Melvin Bonilla Félix, M. D.Professor and Chairman,

Department of Pediatrics-University of Puerto Ricomelvin.bonilla1@upr.edu

Obesity and CKD

Definition of obesity in children Prevalence of obesity in children Relationship between Obesity

and hypertension Relationship between Obesity

and CKD

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.

Obesity Facts

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

Shear CL et al. Hypertension 9: 236-244, 1987

Holm JC et al. J Hypertens 30: 368, 2012

Juonala M et al. NEJM 365:1876, 2011

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)

Obesity and Proteinuria

E. Rashidbeygi et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13 (2019) 830e843

Overweight:Independent Risk Of CKD

J Ejerblad E et. al. Am Soc Nephrol 17: 1695–1702, 2006

Obesity and Renal Disease

Wang Y et. al. Kidney International (2008) 73, 19–33

Obesity and CKD

Garofalo C et. al. Kidney International (2017) 91, 1224–1235

Obesity and IgA

Hall E ey. Al Int J Nephrol and Renovascular Disease 2014:7 75–88

BMI and Risk of ESRD

Hsu CY et. al Ann Intern Med. 2006; 144(1): 21–28.

CKD and Healthy Obese

Jung CH et. al. Kidney International (2015) 88, 843–8

Obesity and Unilateral Nephrectomy

Praga M et. al. Kidney International, Vol. 58 (2000), pp. 2111–2118

Total Body Fat vs

Distribution

Abdominal Obesity and Mortality in ESRD

Postorino M et. al. J Am Coll Cardiol 2009;53:1265–72

Body Fat Distribution and FF

Kwakernaak AJ et. Al. J Am Soc Nephrol 24: 987–994, 201

Renal Sinus Fat “Fatty Kidneys” and CKD

Foster MC et. al. Hypertension. 2011 November ; 58(5): 784–790.

Gender Differences

Obesity, Hypertension and CKD

Hall JE et. al. Circ Res 116: 991, 2015

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

Cassis LA. Curr Hypertens Rep. 2008 April; 10(2): 93–98

Adipose tissue produces angiotensinogen

Adipocytes express AT1 and AT2 receptors

Aldosterone Blockers

De Paula RB et. al. Hypertension. 2004; 43:41-47

Ramipril and Proteinuria in Obese

Mallamaci F et. al. J Am Soc Nephrol 22: 1122–1128, 2011

Ramipril and ESRD in Obese

Mallamaci F et. al. J Am Soc Nephrol 22: 1122–1128, 2011

Adipokine◦ 80% produced by

subcutaneous fat CNS -↓ food intake and

↑ energy expenditure – ↓ weight

↑ Levels in obesity◦ Leptin resistance

Selective

Leptin

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

Adiponectin and Podocytes

Camara NO et. al Nat Rev Nephrol 2017;13:181-190.

Adipokines and Glomerulopathy

D’Agati VD et. al. Nat Rev Nephrol. 2016 Aug;12(8):453-71

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

Role of the Microbiota

Camara NO et. al Nat Rev Nephrol 2017;13:181-190.

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

Cohen AH et. al. Am J Pathol 1975;81:117–130

Obesity-Related Glomerulopathy

The Obesity Paradox

272 Kidney International Reports (2017) 2, 271–281

Kalantar-Zadeh K et. al. Kidney International Reports (2017) 2, 271–2

Mechanisms

Kovesdy CP et. al. Kidney International (2017) 91, 260–262

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

ORG: Effect of Weight Loss

Shen WW et. al. Clin J Am Soc Nephrol 5: 1401–1409, 2010

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

Increasing use in adolescents

Safe

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

108 Children5 – 21 y/oLaparoscopic gastrectomy

Alqahtani SA et al. Ann Surg 2012

How young?

Long-term complications and efficacy?

Bariatric Surgery and Renal Function

Bolignano D et. al. Nephrol Dial Transplant. 2013; 28 Suppl 4:iv82-98

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

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

Thanks