Faculty Bibliography

The timely and rational institution of therapy is a key step towards reducing the global burden of chronic kidney disease (CKD). CKD is a heterogeneous entity with varied aetiologies and diverse trajectories, which include risk of kidney failure but also cardiovascular events and death. Developments in the past decade include substantial progress in CKD risk prediction, driven in part by the accumulation of electronic health records data. In addition, large randomized clinical trials have demonstrated the effectiveness of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists in reducing adverse events in CKD, greatly expanding the options for effective therapy. Alongside angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, these classes of medication have been proposed to be the four pillars of CKD pharmacotherapy. However, all of these drug classes are underutilized, even in individuals at high risk. Leveraging prognostic estimates to guide therapy could help clinicians to prescribe CKD-related therapies to those who are most likely to benefit from their use. Risk-based CKD management thus aligns patient risk and care, allowing the prioritization of absolute benefit in determining therapeutic selection and timing. Here, we discuss CKD prognosis tools, evidence-based management and prognosis-guided therapies.

KEY POINTS:In diabetes and CKD, creatinine- and cystatin C–based eGFR has a strong inverse correlation with plasma TNF receptor 1, TNF receptor 2, and soluble urokinase-type plasminogen activator receptor. Higher plasma soluble TNF receptors 1 and 2 and soluble urokinase-type plasminogen activator receptor were each individually associated with mortality, independent of baseline kidney measures. BACKGROUND:Several plasma biomarkers of kidney health have been associated with CKD progression in persons with diabetes, but their associations with mortality risk have been largely unexplored. METHODS:from the REGARDS cohort study, Cox proportional hazards regression was used to determine hazard ratios of mortality by plasma concentrations of soluble TNF receptors 1 and 2 (TNFR1 and TNFR2), soluble urokinase-type plasminogen activator receptor (suPAR), kidney injury molecule 1 (KIM-1), chitinase 3–like 1 (YKL-40), and monocyte chemotactic protein 1 (MCP-1). Covariates included sociodemographic and clinical factors, urine albumin-to-creatinine ratio (UACR), and creatinine- and cystatin C–based eGFR (eGFRcr-cys). RESULTS:=−0.10 to −0.40). With a median follow-up of 7 years, 332 participants died. In models adjusted for sociodemographic and clinical factors, each SD higher baseline concentration of plasma TNFR1 (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.20 to 1.38), TNFR2 (HR, 1.61; 95% CI, 1.42 to 1.82), suPAR (HR, 1.33; 95% CI, 1.22 to 1.44), KIM-1 (HR, 1.20; 95% CI, 1.08 to 1.33), and YKL-40 (HR, 1.23; 95% CI, 1.11 to 1.38) was associated with higher risk of all-cause mortality, whereas MCP-1 was not. Upon further adjustment for baseline eGFRcr-cys and UACR, only the associations for TNFR1 (HR, 1.16; 95% CI, 1.04 to 1.29), TNFR2 (HR, 1.34; 95% CI, 1.12 to 1.60), and suPAR (HR, 1.23; 95% CI, 1.11 to 1.36) persisted. CONCLUSIONS:Among adults with diabetes and CKD, higher plasma TNFR1, TNFR2, and suPAR were associated with all-cause mortality, independent of baseline kidney function.

RATIONALE & OBJECTIVE/UNASSIGNED:Diabetic kidney disease (DKD) is one of the leading causes of end-stage kidney disease globally. We aim to identify proteomic and metabolomic correlates of histologically confirmed DKD that may improve our understanding of its pathophysiology. STUDY DESIGN/UNASSIGNED:A cross-sectional study. SETTING & PARTICIPANTS/UNASSIGNED:A total of 434 Boston Kidney Biopsy Cohort participants. PREDICTORS/UNASSIGNED:Histopathological diagnosis of DKD on biopsy. OUTCOMES/UNASSIGNED:Proteins and metabolites associated with DKD. ANALYTICAL APPROACH/UNASSIGNED:We performed linear regression to identify circulating proteins and metabolites associated with a histopathological diagnosis of DKD (n = 81) compared with normal or thin basement membrane (n = 27), and other kidney diseases without diabetes (n = 279). Pathway enrichment analysis was used to explore biological pathways enriched in DKD. Identified proteins were assessed for their discriminative ability in cases of DKD versus a distinct set of 48 patients with diabetes but other kidney diseases. RESULTS/UNASSIGNED: = 0.008). LIMITATIONS/UNASSIGNED:A cross-sectional approach and lack of an external validation cohort. CONCLUSIONS/UNASSIGNED:Distinct proteins and biological pathways are correlated with a histopathological diagnosis of DKD.

RATIONALE & OBJECTIVE/UNASSIGNED:Individuals with chronic kidney disease (CKD) are at increased risk of morbidity and mortality, particularly as they progress to kidney failure. Identifying circulating proteins that underlie kidney failure development may guide the discovery of new targets for intervention. STUDY DESIGN/UNASSIGNED:Prospective cohort. SETTING & PARTICIPANTS/UNASSIGNED:703 African American Study of Kidney Disease and Hypertension (AASK) and 434 Boston Kidney Biopsy Cohort (BKBC) participants with baseline proteomics data. EXPOSURES/UNASSIGNED:Circulating proteins measured using SomaScan. OUTCOMES/UNASSIGNED:Kidney failure, defined as dialysis initiation or kidney transplantation. ANALYTICAL APPROACH/UNASSIGNED:Using adjusted Cox models, we studied associations of 6,284 circulating proteins with kidney failure risk separately in AASK and BKBC and meta-analyzed results. We then performed gene set enrichment analyses to identify underlying perturbations in biological pathways. In separate data sets with kidney-tissue level gene expression, we ascertained dominant regions of expression and correlated kidney tubular gene expression with fibrosis and estimated glomerular filtration rate (eGFR). RESULTS/UNASSIGNED:) participants developed kidney failure, respectively. We identified 143 proteins that were associated with incident kidney failure, of which only 1 (Testican-2) had a lower risk. Notable proteins included those related to vascular permeability (endothelial cell-selective adhesion molecule), glomerulosclerosis (ephrin-A1), glomerular development (ephrin-B2), intracellular sorting/transport (vesicular integral-membrane protein VIP36), podocyte effacement (pigment epithelium-derived factor), complement activation (complement decay-accelerating factor), and fibrosis (ephrin-A1, ephrin-B2, and pigment epithelium-derived factor). Gene set enrichment analyses detected overrepresented pathways that could be related to CKD progression, such as ephrin signaling, cell-cell junctions, intracellular transport, immune response, cell proliferation, and apoptosis. At the kidney level, glomerular expression predominated for genes corresponding to circulating proteins of interest, and several gene expression levels were correlated with eGFR and/or fibrosis. LIMITATIONS/UNASSIGNED:Possible residual confounding. CONCLUSIONS/UNASSIGNED:Multimodal data identified proteins and pathways associated with the development of kidney failure.

BACKGROUND/UNASSIGNED:The prevalence of hypertension and uncontrolled hypertension may differ by age and sex. METHODS/UNASSIGNED:We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models. RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:Sex differences in the prevalence of hypertension and uncontrolled hypertension vary by age, with the latter having implications for health throughout the life course.