Subject(s)
Cardiovascular Diseases , Databases, Factual , Glomerulosclerosis, Focal Segmental , Humans , Cardiovascular Diseases/mortality , Male , Female , Adult , Glomerulosclerosis, Focal Segmental/mortality , United States/epidemiology , Renal Insufficiency/mortality , Renal Insufficiency/epidemiology , Middle Aged , Cause of Death , Young AdultABSTRACT
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.
Subject(s)
Glomerulonephritis/mortality , Glomerulosclerosis, Focal Segmental/mortality , Kidney Failure, Chronic/mortality , Renal Dialysis/statistics & numerical data , Urogenital Abnormalities/mortality , Vesico-Ureteral Reflux/mortality , Adolescent , Cause of Death , Child , Child, Preschool , Disease Progression , Female , Glomerular Filtration Rate , Glomerulonephritis/complications , Glomerulonephritis/therapy , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/therapy , Humans , Infant , Infant, Newborn , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/therapy , Male , Retrospective Studies , Risk Assessment/statistics & numerical data , Risk Factors , United States/epidemiology , Urogenital Abnormalities/complications , Urogenital Abnormalities/therapy , Vesico-Ureteral Reflux/complications , Vesico-Ureteral Reflux/therapy , Young AdultABSTRACT
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.
Subject(s)
Glomerulonephritis, IGA/pathology , Glomerulonephritis, Membranous/pathology , Glomerulosclerosis, Focal Segmental/pathology , Kidney Failure, Chronic/prevention & control , Nephrosis, Lipoid/pathology , Academic Medical Centers , Adolescent , Adult , Age Factors , Biopsy, Needle , Child , Diagnosis, Differential , Disease Progression , Female , Glomerulonephritis/mortality , Glomerulonephritis/pathology , Glomerulonephritis/therapy , Glomerulonephritis, IGA/mortality , Glomerulonephritis, IGA/therapy , Glomerulonephritis, Membranous/mortality , Glomerulonephritis, Membranous/therapy , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/therapy , Humans , Immunohistochemistry , Linear Models , Male , Middle Aged , Multivariate Analysis , Nephrosis, Lipoid/mortality , Nephrosis, Lipoid/therapy , Prognosis , Prospective Studies , Risk Assessment , Severity of Illness Index , Sex Factors , Survival Analysis , Young AdultABSTRACT
Our objective is to study the demographical data, clinical course and outcome of children with primary focal segmental glomerulosclerosis (FSGS) in Jordan. A retrospective chart review of patients with a diagnosis of FSGS at a tertiary care hospital from the period July 2010 to July 2016 was conducted. A total of 99 patients were analyzed. The mean age of presentation was 3.71 ± 2.59 years, 66% were male. At presentation, 66.6% of patients were steroid-resistant, 10% had a steroid dependant course and 20.2% had familial FSGS. Cyclosporine was used in 66.6% of children with a response rate of 46.9%. Long-term follow-up showed complete remission in 29.3%, partial remission in 31.3%, end-stage renal disease in 22.2%, and death in 11.1%. There is a high prevalence of familial FSGS in our Jordanian cohort with a high rate of progression to end-stage kidney disease.
Subject(s)
Glomerulosclerosis, Focal Segmental , Child , Child, Preschool , Disease Progression , Female , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/epidemiology , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/therapy , Humans , Infant , Jordan/epidemiology , Male , Retrospective Studies , Tertiary Care CentersABSTRACT
BACKGROUND: Pediatric patients with focal segmental glomerulosclerosis (FSGS) have high rates of disease recurrence and allograft failure after kidney transplantation, but there are few data for long-term survival posttransplantation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 12,303 pediatric patients (aged <18 years), including 1,408 (11%) patients with FSGS, who received a first kidney transplant in 1990 through 2009 and were followed up through June 2015 were identified from the US Renal Data System database. PREDICTORS: Primary cause of end-stage renal disease, FSGS or other. OUTCOMES: All-cause patient mortality and allograft loss. RESULTS: All-cause mortality significantly improved for patients with FSGS who underwent transplantation in the 2000s versus the 1990s (6.72 vs 12.24 deaths/1,000 patient-years; HR, 0.55; 95% CI, 0.39-0.78; P<0.001). Reductions in allograft loss were less dramatic (75.91 vs 89.05 events/1,000 patient-years; HR, 0.85; 95% CI, 0.74-0.98; P=0.02). After adjusting for baseline characteristics at the time of transplantation, patients with FSGS had similar rates of death compared with patients without FSGS (HRs of 0.81 [P=0.6] and 1.06 [P=0.2] among those who underwent transplantation in the 2000s and 1990s, respectively) despite higher rates of allograft loss (HRs of 1.17 [P=0.03] and 1.27 [P<0.001], respectively). Among patients who underwent transplantation in the 2000s, further adjustment for allograft failure as a time-varying covariate demonstrated a lower rate of death among patients with FSGS compared with those without FSGS (HR, 0.70; P=0.02). LIMITATIONS: Lack of information about certain risk factors for mortality, including duration of chronic kidney disease; missing data; and potential primary disease misclassification. CONCLUSIONS: Survival of pediatric kidney transplant recipients with FSGS improved between the 1990s and 2000s and was similar to that of recipients without FSGS. Interestingly, adjustment for allograft failure showed greater survival for pediatric patients with FSGS who underwent transplantation in the 2000s as compared with others, suggesting that effective interventions to decrease allograft loss due to disease recurrence may improve patient survival.
Subject(s)
Cause of Death , Glomerulosclerosis, Focal Segmental/surgery , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/surgery , Kidney Transplantation/mortality , Kidney Transplantation/methods , Adolescent , Age Factors , Allografts , Child , Child, Preschool , Cohort Studies , Databases, Factual , Disease Progression , Female , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/mortality , Graft Rejection , Graft Survival , Humans , Kaplan-Meier Estimate , Kidney Failure, Chronic/diagnosis , Male , Prognosis , Proportional Hazards Models , Quality Improvement , Retrospective Studies , Risk Assessment , Severity of Illness Index , Sex Factors , Survival AnalysisABSTRACT
BACKGROUND: Few data exist on recurrence rates, treatment response, and long-term outcomes in kidney transplant recipients (KTR) with primary focal segmental glomerulosclerosis (FSGS). METHODS: This retrospective, observational study included 1218 consecutive KTR during 2002 to 2016. All patients with primary idiopathic FSGS were identified through application of strict diagnostic criteria. Outcomes were followed over an average of 70.4 months. RESULTS: We identified 48 KTR (3.9%) with primary FSGS. Seven-year death-censored graft survival rate was 81% (primary FSGS) versus 85% (control) (P = .297). Eighteen KTR had FSGS recurrence (predicted incidence, 50% after 7 years). Seven-year death-censored graft survival rate in KTR with FSGS recurrence was significantly worse than in FSGS KTR without recurrence (63% versus 96%, P = .010). In the case of FSGS recurrence, a multi-modal treatment approach was applied, including plasma exchange (PE) (100% of patients), intravenous cyclosporine (50%), rituximab (61%), and the "Multiple Target Treatment" (39%). The median number of PE sessions was 27. Proteinuria decreased significantly and persistently during the course of treatment. Complete remission of FSGS was observed in 7 patients (39%); another 7 patients (39%) had partial remission (PE dependence was observed in 4 patients [22%]). Four patients (22%) with FSGS recurrence had early graft loss (<6 months after transplant) despite all treatment efforts. CONCLUSIONS: In KTR with primary FSGS, a high proportion of recurrence occurred, and recurrence was associated with significantly worse death-censored graft survival rates. However, a multi-modal treatment approach led to improvement of proteinuria and full or partial remission in most patients. Importantly, overall death-censored graft survival rate in KTR with primary FSGS was comparable with that in the control group.
Subject(s)
Glomerulosclerosis, Focal Segmental/therapy , Kidney Transplantation/mortality , Adult , Combined Modality Therapy , Cyclosporine/administration & dosage , Female , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/mortality , Graft Survival , Humans , Immunologic Factors/administration & dosage , Kidney Transplantation/methods , Male , Middle Aged , Plasma Exchange/methods , Postoperative Period , Proteinuria/etiology , Proteinuria/therapy , Recurrence , Remission Induction , Retrospective Studies , Rituximab/administration & dosage , Survival Rate , Treatment OutcomeABSTRACT
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.
Subject(s)
Complement C3/metabolism , Glomerulosclerosis, Focal Segmental/blood , Glomerulosclerosis, Focal Segmental/diagnosis , Adult , Biomarkers , Biopsy , Complement Activation , Complement C3/immunology , Disease Progression , Female , Follow-Up Studies , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/etiology , Glomerulosclerosis, Focal Segmental/mortality , Humans , Kaplan-Meier Estimate , Male , Odds Ratio , Prognosis , Proportional Hazards Models , Severity of Illness Index , Young AdultABSTRACT
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.
Subject(s)
Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/therapy , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/therapy , Kidney/drug effects , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , Creatinine/blood , Disease Progression , Female , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/physiopathology , Humans , Kidney/physiopathology , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/physiopathology , Male , Middle Aged , Proportional Hazards Models , Queensland , Recovery of Function , Remission Induction , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Up-Regulation , Young AdultABSTRACT
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.
Subject(s)
Glomerulonephritis, IGA/mortality , Glomerulosclerosis, Focal Segmental/classification , Immunosuppression Therapy , Podocytes/pathology , Proteinuria/urine , Adolescent , Adult , Biopsy , Child , Female , Follow-Up Studies , Glomerular Filtration Rate , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/pathology , Humans , Hypertrophy/diagnosis , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , Reproducibility of Results , Retrospective Studies , Young AdultABSTRACT
It is well established that racial differences exist in kidney transplant outcomes; however, there are no studies which focus on the role of race in transplant outcomes specifically in children diagnosed with FSGS. Associations between race and transplant outcomes in FSGS children were evaluated using the Organ Procurement and Transplantation Network database from 2000 to 2012. Recipients aged 2-21 years who received a kidney-only transplant were included. Multivariate regression models were used to evaluate transplant outcomes by race. Five hundred and thirty-six recipients (59.7% male, 15.6±3.9 years) were black and 1134 (55.7% male, 14.3±5.0 years) were non-black. Graft survival was significantly shorter in the black group (4.2±3.1 vs 4.6±3.3 years, P=.005). Black race was associated with significantly higher risk of graft failure (HR 1.34, 95% CI=1.21-1.49, P<.0001), acute rejection (OR 1.66 95% CI=1.39-1.97, P<.0001), and delayed graft function (OR 1.51, 95% CI=1.33-1.72, P<.001) compared to non-black race. There were no significant differences in mortality, prolonged hospitalization, or FSGS recurrence between groups. Race is a significant predictor for worse transplant outcomes in children with FSGS.
Subject(s)
Black or African American , Delayed Graft Function/ethnology , Glomerulosclerosis, Focal Segmental/surgery , Graft Rejection/ethnology , Graft Survival , Health Status Disparities , Kidney Transplantation , Adolescent , Child , Child, Preschool , Databases, Factual , Female , Follow-Up Studies , Glomerulosclerosis, Focal Segmental/ethnology , Glomerulosclerosis, Focal Segmental/mortality , Humans , Kidney Transplantation/mortality , Length of Stay/statistics & numerical data , Male , Recurrence , Regression Analysis , Retrospective Studies , Risk Factors , Survival Analysis , United States , Young AdultABSTRACT
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.
Subject(s)
Glomerulosclerosis, Focal Segmental/therapy , Graft Rejection/therapy , Immunoglobulins, Intravenous/therapeutic use , Kidney Transplantation/adverse effects , Rituximab/therapeutic use , Adult , Case-Control Studies , Female , Follow-Up Studies , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/etiology , Glomerulosclerosis, Focal Segmental/mortality , Graft Rejection/etiology , Graft Rejection/mortality , Graft Survival , Humans , Immunologic Factors/therapeutic use , Kidney Failure, Chronic/surgery , Kidney Function Tests , Male , Pilot Projects , Prognosis , Retrospective Studies , Risk Factors , Survival RateABSTRACT
Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.
Subject(s)
Apolipoproteins/genetics , Cyclosporins/therapeutic use , Dexamethasone/therapeutic use , Glomerulosclerosis, Focal Segmental/drug therapy , Glomerulosclerosis, Focal Segmental/genetics , Lipoproteins, HDL/genetics , Mycophenolic Acid/analogs & derivatives , Adolescent , Adult , Apolipoprotein L1 , Child , Female , Follow-Up Studies , Gene Expression Regulation , Genotype , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/mortality , Humans , Kidney Function Tests , Male , Mycophenolic Acid/therapeutic use , Prospective Studies , Risk Assessment , Severity of Illness Index , Survival Rate , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Glomerulosclerosis, Focal Segmental/pathology , Kidney Failure, Chronic/surgery , Kidney Transplantation/methods , Podocytes/pathology , Adaptation, Physiological , Adult , Animals , Autografts , Biopsy, Needle , Disease Models, Animal , Female , Follow-Up Studies , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/physiopathology , Graft Rejection , Graft Survival , Humans , Immunohistochemistry , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/physiopathology , Kidney Transplantation/adverse effects , Male , Middle Aged , Podocytes/metabolism , Postoperative Complications/pathology , Postoperative Complications/physiopathology , Rats , Retrospective Studies , Risk Assessment , Survival RateABSTRACT
This study aimed to analyze the treatment, clinical outcomes, and risk factors that affect the prognosis of patients with primary focal segmental glomerulosclerosis (FSGS) and to provide theoretical evidence for various treatment options in these patients. The study reviewed the clinical, laboratory, and pathological data of 168 patients with primary FSGS treated at Ruijin Hospital between January 2002 and October 2011. Of these patients, 108 were male (64.3%) and 60 were female (35.7%). The median age of disease onset was 38 years (range 12-78 years). The median case history was 10 months (range 4 days to 30 years). The mean proteinuria level was 2.3 ± 0.6 g/day. 75 (44.6%) patients had nephrotic syndrome. The mean serum creatinine was 108.1 ± 8.9 µmol/l. Over a follow-up period of 25.3 ± 11.4 months, end-stage renal failure occurred in 4 patients, and all 4 survived. In the group treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, the following factors were identified as risk factors for experiencing a 50% increase in serum creatinine over the baseline: a baseline eGFR <60 ml/min, proteinuria >1 g/day during the follow-up period, glomerular sclerosis >grade 1, and tubulointerstitial lesions >stage 1. In the group treated with steroids, patients who achieved a stable remission had better preserved renal function and milder glomerular sclerosis than steroid-dependent patients (p < 0.01). Steroid-resistant FSGS patients had a worse histological severity of glomerular sclerosis than steroid-dependent patients (p < 0.01). The prognosis of FSGS was correlated with the amount of proteinuria, the level of serum creatinine, and the severity of glomerular sclerosis and tubulointerstitial lesions. Steroids may be more effective in those who have better preserved renal function and milder glomerular sclerosis.
Subject(s)
Glomerulosclerosis, Focal Segmental/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Child , Female , Glomerulosclerosis, Focal Segmental/mortality , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival RateABSTRACT
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.
Subject(s)
Glomerulonephritis/mortality , Kidney Failure, Chronic/mortality , Adult , Aged , Asian People , Biomarkers/blood , Biopsy , Chi-Square Distribution , Disease Progression , Female , Glomerulonephritis/blood , Glomerulonephritis/ethnology , Glomerulonephritis/pathology , Glomerulonephritis/therapy , Glomerulonephritis, IGA/mortality , Glomerulonephritis, IGA/pathology , Glomerulonephritis, Membranous/mortality , Glomerulonephritis, Membranous/pathology , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/pathology , Hemoglobins/metabolism , Humans , Incidence , Kaplan-Meier Estimate , Kidney/pathology , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/ethnology , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/therapy , Male , Middle Aged , Multivariate Analysis , Nephrosis, Lipoid/mortality , Nephrosis, Lipoid/pathology , Prognosis , Proportional Hazards Models , Proteinuria/mortality , Renal Dialysis , Retrospective Studies , Risk Assessment , Risk Factors , Sex Factors , Taiwan/epidemiology , Time Factors , Young AdultABSTRACT
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.
Subject(s)
AIDS-Associated Nephropathy/etiology , Antiretroviral Therapy, Highly Active , Glomerulosclerosis, Focal Segmental/etiology , HIV Infections/complications , HIV Infections/drug therapy , HIV/pathogenicity , AIDS-Associated Nephropathy/mortality , Adult , Female , Follow-Up Studies , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/mortality , HIV/isolation & purification , HIV Infections/virology , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival Rate , Time FactorsABSTRACT
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.
Subject(s)
Down Syndrome/epidemiology , Glomerulonephritis, IGA/epidemiology , Glomerulosclerosis, Focal Segmental/epidemiology , Kidney Glomerulus/pathology , Renal Insufficiency/epidemiology , Adolescent , Adult , Child , Cohort Studies , Comorbidity , Down Syndrome/mortality , Down Syndrome/pathology , Female , Glomerulonephritis, IGA/mortality , Glomerulonephritis, IGA/pathology , Glomerulosclerosis, Focal Segmental/mortality , Glomerulosclerosis, Focal Segmental/pathology , Humans , Hypothyroidism/epidemiology , Hypothyroidism/pathology , Male , Middle Aged , Minnesota/epidemiology , Renal Insufficiency/pathology , Survival RateABSTRACT
BACKGROUND: Idiopathic focal segmental glomerulosclerosis (FSGS) occurring at young age is known to predispose to poor graft outcome, but the outcome of adulthood-onset FSGS (A-FSGS) has not been thoroughly investigated. Here, we compared the graft outcomes between kidney recipients with A-FSGS and childhood-onset FSGS (C-FSGS). METHODS: We enrolled 47 A-FSGS recipients and 60 C-FSGS recipients with an onset age of ≤ 15, from four of the largest transplant centers in Korea. RESULTS: The baseline characteristics were similar between two groups. The 1- and 3-year cumulative recurrence rates were 20.0 and 22.1%, respectively. FSGS was recurrent in 19 C-FSGS patients [median duration, 2 months (interquartile range, IQR, 1-35)], and 11 patients had recurrent disease in A-FSGS [5 months (IQR, 3-37)]. The recurrence rate was similar between two groups (P = 0.126). The 5- and 10-year graft survival rates were 90.0 and 78.5%, respectively. The overall graft survival rates were not different between two groups. After adjusting baseline characteristics, the development of major outcomes was similar between two groups except acute rejection that was more frequent in A-FSGS. The age of disease onset did not affect recurrence in both groups. While grafts with recurrence had poorer graft survival in the A-FSGS group (P = 0.005), the recurrence was not associated with graft loss in the C-FSGS group (P = 0.558). CONCLUSIONS: The onset age did not affect the graft outcome in patients with FSGS, and the recurrence significantly affected graft survival in A-FSGS. Therefore, the main focus should aim for the management of recurrence.
Subject(s)
Glomerulosclerosis, Focal Segmental/mortality , Graft Rejection/mortality , Graft Survival , Kidney Transplantation , Adult , Child , Female , Follow-Up Studies , Humans , Male , Prognosis , Recurrence , Republic of Korea , Survival Rate , Transplantation, HomologousABSTRACT
BACKGROUND: Given the reported efficacy of mycophenolate mofetil (MMF) in the treatment of glomerular diseases, we question whether MMF can reduce the rate of renal allograft loss due to glomerular disease recurrence compared to azathioprine (AZA) as adjunctive therapy to cyclosporine (CSA)-based immunosuppression. METHODS: This is a retrospective study based on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database designed to compare the Kaplan-Meier rates of graft loss due to disease recurrence stratified by primary renal diagnoses between recipients receiving CSA+AZA versus CSA+MMF. Recipients of primary kidney transplants (both deceased donor and living, related and unrelated) renal transplants performed between 1 January 1988 and 31 December 2007 with the primary renal diagnosis of IgA nephropathy (IgAN), membranous glomerulonephropathy (MGN), membranoproliferative glomerulonephropathy (MPGN), lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) with a functioning allograft at discharge were included. RESULTS: Seven thousand eight hundred and twenty-six recipients of primary deceased donor kidney transplants (DDKT) [CSA + AZA: IgAN (890), MGN (380), MPGN (193), LN (1324), FSGS (1314) and CSA+MMF: IgAN (855), MGN (614), MPGN (116), LN (715), FSGS (1425)] and 5498 recipients of living donor kidney transplants (LDKT) [CSA+AZA: IgAN (694), MGN (229), MPGN (100), LN (592), FSGS (654) and CSA+MMF: IgAN (1066), MGN (435), MPGN (89), LN (530), FSGS (1109)] were included in the analysis. At 10-year follow-up (mean duration was 5.6 to 6.7±1.8 years in DDKT and 6.2 to 7.4±1.7 years in LDKT), mean times of transplantation (era of transplantation) were: 1992±1.6 years and 2002±1.9 years for the CSA+AZA and CSA+MMF groups, respectively. There was no statistically significant difference in the Kaplan-Meier rates of graft loss due to disease recurrence of any glomerular disease studied between the CSA+AZA and CSA+MMF groups in either DDKT or LDKT recipients. Chi-square analysis revealed no statistically significant difference between the two immunosuppressive regimen groups in terms of age, gender and ethnic background. CONCLUSION: The OPTN/UNOS database revealed no difference in the rates of renal allograft loss due to disease recurrence of IgAN, MGN, MPGN, LN and FSGS among recipients receiving either CSA+AZA or CSA+MMF maintenance immunosuppressive therapy at 10-year follow-up.
Subject(s)
Azathioprine/therapeutic use , Cyclosporine/therapeutic use , Glomerulosclerosis, Focal Segmental/etiology , Graft Rejection/drug therapy , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Adolescent , Adult , Aged , Female , Follow-Up Studies , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/drug therapy , Glomerulosclerosis, Focal Segmental/mortality , Graft Rejection/etiology , Graft Survival , Humans , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Prognosis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/therapy , Retrospective Studies , Secondary Prevention , Survival Rate , Tissue Donors , Young AdultABSTRACT
It is well known that lesions morphologically identical with focal segmental glomerulosclerosis (FSGS) may appear in IgA nephropathy (IgAN). Capsular adhesions without underlying abnormalities in the tuft, often the first sign of FSGS, are frequent in IgAN. In this retrospective study, a new cohort of 128 adult patients with IgAN was used to validate the new Oxford classification system of IgAN, and shown to have highly significant associations with clinical and outcome parameters. We then used these patients to determine the extent to which IgAN could be accounted for in terms of FSGS. Some form of lesion consistent with FSGS, notably hyalinosis and collapsing glomerulopathy, was found in 101 of these patients. No glomerular lesions were found in 16 patients, and 11 had mild lesions not definable as FSGS. Those with FSGS had significantly worse renal survival at 80 months than those without. Comparison of pure forms of FSGS (excluding collapsing glomerulopathy) with cases of FSGS having other glomerular lesions (mesangial hyperplasia, endocapillary hypercellularity, glomerular necroses, extracapillary proliferation) revealed that those with FSGS and other superimposed lesions did significantly worse than cases of pure FSGS at 80 months following diagnosis. Importantly, patients with pure FSGS had relatively poor survival even without other superimposed glomerular abnormalities. Thus, the majority of cases of IgAN can be interpreted as representing one or another variant of FSGS. Hence, interpreting IgAN in terms of FSGS emphasizes the role that podocyte lesions may play in the pathogenesis and progression of this disease.