An update on the obesity epidemics in CKD and in ESRD. Does it really matter?

Transcription

1 EURECA-m 2011 An update on cutting-edge Cardiovascular and Renal Medicine themes. An update on the obesity epidemics in CKD and in ESRD. Does it really matter? Francesca Mallamaci

2 BMI>30 25 Ireland 20 Greece England 15 Spain France Germany : 10 Italy 0 Source:

3 Stages 3-5 CKD (all ages) % 15 males % 15 females 8% 4% 10 5 Germany England Italy Belgium Norway Iceland 11% 6% 10 5 Iceland Belgium Italy England Germany Norway 0 0 Zoccali C, Jager K, Kramer A. Eugloreh report NDT 2010

4 RR for CKD 10 RR = Reference >40.0 Body Mass Index (kg/m 2 ) Hsu C et al, Annals of Internal Medicine 144:21-28, (adapted)

5 BMI Kramer H et al., JASN 17: , USRDS Population General Population

6 % USRDS overweight 28% obese 25% malnourished 4% underweight 17% Ideal 16% severely obese 7 % 0 < >40 BMI..the problem seems to be of similar entity in Europe. Courtesy Holly Kramer 2010

7 Association between obesity and CKD and mechanisms whereby overweight and obesity may be conducive to CKD. Therapy of CKD associated with obesity A lingering epidemiological question: is fat protective in ESRD?

8 Hemodynamic alterations in the kidney appear well before individuals develop full-blown obesity. Bosma RJ et al ;65: GFR FF= ERPF Glomerular Filtration Pressure Proteinuria

9 HN C NH NH CH 2 CH2 CH 2 CH NO H 2 N C=OOH HN CH 3 N CH 3 C Angiotensinogen NH CH adipocyte 2 Leptin Insulin CH2 R CH 2 CH H 2 N C=OOH ADMA L-Arginine High Angiotensin II NO inhibition Sympath. Act. Causal factors Glomerular Filtration Pressure

10 Synthesis: Protein Methyl Transferases (PRMT) Degradation: dimethylarginine dimethylaminohydrolase (DDAH) PRMT 4 The full machinery regulating ADMA levels is expressed in adypocytes DDAH 1 PRMT 2 DDAH 2 PRMT 1 Is ADMA synthesised in adipocytes? How can it be ascertained? Real time PCR profiles for amplification of the gene coding ADMA enzymatic system.

11 There is still no controlled trial testing the effect of weight loss on renal disease progression ACE inhibitors are potentially useful to counter the renal hemodynamic dysfunction of obesity but there is still no specific trial testing the effect of these drugs on renal disease progression in overweight and obese patients. Causal factors Angiotensinogen Leptin Insulin R ADMA High Angiotensin II NO inhibition Sympath. Act. Glomerular Filtration Pressure We have mechanistic knowledge on factors implicated in renal damage in obesity. The critical question is whether we can interfere with these mechanisms by body weight reduction interventions and/or with drugs.

12 In the absence of specific clinical trials exploratory evidence can be obtained in Post-hoc analyses of existing trials. 11:1122, Cumulative risk of ESRD BMI BMI < 25 Placebo Ramipril BMI more than 30 P<0.001 Overweight and, particularly so, obese patients are peculiarly sensitive to ACE inhibitors Time (months) Can we take it for granted that ACE inhibitors provide superior nephroprotection in proteinuric CKD patients? Likely, but still unproven.. However, it makes sense to provisionally use these drugs as first line agents in these patients 50 60

13 Association between obesity and CKD and mechanisms whereby overweight and obesity may be conducive to CKD. Therapy of CKD associated with obesity A lingering epidemiological question: is fat protective in ESRD?

14 Conventional wisdom equates high BMI to excessive fat... BMI: 2 components RR (death) Visceral...the fat inverse is of link great between relevance BMI for and insulin survival sensitivity in patients and lipid metabolism... with CKD as a clinical research conundrum...

15 Hazard rate (deaths/100 PY) Does this imply that we shouldn t use BMI any more in ESRD? BMI Kg/m 2 Waist cm

16 CV death ( 100 patients x year) The worst antropometric profile was that combining a large waist and a low BMI, obese sarcopenia > < 24.8 > 24.8 < 94 Waist (cm) BMI (kg/m 2 )

17 Adipokines (Leptin and Adiponectin) and clinical outcomes relationship in ESRD LEPTIN ADIPONECTIN Organ damage Very controversial!! HR +10 ng/dl Leptin Cardiovascular All-Cause Death Death Model including Classical Risk Factors and Risk Factors peculiar to ESRD (Phosphate, Hb) and Adiponectin. Adiponectin NOT significant This hypothesis would receive support if in an analysis excluding Leptin, Adiponectin becomes significantly!! A 10 ng excess in Leptin in ESRD patients with small waist denotes a progressively lower risk of death Zoccali C.2011 J Int Med!! A 10 ng excess in Leptin in ESRD patients with large waist denotes a progressively higher risk of death associated with risk of CV death Stratification criterion for studying the link between adipokines and clinical outcomes cm

18 HR +5 µg/dl Adiponectin Cardiovascular Death Stratification by waist circumference Same appears Model but of paramount excluding importance Leptin for the interpretation of the link between adipokines and clinical outcomes!! A 5 ug excess in Adiponectin in ESRD patients with small Waist denotes a progressively higher risk of death Zoccali C.2011 J Int Med!! A 5 ug excess in Adiponectin in ESRD patients with large Waist denotes a progressively lower risk of death cm

19 the paradoxical inverse relationship of Cholesterol and Triglycerides with clinical outcomes another controvesial issue in ESRD.. All cause mortality Postorino M, Marino C, Tripepi G, Zoccali C. KIdney International, CV mortality Hazard ratio 50 mg/dl excess in triglycerides These observational data suggest that treating patients 5 with large waist circumference makes sense. Hazard ratio 50 mg/dl excess in Secondary analyses (unpublished) cholesterol of 4D and AURORA 3 show a benefit of statins in patients with high LDL Waist circumference (cm) Waist circumference (cm) Stratification by waist circumference is relevant for studying the link between risk factors and clinical outcomes in ESRD

20 Hazard ratio of death Adjusted for: Age, gender, race, comorbidities, smoking, education, income, health insurance, urine albumin/creatinine ratio, egfr, SBP, LDL cholesterol, HDL cholesterol and waist circumference. 2011;58: >40.0 BMI (kg/m 2 ) Hazard ratio of death Adjusted for: Age, gender, race, comorbidities, smoking, education, income, health insurance, urine albumin/creatinine ratio, egfr, SBP, LDL cholesterol, HDL cholesterol and body mass index. 0.6 Males < > 108 Females < > 122 WC (cm)

21 S & C Obesity and renal diseases are a major public health problem worldwide. Obesity is a risk factor for renal diseases by several mechanisms. Overweight and obese CKD patients are peculiarly sensitive to the nephrotective effect of Ramipril Abdominal fat accumulation is a powerful risk factor for death and CV events in ESRD. Stratification by waist circumference is critical for the interpretation of the link between adipokines and risk factors in general and clinical outcomes in ESRD.

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23 % 40 Italy (CREED) Dialysis patients overweight 36% underweight 21% Ideal 25 % 10 0 malnourished 7% obese 10% severely obese 1% < >40 BMI

24 % 40 Italy Dialysis patients (calabria) 30 underweight 24% Ideal 25% overweight 32% malnourished 5% obese 14% severely obese 1% < >40 BMI Progredire 2010

25 Hemodynamic alterations in the kidney appear well before individuals develop full-blown obesity. Bosma RJ et al ;65: GFR FF= ERPF Glomerular Filtration Pressure Proteinuria