Symptom Burden and Its Impact on Quality of Life in Patients With Moderate to Severe CKD: The International Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).

RATIONALE & OBJECTIVE: Recent evidence suggests substantial burden of symptoms experienced by people with non-dialysis chronic kidney disease (ND-CKD), but informative large-scale studies are scarce. We aimed to assess the prevalence of symptoms, and the association of overall symptom burden with quality of life in patients with moderate to severe CKD. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 4430 patients with ND-CKD stages 3-5 enrolled into the CKDopps Study in Brazil, France, and the US between 2013 and 2021. EXPOSURES: 13 individual patient-reported symptoms from the KDQOL-SF questionnaire and an overall symptom burden score (low, intermediate, and high). OUTCOMES: Physical and mental component summary scores (PCS, MCS) of the KDQOL-SF. ANALYTICAL APPROACH: Adjusted prevalence ratios and generalized estimating equations. RESULTS: Patients (mean age: 68 years; 40% women; mean baseline eGFR: 30 mL/min/1.73m2) were very much to extremely bothered by numerous symptoms ["soreness in muscles" (23%), "washed out or drained" (21%), "cramps, shortness of breath, dry skin, diminished sex life, or numbness in hands or feet" (14-17%)]. The adjusted prevalences of "cramps", "washed out or drained", "lack of appetite", "nausea/upset stomach", and "sex life" were greater with more severe CKD, and, except for "sex life", in women. A high overall symptom burden was more common in women, in France, and in patients with severe albuminuria and various comorbidities, but not with lower eGFR. PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high vs. low overall symptom burden. LIMITATIONS: Generalizability limited to patients under nephrology care, residual confounding and inaccurate Brazilian translation of some symptoms. CONCLUSIONS: The high symptom burden observed in this large cohort of ND-CKD patients across three diverse countries and its strong association with poorer HRQOL should inform clinical management of and clinical research in CKD.

Urine dipstick blood and acute kidney injury in infants undergoing cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with hemolysis and acute kidney injury (AKI). The study aim was to determine if urine dipstick blood in infants after CPB was associated with AKI and urine neutrophil gelatinase-associated lipocalin (NGAL). METHODS: Infants who underwent CPB at a single center were enrolled prospectively between October 2017 and June 2019. Urine samples prior to CPB and 6 h after CPB cessation were analyzed in batch for NGAL and dipstick blood. AKI was defined using creatinine-based KDIGO criteria within 72 h of CPB. Spearman correlation examined associations between urine dipstick blood and NGAL at each time point. Linear regression estimated the associations between urine dipstick blood and log-transformed NGAL 6 h after CPB. Logistic regression estimated associations and compared discrimination between urine dipstick blood and NGAL for predicting AKI. RESULTS: At baseline, 7/63 samples (11%) had > trace blood. Six hours after CPB, 62/98 samples (63%) had > trace blood and 26% had 3 + (large) blood. In total, 18/98 (18%) with a 6-h post-CPB sample had postoperative AKI. Urine dipstick blood values correlated with urine NGAL 6 h after CPB (r = 0.52, p < 0.01), but not at baseline (r = 0.06, p = 0.66). Those with 3 + (large) blood on urine dipstick had 6 times higher mean NGAL values compared to those with negative/trace blood (mean ratio 6.6, 95%CI 3.1-14.4, p < 0.01). Those with 3 + (large) blood had 8 times higher odds of AKI (OR 7.99, 95%CI 1.5-41.9, p = 0.01). CONCLUSIONS: Urine dipstick blood post CPB may be a simple and inexpensive tool to help predict AKI in infants.

Vitamin D supplementation in children and young adults with persistent proteinuria secondary to glomerular disease.

BACKGROUND: Vitamin D deficiency is common in glomerular disease. Supplementation may be ineffective due to ongoing urinary losses of vitamin D binding protein. We sought to determine if daily cholecalciferol supplementation would increase vitamin D concentrations in children with glomerular disease and persistent proteinuria, without adverse effects. METHODS: Eighteen participants at least 5 years of age with primary glomerular disease and urine protein:creatinine ratio ≥ 0.5 were enrolled from four pediatric nephrology practices to receive cholecalciferol supplementation: 4,000 IU or 2,000 IU per day for serum 25 hydroxyvitamin vitamin D (25OHD) concentrations < 20 ng/mL and 20 ng/mL to < 30 ng/mL, respectively. Measures of vitamin D and mineral metabolism were obtained at baseline and weeks 6 and 12. Multivariable generalized estimating equation (GEE) regression estimated mean percent changes in serum 25OHD concentration. RESULTS: Median baseline 25OHD was 12.8 ng/mL (IQR 9.3, 18.9) and increased to 27.8 ng/mL (20.5, 36.0) at week 6 (p < 0.001) without further significant increase at week 12. A total of 31% of participants had a level ≥ 30 ng/mL at week 12. Supplementation was stopped in two participants at week 6 for mildly elevated calcium and phosphorus, respectively, with subsequent declines in 25OHD of > 20 ng/mL. In the adjusted GEE model, 25OHD was 102% (95% CI: 64, 141) and 96% (95% CI: 51, 140) higher versus baseline at weeks 6 and 12, respectively (p < 0.001). CONCLUSION: Cholecalciferol supplementation in vitamin D deficient children with glomerular disease and persistent proteinuria safely increases 25OHD concentration. Ideal dosing to fully replete 25OHD concentrations in this population remains unknown. CLINICAL TRIAL: NCT01835639. A higher resolution version of the Graphical abstract is available as Supplementary information.

Tobacco exposure in adults and children with proteinuric glomerulopathies: a NEPTUNE cohort study.

BACKGROUND: Tobacco exposure has been recognized as a risk factor for cardiovascular disease (CVD) and progression of kidney disease. Patients with proteinuric glomerulopathies are at increased risk for cardiovascular morbidity and mortality. Multiple studies have linked tobacco exposure to CVD and chronic kidney disease, but the relationships between smoking and proteinuric glomerulopathies in adults and children have not been previously explored. METHODS: Data from the Nephrotic Syndrome Study Network (NEPTUNE), a multi-center prospective observational study of participants with proteinuric glomerulopathies, was analyzed. 371 adults and 192 children enrolled in NEPTUNE were included in the analysis. Self-reported tobacco exposure was classified as non-smoker, active smoker, former smoker, or exclusive passive smoker. Baseline serum cotinine levels were measured in a sub-cohort of 178 participants. RESULTS: The prevalence of active smokers, former smokers and exclusive passive smoking among adults at baseline was 14.6%, 29.1% and 4.9%, respectively. Passive smoke exposure was 16.7% among children. Active smoking (reference non-smoking) was significantly associated with greater total cholesterol among adults (ß 17.91 95% CI 0.06, 35.76, p = 0.049) while passive smoking (reference non-smoking) was significantly associated with greater proteinuria over time among children (ß 1.23 95% CI 0.13, 2.33, p = 0.03). Higher cotinine levels were associated with higher baseline eGFR (r = 0.17, p = 0.03). CONCLUSION: Tobacco exposure is associated with greater risk for CVD and worse kidney disease outcomes in adults and children with proteinuric glomerulopathies. Preventive strategies to reduce tobacco exposure may help protect against future cardiovascular and kidney morbidity and mortality in patients with proteinuric glomerulopathies.

Kidney Biopsy Features Most Predictive of Clinical Outcomes in the Spectrum of Minimal Change Disease and Focal Segmental Glomerulosclerosis.

BACKGROUND: Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). METHODS: Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed. RESULTS: Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional-e.g., global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy-and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury. CONCLUSIONS: The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.

Quantification of Glomerular Structural Lesions: Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome.

RATIONALE & OBJECTIVE: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). EXPOSURE: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. OUTCOME: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. ANALYTICAL APPROACH: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. RESULTS: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. LIMITATIONS: Low prevalence of some descriptors and biopsy at a single time point. CONCLUSIONS: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

New insights into acute-on-chronic kidney disease in nephrology patients: the CKD-REIN study.

BACKGROUND: Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants and outcomes in patients with CKD. METHODS: We used the Kidney Disease: Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD Stages 3-5 participating in the CKD-Renal Epidemiology and Information Network cohort study (2013-20), and cause-specific Cox models to estimate hazard ratios [HRs; 95% confidence intervals (CIs)] of AKI-associated risk factors. RESULTS: At baseline, 22% of the patients [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were Stage 2 or 3 and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; and a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8/100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight (<2500 g) (adjusted HR 1.98; 95% CI 1.35-2.91) and haemoglobin level (HR 1.21; 1.12-1.32 per 1 g/dL decrease). Within 1 year, only 63% of the patients had recovered their previous kidney function, 13.7% had started kidney replacement therapy and 12.7% had died. CONCLUSIONS: The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anaemia as possible new risk factors in CKD patients.

Assessment of a computerized quantitative quality control tool for whole slide images of kidney biopsies.

Inconsistencies in the preparation of histology slides and whole-slide images (WSIs) may lead to challenges with subsequent image analysis and machine learning approaches for interrogating the WSI. These variabilities are especially pronounced in multicenter cohorts, where batch effects (i.e. systematic technical artifacts unrelated to biological variability) may introduce biases to machine learning algorithms. To date, manual quality control (QC) has been the de facto standard for dataset curation, but remains highly subjective and is too laborious in light of the increasing scale of tissue slide digitization efforts. This study aimed to evaluate a computer-aided QC pipeline for facilitating a reproducible QC process of WSI datasets. An open source tool, HistoQC, was employed to identify image artifacts and compute quantitative metrics describing visual attributes of WSIs to the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository. A comparison in inter-reader concordance between HistoQC aided and unaided curation was performed to quantify improvements in curation reproducibility. HistoQC metrics were additionally employed to quantify the presence of batch effects within NEPTUNE WSIs. Of the 1814 WSIs (458 H&E, 470 PAS, 438 silver, 448 trichrome) from n = 512 cases considered in this study, approximately 9% (163) were identified as unsuitable for subsequent computational analysis. The concordance in the identification of these WSIs among computational pathologists rose from moderate (Gwet's AC1 range 0.43 to 0.59 across stains) to excellent (Gwet's AC1 range 0.79 to 0.93 across stains) agreement when aided by HistoQC. Furthermore, statistically significant batch effects (p < 0.001) in the NEPTUNE WSI dataset were discovered. Taken together, our findings strongly suggest that quantitative QC is a necessary step in the curation of digital pathology cohorts. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia.

BACKGROUND: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. METHODS: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. RESULTS: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. CONCLUSIONS: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

Development and evaluation of deep learning-based segmentation of histologic structures in the kidney cortex with multiple histologic stains.

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

International Comparisons of Native Arteriovenous Fistula Patency and Time to Becoming Catheter-Free: Findings From the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Optimizing vascular access use is crucial for long-term hemodialysis patient care. Because vascular access use varies internationally, we examined international differences in arteriovenous fistula (AVF) patency and time to becoming catheter-free for patients receiving a new AVF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,191 AVFs newly created in 2,040 hemodialysis patients in 2009 to 2015 at 466 randomly selected facilities in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from the United States, Japan, and EUR/ANZ (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand). PREDICTORS: Demographics, comorbid conditions, dialysis vintage, body mass index, AVF location, and country/region. OUTCOMES: Primary/cumulative AVF patency (from creation), primary/cumulative functional patency (from first use), catheter dependence duration, and mortality. ANALYTICAL APPROACH: Outcomes estimated using Cox regression. RESULTS: Across regions, mean patient age ranged from 61 to 66 years, with male preponderance ranging from 55% to 66%, median dialysis vintage of 0.3 to 3.2 years, with 84%, 54%, and 32% of AVFs created in the forearm in Japan, EUR/ANZ, and United States, respectively. Japan displayed superior primary and cumulative patencies due to higher successful AVF use, whereas cumulative functional patency was similar across regions. AVF patency associations with age and other patient characteristics were weak or varied considerably between regions. Catheter-dependence following AVF creation was much longer in EUR/ANZ and US patients, with nearly 70% remaining catheter dependent 8 months after AVF creation when AVFs were not successfully used. Not using an arteriovenous access within 6 months of AVF creation was related to 53% higher mortality in the subsequent 6 months. LIMITATIONS: Residual confounding. CONCLUSIONS: Our findings highlight the need to reevaluate practices for optimizing long-term access planning and achievable AVF outcomes, especially AVF maturation. New AVFs that are not successfully used are associated with long-term catheter exposure and elevated mortality risk. These findings highlight the importance of selecting the best access type for each patient and developing effective clinical pathways for when AVFs fail to mature successfully.

Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia.

BACKGROUND: Iron deficiency (ID) is a common condition in nondialysis-dependent chronic kidney disease (NDD-CKD) patients that is associated with poorer clinical outcomes. However, the effect of ID on health-related quality of life (HRQoL) in this population is unknown. We analyzed data from a multinational cohort of NDD-CKD Stages 3-5 patients to test the association between transferrin saturation (TSAT) index and ferritin with HRQoL. METHODS: Patients from Brazil (n = 205), France (n = 2015) and the USA (n = 293) in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps, 2013-2019) were included. We evaluated the association of TSAT and ferritin (and functional and absolute ID, defined as TSAT ≤20% and ferritin ≥300 or <50 ng/mL) on pre-specified HRQoL measures, including the 36-item Kidney Disease Quality of Life physical component summary (PCS) and mental component summary (MCS) as the primary outcomes. Models were adjusted for confounders including hemoglobin (Hb). RESULTS: TSAT ≤15% and ferritin <50 ng/mL and ≥300 ng/mL were associated with worse PCS scores, but not with MCS. Patients with composite TSAT ≤20% and ferritin <50 or ≥300 ng/mL had lower functional status and worse PCS scores than those with a TSAT of 20-30% and ferritin 50-299 ng/mL. Patients with a lower TSAT were less likely to perform intense physical activity. Adjustment for Hb only slightly attenuated the observed effects. CONCLUSIONS: Low TSAT levels, as well as both low TSAT with low ferritin and low TSAT with high ferritin, are associated with worse physical HRQoL in NDD-CKD patients, even after accounting for Hb level. Interventional studies of iron therapy on HRQoL among NDD-CKD individuals are needed to confirm these findings.

Association between Dipeptidyl Peptidase-4 Inhibitor Prescription and Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients with Diabetes Mellitus.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). METHODS: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4-6 (2009-2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin <10 and mean ESA dose >6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. RESULTS: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. CONCLUSION: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

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.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)-related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non-haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients. METHODS: The study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phase 5 (2012-2015). The outcome was erythropoiesis-stimulating agent hyporesponsiveness (ESA-hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA-hypo and FGF23 was estimated using multivariable-adjusted logistic generalized estimating equation regression models. RESULTS: Patients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin-corrected calcium, phosphorus, PTH, 25(OH)-vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA-hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA-hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively. CONCLUSION: The lowest and highest levels of FGF23 were associated with higher odds of ESA-hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA-hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Ultrastructural Characterization of Proteinuric Patients Predicts Clinical Outcomes.

BACKGROUND: The analysis and reporting of glomerular features ascertained by electron microscopy are limited to few parameters with minimal predictive value, despite some contributions to disease diagnoses. METHODS: We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) from the Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring System. Study pathologists scored 12 descriptors in NEPTUNE renal biopsies from 242 patients with minimal change disease or FSGS, with duplicate readings to evaluate reproducibility. We performed consensus clustering of patients to identify unique electron microscopy profiles. For both individual descriptors and clusters, we used Cox regression models to assess associations with time from biopsy to proteinuria remission and time to a composite progression outcome (≥40% decline in eGFR, with eGFR<60 ml/min per 1.73 m2, or ESKD), and linear mixed models for longitudinal eGFR measures. RESULTS: Intrarater and interrater reproducibility was >0.60 for 12 out of 12 and seven out of 12 descriptors, respectively. Individual podocyte descriptors such as effacement and microvillous transformation were associated with complete remission, whereas endothelial cell and glomerular basement membrane abnormalities were associated with progression. We identified six descriptor-based clusters with distinct electron microscopy profiles and clinical outcomes. Patients in a cluster with more prominent foot process effacement and microvillous transformation had the highest rates of complete proteinuria remission, whereas patients in clusters with extensive loss of primary processes and endothelial cell damage had the highest rates of the composite progression outcome. CONCLUSIONS: Systematic analysis of electron microscopic findings reveals clusters of findings associated with either proteinuria remission or disease progression.

Chronic kidney disease progression and mortality risk profiles in Germany: results from the Chronic Kidney Disease Outcomes and Practice Patterns Study.

BACKGROUND: Chronic kidney disease (CKD) progression among German patients in a representative setting has not been described previously. The Verband Deutsche Nierenzentren and Chronic Kidney Disease Outcomes and Practice Patterns Study established a longitudinal observational cohort among German CKD patients to research variations in patient care and outcomes in real-world nephrology practices. METHODS: A cohort of CKD Stages 3 (25%) and 4 (75%) patients was established from German nephrologist-run CKD clinics in 2013-16. Linear models were used to determine the estimated glomerular filtration rate (eGFR) slope during follow-up and Cox models were used to assess outcomes of end-stage kidney disease (ESKD) and death. RESULTS: A total of 1834 patients (median age 75 years, 58% male, 42% diabetics, median baseline eGFR 25 mL/min/1.73 m2) were followed for a median of 29 months. More than 50% had slow or no decline and 17% declined ≥5 mL/min/1.73 m2/year. After 4.5 years, the incidence of ESKD was 8% and of deaths without ESKD 16% among patients with eGFR ≥30 mL/min/1.73 m2 and 37% and 19% for eGFR <30 mL/min/1.73 m2. Adjusted models showed higher risks of ESKD or death for patients with worse kidney function at baseline, male sex, diabetes and higher blood pressure; a higher risk of ESKD with higher albuminuria; and a higher risk of death with older age or cardiovascular comorbidity. CONCLUSIONS: Routine nephrology care of patients in Germany comprises mostly elderly patients, many with slow CKD progression. Identification of risk factors for CKD progression and mortality may help guide resources by closer follow-up of high-risk patients.

Physical health-related quality of life at higher achieved hemoglobin levels among chronic kidney disease patients: a systematic review and meta-analysis.

BACKGROUND: The impact of anemia treatment with erythropoietin stimulating agents (ESA) on health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients is controversial, particularly regarding optimal hemoglobin (Hb) target ranges. METHODS: We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) with ESA to estimate the effect of different achieved Hb values on physical HRQOL and functionality. We searched PubMed, EMBASE, CENTRAL, PEDro, PsycINFO and Web of Science databases, until May 2020. Two authors independently extracted data from studies. We included observational and RCTs that enrolled CKD patients undergoing anemia treatment with ESA with different achieved Hb levels among groups. We excluded studies with achieved Hb < 9 g/dL. For the meta-analysis, we included RCTs with control groups achieving Hb 10-11.5 g/dL and active groups with Hb > 11.5 g/dL. We analyzed the standardized mean difference (SMD) between groups for physical HRQOL. RESULTS: Among 8496 studies, fifteen RCTs and five observational studies were included for the systematic review. We performed the meta-analysis in a subset of eleven eligible RCTs. For physical role and physical function, SMDs were 0.0875 [95% CI: - 0.0025 - 0.178] and 0.08 [95% CI: - 0.03 - 0.19], respectively. For fatigue, SMD was 0.16 [95% CI: 0.09-0.24]. Subgroup analysis showed that trials with greater achieved Hb had greater pooled effects sizes - 0.21 [95% CI: 0.07-0.36] for Hb > 13 g/dL vs. 0.09 [95% CI: 0.02-0.16] for Hb 11.5-13 g/dL. Proportion of older and long-term diabetic patients across studies were associated with lower effect sizes. CONCLUSION: Achieved hemoglobin higher than currently recommended targets may be associated with small but potentially clinically significant improvement in fatigue, but not in physical role or physical function. Younger and non-diabetic patients may experience more pronounced benefits of higher Hb levels after treatment with ESAs.

Associations of Hemoglobin Levels With Health-Related Quality of Life, Physical Activity, and Clinical Outcomes in Persons With Stage 3-5 Nondialysis CKD.

OBJECTIVE: Conflicting findings and knowledge gaps exist regarding links between anemia, physical activity, health-related quality of life (HRQOL), chronic kidney disease (CKD) progression, and mortality in moderate-to-advanced CKD. Using the CKD Outcomes and Practice Patterns Study, we report associations of hemoglobin (Hgb) with HRQOL and physical activity, and associations of Hgb and physical activity with CKD progression and mortality in stage 3-5 nondialysis (ND)-CKD patients. DESIGN AND METHODS: Prospectively collected data were analyzed from 2,121 ND-CKD stage 3-5 patients, aged ≥18 years, at 43 nephrologist-run US and Brazil CKD Outcomes and Practice Patterns Study-participating clinics. Cross-sectional associations were assessed of Hgb levels with HRQOL and physical activity levels (from validated Kidney Disease Quality of Life Instrument and Rapid Assessment of Physical Activity surveys). CKD progression (first of ≥40% estimated glomerular filtration rate [eGFR] decline, eGFR<10 mL/min/1.73 m2, or end-stage kidney disease) and all-cause mortality with Hgb and physical activity levels were also evaluated. Linear, logistic, and Cox regression analyses were adjusted for country, demographics, smoking, eGFR, serum albumin, very high proteinuria, and 13 comorbidities. RESULTS: HRQOL was worse, with severe anemia (Hgb<10 g/dL), but also evident for mild/moderate anemia (Hgb 10-12 g/dL), relative to Hgb>12 g/dL. Odds of being highly physically active were substantially greater at Hgb>10.5 g/dL. Lower Hgb was strongly associated with greater CKD progression and mortality, even after extensive adjustment. Physical inactivity was strongly associated with greater mortality and weakly associated with CKD progression. Possible residual confounding is a limitation. CONCLUSION: This multicenter international study provides real-world observational evidence for greater HRQOL, physical activity, lower CKD progression, and greater survival in ND-CKD patients with Hgb levels >12 g/dL, exceeding current treatment guideline recommendations. These findings help inform future studies aimed at understanding the impact of new anemia therapies and physical activity regimens on improving particular dimensions of ND-CKD patient well-being and clinical outcomes.

Using All Longitudinal Data to Define Time to Specified Percentages of Estimated GFR Decline: A Simulation Study.

RATIONALE & OBJECTIVE: The standard method to calculate time to the event of a specified percentage decline in estimated glomerular filtration rate (eGFR) uses 2 eGFR assessments, 1 at baseline and 1 at the event time. However, event times may be inaccurate due to eGFR variability and restriction of events to study visit times. We propose a novel method for calculating time to a specified percentage decline in eGFR that uses all available longitudinal eGFR assessments. STUDY DESIGN: Simulation study and comparison of methods in 2 observational cohorts. SETTINGS & PARTICIPANTS: Simulation data and study participants in the Nephrotic Syndrome Study Network (NEPTUNE) and Clinical Phenotyping and Resource Biobank Core (C-PROBE). EXPOSURE: Analytical method for calculating time to a specified percentage decline in eGFR: standard 2-point method versus a regression method incorporating all available longitudinally assessed eGFR assessments. OUTCOME: Time to percentage decline in eGFR. ANALYTIC APPROACH: A 2-point method used only the baseline eGFR and first eGFR below the decline threshold. The comparison method used ordinary linear regression incorporating all longitudinal eGFR assessments to define the baseline measure and 40% decline threshold. Time to a 40% decline in eGFR was defined as the time when the regression line crossed the decline threshold. The 2 outcome calculation methods were compared using simulations to assess the accuracy of estimated event times and power to detect event time differences between groups. Comparison of event times calculated using each method was also implemented using data from NEPTUNE and C-PROBE. RESULTS: The regression method incorporating all eGFR assessments was more accurate than the 2-point method in estimating event times in simulation analyses, particularly when eGFR variability was high, there was a greater correlation among successive eGFR values, or there were more missing data. This method was also more powerful in detecting differences between groups. Using NEPTUNE and C-PROBE data, the standard method estimated a more rapid rate of events, some likely representing transient reductions in kidney function, and was less likely to give accurate estimates in the presence of nonlinear eGFR trajectories. LIMITATIONS: Computations required for our proposed method currently limit its use to research rather than clinical applications. CONCLUSIONS: A regression method using all longitudinal eGFR values to estimate time to a percentage decline in eGFR increases accuracy and power over traditional methods, representing a potential improvement in the ability to discover treatment or biomarker effects on kidney disease progression.