The Endless Story of Markers of Renal Function and Cardiovascular Risk

Luis M. Ruilope; Elena Rodríguez-Sánchez; Gema Ruiz-Hurtado

Disclosures

Eur Heart J. 2019;40(42):3494-3495. 

Kidney and arterial hypertension are intimately related, with the first being considered as culprit and victim of high blood pressure (BP). A derangement in the renal capacity to excrete sodium was considered to be the renal mechanism participating in the initial rise in BP, indicating that an alteration in tubular function is present in the early stages of arterial hypertension.[1] In parallel, the rise in BP promotes progressive chronic kidney disease (CKD) that was initially correlated with elevated diastolic BP that compared with optimal BP exhibited a steady increase in relative risk from 2.8 to 12.4 as diastolic BP increased from 90 to 120 mmHg or higher.[2] In turn, the progression of CKD correlates better with tubulo-interstitial damage than with glomerular damage.[3] On the other hand, the data from the Hypertension Detection and Follow-up Program Cooperative Group showed for the first time that baseline serum creatinine had a significant prognostic value for 8-year all-cause mortality.[4] A few years before, Samuelsson et al.[5] demonstrated that proteinuria was a powerful predictor of higher cardiovascular morbidity and mortality. In 2001, a formula to estimate creatinine clearance was used, and 60 mL/min was considered for the first time as the cut-off point for considering the presence of established CKD.[6] Since then, the relevance of renal function as a predictor of an increase cardiovascular risk in other forms of cardiovascular disease, particularly in patients with heart failure and after myocardial infarction, has been described.[7,8] Simultaneously, the number of biomarkers of renal injury and function participating in the enhancement of cardiovascular risk has steadily increased.[9] Beyond serum creatinine and estimated glomerular filtration rate (eGFR), the most widely considered in clinical practice has been albuminuria, either high or very high.[10] Diverse biomarkers of tubular function have also been considered, but their correlation with adverse clinical events remains partly unexplored.[9]

In the present issue of the European Heart Journal, Garimella et al.[11] using a group of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit have evaluated the association of three markers of tubular function, alpha-1-microglobulin, beta-2-microglobulin, and uromodulin with a composite cardiovascular endpoint and mortality. Take home figure represents the main findings and the renal circumstances surrounding them. The authors have demonstrated that an increase in alpha-1-microglobulin or a decrease in uromodulin predict the development of the components of the composite endpoint and mortality. In contrast, variations in beta-2-microglobulin have no prognostic capacity. These data complete in a relevant manner the role of renal tubular markers and cardiovascular risk. However, they have been obtained in elderly people and with a moderate to advanced stage of CKD where tubular damage is quite severe and explains the findings of an elevation in alpha-1-microglobulin and a diminution in uromodulin. The results described have been shown to be independent of glomerular function and albuminuria; this enhances the validity of these biomarkers if used in an independent manner. Nevertheless, it must be considered that for ages such as those in this study only 24-h creatinine clearance correlates independently and significantly with cardiovascular events.[12] Besides this, it remains to be investigated whether changes in alpha-1-microglobulin and uromodulin levels in individuals with preserved renal function equally predict cardiovascular events and mortality independently of the presence or absence of arterial hypertension in a similar way to eGFR.[13]

Take home figure.

Schematic representation of the role of arterial hypertension in the kidney and the variations in alpha-1-microglobulin, beta-2-microglobulin, and uromodulin levels.11

In conclusion, what we denominated as the Cinderella of cardiovascular risk[14] in 2001 has totally abandoned the ragged clothes and continues to be an object of endless investigation.

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