Rapid decline in estimated glomerular filtration rate in sickle cell anemia: Results of a multicenter pooled analysis

Chronic kidney disease (CKD), typically defined as kidney damage or decreased kidney function for 3 or more months, is common in sickle cell disease (SCD). Increasing evidence suggests that the glomerulopathy of SCD is progressive. CKD is associated with increased mortality in SCD. Based on single center studies, we previously reported on the high prevalence of rapid decline in kidney function, defined as estimated glomerular filtration rate (eGFR) loss >3.0 mL/min/1.73 m2per year, in SCD. In the present study, we further examine rapid eGFR decline in sickle cell anemia, using a pooled analysis of patients to better characterize factors associated with such decline and its association with mortality

Longitudinal study of glomerular hyperfiltration in adults with sickle cell anemia: a multicenter pooled analysis

Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI–2009, 506 patients had baseline estimated GFR (eGFR) $90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR$140 and $130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI–2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P, .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P 5 .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P 5 .001). Using CKD-EPI–2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P, .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P, .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P 5 .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI–2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P 5 .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P 5 .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P 5 .05). Using CKD-EPI–2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P, .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure

Association of Lupus Nephritis Histopathologic Classification With Venous Thromboembolism—Modification by Age at Biopsy

Introduction: Lupus nephritis (LN) is an independent risk factor for venous thromboembolism (VTE). The risk of VTE has not been analyzed by International Society of Nephrology/Renal Pathology Society or World Health Organization LN class. Study goals were to measure VTE incidence in an LN patient cohort, to evaluate associations between VTE and LN class, and to investigate factors modifying associations between VTE and LN class. Methods: A retrospective analysis was performed using Glomerular Disease Collaborative Network data. Image-confirmed VTE was compared between patients with any LN class V lesion and patients with only LN class III or IV. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Effect modification was assessed between main effect and covariates. Results: Our cohort consisted of 534 LN patients, 310 (58%) with class III/IV and 224 (42%) with class V with or without class III/IV, including 106 with class V alone. The VTE incidence was 62 of 534 (11.6%). The odds of VTE were not significantly different between patients with class III/IV and class V in adjusted analyses (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.45−1.48). An age interaction was observed (P = 0.009), with increased odds of VTE with class III/IV diagnosed at a younger age (2.75, 0.90−8.41 estimated at age 16 years) and decreased odds with class III/IV diagnosed at an older age (0.23, 0.07−0.72 estimated at age 46 years), compared to class V. Conclusions: The VTE incidence was similar among patients with LN classes III/IV and V, suggesting that VTE risk is not limited to class V−related nephrotic syndrome and that age may modulate LN class-specific VTE risk

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the nephrotic syndrome study network

Background. Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods. FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results. There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P ¼ 0.02) and mobility (-4.2, P ¼ 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P ¼ 0.009) and anxiety (-2.3, P ¼ 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P ¼ 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (þ9.3, P ¼ 0.03). Conclusions. PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes

Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts: Old concepts revisited

BACKGROUND: Injury to peritubular capillaries and capillary basement membrane multilamination (PTCL) is a hallmark of antibody-mediated chronic renal allograft rejection. However, the predictive diagnostic value of PTCL is incompletely studied. METHODS: We analyzed the diagnostic significance of PTCL and propose diagnostic strategies. We evaluated 360 diagnostic native and 187 transplant kidney specimens by electron microscopy (terminology: PTCL-C, severe; PTCL subgroup C3, very severe multilamination; see Materials and Methods for definitions). RESULTS: PTCL was not pathognomonic for any specific disease. PTCL-C/C3 was rare in native kidneys (C, 6%; C3, 1%), associated mainly with late thrombotic microangiopathy (C: 78%; C3: 11% of cases). In allografts, PTCL-C/C3 was significantly more common, especially in specimens more than 24 months after transplantation (C, 47%; C3, 31%). PTCL-C/C3 was found in acute (C, 20%; C3, 7%) and chronic T-cell rejection (C, 67%; C3, 29%), calcineurin inhibitor toxicity (C, 36%; C3, 18%), or C4d specimens (C, 61%; C3, 50%) with odds ratios between 4 and 36. PTCL-C3 was more predominant in cases with antibody-mediated injury. Highest odds ratios (81-117) for PTCL-C/C3 were noted in combined injuries, that is, mixed chronic T-cell and concurrent chronic antibody-mediated rejection. Positive predictive values of PTCL-C and C3 are the following: all rejection types, 89% and 93%; all Banff chronic rejection types, 69% and 71%; and chronic presumptive antibody rejection, 37% and 49%, respectively. Corresponding negative predictive values of C and C3 for different Banff rejection categories are between 50% and 94%. CONCLUSIONS: The presence of PTCL-C3 is a helpful adjunct finding to diagnose rejection-induced tissue injury but cannot precisely predict the Banff rejection category. Conversely, the absence of PTCL-C3 is helpful in excluding chronic, Banff category II antibody-mediated rejection. Copyright © 2012 by Lippincott Williams &amp; Wilkins