Open Journal Systems

REVIEW ARTICLES

Received: April 29^th 2015

Accepted: January 26^th 2016

Obesity in children and its relationship with chronic kidney disease

Jessie Nallely Zurita-Cruz,^a Miguel Ángel Villasís-Keever^b

^aServicio de Escolares y Adolescentes

^bUnidad de Investigación en Epidemiología Clínica

UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Miguel Ángel Villasís-Keever

Telephone: 5627 6900, extensión 22501

Email: miguel.villasis@imss.gob.mx

In the last decades, obesity and chronic kidney disease (CKD) have increased worldwide, in parallel. This article focuses on the current issues of obesity on renal damage, with special emphasis on what happens at pediatric ages. While obesity has been linked closely with type 2 diabetes mellitus and hypertension, reduced insulin sensitivity is a direct mechanism for renal damage. The pathophysiologic mechanisms on renal damage include glomerular hyperfiltration and hypertrophy, hypCKDellularity and broadening of the mesangial regions, while the lack of sensitivity to insulin increases the effects of angiotensin II, exacerbates proteinuria and induces the production of inflammatory cytokines. Many epidemiological studies have documented the relationship of increased BMI with the development of CKD, but most of these studies have been conducted in adults. In children, the information is scarce, but is consistent with findings in adults. In contrast, there are studies which show that interventions aimed to improve weight loss and limit renal damage and proteinuria is reduced, the blood pressure and glomerular filtration rate. Allthe above make us think on the need to improve efforts to reduce the prevalence of obesity from the early stages of life, which could reduce the number of patients with CKD in the future.

Keywords: Obesity; Chronic renal insufficiency; Adolescent health; Pediatrics

---

Worldwide, in recent decades a significant increase in the prevalence of chronic kidney disease (CKD) in end-stage has been reported, parallel to the growing increase in the frequency of overweight and obesity in the population. It has long been well known that obesity, along with the other components of metabolic syndrome, contributes directly to the development of cardiovascular disease; however, its relationship with CKD is an issue that has gained interest more recently. The increase of overweight or obese children and adolescents is a situation that is currently a public health problem, because of the implications that it will have in the medium- and long-term related to consequences such as diabetes mellitus, dyslipidemia, and hypertension.¹ This article presents a review of the relationship of the problems of obesity with the development of CKD, from basic, epidemiological, and clinical perspectives, paying special attention to what happens in pediatric patients.

Pediatric kidney disease and its relation to obesity

Like obesity, the prevalence of CKD has been increasing both in adults and in children and adolescents. The main causes of CKD in the pediatric population in order of frequency are: glomerular diseases (including primary glomerulonephritis and glomerulosclerosis), reflux nephropathy and obstructive uropathy, hereditary nephropathy (such as cystinosis, Alport syndrome, oxalosis, and nephronoptisis), renal dysplasia and hypoplasia, vascular (including hemolytic-uremic syndrome), among others.²

Evaluation and treatment of patients with CKD requires knowledge about the etiology, comorbidities, disease severity and complications, risk of progressive loss of kidney function, and the presence of cardiovascular disease. In any stage, treatment is aimed at limiting both loss of renal function and complications; the latter include hypertension, anemia, acidosis, and failure to thrive. The prevention and treatment of cardiovascular disease is also important as part of these activities, as this is the leading cause of death children and adults with CKD. An example is the study in pediatric patients who died with CKD in replacement therapy in Europe from 1987 to 1990: it was observed that in 51% of dialysis patients and 37% of renal transplant patients, the cause of death was cardiovascular disease.³

Different studies at the population level have shown that obesity increases the risk of CKD and that the latter is also an independent risk factor for cardiovascular events; however, most of these studies were performed in adults. In children and adolescents the information is controversial, but in general, the findings confirm that obesity in the pediatric stage can also encourage the development of kidney problems, which may even appear before hypertension or diabetes. In the long term, the impact of obesity on CKD and cardiovascular disease in adulthood often has its origin in infancy.^4,5

Obesity as a risk factor for CKD

Information on the relationship of obesity as an independent risk factor for the development of CKD is diverse, and it can be determined that kidney damage can occur directly or indirectly. Thus, CKD has been closely linked to the consequences of obesity and type 2 diabetes mellitus (DM2) or hypertension (HT); while on the other hand different findings imply that CKD can be only secondary to overweight or obesity, which has been associated with reduced insulin sensitivity (IS), which has been considered a sufficient mechanism for kidney damage.⁶

The Framingham Study initiated in 1971 and included 5124 individuals, who were examined about every 4 years; in 2008 it showed that patients with obesity-associated hypertension, dyslipidemia, and diabetes mellitus had a higher risk (OR 1.68, 95% CI 1.10-2.57) of developing stage 3 CKD, compared to the population that did not have these risk factors.⁷ In another study, Gelber et al.⁸ reported a directly proportional association between body mass index (BMI) and risk of stage 3 CKD in 11,104 subjects after 14 years of follow-up; the authors observed that with a BMI > 26.6 kg/m² there is a 26% increase in the probability of developing CKD (OR 1.26; p = 0.007). Like this study, other authors have reported similar findings, where there has been a clear relationship between BMI and increased risk of kidney damage; for this reason and in order to synthesize the information available at the time, in 2008 Wang et al. conducted a systematic review of 25 cohort, 19 case-control, and 3 cross-sectional studies, carrying out a meta-analysis that confirmed the association, but also determined that there is increased risk of CKD the higher the degree of overweight or obesity; so, when comparing normal weight adults with those who had a BMI ≥ 25 kg/m² but < 30 kg/m², the risk of CKD was RR 1.40 (95% CI: 1.30-1.50), but greater with BMI ≥ 30 kg/m² (RR 1.83, 95% CI: 1.57-2.13).⁹

It is worth mentioning that in addition to BMI, waist-hip ratio (WHR) was examined as a risk factor for CKD, which seemed like an earlier marker of kidney damage. Elsayed et al., after studying 21,258 men and women with normal serum creatinine values ​​for about nine years, found that a WHR increase of one standard deviation predicted a 22% increase risk of CKD, which was not observed with BMI.¹⁰ This same observation was found in a similar study, which showed that proteinuria increased with higher WHR, which even occurred in individuals with BMI < 25 kg/m².¹¹

In patients with obesity it has been determined that there is glomerular hypertrophy, which is probably a state of hyperfiltration that occurs chronically, which increases when obesity is accompanied by other co-morbidities. In a Japanese study in 2001 with 41 subjects with obesity, renal biopsies were all found to show glomerular hypertrophy, which was more frequent in subjects with hypercholesterolemia and HT. At 12-month follow-up, only in the group of obesity associated with HT were there patients who progressed to kidney failure.¹²

Originally the presence of microalbuminuria was considered, more than a marker of early diabetic nephropathy, a long-term predictor of mortality from cardiovascular disease in adult subjects, considering that the loss of glomerular albumin reflects general vascular damage and a condition of preclinical atherosclerosis, as well as a sign of endothelial dysfunction;¹³ it is also considered useful as a predictive condition in obese adolescents with microalbuminuria. Burgert et al.¹⁴ studied 277 obese pre-diabetic adolescents (BMI > 97 percentile), with proper thyroid function, identifying microalbuminuria in 10.1%; meanwhile Verhulst et al. in 94 obese patients observed that microalbuminuria was present in 4.6%, which was negatively correlated with insulin, glucose, and C-peptide levels (r = -0.30, r = -0.23, r = -0.23, respectively), which was statistically significant.¹⁵ Both studies support the hypothesis that obesity causes early kidney damage.

As discussed, the available evidence on obesity as a risk factor for CKD specifically in children is scarcer than in adults; these studies not only come from people with overweight or obesity, but include people with varying degrees of renal damage. In one such study, 3607 children with end-stage CKD were followed for seven years, finding that the risk of death was positively correlated with BMI, so a BMI > 1 SD was associated with 6% increased mortality (RR = 1.06, 95% CI: 0.95-1.18); when it was > 2 SD, risk increased by 26% (RR = 1.26, 95% CI: 1.01-1.57), and at 3 SD the risk was 67% (RR = 1.67, 95% CI: 1.14-2.45).¹⁶

Meanwhile, Filler et al. in 2005 analyzed 17 years of experience with 6154 patients treated at a pediatric nephrology center in Canada, noting that there was an increased incidence of CKD patients with obesity. In the period 1984-1992 the median BMI z-score (z-BMI) went from 0.20 to 0.32 for the period 1993-2002 (p = 0.001).¹⁷

The case study by Hanevold et al., conducted in the United States with 6658 children, reported that compared with patients without obesity, patients with obesity and CKD were significantly younger and had been in dialysis for more time. In addition, in patients aged 6 to 12 years who underwent kidney transplantation who were obese had an increased risk of dying, both living-donor graft recipients (RR = 3.65, 95% CI: 1.46-9.11), and cadaveric graft recipients (RR = 2.94, 95% CI: 1.53-5.63).¹⁸ In addition to mortality, it seems that obesity may cause greater likelihood of graft rejection in pediatric kidney transplant patients. In a study published in 2002, dividing 76 pediatric patients according to the presence of obesity (BMI ≥ 95^th percentile), it was determined that the glomerular filtration rate (GFR) was significantly lower than a year after the transplant in those were obese from the time of transplantation (46.1 ± 15.0 mL/min/1.73 m²), compared to those who developed obesity after transplantation (57.7 ± 24.5 mL/min/1.73 m²) or those who were not obese during the follow-up period (60.4 ± 21.5 mL/min/1.73 m²).¹⁹ Recently, Kelishadi et al. studied 113 obese adolescents and compared some markers of renal function among subjects with and without metabolic syndrome, identifying lower GFR in patients with metabolic syndrome (105 ± 20.1 ml/min/1.73 m² versus 127 ± 24.9 mL/min/1.73 m², p = 0.0001) and higher serum cystatin-C (0.87 ± 0.14 mg/L versus 0.81 ± 0.1 mg/L, p = 0.01) and creatinine (0.89 ± 0.1 mg/dl versus 0.78 ± 0.1 mg/dl, p = 0.001); the microalbuminuria/creatinine ratio had no statistically significant difference between the groups.²⁰

On the other hand, interestingly, even though it is known that obesity causes glomerular hyperfiltration, albuminuria, or proteinuria and glomerulomegaly in the kidney, a kidney disorder directly caused by obesity has been recognized for some years, which has been termed obesity-related glomerular disease, first described in 1974 and defined as a condition with the following elements: individuals with BMI > 28 kg/m², proteinuria ≥ 0.4 g/24 h, but not within nephrotic range, glomerulomegaly (glomerular volume > 3.27 '106), with or without focal and segmental glomerular sclerosis.²¹ This condition is reported increasingly often in the literature.⁵

In addition to what is already described, it is important to mention that obesity also has been linked to a negative effect on renal function in patients with any preexisting renal condition, such as nephrotic syndrome, focal segmental glomerular sclerosis, or unilateral nephrectomy, conditions that are common in pediatric patients. Also, as an indirect effect in patients with hypertension and diabetes mellitus, overweight or obesity increases the risk of microalbuminuria; while similarly with IgA glomerulonephritis, greater BMI has been linked to progression in both adult and child patients.^22,23

Pathophysiology of kidney damage by obesity

Various pathophysiological glomerular changes have been described that occur in obesity in both humans and animal models.^24,25 These changes include glomerular hypertrophy, mild hypercellularity, and variable widening of the mesangial regions, which is an important pathogenetic mechanism for the presence of focal segmental glomerular sclerosis. Glomerular hyperfiltration and hyperperfusion are due to maladaptation resulting from vasodilatation of the afferent arteriole. Serum hyperinsulinemia reflects reduced sensitivity to insulin in peripheral tissues, including kidney tissue, which is the pivot of the pathophysiology of damage. Insulin level in the normal renal tubule has an antidiuretic effect, increasing sodium reabsorption without affecting GFR, renal plasma flow, filtered glucose load, and plasma aldosterone levels. In experimental studies, it has been observed that insulin seems to slightly increase the glomerular filtration rate, possibly due to a direct vasodilatory effect.²⁶ More recently a relationship between GFR and reduced insulin sensitivity has been shown; in very obese patients, high GFR may be the result of increased capillary pressure difference. Hyperinsulinemia also seems to be related to a direct and selective increase in the urinary albumin excretion rate in patients with DM2. Insulin also interferes with the renin-angiotensin-aldosterone system, increasing its activity, regardless of the sodium concentration and volume.²⁷ Furthermore, insulin also increases the effects of angiotensin II on mesangial cells, which contributes to hypertension, increases intraglomerular pressure, worsens proteinuria, and induces production of intrarenal inflammatory cytokines and growth factors, as well as apoptosis.²⁸ It was also determined that insulin per se may promote mesangial cell proliferation and the extracellular production of matrix proteins, altering the interstices and basal membrane of collagens by the mesangial cells. It also stimulates the expression of other growth factors such as insulin-like growth factor 1 (IGF-1) and transforming growth factor beta 1 (TGF-beta1), which are involved in numerous mitogenic and fibrotic processes of diabetic nephropathy,²⁹ as well as increasing the activity of connective tissue growth factor, which has profibrogenic action on renal tubular cells and interstitial fibroblasts.³⁰

On the other hand, visceral adipose tissue as a known source of proinflammatory cytokines, including components of the renin-angiotensin-aldosterone system, tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL -6), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), leptin, and resistin, are involved in the reduction of insulin sensitivity, and in renal pathophysiology, contributing to glomerular mesangial increase, remodeling podocytes, loss of pore diaphragm integrity, and basal membrane thickening.³¹

Specifically in the kidney, IL-6 promotes the expression of adhesion proteins and generates oxidative stress in epithelial, mesangial, and endothelial cells,³² while CRP stimulates the production of endothelin-1 and IL-6 from endothelial cells, as well as the release of MCP-1 which facilitates leukocyte migration and endothelial cell apoptosis, secondary to the inhibition of nitric oxide production that induces glomerular damage.^33,34 MCP-1 was measured in obese and non-obese adult male subjects, where obese patients had higher levels that correlated positively with cystatin-C levels, which may suggest initial kidney damage.³⁵ Meanwhile leptin causes increased renin release,³⁶ stimulation of cell proliferation, and production of type IV collagen in glomerular endothelial cells, encouraging renal fibrosis.³⁷

The degree of insulin sensitivity is closely associated with oxidative stress markers and inversely with antioxidant levels,³⁸ in which it contributes to the progression of renal damage. Increased oxidative stress markers have been reported both in patients with early diabetic nephropathy and in patients with stages 3 and 4 CKD.³⁹

Finally, visceral adipose tissue generates high circulating levels of free fatty acids, which together with decreased adiponectin, leptin resistance, cytokine secretion, and macrophage accumulation, causes a reduction in mitochondrial consumption of these fatty acids, promoting their accumulation.⁴⁰ There is evidence that lipids can cause mesangial damage, bringing about progression of kidney damage. Proteinuria observed by the tubular-interstitial and glomerular damage is a result of lipotoxicity by free fatty acids.⁴¹

Measures to prevent kidney damage by overweight/obesity

Preventive and therapeutic strategies to improve nutritional status in pediatric patients with obesity should be applied to prevent the onset or progression of kidney damage, as described in the systematic review prepared by the Cochrane Collaboration, which selected 64 randomized controlled trials (5230 participants) for the treatment of obesity in children (mean age: 18 years), determining the usefulness of the combination of lifestyle changes (i.e., diet, physical activity, and/or behavioral therapy) with drug therapy (metformin, orlistat, or sibutramine), with or without the support of family members, for a minimum of six months.⁴² However, it is recommended that initial obesity treatment (and for about six months) should be based on lifestyle changes, only adding drug treatment in cases of failure of the intensive formal lifestyle modification program, or when severe comorbidities persist despite lifestyle change, particularly in children with a family history of type 2 diabetes or premature cardiovascular disease.⁴³ Bariatric surgery is suggested only for adolescents with Tanner 4 and 5 and BMI > 50 kg/m², or BMI > 40 kg/m² in patients with severe comorbidities, considering that the combination of lifestyle change and drug therapy have failed.⁴⁴ It has been observed that the type of patients with decreased BMI after surgery present reduced albuminuria and increased glomerular filtration and renal plasma flow, irrespective of blood pressure.⁴⁵

There have been several studies on the effects that interventions to reduce or limit kidney damage can have, which are concentrated in two recently published systematic reviews. One of them evaluated the benefits of 13 interventions to reduce weight in patients with CKD not on dialysis but with glomerular hyperfiltration. The meta-analysis of five studies on the effect of diet, exercise, with or without medications, over a period of about seven months, determined that in addition to the significant reduction in BMI (weighted mean difference [WMD] -3.67 kg/m²; 95% CI: -6.56 to -0.78), there was a statistically significant decrease in proteinuria (WMD -1.31 g/24 h, 95% CI: -2.11 to -0.51) and systolic blood pressure (SBP) (WMD -8.98 mmHg; 95% CI: -14.23 to -3.74), but without showing greater decrease in GFR (WMD -4.25; 95% CI: -3.33 to +11.81). This same trend in results was obtained for BMI, SBP, and albuminuria in patients with BMI > 40 kg/m² with glomerular hyperfiltration (GFR > 125 mL/min) who had bariatric surgery; however, the reduction in GFR was very clear (WMD -25.56 ml/min; 95% CI: -36.23 to -14.89).⁴⁶

The most recent systematic review and meta-analysis included the same studies described in the previous paragraph, but with two others added. The authors generally obtained similar results but added that each kilogram of weight loss is associated with 110 mg decrease (95% CI: 60-160 mg, p < 0.001) of proteinuria and 1.1 mg (95% CI: 0.5-2.4 mg, p = 0.011) of microalbuminuria, in both cases a reduction of about 4%. It also mentioned that these results are independent of the use of angiotensin-converting enzyme inhibitor, indicating that creatinine clearance also improves with bariatric procedures.⁴⁷

Conclusions

Recent decades have recognized the kidney damage that causes obesity, independently of the presence of type 2 diabetes or hypertension, which has been associated with an increase in the incidence of patients with CKD, which has paralleled the increase in obesity. This kidney damage has different pathophysiologic mechanisms, but the main one seems to be related to the decrease in insulin sensitivity. Increasing prevalence of overweight and obesity in children and adolescents makes one reflect on the need to increase efforts to improve nutrition starting early in life, which has the potential to prevent the development of kidney disorders or limit existing damage. In this context, scrutiny of renal function in comprehensive management of patients with obesity should also be considered.

References

1. Alicic R, Patakoti R, Tuttle K. Direct and indirect effects of obesity on the kidney. Advs Chronic Kidney Dis. 2013; 20: 121-7.
2. Luque de Pablos A, Morales M, Izquierdo E, Aparicio C, Fernández Escribano A. Insuficiencia renal crónica en niños. Pediatr Integral. 2000; 5: 929-44.
3. Hogg R, Furth S, Lemley K, Portman R, Schwartz G, Coresh J, et al. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease in Children and Adolescents: evaluation, classification, and stratification. Pediatrics. 2003; 111: 1416-21.
4. Savino A, Pellicia P, Chiarelli F, Mohn A. Obesity-related renal injury in childhood. Horm Res Pediatr. 2010; 303-11.
5. Ritz E. Obesity and CKD: How to assess the risk? Am J Kidney Dis. 2008; 52:1-6.
6. Srivastava T. Nondiabetic consequences of obesity on kidney. Pediatr Nephrol. 2006; 21: 463-70.
7. Foster M, Hwang S, Larson M, Lichtman J, Parikh N, Vasan R, et al. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis. 2008; 52: 39-48.
8. Gelber R, Kurth T, Kausz A, Manson J, Buring J, Levey A, et al. Association between body mass index and CKD in apparently healthy men. Am J Kidney Dis. 2005; 46: 871-80.
9. Wang Y, Chen X, Klag M, Caballero B. Epidemic of childhood obesity: implications for kidney disease. Adv Chronic Kidney Dis. 2006; 13: 336-51.
10. Elsayed E, Sarnak M, Tighiouart H, Griffith J, Kurth T, Salem D, et al. Waist-to-hip ratio, body mass index, and subsequent kidney disease and death. Am J Kidney Dis. 2008; 52: 29-38.
11. Pinto-Sietsma S, Navis G, Janssen W, de Zeeuw D, Gans R, de Jong P. A central body fat distribution is related to renal function impairment, even in lean subjects. Am J Kidney Dis. 2003; 41: 733-41.
12. Sasatomi Y, Tada M, Uesugi N, Hisano S, Takebayashi S. Obesity associated with hypertension or hyperlipidemia accelerates renal damage. Pathobiology. 2001; 69: 113-8.
13. Pedrinelli R, Dell’Omo G, Penno G, Mariani M. Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease. Vasc Med 2001; 6: 257-64.
14. Burgert T, Dziura J, Yeckel C, Taksali S, Weiss R, Tamborlane W, et al. Microalbuminuria in pediatric obesity: prevalence and relation to other cardiovascular risk factors. Int J Obes 2006; 30: 273-80.
15. Verhulst S, Van Hoeck K, Schrauwen N, Haentjens D, Rooman R, Van Gaal L, et al. Sleep-disordered breathing and proteinuria in overweight and obese children and adolescents. Horm Res. 2008; 70: 224-9.
16. Wong C, Gipson D, Gillen D, Emerson S, Koepsell T, Sherrard D, et al. Anthropometric measures and risk of death in children with endstage renal disease. Am J Kidney Dis. 2000; 36: 811-9.
17. Filler G, Payne R, Orrbine E, Clifford T, Drukker A, McLaine P. Changing trends in the referral patterns of pediatric nephrology patients. Pediatr Nephrol. 2005; 20: 603-8.
18. Hanevold C, Ho P, Talley L, Mitsnefes M. Obesity and renal transplant outcome: A Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatrics. 2005; 115: 352-6.
19. Mitsnefes M, Khoury P, McEnery P. Body mass index and allograft function in pediatric renal transplantation. Pediatr Nephrol 2002; 7: 535-9.
20. Kelishadi R, Gheissari A, Bazookar N, Esmaeil M, Taslimi M, et al. Kidney function in obese adolescents with or without metabolic syndrome in a nationally-representative sample of pediatric population: First report from the Middle East and North Africa: The CASPIAN-III Study: A Case-Control Study. J Res Med Sci. 2013;18: 178-83.
21. Chen H, Li S, Chen H, Wang Q, Li L, Liu Z. Obesity-related glomerulopathy in China: a case series of 90 patients. Am J Kidney Dis. 2008; 52: 58-65.
22. Bonnet F, Deprele C, Sassolas A, Moulin P, Alamartine E, Berthezène 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: 720-7.
23. Kataoka H, Ohara M, Shibui K, Sato M, Suzuki T, Amemiya N, et al. Overweight and obesity accelerate the progression of IgA nephropathy: prognostic utility of a combination of BMI and histopathological parameters. Clin Exp Nephrol. 2012; 16: 706 – 12.
24. Shimamura t. Focal glomerulosclerosis in obese Zucker rats and prevention of its development. Kidney Int .1983; 24: 5259-62.
25. Yoshikawa Y, Yamasaki K. Renal lesions of hyperlipidemic Imai rats: A spontaneous animal model of focal glomerulosclerosis. Nephon 1991; 59: 471 – 6.
26. Sartori C, Scherrer U. Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation. J Hypertens 1999; 17: 1517-25.
27. El-Atat F, Stas S, McFarlane S, Sowers J. The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol. 2004; 15: 2816-27.
28. Ruster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol. 2006; 17: 2985-91.
29. Morrisey K, Evans R, Wakefield L, Phillips A. Translational regulation of renal proximal tubular epithelial cell transforming growth factor-beta1 generation by insulin. Am J Pathol. 2001; 159: 1905-15.
30. Wang S, Denichilo M, Brubaker C, Hirschberg R. Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy. Kidney Int. 2001; 60: 96-105.
31. Schelling J, Sedor J. The metabolic syndrome as a risk factor for chronic kidney disease: more than a fat chance? J Am Soc Nephrol. 2004; 15: 2773-4.
32. Spoto B, Zoccali C. Spleen IL-10, a key player in obesity-driven renal risk. Nephrol Dial Transplant. 2013;28:1061-4.
33. Pasceri V, Willerson J, Yeh E. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165-2168.
34. Pasceri V, Chang JS, Willerson J, Yeh E. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 2001; 103: 2531-2534.
35. Fu C, Lee I, Sheu W, Lee W, Liang K, et al. The levels of circulating and urinary monocyte chemoattractant protein-1 are associated with chronic renal injury in obese men. Clin Chim Acta. 2012;413:1647-51.
36. Berlin de Chantemele E, Mintz J, Rainey W, Stepp D. Impact of leptin-mediated sumpatho-activation on cardiovascular function in obese mice. Hypertension. 2011; 58:271-9.
37. Gunta S, Mak R. Is obesity a risk factor for chronic kidney disease in children? Pediatr Nephrol. 2013; 28:1949-56.
38. Facchini F, Humphreys M, DoNascimento C, Abbasi F, Reaven G. Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr. 2000; 72: 776-9.
39. Oberg B, McMenamin E, Lucas F, Mc-Monagle E, Morrow J, Ikizler T, et al. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 2004; 65: 1009-16.
40. Bagby S. Obesity-initiated metabolic syndrome and the kidney: A recipe for chronic kidney disease? J Am Soc Nephrol. 2004;15:2775-91.
41. Thomas M, Harris K, Walls J, Furness P, Brunskill N. Fatty acids exacerbate tubulointerstitial injury in proteinoverload proteinuria. Am J Physiol Renal Physiol; 2002;283:F640-7.
42. Luttikhuis O, Baur L, Jansen H, Shrewsbury V, O’Malley C, Stolk R, et al. Interventions for treating obesity in children. Cochrane Database Syst Rev 2009; 1: CD001872.
43. Freemark M. Pharmacotherapy of childhood obesity: an evidence-based, conceptual approach. Diabetes Care 2007; 30: 395-402.
44. Mechanick J, Kushner R, Sugerman H, Gonzalez-Campoy M, Collazo-Clavell M, Guven S, et al American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery Medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Endocr Pract. 2008; 14: 1-83.
45. Amann K, Benz K. Structural renal changes in obesity and diabetes. Semin Nephrol. 2013; 33: 23-33.
46. Navaneethan S, Yehnert H, Moustarah F, Schreiber M, Schauer P, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009; 4: 1565-74.
47. Afshinnia F, Wilt T, Duval S, Esmaeili A, Ibrahim H. Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts. Nephrol Dial Transplant. 2010; 25: 1173-83.

Enlaces refback

• No hay ningún enlace refback.