MS includes a variety of abnormalities including obesity, hypertriglyceridemia, low HDL cholesterol, hypertension and diabetes mellitus. It is a well known fact that diabetes and high blood pressure could cause kidney disease. But the question is without these causative factors could MS by itself be the cause of proteinuria or reduced GFR?
This question was answered in a few longitudinal observational studies. A follow up of 10,000 people in Japan for more than 17 years indicated that the occurrence of CKD and body mass index increased risk to 1.273 for men, after adjusting all other components of MS(1). Similarly, over 3,00,000 people in the USA were followed for 35 years and it was proven that an increased body mass index was associated with CKD(2). There is an increased risk for the development of proteinuria and CKD in MS and the odds ratio for development of these components are 1:89, and 2: 60 respectively, and the risk increases as the components of MS rise.
Obesity increases proteinuria risk. Hormones form adipose tissue including leptin, cytokines like IL6, IF alpha and adiponectin increase renal TGF beta expression and a predisposition to glomerulosclerosis. Leptin acts at the hypothalamus and decreases the threshold to eat. There is leptin resistance in obesity. This results in overeating and increased triglyceride levels (3).
Leptin increases renal sympathetic activity and activates RAAS. There is increased renal sodium reabsorption and a shift of the pressure natriuretic curve. This results in hypertension and glomerular hyperfiltration that leads to renal damage. This results in a glomerular wall stretch, cellular proliferation, matrix accumulation and eventual sclerosis (4).
The abnormal adipose tissue results in insulin resistance and hyperinsulinemia that causes mesangial expansion, loss of integrity of the basement membrane, podocyte injury and basement membrane thickening that leads to glomerulosclerosis and tubule epithelial injury (5).
Activation of RAAS causes the production of ROS and that causes increases vasoconstriction, increased tubulo-glomerular feedback and increased sodium reabsorption. This increases endothelial dysfunction, systemic vascular inflammation and increases cardio renal risk in MS.
Therefore the mechanisms involved in the pathogenesis of renal dysfunction in MS can be summarized by the following diagram (Fig 1) (7).
Figure 1: The mechanisms involved in the pathogenesis of renal dysfunction in MS
Obesity itself causes podocyte injury that is mediated by an oxidative stress injury to the foot processes of the visceral epithelial cells and the characteristic manifestation is proteinuria, usually in the nephrotic range, and progressive renal insufficiency. Histologically, there is glomerulomegaly and peri hilar type of FSGS (Fig 2).
Figure 2: Obesity related FSGS ( picture reference Arkana Labs)
Yes, there is a bidirectional relationship. The development of insulin resistance rises with increasing CKD stages. This resolves once the dialysis is initiated. This observation leads to the belief that dialysable uremic factors are responsible for the development of MS in CKD (8).
Treatment centres around reducing the various components of metabolic syndrome. Weight reduction, increase in physical activity, low fat diet consumption, moderation of smoking and alcohol consumption are important.
The role of RAAS inhibitors over other antihypertensive therapies, in the treatment of MS-induced hypertension and proteinuria has been well described (9). It has been proven that lipid lowering itself helps in slowing down the progression of CKD (10). The use of metformin and glitazones improves insulin sensitivity. The fibrates for reducing hypertriglyceridemia, bariatric surgery for morbid refractory obesity are among the various therapies available.
Dr.R.Balasubramaniyam. MBBS, DNB( Gen.Med), DNB(Neph) Head, Department Of Nephrology. Kauvery Hospital, Alwarpet, Chennai.
