Important Findings

Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification. Dubin RF, Deo R, Ren Y, Wang J, Pico AR, Mychaleckyj JC, Kozlitina J, Arthur V, Lee H, Shah A, Feldman H, Bansal N, Zelnick L, Rao P, Sukul N, Raj DS, Mehta R, Rosas SE, Bhat Z, Weir MR, He J, Chen J, Kansal M, Kimmel PL, Ramachandran VS, Waikar SS, Segal MR, Ganz P; CRIC Study Investigators. Eur Heart J. 2024 May 17:ehae288. doi: 10.1093/eurheartj/ehae288. Online ahead of print. PMID: 38757788
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Proteomics of CKD progression in the chronic renal insufficiency cohort. Dubin RF, Deo R, Ren Y, Wang J, Zheng Z, Shou H, Go AS, Parsa A, Lash JP, Rahman M, Hsu CY, Weir MR, Chen J, Anderson A, Grams ME, Surapaneni A, Coresh J, Li H, Kimmel PL, Vasan RS, Feldman H, Segal MR, Ganz P; CRIC Study Investigators; CKD Biomarkers Consortium. Nat Commun. 2023 Oct 10;14(1):6340. doi: 10.1038/s41467-023-41642-7. PMID: 37816758; PMC10564759.
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Many nephrologists and opinion leaders have come to accept that even mild to moderate cases of acute kidney injury (AKI) cause accelerated progression of chronic kidney disease (CKD). Challenging this reigning paradigm, we showed that after rigorously controlling for differences in characteristics among those who did and did not experience AKI, the impact of AKI on CKD progression is in reality likely only very small.
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Chronic kidney disease is common in the US population, and we understand that it increases the risk of cardiovascular disease. However, risk scores have not been generated specifically for identifying CKD patients, who are most likely to develop heart disease. In this large-scale proteomics study, we measured nearly 5,000 proteins and used machine learning methods to generate and validate a 32-protein risk score. This score surpassed clinical risk models for predicting incident cardiovascular disease.
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This study showed that a new way of calculating a patient’s kidney function, without using their race, has the same ability to predict who will or will not have kidney failure. This is important because it showed that race is not needed to calculate kidney function and provided evidence to improve fair access to kidney care, regardless of race.
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Work done by the Chronic Kidney Disease - Epidemiology Collaboration opens an important path forward by providing new data and racially-neutral options for assessing kidney function. The research team pooled more than 20 diverse populations to develop and test new equations based on creatinine as well as on levels of a different protein, cystatin. They found that their improved creatinine-based estimate offered acceptable accuracy across all populations. They also found that combining creatinine and cystatin yielded the most accurate estimates.
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Given the concerns about potential racial/ethnic discrimination through the use of various medical calculators, the inclusion of a coefficient for a person’s race in equations that estimate the level of glomerular filtration rate (GFR) based on serum creatinine level has become very controversial. The conclusions from this study is that use of serum creatinine level to estimate the GFR without including information on self-reported race (or genetic ancestry) introduced systematic error that could not be eliminated even when numerous factors that influence the level of serum creatinine were taken into account. However, using the alternative filtration marker, serum cystatin C, does not have the same problem and can provide similar accuracy for estimating a person’s actual GFR without the need to include information on race.
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A team of external researchers analyzed data from the CRIC study obtained from the NIH repository and reported that the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation estimated glomerular filtration rate (eGFR) was higher than the iothalamate clearance glomerular filtration rate (iGFR) among self-reported Black CRIC study participants whose iGFR was less than 45 mL/min/1.73 m2, suggesting potential systematic error in this high-risk population. However, we showed that this observation is not due to actual bias in the CKD-EPI estimating equation but rather was an artefact of their statistical modeling approach.
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Albuminuria (measured as urine albumin-to-creatinine ratio; ACR) is the preferred measure for definition and staging of chronic kidney disease (CKD), but total urine protein or dipstick protein is often measured instead due to lower costs, traditions, or other considerations. This paper developed equations for the conversion of urine protein-to-creatinine ratio (PCR) or urine dipstick protein categories to ACR using random-effects meta-analysis in 33 multinational cohorts. These results indicate that when ACR measurement is not available, predicted ACR from PCR or urine dipstick may be useful and informative for the purpose of harmonizing across research studies, CKD screening and classification efforts, and use in risk prediction equations.
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Diabetic kidney disease (DKD) is the most common cause of chronic and end-stage renal failure in the world. In a genetically susceptible host, poor metabolic control contributes to DKD development. The epigenome integrates signals from sequence variations and environmental alterations. We performed genome-wide DNA methylation association analysis in one of the best-characterized kidney disease cohorts: The Chronic Renal Insufficiency Cohort study. Complex computational integration analysis indicated the key role of genetic variations in DNA methylation. Our analysis highlighted loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation of high-confidence genes suggested the causal role of inflammation, specifically, complement activation and apoptotic cell clearance in kidney disease development.
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Oxalate is a toxic terminal metabolite that can crystallize urine, causing kidney stones. In this paper, higher amounts of dissolved oxalate in 24h urine samples were shown to predict the future development of CKD progression. The CRIC findings could mean that oxalate (which is found in many foods) may be a modifiable dietary risk factor in CKD; further research on this topic is under way.
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The buildup of calcium deposits in heart blood vessels is common in patients with chronic kidney disease. The findings from the CRIC study showed that calcium deposit in heart blood vessels is associated with increased risk of cardiovascular disease, myocardial infarction, and heart failure in patients with chronic kidney disease. These findings may lead to better prediction of heart disease in patients with chronic kidney disease and further investigation on new treatment to reduce heart disease.
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Patients with chronic kidney disease have high rates of heart disease, including abnormal heart rhythms, such as atrial fibrillation. Patients with chronic kidney disease also have elevated levels of a hormone called fibroblast growth factor 23, which helps regulate vitamin D and phosphorus in our body. This study found that elevated levels of fibroblast growth factor 23 was associated with atrial fibrillation, likely through a pathway that affected the the heart muscle causing enlargement or hypertrophy and through heart failure events. It provides one possible explanation of why patients with chronic kidney disease may have high rates of atrial fibrillation.
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Among patients with CKD, high dietary sodium intake (salt) is associated with higher risk of cardiovascular disease, such as heart attacks, stroke, and heart failure. In addition, higher dietary potassium is also associated with higher risk of cardiovascular disease among patients with CKD.
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High blood pressure has long been known as a risk factor for progressive CKD, but the optimal targets for blood pressure control among those with CKD is highly debated. Much of the controversy stems from a lack of consistent evidence across clinical trials and observational studies and some biased approaches in some studies. This publication in the Annals of Internal Medicine addressed this question utilizing sophisticated models to address bias, and underscored that this established risk factor has an even stronger relationship with CKD progression than previously appreciated.
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Renal high-risk variants in APOL1 were associated with an increased risk of progression of chronic kidney disease among black patients, even among those with well-controlled blood pressure. These variants may explain, in part, the markedly increased risk of end-stage renal disease among black patients, as compared with white patients, regardless of diabetes status. These results also highlight the need to identify other risk factors that can account for residual disparities in end-stage renal disease between black patients and white patients.
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Genetic loci predisposing to coronary artery calcification (CAC) (e.g. chr9p21, COL4A1, ATP2B1 and ABCA4) were identified in CRIC, and found to relate to CAC in independent samples, as well as to myocardial infarction in a general population sample. Chronic kidney disease (CKD) imparts a high risk of coronary heart disease and studying CKD samples may aid discovery of novel disease genes and pathways.
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In CRIC participants without heart failure, serum cardiac troponin T (cTnT) is associated with left ventricular hypertrophy (LVH) and LV systolic dysfunction but not with LV diastolic dysfunction.
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In CRIC participants without heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP) had strong associations with prevalent left ventricular hypertrophy (LVH) and LV systolic dysfunction.
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Retinopathy is associated with an increased likelihood of cognitive impairment which suggests that evaluation of retinal microvascular abnormalities may be a promising tool for identifying patients with CKD who are at increased risk of cognitive impairment.
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Findings from CRIC indicate that there is a relationship between 24-hour urinary sodium excretion and proteinuria that is modified by a number of clinical and demographic factors which reduce the contribution of dietary sodium on 24-hour excretion.
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Low serum bicarbonate is an independent risk factor for kidney disease progression, particularly for participants with preserved renal function. The risk of heart failure is increased at serum bicarbonate above 24 mEq/L.
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The CRIC study indicates that abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function are associated with the prevalence of high coronary artery calcification, independent of the traditional risk factors in patients with chronic kidney disease.
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New urine marker identified which may help doctors better forecast which patients with chronic kidney disease will lose kidney function more quickly.
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Lower extremity amputation (LEA) is a life-altering complication of diabetes. Genetic variation in neuronal nitric oxide synthase associated protein (NOS1AP) is associated with LEA and diabetic peripheral neuropathy (DPN). For example, in whites, in those with diabetes, NOS1AP SNP rs1963645 was strongly associated with LEA (1.73 (1.23, 2.44)) and DPN (16.97 (2.38, 120.97))
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Greater severity of retinopathy in CRIC participants is associated with increased prevalence of any CVD and this association persists after adjustment for traditional risk factors for CVD. This suggests that retinovascular pathology may indicate macrovascular disease even after adjustment for renal dysfunction and traditional risk factors.
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Retinal vascular pathology may reflect renal disease. Results show a strong association between the severity of retinopathy observed in eye fundus photographs and kidney function. This association remains after adjustment for traditional and non-traditional risk factors for chronic kidney disease, suggesting that retinal vascular pathology may reflect renal disease.
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Depression affects over 25% of CRIC and H-CRIC participants. Antidepressant medications are used in only a third of CRIC and H-CRIC participants with severe depression. CRIC and H-CRIC participants of racial/ethnic minority backgrounds and with more severe CKD are much more likely to have depression.
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Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD.
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Disordered mineral metabolism is more severe and potentially develops earlier in the course of CKD in patients with diabetes compared to those without diabetes.
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Despite high prevalence of depressive symptoms in individuals with CKD, the use of antidepressant medications is low. Individuals of racial and ethnic minority background and with more advanced CKD have a greater burden of depressive symptoms and lower use of antidepressant medications.
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A significant association of novel risk factors hsCRP, WBC, fibrinogen, uric acid, HbA1c, HOMA-insulin resistance, and cystatin C with the risk of peripheral arterial disease (PAD) is reported. These associations were independent of traditional CVD risk factor
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Fibroblast growth factor 23 is a hormone that regulates phosphate levels in the blood. This study of the CRIC participants showed that elevated levels of fibroblast growth factor 23 are associated with an increased risk of kidney failure and death among patients with chronic kidney disease.
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Hispanics with chronic kidney disease (CKD) are found to be more likely to have diabetes and uncontrolled hypertension than non-Hispanic blacks and whites. Abnormalities in hematologic, metabolic, and bone metabolism parameters are also more prevalent in Hispanics with CKD.
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Hispanics with chronic kidney disease are found to be at higher risk of left ventricular hypertrophy than non-Hispanic whites, and have more severe coronary artery calcification than non-Hispanic blacks.
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CRIC data question the common assumption in nephrology that measured GFR is a better indicator of "kidney function" than estimated GFR. The fundamental question in nephrology regarding what is the 'gold standard measure' of 'kidney function' in research and clinical care is investigated.
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Use of loop diuretics in CRIC participants is associated with greater urinary calcium excretion, higher parathyroid hormone levels and greater likelihood of secondary hyperparathyroidism compared to no use of loop diuretics. These associations are attenuated if there was co-administration of thiazides demonstrating that diuretic choice is a potentially modifiable determinant of secondary hyperparathyroidism in CKD.
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Levels of the bone remodeling regulating cytokine, osteoprotegerin, are not associated with differences in bone mineral content, or circulating markers of bone metabolism in CRIC patients. However, higher osteoprotegerin levels are associated with greater aortic stiffness even after accounting for other vascular risk factors.
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Results from the CRIC Study reveal that increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH elevation. Thus, FGF23 may be an early biomarker of disordered mineral metabolism in the initial stages of CKD.
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Results from the examinations of the relationship between estimated GFR and coronary artery calcification demonstrate the independent relationship between differing levels of coronary artery calcium and renal function.
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Brachial artery systolic blood pressure and aortic pulse wave velocity are both associated with variations of proteinuria in patients with CKD.
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Data from the CRIC Study establishes a link between early stages of chronic kidney disease and atrial fibrillation.
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Ocular fundus pathology is present in about 45% of CRIC participants, a finding that supports recommendations for complete eye examinations in individuals with chronic kidney disease.
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Presence of retinopathy is associated with higher prevalence of cardiovascular disease (CVD) even after adjustment for traditional CVD risk factors. This suggests that retinal vascular pathology may be indicative of macrovascular disease, and that the assessment of retinal morphology may be a valuable tool in studies of CVD in chronic kidney disease.
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Hypertension is shown to be very common, affecting almost 90% of CRIC participants. Almost all participants with hypertension are aware of their diagnosis of hypertension and receive treatment. However, many participants with hypertension do not achieve blood pressure control to levels recommended by treatment guidelines.
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Among 2,879 participants in the Chronic Renal Insufficiency Cohort Study, participants with the lowest income or who were unemployed have higher serum phosphate concentrations than those with the highest income or who were employed. In addition, when compared to whites with the highest income, both blacks and whites with the lowest income have more than twice the likelihood of hyperphosphatemia in multivariable-adjusted analysis, irrespective or race.
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Pulse wave analysis derived measures are associated with carotid intima media thickness (IMT) and plaque in CKD. Of these measures, central pulse pressure had the strongest association with carotid IMT and plaque.
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Among 3612 black, white and Hispanic adults with mild-to-moderate chronic kidney disease from seven U.S. CRIC clinical centers, nearly half of whom had diabetes, low levels of kidney function are associated with low socioeconomic status and increased prevalence of cardiovascular disease.
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