Stroke volume and proteinuria in obesity‐related glomerulopathy: potential role in pathogenesis and choice of antihypertensive regimen (2018)

To the Editor, Obesity-related glomerulopathy (ORG) is a strong risk factor for new-onset chronic kidney disease.1, 2 With the prevalence of obesity reaching a worldwide epidemic, ORG has become an important contributor to the increasing rates of chronic kidney disease and end-stage renal disease.2, 3 Mechanisms involved in the pathogenesis of ORG are complex, with glomerular hyperfiltration through alterations in renal hemodynamics suggested to play a critical role.4, 5 Obesity has been attributed to an increase in glomerular filtration rate, renal plasma flow, and filtration fraction, as well as in proximal tubular hypertrophy, mechanisms important in glomerular hyperfiltration.6-8 On the other hand, obesity has been shown to lead to high cardiac output, high intravascular volume, and inappropriately normal peripheral resistance.9 Current emphasis and thus management of ORG has focused on renal hemodynamics while little attention has been paid to the systemic hemodynamic effects of obesity, which may play a role in ORG. In this report, we studied the relationship between estimated stroke volume (SV) and proteinuria, a marker of glomerular hyperfiltration using the National Institutes of Health–funded Modification of Diet in Renal Disease (MDRD) baseline data set. Using SPSS version 24 (IBM), we computed SV using a validated equation comprising noninvasive parameters (100 – 0.6 age – 0.6 diastolic pressure + 0.5 pulse pressure × patients body surface area [m2]” over 1.7).10 Using the entire MDRD cohort, we performed bivariate correlation (Pearson) between SV, heart rate, and body mass index (BMI) as predictors and proteinuria as the dependent variable. We then repeated the analysis by including patients with proteinuria ≤1 g (to attenuate effects of severe proteinuria on intravascular volume) and BMI ≥28. Our results show significant correlation between SV, heart rate, BMI, and proteinuria in all patients. When only persons with proteinuria ≤1 g and BMI ≥28 were included, correlation with SV maintained statistical significance as shown in the Table. Moreover, BMI strongly positively correlated with SV and heart rate (Pearson correlation 0.18 and 0.12, respectively, with P < .001). Increased SV is the main determinant of increased cardiac output in obese patients9 and may contribute to the pathogenesis of ORG. There are few lessons learned from human and animal studies focusing on systemic factors and proteinuria that can support our observation. In a small double-blinded cross-over study, atenolol reduced glomerular filtration rate, which correlated with reduction in proteinuria more than enalopril.11 In the AASK (African American Study of Kidney Disease and Hypertension) trial, sustained-release metoprolol had antiproteinuric effects nearly equal to that of ramipril and better than that of amlodipine.12 This can be supported by the fact that the use of diuretics or β-blockers is associated with a decrease in cardiac output.13 Moreover, an experimental study showed that low doses of the sympatholytic drug moxonidine that failed to affect blood pressure in rats by telemetry significantly reduced albuminuria and interfered with the development of glomerulosclerosis.14 In conclusion, SV is increased in obese patients and correlates with proteinuria, a marker for ORG. Future studies are needed to dissect some element of causation in this association where pharmacologic interventions targeting modulation of SV in patients with ORG, such as β-blockers and diuretics, may provide a new hemodynamic management strategy in optimization of care. The MDRD study was conducted by the MDRD investigators and was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The data from the MDRD reported here were supplied by the NIDDK Central Repositories. This article was not prepared in collaboration with investigators of the MDRD study and does not necessarily reflect the opinions or views of the MDRD study, the NIDDK Central Repositories, or the NIDDK. All authors declare no conflicts of interest. Each author contributed important intellectual content during article drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.