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OBJECTIVES:

OBJECTIVES:. To present two case reports on Calcium Oxalate Nephropathy secondary to Orlistat Overview on Metabolic Syndrome/Obesity Mechanism of action, pharmacokinetic properties, contraindications and side effects of Orlistat Clinical Trials on the Safety Profile and Adverse Events

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OBJECTIVES:

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

  2. 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 153-157

  3. 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

  4. 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.

  5. Past medical history 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

  6. Past medical history 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).

  7. Laboratory Results: Physical Examination:Unremarkable 3 months ago: BUN – 16 mg/dL (5.7 mol/L) Creatinine - 2.5 mg/dL (221 mol/L) Current results: BUN - 22 mg/dL (7.9 mmol/L) Creatinine - 3.8 mg/dL (336 mol/L) serum bicarbonate - 26 mEq/L (26 mmol/L) serum albumin - 4.2 g/dL (42 g/L) serum calcium - 10.4 mg/dL (2.59 mmol/L) Liver function test results and coagulation profile - Normal

  8. Laboratory Results: 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.

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

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

  11. Course in the ward: 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.

  12. 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.)

  13. Renal Biopsy: 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. 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.

  14. Renal Biopsy: 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.

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

  16. Follow up: At 3 weeks’ follow-up: Creatinine - 3.2 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]).

  17. Second Biopsy: NO calcium oxalate crystals within tubules or interstitium; Diffuse chronic interstitial fibrosis Otherwise, there were no new or acutehistopathologic changes present. Other repeat labs: 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]

  18. CASE # 2

  19. 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

  20. 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 Retinopathy Obesity CKD Gout HTN Ischemic Stroke (15 yrs ago)

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

  22. Personal and Family History: NO personal or family history of renal stone disease or traditional risk factors for calcium oxalate crystallization. Renal Function: Over 5 years of follow-up - stable decline of 3 ml/min/year Creatinine - 141 mmol/l and eGFR - 66 ml/min/1.73m2 (5 months before presentation)

  23. Physical Examination: BMI - 35 kg/m2 BP - 176/86 mmHg UNREMARKABLE Laboratory Results: Creatinine - 626 mmol/l eGFR 12 ml/min/1.73m2 Metabolic acidosis Hyperkalaemia (6.8 mmol/l).

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

  25. Clinical course: • 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

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

  27. 24 months later….

  28. OBESITY AS A DISEASE

  29. OBESITY 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. World Health Organization, the International Association for the Study of Obesity and the International Obesity Task Force.

  30. Classification of Obesity based on BMI (Caucasians)

  31. Asia-Pacific Classification of Obesity based on BMI

  32. The metabolic syndrome • Metabolic syndrome (MS) is the clustering of cardiovascular risk factors • Most common definition (NCEP ATPIII1) is 3 of: • Abdominal obesity, waist >102 cm ♂ or >88 cm ♀ • Blood pressure 130/85 mmHg • Triglycerides 1.7 mmol/L • HDL cholesterol <1 mmol/L ♂ or <1.3 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 disease2, 3 1US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) JAMA 2001; 285: 2486–97 2Laaksonen et al. Am J Epidemiol 2002; 156: 1070–7 3Lakka et al. JAMA 2002; 288: 2709–16

  33. Mortality, especially cardiovascular mortality, is increased in subjects with MS 20 15 10 5 0 Subjects (%) No MS 18.0%* MS 12.2%* 4.6% 2.2% Cardiovascular mortality Total mortality Results of a 7-year follow-up*p<0.001 vs. subjects without MS Isomaa et al. Diabetes Care 2001; 24: 683–9

  34. 61.0 27.0 Overweight(54 yr) Obese(54 yr) Prevalence of MS (ATP III)in a non-diabetic population – St. Georgen Study Proportion with MS (%) 70 60 50 40 30 20 10 0 7.0 Normal(48 yr) Mean age Jacob et al. ADA presentation 2005

  35. 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. 1998.  IOTF-WHO classification of obesity Prevalence of obesity in medical practice in the Philippines is 21%, While 25% of  consulting patients are overweight.   Litonjua, Sy et al: PASOO

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

  37. The population attributable fractions because of overweight and obesity 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. Obesity Reviews, Volume 8, Number 3, May 2007 , pp. 191-196(6)

  38. TREATMENT

  39. Pharmacotherapy should only be used as an adjunct to diet and exercise: 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 The Asia-Pacific perspective:Redefining obesity and its treatment

  40. Anti-obesity drugs 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

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

  42. Triglycerides remain intact …inhibiting lipase

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

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