Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Incidence of and Risk Factors for Active Tuberculosis Disease in Individuals With Glomerular Disease: A Canadian Cohort Study.

RATIONALE & OBJECTIVE: Kidney failure is an established risk factor for active tuberculosis (TB) but the risk of TB has not been reported in specific kidney diseases. We sought to determine the incidence of and risk factors for active TB in patients with glomerular disease. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A provincial kidney pathology registry (2000-2012) was used to identify 3,079 adult patients with IgA nephropathy, focal segmental glomerulosclerosis (FSGS), antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis, lupus nephritis, membranous nephropathy, minimal change disease, or "other" glomerular diseases in British Columbia, Canada. EXPOSURE: Predictors included demographics, immigration status, comorbidities, immunosuppression use, estimated glomerular filtration rate (eGFR), and proteinuria. OUTCOME: A diagnosis of active TB was ascertained using administrative data linkages and defined based on (1) the dispensation of 1 or more unique combinations of medications used to treat active TB, or (2) physician or hospital visits for active TB. ANALYTICAL APPROACH: The definition of TB was validated in an external cohort linked to the Provincial TB registry at the BC Centre for Disease Control (BCCDC). Standardized incidence ratios were calculated using the age-matched general population. Risk factors for active TB were identified using Cox proportional hazards regression analysis. RESULTS: The sensitivity and specificity of the outcome definition of active TB were 87.6% and 99.5%, respectively. During a median follow-up of 6.2 years, 41 patients developed active TB with an incidence of 197 of 100,000 person-years, approximately 23 times as high as the general population and>6 times higher than the threshold of 30 per 100,000 used to define high TB incidence. A high incidence was observed in all glomerular diseases (range, 110-403 per 100,000), in both Canadian- and foreign-born patients (range, 124-424 per 100,000), and in patients exposed or not to immunosuppression (282 vs 147 per 100,000). Factors associated with higher TB risk included immigration from a high-incidence country (HR, 3.90 [95% CI, 1.75-8.68]), diminished eGFR (HR, 2.81 [95% CI, 1.18-6.69]), higher levels of proteinuria (HR, 1.15 [95% CI, 1.04-1.27]), lupus nephritis (HR, 2.79 [95% CI, 1.37-5.68]), and immunosuppression use (HR, 2.13 [95% CI, 1.13-4.03]). LIMITATIONS: A relatively low number of events contributed to uncertainty in risk estimates. CONCLUSIONS: Patients with glomerular disease have a high incidence of active TB irrespective of disease type, demographics, or use of immunosuppression. Prospective studies are needed to evaluate the utility of screening for latent TB infection in this population. PLAIN-LANGUAGE SUMMARY: Patients with kidney failure are at high risk of developing tuberculosis (TB), a major infection that can be prevented by identifying and treating patients who have had prior exposure to TB. The risk of TB in specific kidney diseases is unknown. In this Canadian study of 3,079 patients with glomerular disease, a group of autoimmune kidney conditions, the rate of TB was 23 times higher than in the general population. The rate was high irrespective of the use of immunosuppressive drugs or whether patients had immigrated to Canada from another country. These findings suggest that screening patients with glomerular disease for prior TB exposure may be beneficial; however, this needs to be evaluated in a prospective study.

Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy.

BACKGROUND: The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. METHODS: We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ). RESULTS: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67). CONCLUSIONS: In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.

Albuminuria post-liver transplant is a predictor of kidney disease progression and mortality.

BACKGROUND: Albuminuria is a marker of chronic kidney disease (CKD) associated with an increased risk of end-stage kidney disease (ESKD) and mortality in the general population, but it is uncertain whether the same association exists in liver transplant (LT) recipients. This study examined the association between albuminuria and kidney failure and mortality in LT recipients.METHODS: Retrospective cohort study of 294 adults who received a LT between January 1, 1989, and December 31, 2011, in British Columbia, Canada. Cox multivariable regression was used to determine the association between ACR and a primary combined outcome of mortality, doubling of serum creatinine, or ESKD; and a secondary outcome of a decrease in estimated glomerular filtration rate (eGFR) ≥30%. RESULTS: At baseline, mean eGFR was 67 (SD 20.9) mL/min/1.73 m2, and 10% had severe albuminuria (ACR >30 mg/mmol). The primary outcome occurred in 20.4% (60) of patients and was associated with ACR >30 mg/mmol (HR 2.77, 95% CI 1.28-6.04; P = 0.01). A decline in eGFR ≥30% occurred in 21.8% (64) of patients, and was associated with ACR >30 mg/mmol (HR 4.77, 95% CI 2.31-9.86; P < 0.0001). CONCLUSIONS: Severe albuminuria (ACR >30 mg/mmol) was associated with an increased risk of loss of kidney function and mortality after LT. Prospective studies are needed to determine if specific interventions directed at reducing albuminuria can improve long-term outcomes in LT recipients.

Improving treatment decisions using personalized risk assessment from the International IgA Nephropathy Prediction Tool.

Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Socioeconomic Position and Incidence of Glomerular Diseases.

BACKGROUND AND OBJECTIVES: Social deprivation is a recognized risk factor for undifferentiated CKD; however, its association with glomerular disease is less well understood. We sought to investigate the relationship between socioeconomic position and the population-level incidence of biopsy-proven glomerular diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective cohort study, a provincial kidney pathology database (2000-2012) was used to capture all incident cases of membranous nephropathy (n=392), IgA nephropathy (n=818), FSGS (n=375), ANCA-related GN (ANCA-GN, n=387), and lupus nephritis (n=389) in British Columbia, Canada. Quintiles of area-level household income were used as a proxy for socioeconomic position, accounting for regional differences in living costs. Incidence rates were direct standardized to the provincial population using census data for age and sex and were used to generate standardized rate ratios. For lupus nephritis, age standardization was performed separately in men and women. RESULTS: A graded increase in standardized incidence with lower income was observed for lupus nephritis (P<0.001 for trend in both sexes) and ANCA-GN (P=0.04 for trend). For example, compared with the highest quintile, the lowest income quintile had a standardized rate ratio of 1.7 (95% confidence interval, 1.19 to 2.42) in women with lupus nephritis and a standardized rate ratio of 1.5 (95% confidence interval, 1.09 to 2.06) in ANCA-GN. The association between income and FSGS was less consistent, in that only the lowest income quintile was associated with a higher incidence of disease (standardized rate ratio, 1.55; 95% confidence interval, 1.13 to 2.13). No significant associations were demonstrated for IgA nephropathy or membranous nephropathy. CONCLUSIONS: Using population-level data and a centralized pathology database, we observed an inverse association between socioeconomic position and the standardized incidence of lupus nephritis and ANCA-GN.

Disease-specific incident glomerulonephritis displays geographic clustering in under-serviced rural areas of British Columbia, Canada.

There is little known about geographic variability in the incidence of glomerular disease and its potential implications for care delivery. To evaluate this, we performed a population-level cohort study using a provincial renal pathology database (2000-2012) to capture all incident cases of glomerulonephritis in British Columbia, Canada. This included 401 patients with membranous nephropathy (MN), 824 patients with IgA nephropathy (IgAN), 385 patients with focal segmental glomerulosclerosis (FSGS), 397 patients with lupus nephritis (LN) and 399 patients with ANCA-related glomerulonephritis (ANCA-GN). Geographic clusters were identified using Bayesian spatial models to estimate the incidence of each disease in 74 regions compared to the mean incidence in the entire province (incidence rate ratio, [IRR]), adjusted for region-level age, sex and race. The proportion of overall variability in incidence attributed to inter-regional differences varied by disease: 18% in MN, 81% in IgAN, 18% in FSGS, 59% in ANCA-GN, and 89% in LN. Except for LN, clustering was not explained by demographics. All IgAN and LN clusters were in urban regions close to nephrology centers, whereas ANCA-GN, MN and FSGS clustered mainly in rural regions. All ANCA-GN clusters were rural with median population density 1.2 persons/km2 and driving distances of 10-676 km to the nearest nephrology center. Thus, we found significant geographic clustering in the incidence of different glomerular diseases. MN, FSGS and ANCA-GN clustered in sparsely populated regions with limited access to care, underscoring the importance of regional variability in glomerular diseases to inform health services delivery.