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Melvin Bonilla Félix, M. D.Professor and Chairman,
Department of Pediatrics-University of Puerto [email protected]
Obesity and CKD
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Definition of obesity in children Prevalence of obesity in children Relationship between Obesity
and hypertension Relationship between Obesity
and CKD
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Obesity Facts – WHO 2016• 41 million children < 5 y/o are overweight or obese• >340 million children 5-19 y/o are overweight or obese• Once considered a high-income country problem, overweight
and obesity are now on the rise in low- and middle-income countries, particularly in urban settings.
• Africa• the number of overweight children under 5 has increased by nearly 50% since
2000.
• The prevalence of overweight and obesity among children and adolescents aged 5-19 y/o has risen from 4% in 1975 to > 18% in 2016.
• The rise has occurred similarly among both boys and girls: in 2016 18% of girls and 19% of boys were overweight.
• While just under 1% of children and adolescents aged 5-19 were obese in 1975, 6% of girls and 8% of boys were obese in 2016.
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Obesity Facts
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Risk of Adult Obesity
Ward ZJ et. Al N Engl J Med 2017;377:2145-53.
Early development of obesity predicts obesity in adulthood, especially for children who are
severely obese
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Shear CL et al. Hypertension 9: 236-244, 1987
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Holm JC et al. J Hypertens 30: 368, 2012
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Juonala M et al. NEJM 365:1876, 2011
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Became non-significant (OR 1.09, 95%CI 0.69-1.73, p=0.70) in multivariate analysis after adjustment for hypertension and
diabetes
Similar findings were observed when BMI was modeled as a continuous variable or as quartiles.
Am J Kidney Dis. 2008 July ; 52(1): 39–48
Obese individuals had a 68% increased odds of developing stage 3 CKD
(OR 1.68, 95%CI 1.10-2.57, p=0.02)
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Obesity and Proteinuria
E. Rashidbeygi et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13 (2019) 830e843
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Overweight:Independent Risk Of CKD
J Ejerblad E et. al. Am Soc Nephrol 17: 1695–1702, 2006
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Obesity and Renal Disease
Wang Y et. al. Kidney International (2008) 73, 19–33
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Obesity and CKD
Garofalo C et. al. Kidney International (2017) 91, 1224–1235
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Obesity and IgA
Hall E ey. Al Int J Nephrol and Renovascular Disease 2014:7 75–88
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BMI and Risk of ESRD
Hsu CY et. al Ann Intern Med. 2006; 144(1): 21–28.
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CKD and Healthy Obese
Jung CH et. al. Kidney International (2015) 88, 843–8
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Obesity and Unilateral Nephrectomy
Praga M et. al. Kidney International, Vol. 58 (2000), pp. 2111–2118
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Total Body Fat vs
Distribution
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Abdominal Obesity and Mortality in ESRD
Postorino M et. al. J Am Coll Cardiol 2009;53:1265–72
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Body Fat Distribution and FF
Kwakernaak AJ et. Al. J Am Soc Nephrol 24: 987–994, 201
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Renal Sinus Fat “Fatty Kidneys” and CKD
Foster MC et. al. Hypertension. 2011 November ; 58(5): 784–790.
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Gender Differences
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Obesity, Hypertension and CKD
Hall JE et. al. Circ Res 116: 991, 2015
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Hemodynamic Changes in Obesity
Chagnac A et. al. Am J Physiol 278: F817–F822, 2000 Henegar JR et. al, J Am Soc Nephrol 12: 1211–1217, 2001
D’Agati VD et. al. Nat Rev Nephrol 12: 453 – 471, 2016
•↑ Renal Blood Flow•Hyperfiltration•↑ Filtration Fraction
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Cassis LA. Curr Hypertens Rep. 2008 April; 10(2): 93–98
Adipose tissue produces angiotensinogen
Adipocytes express AT1 and AT2 receptors
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Aldosterone Blockers
De Paula RB et. al. Hypertension. 2004; 43:41-47
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Ramipril and Proteinuria in Obese
Mallamaci F et. al. J Am Soc Nephrol 22: 1122–1128, 2011
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Ramipril and ESRD in Obese
Mallamaci F et. al. J Am Soc Nephrol 22: 1122–1128, 2011
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Adipokine◦ 80% produced by
subcutaneous fat CNS -↓ food intake and
↑ energy expenditure – ↓ weight
↑ Levels in obesity◦ Leptin resistance
Selective
Leptin
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4
Mark AL et al. J Hypertens 1999; 17:1949 - 1953
Mutations in Leptin gene in humans leads to severe obesity, but normal BP
Ozata M et al. J Clin Endocrinol Metab 1999; 84: 3686 – 3695
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Adiponectin and Podocytes
Camara NO et. al Nat Rev Nephrol 2017;13:181-190.
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Adipokines and Glomerulopathy
D’Agati VD et. al. Nat Rev Nephrol. 2016 Aug;12(8):453-71
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Renal Lipotoxicity
• Lipids may cause renal mesangial and epithelial cell injury and may promote renal disease progression
Moorhead JF et. al. Lancet 2: 1309–1311, 1982
Ruan XZ et al. Biochem Soc Trans 32: 88–91, 2004
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Role of the Microbiota
Camara NO et. al Nat Rev Nephrol 2017;13:181-190.
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Histopathology of Obese CKD• Obesity-related Glomerulopathy
• Glomerulomegaly
Rea DJ, Heimbach JK, Grande JP, Textor SC, Taler SJ, Prieto M, Larson TS, Cosio FG, Stegall MD: Glomerular
volume and renal histology in obese and non-obese living kidney donors. Kidney Int 70: 1636–1641, 2006
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Cohen AH et. al. Am J Pathol 1975;81:117–130
Obesity-Related Glomerulopathy
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The Obesity Paradox
272 Kidney International Reports (2017) 2, 271–281
Kalantar-Zadeh K et. al. Kidney International Reports (2017) 2, 271–2
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Mechanisms
Kovesdy CP et. al. Kidney International (2017) 91, 260–262
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Therapeutic Lifestyle Changes
The JNC 7 Report. JAMA. 2003; 289: 2560 – 2572
Change Effect on BP⇓ Weight 5–20ºmmHg/10 kg ⇓ weight
DASH Diet(⇑ Fruits, vegetables ⇓ dairy products and fat)
8–14 mmHg
⇓ Na+ 2–8 mmHg (Greater effect in obese)
⇑ Physical activity 4–9 mmHg
⇓ Alcohol consumption 2–4 mmHg
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ORG: Effect of Weight Loss
Shen WW et. al. Clin J Am Soc Nephrol 5: 1401–1409, 2010
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Avoid agents that increase insulin resistance◦ β blockers◦ Thiazide diuretics
Combination of these agents can be diabetogenic (ALLHAT)
Use agents that enhance insulin sensitivity◦ ACE inhibitors
Enalapril ↑adiponectin*◦ Angiotensin receptor
blockers May prevent diabetes
◦ α Blockers Beneficial effect on lipids
◦ Calcium channel blockers Dihydropyridines -↑HR Nondihydropyridines -
↓cardiac contractility ◦ α +β blocker
Carvedilol, Labetalol
Fontana V et al. Basic Clin Pharmacol Toxicol 2014
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Increasing use in adolescents
Safe
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Consider surgery only after youth have tried for at least 6 months to lose weight and have not had success
Should meet the following criteria:◦ Have extreme obesity (BMI > 40 )◦ Be their adult height (usually at age 13 or older
for girls and 15 or older for boys)◦ Have serious health problems linked to weight,
such as type 2 diabetes or sleep apnea, that may improve with bariatric surgery
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108 Children5 – 21 y/oLaparoscopic gastrectomy
Alqahtani SA et al. Ann Surg 2012
How young?
Long-term complications and efficacy?
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Bariatric Surgery and Renal Function
Bolignano D et. al. Nephrol Dial Transplant. 2013; 28 Suppl 4:iv82-98
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Summary-1• The incidence of ORG is increasing in parallel with
the worldwide obesity epidemic• Pathologic features include glomerulomegaly and
FSGS, particularly the perihilar variant; the degree of foot process effacement in ORG is usually less than in primary FSGS
• Subnephrotic proteinuria is the most common clinical presentation of ORG• some patients have nephrotic-range proteinuria and
progressive loss of renal function but full nephrotic syndrome is highly unusual
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Summary-2• Major renal physiologic responses to obesity include
increases in GFR, RPF, FF, and tubular reabsorption of sodium
• Adipokines and ectopic lipid accumulation in the kidney promote maladaptive responses of renal cells to the mechanical forces of hyperfiltration, leading to podocyte depletion, proteinuria, FSGS and interstitial fibrosis
• Therapeutic interventions include RAAS inhibition and weight loss; novel strategies involve administration of small molecules that specifically modulate deleterious pathways of fatty acid and cholesterol metabolism
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Thanks