aInstitute for Clinical Pharmacology, Medical School Hannover, Hannover, Germany
bClinica Medica, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy
Correspondence to Professor Jens Jordan, Institute of Clinical Pharmacology, Medical School Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany E-mail: firstname.lastname@example.org, www.mh-hannover.de/klinpharm.html
Obesity, particularly visceral obesity, predisposes to arterial hypertension, insulin resistance and overt type 2 diabetes mellitus, dyslipidemia, and low-grade systemic inflammation. However, expression of these cardiovascular and metabolic risk factors varies markedly between obese individuals. Some obese patients show normal blood pressure readings and are metabolically healthy. In others, modest adiposity drives an increase in cardiovascular and metabolic risk. Metabolic syndrome diagnostic criteria are useful in identifying the high-risk subgroup in the clinic. The kidney contains delicate and highly specialized blood vessels receiving approximately 20% of resting cardiac output. No surprise, the kidney vasculature is an important target for many cardiovascular and metabolic risk factors, including the metabolic syndrome. We will briefly review evidence suggesting that obesity and the metabolic syndrome increase the risk for renal disease, that renal disease heralds cardiovascular risk, and that lifestyle interventions hold promise in the prevention of renal disease progression. The facts that obesity and the metabolic syndrome confer increased renal risk and that renal disease is an important cardiovascular risk factor have been firmly established. What to do about these risks is less well studied. The study by Straznicky et al.  suggests that comprehensive lifestyle interventions may be beneficial in this setting. Moreover, the study suggests mechanisms that could mediate beneficial effects on the kidney and cardiovascular system in the long-term.
Increased risk for renal disease in obesity and metabolic syndrome
Pathophysiological and epidemiological studies suggest that obesity and metabolic syndrome appear to be renal risk factors throughout the transition from subclinical early stages to end-stage renal disease requiring dialysis or renal transplantation. In addition to increasing the risk for arterial hypertension and diabetes mellitus, obesity elicits an activation of the sympathetic nervous system and the renin–angiotensin system in many patients [2–4]. The neurohumoral activation contributes to arterial hypertension and may elicit vascular damage in the kidney and elsewhere in the body .
Early stage microvascular disease, which is difficult to diagnose in many other tissues, can easily be detected by analyzing urine samples for albumin. Excessive urinary albumin excretion indicates disordered endothelial barrier function in the kidney and elsewhere in the body. However, observations in morbidly obese individuals suggest that histological lesions resembling those of early diabetic nephropathy may occur even before the appearance of microalbuminuria . Early on, spared glomerular capillaries maintain filtration rate limiting the utility of creatinine clearance estimates in diagnosing early renal disease. As more and more glomerular vessels are damaged, filtration declines, signaling later stage renal as well as systemic microvascular disease. The Prevention of Renal and Vascular ENd-stage Disease (PREVEND) study showed a positive correlation between urinary albumin excretion and BMI . Remarkably, the relationship was more pronounced in men compared with women.
A recent cohort study assessed risk factors for end-stage renal disease in 177 570 individuals who underwent health checkups between 1964 and 1973 . The investigators assessed occurrence of end-stage renal disease and death through the year 2000. Compared with normal body weight, the hazard ratios for end-stage renal disease were 1.65 for overweight, 3.11 for class 1 obesity, and 4.39 for class 2 to class 3 obesity. Earlier studies arrived at similar conclusions . Type 2 diabetes mellitus and arterial hypertension are often caused or exacerbated by obesity. Between 1996 and 2002, the number of patients with end-stage renal disease due to diabetes mellitus increased approximately 37% in the United States. During this period, the number of patients with end-stage renal disease caused by arterial hypertension increased 22%. Rates of end-stage renal disease due to diabetes and hypertension continued to increase 2.0–2.1% in both 2007 and 2008 (www.usrds.org). It is tempting to speculate that the trend is at least in part explained by the epidemic increase in obesity prevalence. The idea that obesity may contribute to end-stage renal disease is supported by observations in renal transplant recipients. The proportion of patients who were obese at the time of renal transplantation increased 116% from 1987 to 2001 . Finally, a meta-analysis including articles published in PubMed between 1980 and 2006 estimated that of the kidney disease cases in industrialized countries, 13.8% in men and 24.9% in women could be related to overweight and obesity .
Obesity may also damage the kidney independently of arterial hypertension and type 2 diabetes mellitus. Higher BMI was a risk factor for end-stage renal disease in multivariable models adjusted for age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, urinalysis proteinuria, urinalysis hematuria, and serum creatinine. Increased BMI remained an independent predictor after additional adjustments for blood pressure and presence of diabetes mellitus . Another prospective cohort study followed 143 802 Chinese men and women 40 years and older. After adjustment for several important variables, the authors observed J-shaped relationship between BMI and occurrence of end-stage renal disease . The J-shaped relationship was maintained after additional adjustment for SBP and history of diabetes and cardiovascular disease. A characteristic though rare renal disorder associated with severe obesity is focal segmental glomerulosclerosis (FSGS). In a retrospective analysis of 6818 renal biopsies obtained between 1986 and 2000, obesity-associated FSGS increased continuously from 0.2 to 2.0% at the end of the observation period . Together, all these findings suggest that obesity and metabolic syndrome are important and potentially reversible causes of renal disease.
Diseased kidneys and diseased hearts
Somewhat counterintuitively, end-stage renal disease is not the prime cause of death in patients with diseased kidneys. Instead, patients with impaired renal function are exposed to an unacceptably high cardiovascular risk . Even subtle renal impairment profoundly increases cardiovascular morbidity and mortality. A Norwegian community-based study followed 9709 participants for 8.3 years . At baseline, glomerular filtration rate was estimated from serum creatinine measurements. The urine albumin to creatinine ratio was also determined. Reduced estimated glomerular filtration rate and albuminuria were synergistic cardiovascular mortality risk factors. However, the interaction between both risk factors may be complex as suggested by the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study . Another study examined the association between renal function and cardiovascular outcomes among 1 120 295 adults within a large, integrated healthcare delivery system . Compared with participants having normal renal function, the adjusted hazard ratio for death was 1.2 with an estimated glomerular filtration rate of 45–59 ml/min per 1.73 m2 with a gradual further increase up to 5.9 with an estimated glomerular filtration rate of less than 15 ml/min per 1.73 m2. The adjusted hazard ratio for cardiovascular events also increased inversely with estimated glomerular filtration rate. The prognosis is much worse in patients with end-stage renal disease requiring dialysis despite improvements over the years .
Why lifestyle interventions might work?
The idea that weight loss and physical exercise may ameliorate obesity-associated renal disease is appealing. However, whether lifestyle interventions indeed prevent hard renal endpoints has not been sufficiently tested. Moderate weight loss through caloric restriction and physical exercise induces a massive and sustained reduction in type 2 diabetes mellitus incidence [19,20]. The reduction in type 2 diabetes mellitus risk by itself could reduce the risk for renal disease. Diet-based and exercise-based lifestyle interventions have also been effective in the management of arterial hypertension. Other studies showed weight loss and exercise improve sympathetic and renin–angiotensin system activation [21–23]. In addition to improving risk factors for renal disease, weight loss in overweight and obese adults with mild-to-moderate chronic kidney disease resulted in a significant decrease in albuminuria, regardless of study designs and weight loss method . Furthermore, in patients with more severe kidney damage indicated by gross proteinuria, dietary weight loss reduced proteiuria by 1.7 g . An acute bout of intense exercise elicits a nonsustained increase in urinary albumin excretion . In contrast, endurance training over a longer period appeared to reduce albuminuria in patients with type 2 diabetes mellitus .
Now, Straznicky et al.  tested the hypothesis that physical exercise may provide additional beneficial influences on the kidney. The authors included middle-aged individuals fulfilling metabolic syndrome diagnostic criteria in their study. The mean BMI was in the obese range. Participants were randomized to dietary weight loss, combination of aerobic exercise with dietary weight loss, or to no treatment for 12 weeks. The hypocaloric intervention was composed of a modified Dietary Approaches to Stop Hypertension (DASH) diet with calorie restriction of 600 calories per day below the estimated requirements. In addition, participants randomized to the diet with exercise group trained 40 min every other day at a constant moderate intensity on a stationary bike. Body weight decreased approximately 8% in the diet only and almost 11% in the diet and exercise group. Albuminuria and estimated glomerular filtration rate was improved with diet-induced weight loss. Endurance exercise provided an additional benefit. Moreover, the authors observed reductions in muscle sympathetic nerve activity and plasma renin activity with lifestyle intervention. The study is not without limitations. The sample size was small. Moreover, more accurate estimates of glomerular filtration rate may be required to gauge the beneficial effect of lifestyle interventions on renal function. Finally, the investigators were well aware that biomarkers cannot serve as surrogates for hard clinical endpoints. Despite these issues, the study is important because it provides an impetus for larger and more long-term clinical trials. We strongly believe that patients adhering to an intense lifestyle intervention may experience long-term benefits in terms of renal and cardiovascular risk. Unfortunately, access to good quality lifestyle programs is limited in many places or not covered by health insurance. Finally, some patients cannot or do not wish to adhere to these interventions. Perhaps, as physicians, we sometimes fail to advise our patients properly. Run kidney, run.
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