Faculty Bibliography

RATIONALE & OBJECTIVE/OBJECTIVE:Albuminuria is a predictor of adverse health outcomes. Early detection enables timely clinical management, yet little is known about how clinicians respond to newly detected albuminuria in routine practice. This study sought to characterize clinical care processes for patients with newly detected albuminuria. STUDY DESIGN/METHODS:Retrospective, population-based cohort study. SETTING & PARTICIPANTS/METHODS:215,035 adults with newly detected albuminuria between 2010 and 2021 in Stockholm, Sweden. EXPOSURES/METHODS:Albuminuria severity, categorized as moderate (≥30-299 mg/g), severe (300-999 mg/g), or very severe (≥1000 mg/g). All methods of albuminuria testing were considered: dipstick albuminuria or proteinuria tests as well as 24-h and spot albumin concentrations. OUTCOMES/RESULTS:Proportion of patients re-tested for albuminuria, frequency of the methods used for re-testing, rates of nephrology referral, and rates of initiation of treatment with renin-angiotensin system or sodium-glucose cotransporter-2 inhibitors. ANALYTICAL APPROACH/METHODS:Descriptive analysis of proportions and cumulative incidence of outcomes based on time-to-event analysis accounting for the competing risks of death and kidney failure. RESULTS:90% of participants had moderate, 8% had severe, and 2% had very severe albuminuria. Re-testing rates within one year were 46%, ranging from 45% for moderate albuminuria to 70% for very severe albuminuria, with lower rates among individuals without diabetes. Only 28% of those with an indication were referred to a nephrologist, and renin-angiotensin system/sodium-glucose cotransporter-2 inhibitor initiation rates at one year were 10%, 12%, and 37% for moderate, severe, and very severe albuminuria, respectively, with substantially lower rates in individuals without diabetes. LIMITATIONS/CONCLUSIONS:The findings are specific to Stockholm's healthcare system and may not be generalizable to other regions, healthcare models, or cultures. CONCLUSIONS:This study identified important care gaps in the Swedish management of albuminuria. A substantial proportion of individuals, including those with very severe albuminuria, lacked monitoring and failed to receive antiproteinuric treatments. Strategies to improve clinician awareness and adherence to guideline-recommended care may mitigate the long-term consequences of chronic kidney disease progression.

IMPORTANCE/UNASSIGNED:Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear. OBJECTIVES/UNASSIGNED:To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes. DATA SOURCES/UNASSIGNED:Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC). STUDY SELECTION/UNASSIGNED:Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. RESULTS/UNASSIGNED:A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

BACKGROUND:Although numerous biological processes have been implicated in Alzheimer's disease (AD) pathogenesis, plasma biomarkers have been largely limited to measures of amyloid-b and p-tau. We used a large-scale plasma and brain tissue proteomic analyses to (i) identify early plasma biomarkers of AD and (ii) assess the mechanistic relevance of identified proteins. METHOD/METHODS:We applied the SomaScan proteomic platform to measure the abundance of 4,877 plasma proteins among middle-aged adults in the ARIC study. Dementia was assessed over the subsequent 25-year period. Cox proportional hazards models adjusted for demographic characteristics and cardiovascular risk factors were used to relate each plasma protein to 25-year dementia risk. Using brain tissue proteomic results from the ROSMAP cohort, we (i) examined the extent to which identified proteins were differentially expressed in AD, (ii) identified brain tissue protein quantitative trait loci (pQTL), and (iii) used two-sample Mendelian randomization to assess the causal link between candidate plasma proteins and AD dementia. RESULT/RESULTS:In proteome-wide analyses of 10,981 adults (baseline age: 60 (SD 6); 21% Black; 54% women), we identified 32 plasma proteins associated with subsequent dementia risk, most of which were involved in biological processes such as proteostasis, immunity, extracellular matrix organization, and synaptic function (CPLX1, CPLX2, CBLN4). Synaptic proteins CPLX1 and CPLX2 were upregulated in plasma among those at risk for dementia over a 25-year follow-up period, whereas CBLN was down-regulated among individuals at risk for dementia over a 15-year follow-up period. While the majority of the 32 dementia-associated proteins were expressed across multiple tissue, synaptic proteins were primarily expressed in the central nervous system (CNS), and each synaptic protein was down-regulated in AD brains, compared to control brains. Brain tissue pQTLs were identified for CPLX1. Two-sample Mendelian randomization supported the causal link between brain CPLX1 levels and AD dementia (Z=2.13; p = 0.03). CONCLUSION/CONCLUSIONS:These results suggest that synaptic proteins are released from the CNS into the blood well before symptom onset. Synaptic proteins measured in blood, such as CPLX1, may represent mechanistically relevant biomarkers of AD dementia risk.

Recognizing kidney disease as a major global health issue, the International Society of Nephrology convened a 2-day international, multi-stakeholder meeting to develop a road map for advancing clinical research in nephrology. The meeting focused on promoting the use of patient-reported outcome measures, moving beyond single biomarker targets, adopting innovative trial designs, and incorporating hierarchical composite end points. Participants included clinicians, trialists, regulators, patient partners, and industry experts invited from all International Society of Nephrology regions. Discussions emphasized the importance of inclusive trial design, validation of patient-reported outcome measures, predictive enrichment strategies, and broader trial accessibility across resource settings. Key recommendations included enhancing diversity in trial populations, avoiding overreliance on isolated biomarkers, adopting novel study designs, strengthening public-private partnerships, and validating composite end points. A coordinated effort was deemed essential to implement these strategies in both research and practice, ensuring sustainable progress and reducing the global burden of kidney disease.

BACKGROUND:Prior prediction equations for heart failure (HF) omitted cardiac biomarkers and used select populations. We assessed the added value of NT-proBNP (NT-terminal pro-brain natriuretic peptide) and hsTnT (high-sensitivity troponin T) as predictors of HF, across a broad population, including participants with chronic kidney disease or atherosclerotic cardiovascular disease. METHODS:Among 41 427 individuals free of HF from 9 prospective cohort studies, we performed an individual-participant data meta-analysis, quantifying the associations of NT-proBNP and hsTnT with incident HF when added to a clinical model. Changes in Harrel's C-statistic with and without NT-proBNP or hsTnT were estimated within each cohort and then pooled using random effects meta-analysis. RESULTS:<0.001). CONCLUSIONS:NT-proBNP improved risk discrimination of incident HF when added to traditional HF risk factors, even in individuals with chronic kidney disease and atherosclerotic cardiovascular disease. The contribution of hsTnT was modest. Measurement of NT-proBNP may help identify individuals at risk of HF.

RATIONALE & OBJECTIVE/UNASSIGNED:Acute kidney injury (AKI) is associated with prolonged hospitalization and increased in-hospital mortality risk. However, the prediction of incident AKI is inaccurate, and additional predictors of AKI are strongly needed. Arterial stiffness, as measured using carotid-femoral pulse wave velocity (cfPWV), is associated with kidney function decline and may serve as a plausible predictor of AKI. We hypothesized a higher cfPWV at baseline would be independently associated with AKI risk in community-dwelling older adults who participated in the Atherosclerosis Risk in Communities study. STUDY DESIGN/UNASSIGNED:Observational cohort study. SETTING & PARTICIPANTS/UNASSIGNED:Community-dwelling older adults from the Atherosclerosis Risk in Communities study. PREDICTORS/UNASSIGNED:The primary predictor was cfPWV and secondary predictors were heart-femoral pulse wave velocity (PWV), heart-carotid PWV, heart-ankle PWV, and brachial-ankle PWV, and femoral-ankle PWV. OUTCOMES/UNASSIGNED:Time to AKI, defined by International Classification of Diseases (ICD) codes. ANALYTICAL APPROACH/UNASSIGNED:Cox proportional hazard models were used to examine the association between PWV measures and time to AKI. Given its J-shaped relation with AKI, PWV was modeled as a categorical variable in quartiles (Q), with Q2 serving as the reference category. RESULTS/UNASSIGNED:A total of 4,245 participants (44% male; 77% White; mean ± SD age 75 ± 5 years; cfPWV 11.9 ± 3.9 m/s) were included. There was a J-shaped association between cfPWV and AKI risk (Q1, hazard ratio 1.15 [95% confidence interval 0.90-1.46]; Q4, 1.38 [1.08-1.77] vs Q2 reference) after fully adjusting for demographics, cardiovascular disease risk factors, and markers for kidney function and peripheral artery disease. LIMITATIONS/UNASSIGNED:Most of the participants were White; and AKI was defined based on ICD codes. CONCLUSIONS/UNASSIGNED:Higher arterial stiffness, measured by cfPWV, may potentially serve as a predictor of AKI risk in community-dwelling older adults.

BACKGROUND:Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results. METHODS:This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure. RESULTS:Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06-1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis. DISCUSSION/CONCLUSIONS:Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

In people of African ancestry, apolipoprotein L1 gene (APOL1) variants have been identified as causing increased risk of progressive chronic kidney disease (CKD). In April of 2024, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on APOL1 Kidney Disease in Accra, Ghana. The goals of the conference were to review and discuss current evidence and controversies on APOL1 kidney disease, including naming, epidemiology, pathophysiology, APOL1 testing, treatment, and future research needs. Participants considered various terminologies for diseases related to APOL1 risk variants (such as APOL1-mediated or -induced kidney disease) and had highest support for using APOL1 kidney disease to describe kidney pathologies associated with the APOL1 G1 and G2 risk variants. Clinically, the term APOL1 kidney disease can be used on its own or as an overall category of kidney disease, with further specification added as needed (for example, APOL1 kidney disease, focal segmental glomerulosclerosis). Given that there currently are no established treatments for APOL1 kidney disease, and APOL1 genotype results are not by themselves actionable, there is insufficient evidence to guide recommendations for APOL1 population screening or routine testing. However, genotyping can be an important clinical consideration for individuals to inform risk stratification, frequency of follow-up, living kidney donation, as well as clinical trial eligibility. Key areas of need and strategies for future research were delineated and are reported here.

Obesity and chronic kidney disease (CKD) are complex diseases that are interlinked directly and indirectly. In October 2024, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference on obesity and CKD to examine the most recent evidence regarding the epidemiology, pathophysiology, and treatment of obesity and CKD as well as to articulate priorities for research. A key conference theme was increasing awareness of obesity-related CKD. Long-term, early-onset obesity and prolonged exposure to obesity carry the highest risk of developing CKD. Identifying early biomarkers of kidney dysfunction and refining assessment methods in the context of obesity could provide opportunities for preventing loss of kidney function. The foundation for managing obesity in CKD comprises modifications to diet, physical activity level, and behaviors related to both. However, these strategies can be unsuccessful in achieving or maintaining weight loss for a myriad of reasons. Pharmacotherapies, such as those including glucagon-like peptide-1 receptor agonists, are effective in weight reduction and have been shown to have kidney-protective and cardiovascular benefits. Metabolic and bariatric surgery has also demonstrated benefits in reducing obesity-related complications. Appropriateness and choice of management strategies will vary depending on age and comorbidities and may change over time. Patient-lead goal setting is a foundation for dietary and physical activity interventions focusing on incremental, achievable changes toward healthy eating and an active lifestyle. Health care professionals require training to deliver these interventions and provide ongoing support with positive messaging using nonjudgmental, stigma-free language. Evaluating the optimal duration of therapy, long-term safety of novel pharmacotherapies, and therapies in the context of early and later stages of CKD is a key priority for research. Multidisciplinary collaboration is important both for optimizing patient care and for advancing research.