Primary causes of kidney disease and mortality in dialysis-dependent children.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) is associated with a slower progression to end-stage renal disease (ESRD) in pre-dialysis patients. However, little is known about the associated mortality risks after transitioning to dialysis. METHODS: This retrospective cohort study included 0-21 year-old incident dialysis patients from the United States Renal Data System starting dialysis between 1995 and 2016. We examined the association of CAKUT vs. non-CAKUT with all-cause mortality, using Cox regression adjusted for case mix variables. We also examined the mortality risk associated with 14 non-CAKUT vs. CAKUT ESRD etiologies and under stratification by estimated glomerular filtration rate (eGFR). RESULTS: Among 25,761 patients, the median (interquartile range) age was 17 (11-19) years, and 4780 (19%) had CAKUT. CAKUT was associated with lower mortality, with an adjusted hazard ratio (aHR) of 0.72 (95%CI, 0.64-0.81) (reference: non-CAKUT). In age-stratified analyses, CAKUT vs. non-CAKUT aHRs (95%CI) were 0.66 (0.54-0.80), 0.56 (0.39-0.80), 0.66 (0.50-0.86), and 0.97 (0.80-1.18) among patients < 6, 6-< 13, 13-< 18, and ≥ 18 years at dialysis initiation, respectively. Among non-CAKUT ESRD etiologies, the risk of mortality associated with primary glomerulonephritis (aHR, 0.93; 95%CI 0.80-1.09) and focal segmental glomerulosclerosis (aHR, 0.89; 95%CI, 0.75-1.04) were comparable or slightly lower compared to CAKUT, whereas most other primary causes were associated with higher mortality risk. While the CAKUT group had lower mortality risk compared to the non-CAKUT group patients with eGFR ≥5 mL/min/1.73m2, CAKUT was associated with higher mortality in patients with eGFR < 5 mL/min/1.73 m2. CONCLUSIONS: CAKUT is associated with lower mortality among children < 18 years old, but showed comparable mortality with non-CAKUT among patients ≥ 18 years old. ESRD etiology should be considered in risk assessment for children initiating dialysis.

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.

RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Serum C3 and Renal Outcome in Patients with Primary Focal Segmental Glomerulosclerosis.

The role of complement (C) in the pathogenesis or progression of focal segmental glomerulosclerosis (FSGS) is uncertain. The present study assessed the relationship between serum C3, the baseline characteristics, and the progression of FSGS in the cohort and identified the clinical implications of serum C3 levels in patients with FSGS. Compared to the patients with C3 ≥ 85 mg/dL (N = 474), those with C3 < 85 mg/dL (N = 117) presented a higher level of serum creatinine, lower levels of eGFR, hemoglobin, proteinuria, triglyceride, cholesterol, IgA, as well as, severe tubulointerstitial injury (TI). Of the 221 patients with a mean follow-up of 53.3 months, the risk of reaching end-stage renal disease (ESRD) was significantly higher in patients with low serum C3 level (p < 0.001). An additional 40 patients with primary FSGS revealed a significant correlation between MAC and AP (p = 0.003), MAC and serum C3 (p = 0.018), and AP and serum C3 (p = 0.028). Compared to patients with none-to-mild TI, those with moderate-to-severe TI exhibited a lower level of serum C3 and AP, and a higher level of serum MAC. In conclusion, complement activation occurring in patients with FSGS is associated with clinical and histological severities. Low serum C3 was an independent risk factor for poor renal outcome in patients with FSGS.

Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Clinical presentation, treatment and outcome of focal segmental glomerulosclerosis in Far North Queensland Australian adults.

AIM: The aim is to describe the clinical features, treatment and outcomes in Australian adults with focal segmental glomerulosclerosis and identify predictors of disease progression and all-cause mortality. METHODS: The study included all patients with biopsy confirmed focal segmental glomerulosclerosis between January 1997 and June 2014 at participating hospitals. Clinical factors, histopathological findings, biochemical markers and treatments were analysed and potential predictors of doubling serum creatinine, end stage kidney disease or death identified. RESULTS: A total of 98 patients were included with a median follow up of 4.3 years. Thirty-four (35%) patients were Aboriginal or Torres Strait Islander. Focal segmental glomerulosclerosis not-otherwise-specified was the most common variant. Seventeen (59%) patients initially treated with immunosuppression experienced an improvement in renal function. At the end of follow up, 43 (44%) patients had progressed to the composite outcome. Baseline tubulointerstitial scarring and lower haemoglobin predicted shorter time to doubling serum creatinine. Dual diagnosis, higher serum creatinine, lower estimated glomerular filtration rate and doubling creatinine were associated with shorter time to end stage kidney disease with remission the only protective factor. Age was the only variable associated with all-cause mortality. CONCLUSION: Focal segmental glomerulosclerosis holds serious implications for patients. Concomitant diabetic nephropathy, higher serum creatinine and lower estimated glomerular filtration rate at renal biopsy were associated with poorer renal prognosis. Indigenous people had a female predominance and are over-represented in relation to their population size, however, were not associated with poorer prognosis. Remission was the only modifiable variable and thus should be at the forefront of patient management goals and future studies.

Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study.

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

The two kidney to one kidney transition and transplant glomerulopathy: a podocyte perspective.

The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10- to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting.

Clinical outcomes and predictors for ESRD and mortality in primary GN.

BACKGROUND AND OBJECTIVES: Relatively little is known about the long-term outcomes of different histologic types of primary glomerulonephritis in Asian populations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From 1993 to 2006, 987 patients undergoing renal biopsy were studied, and 580 patients (mean age=44.4 years, male=58.5%) with the four most common forms of glomerulonephritis (membranous nephropathy, focal and segmental glomerulosclerosis, IgA nephropathy, and minimal change disease) were selected for analysis. Median follow-up period was 5.9 (interquartile range=5.7) years. RESULTS: The focal and segmental glomerulosclerosis group displayed the highest incidence of ESRD (25.8%) and the fastest decline of estimated GFR (4.6 ml/min per 1.73 m(2) per year). The IgA nephropathy group also had a higher rate of ESRD than the membranous nephropathy patients (19.2% versus 4.3%, P<0.001). In contrast, the membranous nephropathy group exhibited an overall death rate similar to the focal and segmental glomerulosclerosis group (17.2% versus 14.4%) but higher than the IgA nephropathy and minimal change disease patients (4.6% and 3.7%, respectively, P<0.001). The most powerful predictor for ESRD was focal and segmental glomerulosclerosis, whereas the strongest predictor for all-cause mortality was membranous nephropathy with higher proteinuria. Protectors against ESRD included male sex and higher hemoglobin. CONCLUSIONS: Most predictors for ESRD and overall mortality found in this ethnic Chinese cohort were similar to other studies. However, some risk factors linked with distinct glomerular pathologies displayed differential clinical outcomes.

HIV-associated kidney glomerular diseases: changes with time and HAART.

BACKGROUND: Treatment and co-morbidities of human immunodeficiency virus (HIV)-infected individuals have changed dramatically in the last 20 years with a potential impact on renal complications. Our objective was to assess the change in distribution of the glomerular diseases in HIV patients. METHODS: We retrospectively analysed demographic, clinical, laboratory and renal histopathological data of 88 HIV-infected patients presenting with a biopsy-proven glomerular disease between 1995 and 2007. RESULTS: In our study including 66% Black patients, HIV-associated nephropathy (HIVAN) was observed in 26 cases, classic focal segmental glomerulosclerosis (FSGS) in 23 cases, immune complex glomerulonephritis in 20 cases and other glomerulopathies in 19 patients. HIVAN decreased over time, while FSGS emerged as the most common cause of glomerular diseases (46.9%) in HIV-infected individuals undergoing kidney biopsy in the last 2004-07 period. Patients with HIVAN were usually Black (97%), with CD4 <200/mL (P = 0.01) and glomerular filtration rate <30 mL/min/1.73 m(2) (P < 0.01). Compared to HIVAN, patients with classic FSGS were less often Black (P < 0.01), have been infected for longer (P = 0.03), were more often co-infected with hepatitis C virus (P = 0.05), showed more often cardiovascular (CV) risk factors (P < 0.01), had less often CD4 <200/mL (P = 0.01), lower HIV viral load (P = 0.01) and tended to be older (P = 0.06). CONCLUSIONS: Classic FSGS associated with metabolic and CV risk factors has overcome HIVAN in HIV-infected patients. Compared with other glomerulopathies, HIVAN remains strongly associated with severe renal failure, Black origin and CD4 lower than 200/mL at presentation.

Acquired glomerular lesions in patients with Down syndrome.

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.

[Schimke immuno-osseous dysplasia. A pediatric disease reaches adulthood]. / Schimke-immunoossäre Dysplasie. Eine pädiatrische Erkrankung wird erwachsen.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). CLINICAL FEATURES: Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vaso-occlusive processes. Only a few patients reached adulthood. CASE REPORTS: The clinical course of four adult SIOD patients is presented. CONCLUSION: Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.

Clinical course of 110 children and adolescents with primary focal segmental glomerulosclerosis.

The purpose of this retrospective cohort study was to report the clinical course of children and adolescents with primary focal segmental glomerulosclerosis (FSGS). The records of 110 patients with biopsy-proven FSGS admitted between 1972 and 2004 were retrospectively reviewed. Demographic, clinical and laboratory data were recorded and histopathological data were reanalyzed by one pathologist who had no information about the outcome of the patients. Renal survival analysis was performed using the Kaplan-Meier method. Differences between subgroups (response to corticosteroids) were assessed by the two-sided log rank test. The median age at admission was 5 years (range: 1-15 years). Forty-two patients (38.2%) presented with hematuria at admission, and 55 (50%) presented blood pressure levels above the 95th percentile. Mean follow-up time was 10 years (SD 5.5). Twenty-four patients (21.8%) presented chronic kidney disease (CKD). It was estimated that the probability of CKD was 8% at 5 years, 17% at 10 years, and 32% at 15 years after diagnosis of nephrotic syndrome. In conclusion, on the basis of the clinical and histological characteristics observed, apparently our cohort of idiopathic FSGS is comparable with other published series. However, the long-term overall renal survival seems to be better in our cohort.

Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants.

The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P = 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P < 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P = 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P = 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.

Reasons for non-use of recovered kidneys: the effect of donor glomerulosclerosis and creatinine clearance on graft survival.

BACKGROUND: In 2000, the United Network for Organ Sharing/Organ Procurement and Transplantation Network Registry reported 540 recovered kidneys were discarded because of biopsy results, and 210 were discarded because of poor organ function. We compared the percentage of glomerulosclerosis (GS) and creatinine clearance (CrCl) of both discarded and transplanted cadaveric kidneys and examined their effect on graft survival and function. METHODS: The cohort consisted of all cadaveric kidneys (n= 3,444) with reported biopsy results between October 25, 1999 and December 31, 2001. Graft survival was calculated by univariate and multivariate models. RESULTS: Fifty-one percent of discarded kidneys had GS of less than 20%, 27% had a CrCl greater than 80 mL/min, and 15% (129 kidneys) had both GS less than 20% and a CrCl of greater than 80 mL/min. Univariate analyses of kidneys with less than or equal to 20% GS revealed no difference in 1-year graft survival when the CrCl was greater than or less than or equal to 80 mL/min. When GS was greater than 20%, 1-year graft survival of kidneys with a CrCl of greater than 80 mL/min was significantly greater than that of kidneys with a CrCl of less than or equal to 80 mL/min. Multivariate results showed no significant difference in relative risk of graft loss with GS greater than 20% versus less than or equal to 20% when the CrCl was either 50 or 80 mL/min. With both GS less than or equal to 20% and greater than 20%, serum creatinine at 1 year was significantly lower in kidneys with CrCl greater 80 mL/min. CONCLUSIONS: Calculated donor CrCl does, and percentage GS on donor kidney biopsies does not, correlate well with 1-year graft survival and function, and percentage GS should not be used as the sole criterion for discarding recovered cadaveric kidneys.

Long-term outcome of heavy proteinuria in patients under 2 years of age.

From January 1985 to July 2000, a retrospective study of 53 patients in Taiwan was performed in order to evaluate the underlying diseases causing heavy proteinuria and the clinical outcome in children under 2 years of age (33 boys and 20 girls). Renal biopsy or autopsy was performed in 26 of the children. Renal pathology revealed 2 patients with congenital nephrosis (CNS) (7.7%), 4 with diffuse mesangial sclerosis (DMS) (15.4%), 4 with minimal change nephrotic syndrome (MCNS) (15.4%), 5 with focal segmental glomerulosclerosis (FSGS) (19.2%), 9 with IgM nephropathy in (34.6%), and 2 with hepatitis B virus-associated membranous glomerulonephritis (7.7%). Based on available histology and family history of heavy proteinuria progressing to end-stage renal disease (ESRD), patients were divided into two groups. Group I comprised 10 patients, including CNS (2 cases), DMS (4 cases), and 4 children with a familial history of heavy proteinuria progressing to ESRD. All patients in group I were initially steroid resistant. After methylprednisolone pulse therapy plus cyclosporin A treatment, no patients with CNS or DMS responded, but the other 4 patients experienced a remission. Group II comprised 43 patients; 19 patients (44.2%) were initially steroid resistant. Of these steroid-resistant patients, all experienced remission after methylprednisolone pulse therapy plus cyclosporin A, except 3 children with FSGS. One experienced a thromboembolic event during his clinical course. In conclusion, steroid-resistant nephrotic syndrome (NS) was more common than steroid-sensitive NS in Chinese patients under 2 years of age. Patients with CNS, DMS, or a family history of heavy proteinuria progressing to ESRD had a poor prognosis. Methylprednisolone pulse therapy plus cyclosporin A treatment achieved remission in some children who were initially steroid resistant. This study indicates that children with conditions associated with poor steroid responsiveness (e.g., CNS, DMS) do not respond to immunosuppressive therapy, but other children under 2 years of age, including those with a family history of progression to ESRD, may benefit from aggressive immunosuppressive therapy.

Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis.

BACKGROUND: Progression of idiopathic membranous glomerulonephritis (IMGN) to renal insufficiency depends on various clinical and laboratory factors that have been taken into account in most therapeutic trials based on such aggressive drugs as alkylating agents or cyclosporine. However, few studies have envisaged the prognostic significance of morphological factors and their importance for stratification of patients enrolled in therapeutic trials. METHODS: Records of patients with membranous glomerulonephritis (MGN) from 1976 to 2001 from five nephrology units were reviewed retrospectively. Secondary causes were ruled out, especially occult malignancy. Eligible cases were analyzed according to clinical profile, abundance of proteinuria, blood pressure, and standard renal pathological characteristics, including MGN staging, vascular lesions, and degree of interstitial fibrosis on a semiquantitative scale. Renal survival curves from renal insufficiency were calculated by the Kaplan-Meier method. Mean follow-up was 68 months. RESULTS: Initial multiple regression analysis showed that the most significant prognostic variable was the presence of focal segmental glomerulosclerosis (FSGS)-type glomerular lesions (P < 0.001), and patients therefore were divided into two groups: 42 patients had MGN only (group I) and 30 patients had superimposed FSGS (group II). Group II patients were more hypertensive, and all renal lesions were significantly more severe, with a higher mean stage of membranous lesions, more obsolescent glomeruli, greater mesangial proliferation, and worse interstitial fibrosis and vascular lesions. Renal survival for group II was significantly lower (P < 0.001, log-rank test). Only one remission occurred in group II, whereas 38% of group I patients experienced remission (P = 0.002). We pooled our results with those of three previous studies in the literature, totaling 282 patients (156 patients, MGN alone; 126 patients, MGN plus FSGS). Remission rates were 32% and 12.7%, respectively (P < 0.001). The prognostic value of hypertension was noted in three of the four series, including ours. CONCLUSION: FSGS lesions superimposed on IMGN are common and portend a significantly worse outcome in terms of nephrotic syndrome and renal insufficiency. Therefore, we consider that future therapeutic trials of IMGN should include case stratification based on the presence or absence of FSGS on pretreatment biopsy.

[Idiopathic nephrotic syndrome in children: report of 57 cases]. / Le syndrome nephrotique idiopathique de l'enfant: a propos de 57 observations.

The aim of this study was to analysis epidemiological, clinical, biochemical and histopathological profile of INS in children and to document their management and their final course. A retrospective study of 57 children with INS hospitalized in the pediatric department of Monastir hospital from the 1st of January 1989 to the 31 th of December 1999 was conducted. The annual rate was of 3,2 cases 1000 admissions, sex ratio was of 1,28 with 32 boys and 25 girls. The mean age at the onset of the affection was of 5 years and 3 months. The renal biopsy was performed in 18 children. The histological finding were a minimal change histology in 50% of cases, a focal segmental glomerulosclerosis in 33% of cases and membrano-proliferative glomerulonephritis in 11% of cases. A cortico-therapy was initiated in all children. 87,5% of them were steroid sensitive. 22,4% of patients had steroid dependent nephrotic syndrome and 12,5% of patients had steroid resistant nephrotic syndrome. All children steroid resistant underwent immunosuppressive therapy; however chronic failure was observed in 57% of them. After a mean follow up period of 46 months, recovery was obtained in 48,2%, complete remission in 28,5% and death in 5,3% of cases.

Early progressive interstitial fibrosis in human renal allografts.

BACKGROUND: Early fibrosis has been described in renal allografts and implicated in the progression of chronic allograft nephropathy (CAN). The precise factors implicated in the initiation and progression of early allograft fibrosis remain uncertain. PATIENTS AND METHODS: We studied retrospectively 23 cadaveric renal allograft recipients over a 3-year period, who had paired renal biopsies (Bx) (at implantation and as clinically indicated) within 3 months of transplantation (Tx). Eight of them have progressed over an average period of 3.16 +/- 0.83 years to CAN. Histological evaluation of interstitial fibrosis (IF) relied on point count analysis of Masson's trichrome (MT) staining as well as immunostainable collagens III (iCol III) and IV (iCol IV). The severity of the IF scores was correlated with the clinical, biochemical and histological parameters. The nature and severity of the interstitial inflammatory infiltrate were also evaluated by immunofluorescence. In addition, patients were subdivided into those whose fibrosis progressed (> 50% increase in IF/iCol IlI; Group 1) and non-progressors (< 50% increase in fibrosis score; Group 2) in an attempt to determine discriminatory features. RESULTS: In the whole group, there was a significant increase in the IF score, as estimated by MT staining and iCol III, from implantation to follow-up Bx (p = 0.0027 and p = 0.0088, respectively). The changes in iCol IV were not significant. Further, the increase in interstitial inflammatory infiltrate of total T lymphocytes, and not of macrophages, from implantation (modal category = 2) to follow-up (modal category = 0) was significant (p = 0.0121). The predictive value of such increase was significant (R2 = 0.617, p = 0.03). The donor's age (R2 = 0.892, p = < 0.0001), death from cerebrovascular accident (CVA) (R2 = 0.822, p = 0.047), as well as recipient's body weight (R2 = 0.892, p = 0.001), male gender (R2 = 0.687, p = 0.041) and elevated mean arterial pressure (MAP) (R2 = 0.892, p = < 0.0001) were all significant risk factors for early IF. Delayed graft function (DGF) proved to be a significant predictor of early IF (R2 = 0.822, p = 0.003) and became more significant in the presence of superimposed acute rejection (AR) (p = 0.0001). Proteinuria > 1 g/day (R2 = 0.882, p = 0.004) and hypertriglyceridemia > 2.25 mmol/l (R2 = 0.808, p = < 0.0001) were also associated with early IF. Of the implantation histological parameters, iCol III proved to be a highly significant predictor of early IF (R2 = 0.892, p = < 0.0001). Interestingly, the predictive value of iCol III for graft survival in terms of CAN was significant (Cox p = 0.088). Group 1 progressor patients (n = 10) were all males (p = 0.038) and received their kidneys from donors who died from CVAs in 90% of cases (p = 0.011). They had, compared to non-progressors, a lower cyclosporin A level (p = 0.047), a higher incidence of AR episodes (80% versus 54%), a higher serum creatinine at 10 days post-Tx (p = 0.005), a higher proteinuria (2.07 +/- 3.89 g/l vs 0.96 +/- 0.97 g/l, p = 0.041) and a higher serum triglyceride (2.48 +/- 1.37 mmol/l vs 1.69 +/- 0.81 mmol/l, p = 0.039) level. 8% of Group 1 patients had DGF compared to 30% in Group 2 (p = 0.023). Of note, the modal category of cytotoxic: helper T lymphocytes ratio was greater than 1 in Group 1 (2:1) patients and not in Group 2 (1:1). CONCLUSION: Implantation histology, and in particular iCol III, is a predictor of early IF in a subgroup of patients with DGF and AR. Additional risk factors include hypertension, proteinuria and hypertriglyceridemia especially in patients receiving kidneys from older donors who died of CVAs.

Renovascular hypertension does not influence repair of glomerular lesions induced by anti-thymocyte glomerulonephritis.

BACKGROUND: Systemic hypertension is a risk factor for progression of renal disease. However, it is not clear whether hypertension has an effect on healing or regression of immune-mediated glomerular damage. To evaluate this effect, we applied a model of glomerulonephritis in rats with two-kidney, one-clip hypertension and studied the effect of hypertension on the healing process of this nephritis. METHODS: The anti-thymocyte serum (ATS) glomerulonephritis was induced in rats six weeks after initiation of two-kidney, one-clip hypertension, when blood pressure was already increased. Renal structure and function were examined six weeks later. Glomerular expression of alpha smooth muscle actin, the cell cycle inhibitor p27Kip1, and transforming growth factor-beta (TGF-beta) was evaluated by Western blotting. Glomerular proliferation, monocyte infiltration, and fibronectin were examined by immunohistochemistry. RESULTS: Decreased survival, an increase of proteinuria, as well as increased glomerular and tubulointerstitial damage, were found in hypertensive rats compared with normotensive rats. Expression of fibronectin, alpha-smooth muscle actin, TGF-beta, and p27Kip1 was increased in the nonclipped kidney. Complete healing of the glomerular changes associated with the nephritis occurred in normotensive nephritic rats. Surprisingly, complete healing of the nephritis was also found in the clipped as well as nonclipped kidneys of renovascular hypertensive rats. No significant differences could be found for survival, proteinuria, glomerular size, proliferation, monocyte/macrophage infiltration, sclerosis, tubulointerstitial damage, as well as expression of alpha-smooth muscle actin, TGF-beta, fibronectin, and p27Kip1 between hypertensive rats with and without nephritis. CONCLUSION: These data demonstrate that renovascular hypertension does not influence healing of the glomerular lesions in the anti-thymocyte serum nephritis. This is a rather surprising observation and leaves the question open of which role, in fact, blood pressure may have on the reparative phase of an acute glomerulonephritis, or whether its role depends on the type of glomerulonephritis.

[Primary focal segmental glomerulosclerosis: clinical and morphological prognostic factors]. / Pervichnyi fokal'no-segmentarnyi glomeruloskleroz: klinicheskie i morfologicheskie faktory prognoza.

AIM: To retrospectively analyze clinical course and results of immunodepressive therapy of patients with primary focal-segmental glomerulosclerosis (FSGS), to reveal prognostic factors of the disease progression and patients' sensitivity to immunosuppressive therapy. MATERIAL AND METHODS: Morphological diagnosis was specified, morphological indices of activity and sclerosis were estimated, renal survival was analysed, mono- and multivariate analysis of prognostic factors was made by the evidence obtained in the study of 135 biopsy specimens from CRF patients meeting the criteria of FSGS. RESULTS: At the moment of the disease onset only age of the patients was related to FSGS: 5- and 10-year survival was 100% if the disease started under 16 years of age, if older--the survival was 80 and 65%, respectively. Nephrotic syndrome, hematuria, high creatinine, racemose alterations in the glomeruli worsened the disease prognosis. When cytostatics and corticosteroids were used in combination they produced better results and were associated with better prognosis than each of them in monotherapy. Patients with marked hematuria and low proteinuria were less sensitive to therapy than those with weak hematuria and high proteinemia. Patients with FSGS having high IA and SI required more aggressive therapy for response. CONCLUSION: Renal biopsy with quantitation of IA and IS increases the prognosis accuracy and is important for choice of the treatment policy in patients with primary FSGS.