Glomerulopatía de la Obesidad

Sociedad Norte de Nefrología Bilbao 25-26 Noviembre 2016

Nature Reviews Nephrology , August 2016

Caso Clínico (1) Ø  Varón de 60 años, Obesidad (IMC >35 Kg/m2) > 20 años Ø  Enviado por Creatinina sérica de 1.4 mg/dl, proteinuria 4.5 g/24h, TA 135/90 mmHg Ø  No otras enfermedades relevantes, exploración clínica normal salvo la obesidad Ø  Analítica: Glucosa 105 mg/dl, hemoglobina glicada 6%, Colesterol 223 mg/dl, triglicéridos 325 mg/dl, HDL-C 35 mg/dl. Albúmina sérica 4.2 g/dl. Resto de estudio sin datos relevantes

Ø  Ecografia renal normal Ø  Diagnóstico

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

Which is the link between Obesity and renal disease? (Obesity-related glomerulopathy) (ORG) Glomerulomegaly alone or accompanied by Focal Segmental Glomerulosclerosis (FSGS), the commonest lesion in renal biopsies of obese

Figure 1 Pathologic features of obesity-related glomerulopathy (ORG)

D’Agati, V. D. et al. (2016) Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.75

Obesity-related FSGF vs primary FSGS Obesity-related-FSGS

Primary FSGS

–  Glomerulomegaly

–  Normal glomerular volume

–  Irregular foot process effacement

–  Diffuse foot process effacement

Kidney International 2008

ORG-Características clínicas •  Proteinuria aislada, asintomática, en rango nefrótico en un 10-40% de los casos •  HTA 50-75% •  Dislipemia 70-80% •  Curso clínico de lenta evolución pero un 10-35% progresan a ESRD

CLINICAL CHARACTERISTICS OF OBESITY-RELATED GLOMERULOPATHY How can ORG be distinguished from other glomerular diseases appearing in obese people? Obese people can also be affected by glomerular diseases other than obesity-related glomerulopathy: Minimal change disease, Membranous nephropathy,…. or even “Primary” FSGS.

ABSENCE OF HYPOALBUMINEMIA DESPITE MASSIVE PROTEINURIA IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS SECONDARY TO HYPERFILTRATION Praga M et al, Am J Kidney Dis 1999

Obesity-related FSGF vs primary FSGS Patients with FSGS secondary to hyperfiltration do not develop hypoalbuminemia nor the other characteristic complications of nephrotic syndrome, even in the presence of massive proteinuria Obesity-related FSGS --- NORMAL SERUM ALBUMIN –  Slowly increasing proteinuria –  Lower Proteinuria

Primary FSGS --- COMMON HYPOALBUMINEMIA –  Sudden onset of proteinuria –  Higher Proteinuria

Renal survival in patients with obesity‐associated FSG (OB‐FSG) and idiopathic FSG (I‐FSG).

Praga M et al. Nephrol. Dial. Transplant. 2001;16:1790-1798 European Renal Association-European Dialysis and Transplant Association

Can proteinuric ORG alone account for the significant impact of obesity on CKD?

Non-diabetic Obese patients with severe proteinuria (>1-2 g/d)

Kidney Int 2008 Renal biopsy in 93 extremely obese patients undergoing bariatric surgery, with normal renal function and negative or mild albuminuria. FSGS lesions, mesangial matrix expansion, glomerulomegaly, podocyte hypertrophy….

Non-proteinuric pathways of obesity-related Glomerulopathy?

Another link between Obesity and CKD

The detrimental effect of Obesity SUPERIMPOSED on chronic renal diseases

Caso Clínico (2) Varón de 35 años. LES. GN Membranosa lúpica 6 años antes Buena evolución con esteroides+Ciclofosfamida Proteinuria 0.5-0.9 g/24 h Obesidad, empeorada en los ultimos meses. (IMC 38 Kg/m2) Proteinuria que ha aumentado a 5.3 g/24 en los últimos 12 meses. Función renal estable, ANA 1/160, anti-DNA (-)

Complicaciones post-biopsia: hematoma infectado, fiebre, ingreso prolongado. Pérdida de peso notable (>10 Kg) 6

132 130 128 126 124 122 120 118 116 114 112

5 4 3 2 1 0 1

5

10

20 Proteinuria

30 Peso

40

60

Caso Clínico (3)

ACEI ACEI + ARB

Caso Clínico (3)

ACEI ACEI + ARB

Figure 2 Haemodynamic alterations in obesity

D’Agati, V. D. et al. (2016) Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.75

HYPERFILTRATION HYPOTHESIS Ablation > 3/4 – 5/6 renal mass

Vasodilation Aferent Arterioles Increased Filtration Fraction Increased Hydrostatic Pressure in glomerular capillaries

Proteinuria, Hypertension, ESRD Glomerulosclerosis, Tubulointerstitial damage

A way to explain the non-specific progression of renal diseases, independently of their cause

CRITICAL REDUCTION IN THE NUMBER OF FUNCTIONING NEPHRONS

González, E et al. Kidney Int 2005 54 patients with severe reduction of renal mass: -33 unilateral renal agenesis -21 “remnant kidney” (> ¾ loss of functioning renal mass) : Bilateral renal Tuberculosis (8), Bilateral nephrolithiasis and superimposed pyelonephritis (5), Bilateral Renal carcinoma (4), Bilateral recurrent Pyelonephritis (3), and Bilateral renal Angiomyolipoma (1)

Factors that directly or indirectly affect fetal development and may thus favour programming of diseases that occur in later life.

Koleganova N et al. Nephrol. Dial. Transplant. 2012;27:3003-3007 © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: [email protected]

Figure 2. Cumulative risk for ESRD in men and women, by age and birth weight

Vikse, B. E. et al. J Am Soc Nephrol 2008;19:151-157

Compared with birth weight in the 10th to 90th percentiles, births 8 años Desarrollo de CKD (Proteinuria o GFR 50% of baseline values during follow-up.

Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases. Morales E et al, NDT 2013

21 patients: UACR >300 mg/g eGFR >30 ml/min/1.73 m2 Prospective Randomized, Crossover Trial T1: Spironolactone 25 mg/d T2: Hydrochlorothiazide 50 mg/d T3: Hydrochlorothiazide 50 mg/d + Amiloride 5 mg/d On top of Enalapril 40 mg/d

BENEFICIAL EFFECTS OF WEIGHT LOSS IN OVERWEIGHT PATIENTS WITH PROTEINURIC NEPHROPATHIES. Morales E,Valero MA, León M, Hernández E, Praga M. Am J Kidney Dis 2003; 41:319-327

R=0.62, p