The Influence of Obesity on Kidney Health

Obesity is a major challenge to domestic and international public health. As of 2008 in the United States nearly one in four adults was obese (1). In that same year, the World Health Organization estimated that approximately 500 million adults throughout the globe were obese (with an additional 1 billion being overweight) (2).

Obesity is widely considered a harbinger for a multitude of diseases, particularly diabetes and hypertension. In recent years a growing body of evidence has suggested that kidney disease, too, may be included in this list of illnesses. In fact, one published report estimates that up to one third of kidney disease in the United States could be related to obesity (3). But how strong is the evidence that obesity has deleterious effects on kidney health, and what therapeutic interventions are available? These questions are increasingly relevant to every practicing nephrologist.

An association between obesity and kidney disease was noted in the modern medical literature as early as 1923, when Boston practitioner William Preble described a high rate of albuminuria and nephritis in his large cohort of obese patients (4). From the 1970s onward, a series of case reports described the existence of proteinuria and glomerular hyperfiltration in severely obese individuals. Interestingly, weight loss almost immediately reversed these conditions. Subsequent animal studies have confirmed that renal changes accompany obesity. In one such study, Henegar and colleagues induced obesity in a cohort of dogs and noted structural and immunohistochemical changes in the kidney, although they could not isolate the independent effects of obesity from the development of other pathologic states such as hypertension and insulin resistance (5). More recently many, but not all, observations in humans have confirmed a link between obesity and glomerular hypertrophy/hyperfiltration and proteinuria (6). A minority of obese individuals also appear to develop obesity-related glomerulopathy, a process that can be associated with focal segmental glomerular sclerosis and progression to end stage renal disease (ESRD)(7).

A growing body of epidemiologic evidence supports the direct association between obesity and kidney disease, even after accounting for intermediate disease states like hypertension and diabetes. In one such study, conducted in a cohort of over 300,000 Kaiser Permanente patients, increasing body mass index was linked with a stepwise increase in the risk of ESRD during decades of follow-up (8). Individuals with extreme obesity (body mass index ≥40) actually had more than a seven times greater risk of developing ESRD over the follow-up period than did persons of normal weight. Adjustment for the presence of diabetes and hypertension attenuated the relationship somewhat, but the risk conferred by obesity was still greatly elevated. Similar findings have been documented in other populations (9, 10). Obesity has also been implicated as an independent risk factor leading to the accelerated progression of other primary renal diseases, such as IgA nephropathy (11).

Scientific data increasingly support the hypothesis that obesity has adverse effects on kidney health, yet several central questions remain. For example, the mechanisms are poorly understood. Investigators have implicated several possible factors (Table 1), including alterations in levels of adipocyte-related cytokines such as leptin and adiponectin (as well as other hormones), upregulation of the renin-angiotensin axis and sympathetic nervous activity, insulin resistance, renal-associated lipotoxicity, protein consumption, and hemodynamic factors such as hyperfiltration and hypertension. However, the exact pathogenesis is still unknown. Of note, it is also not well understood whether the hallmark hemodynamic changes and increased proteinuria observed in obese individuals are simply functional, benign adaptations, or truly pathologic. Why obesity affects kidney health in some but not all obese individuals is yet another mystery. Preliminary research raises the possibility that preterm birth may predispose certain obese individuals to renal disease, perhaps through the underdevelopment of nephron mass (12).

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A final question relates to identifying effective treatment strategies. Some insight into this issue has been gleaned from the study of bariatric surgery patients before and after surgery-induced weight loss. The advantage of using this model, which is not without limitations, is that investigators can compare changes in renal function and health within individual patients after guaranteed (and usually profound) weight loss.

Studies performed in relatively healthy bariatric surgery patients essentially confirm the findings from animal models that weight loss reduces glomerular hyperfiltration and proteinuria (13). It is not known whether this effect is renoprotective because so few patients with pre-existing kidney disease have been studied before and after bariatric surgery. Yet a fairly consistent proteinuria-reducing effect has been noted from nonsurgical weight loss therapies in patients with proteinuric nephropathies (14). Thus, the intuitive concept that weight loss ameliorates obesity-related kidney disease (or at least proteinuria) is supported by the limited scientific data currently available, although the minimum weight loss required is not known, nor is the persistence of this effect over time.

Researchers have also focused on blockade of the renin-angiotensin axis as a potential treatment, given the acknowledged deleterious effects of an upregulated renin-angiotensin system common in obesity. A recent post-hoc analysis of a randomized, controlled trial found that the angiotensin-converting enzyme inhibitor ramipril had disproportionately greater effects on reducing proteinuria and the risk of ESRD in overweight and obese grossly proteinuric kidney disease patients than it did in similarly diseased lean patients (15).

The intimate connection between the obesity crisis and the growth of the chronic kidney disease population makes it likely that this topic will become increasingly prominent in coming years. It is also expected that the many unanswered questions surrounding both the causes of obesity-related kidney disease and its optimal treatment will be tackled with greater urgency.

Notes

[1] Allon Friedman, MD, FASN, is a nephrologist and clinical investigator at Indiana University School of Medicine.

References

1. legal KM, et al. Prevalence and trends in obesity among U.S. adults, 1999–2008. JAMA 2010; 303:235–241.

3. Wang Y, et al. Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int 2008; 73:19–33.

4. Preble W. Obesity: observations on one thousand cases. Boston Med Surg J 1923; 188:617–621.

5. Henegar JR, et al. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 2001; 12:1211–1217.

6. Serra A, et al. Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008; 73:947–955.

7. Kambham N, et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001; 59:1498–1509.

8. Hsu CY, et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006; 144:21–28.

9. Iseki K, et al. Body mass index and the risk of development of end-stage renal disease in a screened cohort. Kidney Int 2004; 65:1870–1876.

10. Fox CS, et al. Predictors of new-onset kidney disease in a community-based population. JAMA 2004; 291:844–850.

11. Bonnet F, et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis 2001; 37:720–727.

12. Abitbol CL, et al. Obesity and preterm birth: additive risks in the progression of kidney disease in children. Pediatr Nephrol 2009; 24:1363–1370.

13. Chagnac A, et al. The effects of weight loss on renal function in patients with severe obesity. J Am Soc Nephrol 2003; 14:1480–1486.

14. Afshinnia F, et al. Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts. Nephrol Dial Transplant 2009; 25:1173–1183.

15. Mallamaci F, et al. ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol 2011; 22:1122–1128.

October-November 2011 (Vol. 3, Number 10 & 11)