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

– Glomerulomegaly

–  Irregular foot process effacement

Primary FSGS

–  Normal glomerular volume

–  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

Obesity-related FSGS --- NORMAL SERUM ALBUMIN

–  Slowly increasing proteinuria –  Lower Proteinuria

Primary FSGS --- COMMON HYPOALBUMINEMIA

–  Sudden onset of proteinuria –  Higher Proteinuria

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

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 (-)

0

1

2

3

4

5

6

1 5 10 20 30 40 60112114116118120122124126128130132

Proteinuria Peso

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

ACEI ACEI + ARB

Caso Clínico (3)

ACEI ACEI + ARB

Caso Clínico (3)

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: journals.permissions@oup.com

Copyright ©2008 American Society of Nephrology

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

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

Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001).

Barker DJ et al: J Hypertens 20: 1951, 2002

Mean z Scores for Height, Weight, and Body-Mass Index in the First 11 Years after Birth among Boys and Girls Who Had

Coronary Heart Disease as Adults

Barker D et al. N Engl J Med 2005;353:1802-1809

CJASN 2015

3136 Japoneses seguidos >8 años Desarrollo de CKD (Proteinuria o GFR <60) Metabollically Healthy: TA, Triglicéridos, HDL-Colesterol, Glucosa en ayunas Incidencia de CKD Metabollically Healthy non-obese…… 2.6% Metabollically Healthy Obese………. 2.6% Metabollically Unhealthy non-obese … 6.7% Metabollically Unhealthy Obese …… 10.9%

Body fat distributions in metabolically healthy and metabolically at-risk obese individuals Individuals with metabolically healthy obesity have more subcutaneous, less visceral fat mass, and lower ectopic fat deposition in the liver and in the skeletal muscle than do metabolically at-risk obese individuals.

Stefan N et al Lancet Diabetes&Endocrinology 2013

Lancet Diabetes&Endocrinology 2014

Proposed pathways of obesity-related kidney disease Obesity-related glomerulomegaly can render the glomerulus increasingly susceptible to hypertension for any given intracapillary pressure. Mesangial foam-cell transformation can contribute to glomerular rarefaction. Ectopic lipid can lead to insulin-resistant podocytes, podocyte apoptosis, and a maladaptive response of remaining podocytes to glomerulomegaly. Resultant albuminuria, coated with non-esterified fatty acids, can be absorbed in the proximal tubulus leading to tubular hypertrophy, insulin resistance, and increased renal gluconeogenesis.

Caso Clínico (1)

Ø  Diagnóstico: FSGS secundaria a obesidad

Ø  Tratamiento:

Ø  Dieta hipocalórica

Ø  Enalapril

Ø  Estatina

Effects of body-weight loss and captopril treatment on proteinuria associated with obesity. M. Praga et al,Nephron 70: 35-41, 1995

The anti-proteinuric effect of ramipril is maximal on obese patients and minimal in patients with normal BMI.

Mallamaci F et al. JASN 2011;22:1122-1128

©2011 by American Society of Nephrology

Caso Clínico (1)

Ø  Diagnóstico: FSGS secundaria a obesidad

Ø  Tratamiento:

Ø  Dieta hipocalórica

Ø  Enalapril en dosis crecientes

Ø  Estatina

Ø  Descenso inicial de proteinuria desde 4.5 a 2.9 g/24 h. Pero a partir del

primer año, nueva tendencia al incremento.

Ø  Peso: Reducción inicial de 2-3 Kg, posteriormente «rebote»

Evolution of proteinuria during follow-up. Percentage of patients with proteinuria reduction >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

-100-80-60-40-20020406080

-12-10-8-6-4-2024

R=0.62, p<0.01

Weight loss (%)

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

Change in overt proteinuria with weight loss by diet caloric restriction.

Weight loss and proteinuria: a systematic review of clinical trials and comparative chorts Afshinnia et al, NDT 2010

Caso Clínico (1)

Ø  Diagnóstico: FSGS secundaria a obesidad

Ø  Tratamiento:

Ø  Dieta hipocalórica

Ø  Enalapril en dosis crecientes

Ø  Estatina

Ø  Descenso inicial de proteinuria desde 4.5 a 2.9 g/24 h. Pero a partir del

primer año, nueva tendencia al incremento.

Ø  Peso: Reducción inicial de 2-3 Kg, posteriormente «rebote»

Ø  Tras 5 años de evolución, Creatinina en 2 mg/dl, IMC en 39 Kg/m2.

Ø  ¿Qué HACER?

Mean Changes in Measures of Diabetes Control from Baseline to 3

Schauer PR et al. N Engl J Med 2014;370:2002-2013

Bariatric surgery in ORG Need of prospective controlled studies

Clinical Case (4)

Ø  38-year-old man. Severe obesity since childhood. Sudden appearance of edema 3 months before

admission

Ø  BP 138/85 mmHg. Weight 125 Kg, BMI 45 Kg/m2 Pitting edema in legs Ø  Serum creatinine 0.7 mg/dl, Proteinuria 8 g/d, Serum albumin 2 g/dl, Serum cholesterol 450 mg/dl Ø  Failed attempt of kidney biopsy

Caso Clínico 4

1.  IECA+ARA 2.  IECA+Espironolactona 3.  Cirugía Bariátrica 4.  Prednisona

Clinical Case 4

Ø  Prednisone, 80 mg/d

Ø  5 days later, Proteinuria started to decrease

Ø  3 weeks after Onset of Prednisone, complete nephrotic syndrome remission (negative proteinuria)

Ø  Diagnosis: (Likely) Minimal change Disease

Caso Clínico 5 •  Varón de 60 años. Desarrolla Síndrome nefrótico completo, con

proteinuria de 9 g/d, albúmina sérica de 2.6 g/dl. Crs 1 mg/dl

•  Edema (++++), Peso 95 Kg

•  Biopsia renal: Membranosa. Anti-PLA2R (+)

•  Tratamiento con Tacrolimus + Rituximab hace remisión parcial del SN (proteinuria 2 g/d)

•  Desaparece el edema, peso 80 Kg

Caso Clínico 5

•  1 año después del tratamiento, es remitido de nuevo por RECAIDA •  Proteinuria 8 g/d, albúmina 3.8 g/d, no edema. Creatinina 1.1 mg/dl,

anti-PLA2R (-) •  Peso 93 Kg, no edema

•  ¿Qué hacer?: 1 Esteroides+Ciclofosfamida 2. Micofenolato 3 Repetir Rituximab 4. IECA, Dieta , no inmunosupresión

Caso Clínico 5

•  ¿Qué hacer?: 1 Esteroides+Ciclofosfamida 2. Micofenolato 3 Repetir Rituximab 4. IECA, Dieta , no inmunosupresión Un año después ha perdido 6 Kg (86 Kg), proteinuria 3.5 g/d, albúmina

sérica normal, función renal normal

JD: Proteinuria residual de una membranosa…. ……exacerbada por ganancia de peso

Muchas Gracias

CONCLUSIONS Ø  Obesity-related glomerulopathy (ORG), an important cause of

and contributor to CKD

Ø  Differentiation of ORG from other renal diseases occurring in obese people

Ø  Regular monitoring of people at special risk of developing ORG (very low birth weight, obesity associated with reduced renal mass)

Ø  The long-term influence of dietary interventions, low-calorie-induced weight loss, and bariatric surgery should be investigated by means of large prospective RCT

Nephrotic proteinuria without hypoalbuminemia: Clinical characteristics and response to angiotensin-converting enzyme inhibition. Praga M et al. AJKD 1991

Long-term beneficial effects of ACEI in Patients with Nephrotic Proteinuria Praga M et al AJKD 1992

Ø Most of patients with nephrotic proteinuria without hypoalbuminemia had diagnoses suggesting glomerular hyperfiltration: FSGS associated with vesicoureteral reflux, reduction of renal mass, sclerotic phase of crescentic GN, or Obesity Ø Better antiproteinuric response to ACEI as compared to patients with hypoalbuminemia

Obesity-associated pathways in the development of CKD.

Norbert Stefan et al. Nephrol. Dial. Transplant. 2014;ndt.gfu081

© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Perivascular renal sinus fat in humans.

Norbert Stefan et al. Nephrol. Dial. Transplant. 2014;ndt.gfu081

© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

(Upper panel) Classic vs (lower panel) contemporary view on the relation between obesity and development of end-stage renal disease (ESRD).

Stephan J. L. Bakker et al. Nephrol. Dial. Transplant. 2007;22:15-20

© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org