Metabolic Abnormality and Obesity Associated with Rate of CKD Progression

Obesity, a worldwide major health problem, is associated with increased risk for type 2 diabetes mellitus, cardiovascular disease, cerebrovascular events, and malignancy, resulting in increased rates of cardiovascular and all-cause mortality. Studies have also demonstrated an increased risk of developing incident chronic kidney disease (CKD); however, it is unclear whether obesity itself worsens kidney function in patients with CKD. Results of a recent meta-analysis found that in patients with CKD, the association between body mass index (BMI) and progression to end-stage renal disease (ESRD) is weak; only extremely high BMI was found to contribute to development of ESRD.

There are few data on whether metabolic abnormalities accelerate the rate of progression of CKD. In a previous single-center Japanese cohort study, patients with metabolic syndrome had a greater risk of decline in estimated glomerular filtration rate (eGFR) or ESRD than those without metabolic syndrome. Hae-Ryong Yun, MD, and colleagues conducted a study designed to clarify the complex association among obesity, metabolic abnormality, and progression of kidney disease in patients with CKD. The study also aimed to examine whether there is an adverse association between obesity without metabolic disturbances and renal outcomes. Results were reported in the American Journal of Kidney Diseases [2018;72(3):400-410].

The study population included 1940 participants in the KNOW-CKD (Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease), a nationwide prospective cohort study at nine tertiary-care general hospitals in Korea. Patients aged 20 to 75 years with CKD stages 1 to 5 were eligible to participate; patients with CKD stage 5 prior to dialysis therapy were included. The primary outcome of interest was a composite of the first occurrence of a 50% decline in eGFR from the baseline value or the onset of ESRD during follow-up. ESRD was defined as initiation of dialysis therapy or kidney transplantation.

The study utilized five clinical and laboratory parameters to define metabolic abnormality: (1) hypertension (systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or use of antihypertensive medications); (2) fasting glucose level >125 mg/dL or presence of type 2 diabetes mellitus; (3) triglyceride level >150 mg/dL or use of lipid-lowering drugs; (4) high-density lipoprotein cholesterol ≤40 mg/dL in men (≤50 mg/dL in women); or (5) high-sensitivity C-reactive protein level >1 mg/L. Because there was significant increase in the risk for progression of CKD in patients with ≥3 of those components, metabolic abnormality was defined as ≥3 of the parameters.

Of the 1940 participants, 61.1% (n=1185) were men, mean age was 53.5 years, and 41.8% (n=812) were obese (defined as BMI ≥25.0 kg/m2). Compared with nonobese patients, obese patients were older, had a higher incidence of diabetes (P<.001) and hypertension (P<.001), and had more metabolically abnormal parameters. When patients were categorized based on the presence of metabolic disturbance, 62.3% (n=1210) had metabolic abnormality. Those patients were more likely to have hypertension, dyslipidemia, and inflammation compared with patients without metabolic abnormality; further, eGFRs were lower in patients with metabolic abnormality subtypes (P<.001).

The overall cohort was stratified into four subtypes based on the presence of obesity and/or metabolic abnormality: (1) nonobesity without metabolic abnormality (n=525, 27.1%); (2) nonobesity with metabolic abnormality (n=603; 31.1%); (3) obesity without metabolic abnormality (n=205; 10.6%); and (4) obesity with metabolic abnormality (n=607; 31.3%).

During a mean follow-up of 3.1 years, the primary outcome occurred in 21.0% of non-obese patients (n=239) and 19.4% of obese patients (n=158). The unadjusted hazard ratios (HRs) were similar between the two groups. Following adjustment for confounding factors, results of multivariable analyses demonstrated a significant association between obesity and increased risk for CKD, compared with nonobesity (HR, 1.41; 95% confidence interval [CI], 1.08-1.83; P=.01).

In analysis of the association between metabolic abnormality and renal outcome, 24.2% (n=294) of patients with metabolic abnormality reached the end point, compared with 13.8% (n=101) of those with no metabolic abnormality (P<.001). In a model adjusted for multivariables, there was a significant association between metabolic abnormality and increased risk for progression of CKD (HR, 1.38; CI, 1.03-1.85; P=.03). In analysis using the multivariable cause-specific hazards model, there was significant interaction between obesity and metabolic abnormality (P=.03).

In multivariable cause-specific hazards models adjusted for confounding factors, obese patients with and without metabolic abnormality had significantly increased risk for progression of CKD compared with nonobese patients without metabolic abnormality. After adjustment for renal parameters, obesity with metabolic abnormality was associated with a 1.53-fold increased risk for the composite outcome compared with nonobesity without metabolic abnormality (HR, 1.53; 95% CI, 1.03-2.27; P=.03). In obese patients without metabolic abnormality compared with nonobese patients without metabolic abnormality, the risk was also increased (HR, 1.97; 95% CI, 1.17-3.39; P=.01).

The researchers confirmed those findings using the same analyses in 1812 patients with complete data for all parameters in multivariable models. Following exclusion of 120 patients with baseline eGFR <15 mL/min/1.73 m2, results were similar; similar results were also observed when the composite renal outcome was determined according to protocol-based creatinine measurements.

In comparisons of rates of decline in kidney function among the four metabolic subgroups, compared with those with neither obesity of metabolic abnormality, those in the other three groups had faster declines in eGFR.

The researchers cited some limitations to the study, including the possible variation in the prevalence of metabolic subtypes depending on what criteria were used; the lack of in-depth analysis of cardiovascular disease and all-cause and cardiovascular mortality; the lack of data on why there was an association between obesity without metabolic abnormality and progression of CKD; and the possibility that the findings may not be generalizable to ethnic groups other than Koreans.

In conclusion, the researchers said, “We demonstrated that both obesity and metabolic abnormality were associated with adverse renal outcomes in patients with CKD. Moreover, our findings raise doubts about the previous notion that obese persons without metabolic abnormality are healthy because we found that they also have higher risk for kidney disease progression. This can be partly explained by the lower adiponectin levels and higher left ventricular mass index and protein excretion in these patients. Further long-term studies are required to confirm our findings.”

Takeaway Points

  1. Researchers in Korea conducted a prospective observational cohort study to examine whether metabolic abnormalities accelerate the rate of progression of chronic kidney disease (CKD).
  2. Compared with patients with neither obesity or metabolic abnormality, those with obesity and metabolic abnormality had a greater risk for CKD progression (hazard ratio [HR], 1.53; P=.03).
  3. The rate of CKD progression was also higher in patients with obesity without metabolic abnormality (HR, 1.97; P=.01).