean percentage of glomeruli with crescents, however, significantly decreased from 57 to 30% (P<0.001). The percentage of glomerulosclerosis significantly increased from 12 to 39% (P<0.001). The data were independent of diagnosis, gender, age, time interval between the biopsies, and treatment. This is the first study to quantify glomerular changes between two time points in patients with renal vasculitis. Our results suggest that, on average, no new glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.

Determination of optimal blood pressure for patients with IgA nephropathy based on renal histology.

To evaluate the optimal BP control for patients with IgA nephropathy (IgAN) based on the histologic severity of the nephropathy and the degree of renal dysfunction. We analyzed 332 consecutive renal biopsy specimens and clinical data from patients with IgAN. Patients were divided into three groups based on their BP at the time of biopsy: an optimal BP (SBP<120 mmHg and DBP<80 mmHg), a hypertensive BP (SBP > or = 140 mmHg and/or DBP > or = 90 mmHg), and an intermediate BP group. Each biopsy specimen was evaluated for mesangial proliferation, degree of sclerosis and/or hyalinosis of the arterioles and the interlobular artery using a semiquantitative method. Creatinine clearance and the percentage of sclerosed glomeruli were also determined. Both the degree of renal dysfunction and the histologic changes correlated significantly with BP, even in patients with a BP <140/90 mmHg. The patients with an optimal BP at the time of biopsy had significantly less histologic damage with respect to mesangial proliferation and vessel changes than those with an intermediate or hypertensive BP. In the patients with a hypertensive BP, the percentage of sclerotic glomeruli was significantly higher and the creatinine clearance was significantly lower. The optimal BP proposed by the WHO in 1999 prevents histologic evidence of renal damage for patients with IgAN.