Reviews in Cardiovascular Medicine  2020, Vol. 21 Issue (1): 41-56     DOI: 10.31083/j.rcm.2020.01.5102 Special Issue: Cardiovascular disorders in chronic kidney disease Insulin resistance underlies the elevated cardiovascular risk associated with kidney disease and glomerular hyperfiltration María M. Adeva-Andany1, *(), Carlos Fernández-Fernández1, Natalia Carneiro-Freire1, Elvira Castro-Quintela1, Ana Pedre-Piñeiro1, Mónica Seco-Filgueira1 1 Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain Abstract:

The curve that describes the relationship between glomerular filtration rate (GFR) and cardiovascular risk is U-shaped, indicating that both reduced GFR (kidney failure) and elevated GFR (glomerular hyperfiltration) are equivalent cardiovascular risk factors. The elevated cardiovascular risk associated with abnormal GFR is not explained by standard cardiovascular risk factors. The relationship between GFR and all-cause mortality follows a similar pattern, so that altered GFR (either low or high) increases the risk for overall mortality. Glomerular hyperfiltration is an adaptive process that arises under conditions that demand improved kidney excretory capacity, such as animal protein ingestion and kidney failure. Unlike vegetable protein, animal protein consumption increases dietary acid load and requires an elevation of the GFR to restore acid-base balance. The loss of functioning nephrons in diseased kidneys requires a compensatory increase of the GFR in the nephrons that remain working to enhance whole-kidney GFR. A major factor that raises GFR is the pancreatic hormone glucagon. Glucagon infusion and endogenous glucagon release increase GFR in healthy subjects and patients with kidney failure. In addition to its kidney hemodynamic effect, glucagon causes insulin resistance. Like hyperglucagonemia, insulin resistance develops across the entire spectrum of abnormal GFR, from glomerular hyperfiltration to advanced kidney disease. Insulin resistance is associated with subclinical vascular injury in the general population and patients with diabetes and kidney failure, being a strong cardiovascular risk factor in these population groups. Animal protein consumption activates glucagon secretion and promotes insulin resistance, having a detrimental effect on cardiovascular disease and renal outcomes.

Submitted:  04 December 2019      Accepted:  09 March 2020      Published:  30 March 2020      *Corresponding Author(s):  María M. Adeva-Andany     E-mail:  madevaa@yahoo.com Service E-mail this article Add to citation manager E-mail Alert RSS Articles by authors María M. Adeva-Andany    Carlos Fernández-Fernández    Natalia Carneiro-Freire    Elvira Castro-Quintela    Ana Pedre-Piñeiro    Mónica Seco-Filgueira   

Figure 1.  Relationship between glucagon-induced insulin resistance and cardiovascular disease. Kidney failure and animal protein intake activate glucagon secretion, which in turn causes insulin resistance and increases glomerular filtration rate (GFR). Insulin resistance induces subclinical vascular injury and cardiovascular disease. Elevated GFR achieves optimal kidney function in patients with kidney disease and induces glomerular hyperfiltration in healthy subjects.

Table 1.  Glomerular hyperfiltration is associated with increased risk of cardiovascular disease and all-cause mortality

Population / Number of subjectsType of studyGlomerular filtration rate (GFR)Main findingsSchmieder 1990Subjects with essential hypertension / 111Cross-sectionalEndogenous creatinine clearanceGlomerular hyperfiltration is associated with left ventricular hypertrophyEriksen, 2014General population (Norway) / 1,521Cross-sectionalIohexol clearanceGlomerular hyperfiltration is associated with subclinical vascular disease in healthy subjects from the general population.Choi, 2015General population (Korea) / 6,986Cross-sectionalChronic kidney disease-Epidemiology Collaboration (CKD-EPI) equationGlomerular hyperfiltration is associated with coronary artery calcification in healthy men from the general populationReboldi, 2018A total of 8,794 participants (89% hypertensive) / 8,794Prospective
Follow-up: 6.2 yearsCKD-EPI equationGlomerular hyperfiltration is associated with higher risk of cardiovascular events in a multiethnic populationAltay, 2014Subjects without kidney disease / 789Prospective
Follow-up: 3 yearsModification of diet in Renal Disease (MDRD) study equationGlomerular hyperfiltration is associated with higher risk of death and cardiovascular disease.Cox, 2008General population / 33,386Cross-sectionalMDRD equationGlomerular hyperfiltration predicts an increased mortality among community living subjectsMatsushita, 201021 general population cohorts / 105,872Meta-analysisMDRD equationAll-cause mortality risk was higher at GFR > 105 ml/min/1.73 m2 compared with at GFR 75-105 ml/min/1.73 m2.Tonelli, 2011Population-based laboratory data set /
1,526,437Cross-sectionalCKD-EPI equationAn elevated GFR predicts an elevated risk of all-cause mortalityPark, 2015General population (Korea) / 43,503
Prospective
Follow-up: 12.4 yearsCKD-EPI equationGlomerular hyperfiltration is associated with increased all-cause mortality in a healthy population.

Table 2.  Association between glomerular hyperfiltration and insulin resistance in healthy subjects and obese patients

Study population / Number / Type of studyAssessment of insulin sensitivityGlomerular filtration rate (GFR)Main findingsNaderpoor, 2017Healthy subjects and obese patients / 104 / Cross-sectionalHyperinsulinemic euglycemic clampChronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equationInsulin resistance is strongly and independently associated with elevated GFRMelsom, 2011General population
(Norway) / 1,594 /
Longitudinal cohortImpaired glucose tolerance (IGT)Iohexol clearanceGlucose intolerance is independently associated with elevated GFRTomaszewski, 2007Young healthy men / 1,572 / Cross-sectionalClinical features (metabolic syndrome)Creatinine clearance (Cockcroft-Gault equation)The presence of the metabolic syndrome is independently associated with elevated GFRLee, 2017Adolescents (US) / 8,793 / Cross-sectionalHomeostasis model assessment-insulin resistance (HOMA-IR)Schwartz equation (Chronic Kidney Disease in Children study)Glomerular hyperfiltration was independently associated with insulin resistanceKelishadi, 2018Pediatric population Iran / 3,800 / Cross-sectionalClinical features (high blood pressure, obesity)Modified Schwartz equationElevated GFR is associated with clinical features of insulin resistance in childrenOkada, 2012General population (Japan) / 99,140 / Cross-sectionalClinical features (prehypertension, IGT)Modification of Diet in Kidney Disease (MDRD) equationThe prevalence of glomerular hyperfiltration increased with worsening insulin resistanceKawata, 2019General population Japan / 24,524 / Longitudinal retrospectivePrediabetes by the American Diabetes Association vs IECEquation developed for Japanese subjectsPrediabetes defined by the International Expert Committee (IEC) is an independent risk for incident glomerular hyperfiltration.Dengel, 1996Obese subjects / 10 / Cross-sectionalHyperinsulinemic euglycemic clamp99mTc-diethylenetriamine-pentaacetic acid clearanceInsulin resistance is associated with glomerular hyperfiltrationChagnac, 2000Body mass index > 38 kg/m2 /21 / Cross-sectionalOral glucose tolerance testInulin clearanceInsulin resistance is positively correlated with GFRChagnac, 2003Obese subjects / 17 / Interventional gastroplastyHyperinsulinemia, IGTInulin clearanceAfter surgery, there was a marked improvement of GFR and insulin resistance [1] Adeva-Andany, M.,Martinez-Rodríguez, J.,González-Lucán, M.,Fernandez-Fernandez, C. and Castro-Quintela, E. 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