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ENDO -NEPHRO GRANDROUNDS Joy Duenas, M.D. Edgar M. Lim, M.D. October 4, 2007.

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Presentation on theme: "ENDO -NEPHRO GRANDROUNDS Joy Duenas, M.D. Edgar M. Lim, M.D. October 4, 2007."— Presentation transcript:

1 ENDO -NEPHRO GRANDROUNDS Joy Duenas, M.D. Edgar M. Lim, M.D. October 4, 2007

2 OBJECTIVES: 1.To present two case reports on Calcium Oxalate Nephropathy secondary to Orlistat 2.Overview on Metabolic Syndrome/Obesity 3.Mechanism of action, pharmacokinetic properties, contraindications and side effects of Orlistat 4.Clinical Trials on the Safety Profile and Adverse Events 5.Pathophysiology of Calcium Oxalate Nephropathy in the use of Orlistat 6.Recommendations on the use of Orlistat among CKD patients

3 CASE REPORT 1 Acute Oxalate Nephropathy Associated With Orlistat, a Gastrointestinal Lipase Inhibitor Ashutosh Singh, MD, FASN, Shubho R. Sarkar, MD, FASN, Lillian W. Gaber, MD, and Mark A. Perazella, MD, FACP American Journal of Kidney Diseases, Vol 49, No 1 (January), 2007: pp

4 CASE REPORT 2 Rapidly progressive renal failure associated with successful pharmacotherapy for obesity Aisling E. Courtney1, Declan M. O’Rourke2 and Alexander Peter Maxwell1 Nephrol Dial Transplant (2007) 22: 621–623

5 Case # 1 – 57 year old, female Clinical history: Progressive worsening of kidney function during a 2-month period Generalized malaise, weakness, and episodes of loose oily stools 3 weeks prior to evaluation.

6 Hypertension (10 years) - Diltiazem, 240 mg/d Furosemide, 40 mg/d Type 2 diabetes mellitus (4 years) - Glimeperide 4 mg/d Stage 3 CKD ( 2’ to HTNsive nephrosclerosis) GERD - Pantoprazole, 20 mg/d Asthma - Montelukast sodium (Singulair) 10 mg/d Atrovent MDI puffs as required Gouty arthritis - Colchicine 0.6 mg 3 times as needed Hypothyroidism - Calcitriol 1 g/d Levothyroxine 75 g/d Past medical history

7 Other Meds: A. Paroxetine B. Orlistat 120 mg 3 times daily with meals (increased from 120 mg twice daily 2 months prior). Denied ingestion of : 1. Nonsteroidal antiinflammatory drugs 2. Ascorbic acid 3. Herbal or natural products, 4. Intoxicants (ie, ethylene glycol). Past medical history

8 Laboratory Results: 3 months ago: BUN – 16 mg/dL (5.7 mol/L) BUN – 16 mg/dL (5.7 mol/L) Creatinine mg/dL (221 mol/L) Creatinine mg/dL (221 mol/L) Current results: BUN - 22 mg/dL (7.9 mmol/L) BUN - 22 mg/dL (7.9 mmol/L) Creatinine mg/dL (336 mol/L) Creatinine mg/dL (336 mol/L) serum bicarbonate - 26 mEq/L (26 mmol/L) serum bicarbonate - 26 mEq/L (26 mmol/L) serum albumin g/dL (42 g/L) serum albumin g/dL (42 g/L) serum calcium mg/dL (2.59 mmol/L) serum calcium mg/dL (2.59 mmol/L) Liver function test results and coagulation profile - Normal Liver function test results and coagulation profile - Normal Physical Examination: Unremarkable

9 Urinalysis - pH 6.5 trace blood trace proteinuria RBC – 0 to 2 rbc/hpf WBC - 20 to 30 wbc/HPF Numerous calcium oxalate crystals No cellular or granular casts were present Fractional excretion of sodium – 2.4% Spot urine protein-creatinine ratio was 450 mg of protein/g of creatinine. Laboratory Results:

10 Sonogram showed normal-sized nonhydronephrotic kidneys with slightly increased echogenicity. Renal Ultrasound: Laboratory Results

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12 Figure: Urinary oxalate concentrations in the patient presented show increased urinary oxalate excretion with orlistat that decreased after discontinuation of drug.

13 Hemodynamically stable Tx: intravenous normal saline All admission medications were discontinued except 1. Diltiazem 2. Levothyroxine 3. Alprazolam 4. Montelukast sodium 5. Glimepiride. A kidney biopsy was performed for nonoliguric acute kidney injury. Course in the ward:

14 Photomicrograph of a representative field shows the presence of birefringent crystals (calcium oxalate) lodged in the lumen of a renal tubule. The affected portion of the tubule is dilated, and the epithelial lining is flattened. (Hematoxylin and eosin stain; original magnification 200.)

15 Light microscopy: Light microscopy: Several calcium oxalate crystals within tubules and interstitium, with positive birefringence visualized under polarized light.Some crystals were engulfed by foreign body giant cells. Several calcium oxalate crystals within tubules and interstitium, with positive birefringence visualized under polarized light.Some crystals were engulfed by foreign body giant cells. Diffuse chronic interstitial fibrosis and tubular simplification, dilatation, and atrophy also were present. Diffuse chronic interstitial fibrosis and tubular simplification, dilatation, and atrophy also were present. Glomeruli showed chronic ischemic retraction, whereas blood vessels showed thickening and sclerosis, findings consistent with hypertensive nephrosclerosis. Glomeruli showed chronic ischemic retraction, whereas blood vessels showed thickening and sclerosis, findings consistent with hypertensive nephrosclerosis. Renal Biopsy:

16 Immunofluorescence and electron microscopy: Did not show immune staining or electron-dense deposits within glomeruli, respectively. Glomerular basement membranes were irregularly folded with a slight increase in mesangial matrix. There was no effacement of foot processes. Renal Biopsy:

17 Discharged improved Advised to drink fluids liberally everyday Orlistat therapy was discontinued Disposition:

18 At 3 weeks’ follow-up: Creatinine and 3.5 mg/dL (283 and 309 mol/L) One month after the first biopsy Patient underwent a second kidney biopsy to ascertain the cause of delayed improvement in kidney function to baseline (serum creatinine, 2.8 mg/dL [248 mol/L]). Follow up:

19 NO calcium oxalate crystals within tubules or interstitium; Diffuse chronic interstitial fibrosis Otherwise, there were no new or acute histopathologic changes present. Second Biopsy: Urinary oxalate excretion returned to low levels 11 days after the second collection Approximately 2 weeks after the second biopsy - Creatinine, 2.5 mg/dL [221 mol/L] Other repeat labs:

20 CASE # 2

21 Case Report 2 Rapidly progressive renal failure associated with successful pharmacotherapy for obesity Aisling E. Courtney1, Declan M. O’Rourke2 and Alexander Peter Maxwell1 Nephrol Dial Transplant (2007) 22: 621–623

22 Case # 2 – 55 year old, female Chief complaint: Recurrent episodes of hypoglycemia over 4 weeks Clinical history: - Known type 1 diabetec for 35 years Tx: Insulin basal bolus regime - Self-regulated an insulin basal bolus regime and hypoglycaemic episodes had been rare Comorbidities RetinopathyObesity CKDGout HTNIschemic Stroke (15 yrs ago)

23 Other Medications: Statin Six anti-hypertensive agents Warfarin Orlistat had been commenced 5 months previously with a subsequent 12 kg weight reduction

24 NO personal or family history of renal stone disease or traditional risk factors for calcium oxalate crystallization. Personal and Family History: Renal Function: Over 5 years of follow-up - stable decline of 3 ml/min/year Creatinine mmol/l and eGFR - 66 ml/min/1.73m2 (5 months before presentation)

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26 Physical Examination: BMI - 35 kg/m2 BP - 176/86 mmHg UNREMARKABLE Laboratory Results: Creatinine mmol/l eGFR 12 ml/min/1.73m2 Metabolic acidosis Hyperkalaemia (6.8 mmol/l).

27 Urinalysis – proteinuria Ultrasound - both kidneys were non-obstructed and anatomically normal. The bladder was empty. Inflammatory markers – normal Immunological investigations – negative Laboratory Results:

28 - NO improvement in renal function, and persistent hyperkalaemia necessitated hemodialysis Renal Biopsy: - diabetic nephropathy with moderate interstitial scarring and widespread glomerulosclerosis. - extensive, superimposed, intra-tubular deposition of calcium oxalate crystals in the kidney, with mild to moderate tubulo-interstitial inflammation Clinical course:

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30 2-weeks course of oral steroid therapy NO objective improvement NO recovery of renal function Management:

31 24 months later….

32 OBESITY AS A DISEASE

33 Defined as a condition in which there is an excess of body fat. The operational definitions of obesity and overweight however are based on body size (BMI) which is closely correlated with body fatness. OBESITY World Health Organization, the International Association for the Study of Obesity and the International Obesity Task Force.

34 Classification of Obesity based on BMI (Caucasians)

35 Asia-Pacific Classification of Obesity based on BMI

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37 The metabolic syndrome Metabolic syndrome (MS) is the clustering of cardiovascular risk factors Metabolic syndrome (MS) is the clustering of cardiovascular risk factors Most common definition (NCEP ATPIII 1 ) is  3 of: Most common definition (NCEP ATPIII 1 ) is  3 of: Abdominal obesity, waist >102 cm ♂ or >88 cm ♀ Abdominal obesity, waist >102 cm ♂ or >88 cm ♀ Blood pressure  130/85 mmHg Blood pressure  130/85 mmHg Triglycerides  1.7 mmol/L Triglycerides  1.7 mmol/L HDL cholesterol <1 mmol/L ♂ or <1.3 mmol/L ♀ HDL cholesterol <1 mmol/L ♂ or <1.3 mmol/L ♀ Fasting plasma glucose  6.1 mmol/L Fasting plasma glucose  6.1 mmol/L Patients with MS are more likely to have comorbidities such as type 2 diabetes and cardiovascular disease 2, 3 Patients with MS are more likely to have comorbidities such as type 2 diabetes and cardiovascular disease 2, 3 1 US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) JAMA 2001; 285: 2486–97 2 Laaksonen et al. Am J Epidemiol 2002; 156: 1070–7 3 Lakka et al. JAMA 2002; 288: 2709–16

38 Mortality, especially cardiovascular mortality, is increased in subjects with MS Isomaa et al. Diabetes Care 2001; 24: 683–9 Results of a 7-year follow-up *p<0.001 vs. subjects without MS Subjects (%) 12.2%* 18.0%* 2.2% 4.6% No MS MS Cardiovascular mortalityTotal mortality

39 Overweight and obesity in a non-diabetic population – St. Georgen Study Jacob et al. ADA presentation 2005 n=671 BMI >30 kg/m 2 19% BMI <25 kg/m 2 39% BMI 25  30 kg/m 2 42%

40 Prevalence of MS (ATP III) in a non-diabetic population – St. Georgen Study Proportion with MS (%) 7.0 Mean age 61.0 Obese (54 yr) Normal (48 yr) 27.0 Overweight (54 yr) Jacob et al. ADA presentation 2005

41 IOTF-WHO classification of obesity Prevalence of obesity in medical practice in the Philippines is 21%, While 25% of consulting patients are overweight. Prevalence of obesity in medical practice in the Philippines A total of 1220 patients was included in the study which extended from April 1996 to Dec Litonjua, Sy et al: PASOO

42 The burden of overweight and obesity in the Asia-Pacific region

43 Obesity Reviews, Volume 8, Number 3, May 2007, pp (6) 1. CAD Mortality - 0.8% to 9.2% 2. Haemorrhagic stroke mortality - 0.2% to 2.9% 3. Ischaemic stroke mortality – 0.9% to 10.2%. These results indicate that consequences of overweight and obesity for health and the economy of many of these countries are likely to increase in coming years. The population attributable fractions because of overweight and obesity

44 TREATMENT

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46 1. Hunger or overt hyperphagia are recognised factors contributing to weight gain 2. There are associated co-morbidities including impaired glucose tolerance, dyslipidaemia and hypertension 3. Symptomatic complications of obesity exist such as severe osteoarthritis,obstructive sleep apnoea, reflux oesophagitis, and the compartment syndrome Pharmacotherapy should only be used as an adjunct to diet and exercise: The Asia-Pacific perspective:Redefining obesity and its treatment

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48 I. Acting on the central nervous system to influence appetite A. Drugs acting via serotoninergic (5HT) pathways Fenfluramine and Dexfenfluramine Fluoxitene B. Drugs acting via noradrenergic pathways Ephedrine and Caffeine Phentermine and Diethylproprion C. Drugs acting via serotoninergic and noradrenergic pathways Sibutramine II. Acting on the gastrointestinal system to reduce absorption. A. Orlistat Anti-obesity drugs

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51 51 Xenical binds to the lipase active site...

52 …inhibiting lipase Triglycerides remain intact

53 53 Xenical prevents the absorption of up to 30% of dietary fat...

54 …which pass through the body undigested and are excreted. 30% of triglycerides pass undigested and are excreted.

55 Pharmacokinetics: Absorption: Systemic absorption is minimal Plasma concentrations of intact Orlistat were near the limits of detection (<5ng/ml) No evidence of accumulation Bioavailability: male rats mg/kg/day (0.12%) mg/kg/day (0.59%) mg/kg/day (0.59%) male dogs -100 mg/kg/day (0.7%) mg/kg/day (1.9%) mg/kg/day (1.9%)

56 Pharmacokinetics: Distribution: In vitro - >99% bound to plasma proteins Metabolism: - occurs mainly in the gastrointestinal wall - the metabolites (M1 & M3 moiety) are pharmacologically inconsequential

57 Pharmacokinetics: Elimination: F ecal excretion (97%), 87% - unchanged Orlistat Renal excretion <2% Time to reach complete excretion (fecal + urinary) = 3 to 5 days (fecal + urinary) = 3 to 5 days Half-life: Half-life: 1 to 2 hours (absorbed Orlistat) 1 to 2 hours (absorbed Orlistat)

58 Xenical is safe in obese patients with co- morbidities Xenical is safe in overweight and obese patients with: type 2 diabetes 1,2,3 type 2 diabetes 1,2,3 hypertension 4,5 hypertension 4,5 dyslipidaemia 6,7,8 dyslipidaemia 6,7,8 multimorbidities 8 multimorbidities 8 Xenical is safe in obese adolescent patients 9. Xenical is safe in obese adolescent patients 9. 1 Hollander et al. Diabetes Care 1998; 21: ; 2 Kelley et al. Diabetes Care 2002; 25: ; 3 Miles et al. Diabetes Care 2002; 25: ; 4 Sharma & Golay. J Hypertens 2002; 20: ; 5 Zavoral. J Hypertens 1998; 16: ; 6 Muls et al. Int J Obes Relat Metab Disord 2001; 25: ; 7 Broom I et al, on behalf of the Orlistat UK Study Group. Br J Cardiol 2002; 9: ; 8 Broom et al, on behalf of the UK Multimorbidity Study Group. Int J Clin Pract 2002; 56: Chanoine et al,. JAMA In press

59 Xenical has a similar safety profile to placebo Respiratory Infections Musculo- skeletal Nervous system Cardiac Skin / subcutaneous Gastrointestinal General Patients (%) 4080 Torgerson et al. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 1): S124. Toplak et al. Diabet Obes Metabol 2005, in 8% 66% Adverse events reported in year four 36% 12% 11% 23% 9% 6% 15% 13% 45% 43% 63% Placebo + lifestyle (n=1655) Xenical + lifestyle (n=1649)

60 Most patients on Xenical experience only 1 or 2 gastrointestinal events Xenical + diet Patients experiencing fatty/oily stools (%) 1>22Overall Number of episodes Data on file, F. Hoffmann-La Roche Ltd 20.0% 14.5% 3.6% 1.9%

61 Gastrointestinal32(2)32(2) Infections25(2)30(2) Musculoskeletal19(1)23(1) Nervous system11(<1)21(1) General18(1)12(<1) Respiratory4(<1)4(<1) Metabolism/nutrition3(<1)1(<1) Cardiac22(1)40(2) Skin/subcutaneous3(<1)2(<1) Neoplasms17(1)22(1) Death7(<1)2(<1) Fraction of patients with serious adverse events during years 1 – 4 Placebo + lifestyle n (%) Xenical + lifestyle n (%) XENDOS; Torgerson et al. Diabetes Care 27:

62 Zhaoping Li et al; 5 April 2005 Annals of Internal Medicine Volume 142 Number 7

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64 Xenical acts locally in the gut and is minimally absorbed Xenical does not act on the central nervous system Xenical inhibits gastrointestinal lipase action Xenical acts locally 30% of dietary fat is not absorbed Non-systemic 1 Minimal drug-drug interactions 1 >96% drug elimination in the faeces 1 Safe with concomitant medications 1 Suitable for overweight/obese patients with co-morbidities 2,3 Side effects are transient and mild 4 1 Guerciolini. Int J Obes Relat Metab Disord 1997; 21 (Suppl. 3): S12-S23 2 Hollander et al. Diabetes Care 1998; 21: Muls et al. Int J Obes Metab Disord 2001; 25: Hauptman. Int J Obes Relat Metab Disord 1998; 22 (Suppl. 3): P678

65 Thank You for Your Attention!!

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70 OBESITY AS A DISEASE

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85 Classification of Obesity based on BMI (Caucasians)

86 Asia-Pacific Classification of Obesity based on BMI

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89 Adverse Event by Drug Pooled OR (95% CI) Relative Risk Number Needed To Treat for Harm† Orlistat Diarrhea (44.88–67.48) Flatulence 3.72 (3.16–4.39) Bloating, abdominal pain, and dyspepsia 1.55 (1.18–2.06) Headache 1.18 (0.68–2.05) Not calculated Not calculated Nausea and vomiting 0.95 (0.46–1.98) Not calculated Not calculated Gallbladder problems 0.71 (0.27–1.82) Not calculated Not calculated Depression and mood change 0.33 (0.01–4.15) Not calculated Not calculated

90 Meta-Analysis: Pharmacologic Treatment of Obesity Zhaoping Li, MD, PhD; Margaret Maglione, MPP; Wenli Tu, MS; Walter Mojica, MD; David Arterburn, MD, MPH; Lisa R. Shugarman, PhD; Lara Hilton, BA; Marika Suttorp, MS; Vanessa Solomon, MA; Paul G. Shekelle, MD, PhD; and Sally C. Morton, PhD

91 P h a rm a c o t h e r a p y In certain cases pharmacological treatment may need to be considered in addition to diet, exercise and behaviour modification (see Table 6.2). To date, there is little published scientific evidence reporting the long-term safety and efficacy of currently available anti-obesity drugs, thus no particular drug can be recommended for routine use. There is also no available data on the effects of combining two or more types of these anti-obesity drugs.

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95 Thank You for Your Attention!!

96 The burden of overweight and obesity in the Asia-Pacific region

97 Obesity Reviews, Volume 8, Number 3, May 2007, pp (6) 1. CAD Mortality - 0.8% to 9.2% 2. Haemorrhagic stroke mortality - 0.2% to 2.9% 3. Ischaemic stroke mortality – 0.9% to 10.2%. These results indicate that consequences of overweight and obesity for health and the economy of many of these countries are likely to increase in coming years. The population attributable fractions because of overweight and obesity

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102 ENDO- NEPHRO CONFEREN CE Joy Duenas, M.D. Edgar M. Lim, M.D.

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