ENDO -NEPHRO GRANDROUNDS Joy Duenas, M.D. Edgar M. Lim, M.D. October 4, 2007.
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Transcript of ENDO -NEPHRO GRANDROUNDS Joy Duenas, M.D. Edgar M. Lim, M.D. October 4, 2007.
OBJECTIVES:OBJECTIVES:
1. To present two case reports on Calcium Oxalate Nephropathy secondary to Orlistat
2. Overview on Metabolic Syndrome/Obesity3. 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
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
CASE REPORT 2
Rapidly progressive renal failure associated with successfulpharmacotherapy for obesity
Aisling E. Courtney1, Declan M. O’Rourke2 and Alexander Peter Maxwell1
Nephrol Dial Transplant (2007) 22: 621–623
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.
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
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 acid3. Herbal or natural products,4. Intoxicants (ie, ethylene glycol).
Past medical history
Laboratory Results:Laboratory Results:
3 months ago:3 months ago: BUN – 16 mg/dL (5.7 mol/L)BUN – 16 mg/dL (5.7 mol/L) Creatinine - 2.5 mg/dL (221 mol/L) Creatinine - 2.5 mg/dL (221 mol/L)
Current results:Current results: BUN - 22 mg/dL (7.9 mmol/L)BUN - 22 mg/dL (7.9 mmol/L) Creatinine - 3.8 mg/dL (336 mol/L) Creatinine - 3.8 mg/dL (336 mol/L) serum bicarbonate - 26 mEq/L (26 mmol/L)serum bicarbonate - 26 mEq/L (26 mmol/L) serum albumin - 4.2 g/dL (42 g/L) serum albumin - 4.2 g/dL (42 g/L) serum calcium - 10.4 mg/dL (2.59 mmol/L) serum calcium - 10.4 mg/dL (2.59 mmol/L) Liver function test results and coagulation Liver function test results and coagulation
profile - Normalprofile - Normal
Physical Examination:Physical Examination: UnremarkableUnremarkable
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:
Sonogram showed normal-sized nonhydronephrotic kidneys with slightly increased echogenicity.
Renal Ultrasound:
Laboratory Results
Figure: Urinary oxalate concentrations in the patient presented show increased urinary oxalate excretion with orlistat that decreased after discontinuation of drug.
Hemodynamically stable Tx: intravenous normal saline All admission medications were discontinued except
1. Diltiazem2. Levothyroxine3. Alprazolam4. Montelukast sodium5. Glimepiride.
A kidney biopsy was performed for nonoliguric acute kidney injury.
Course in the ward:
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.)
Light microscopy:Light microscopy:
Several Several calcium oxalate crystalscalcium oxalate crystals within within tubules and interstitium, with positive birefringence tubules and interstitium, with positive birefringence visualized visualized under polarized light.Some crystals under polarized light.Some crystals were engulfed by foreign body giant cells.were engulfed by foreign body giant cells.
Diffuse chronic interstitial fibrosis and Diffuse chronic interstitial fibrosis and tubular simplification, dilatation, and atrophy also tubular simplification, dilatation, and atrophy also were present. were present.
Glomeruli showed chronic ischemic Glomeruli showed chronic ischemic retraction, whereas blood vessels showed retraction, whereas blood vessels showed thickening and sclerosis, findings consistent with thickening and sclerosis, findings consistent with hypertensive nephrosclerosis.hypertensive nephrosclerosis.
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.
Renal Biopsy:
Discharged improved Advised to drink fluids liberally everyday
Orlistat therapy was discontinued
Disposition:
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]).
Follow up:
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:
CASE # 2CASE # 2
Case Report 2
Rapidly progressive renal failure associated with successfulpharmacotherapy for obesity
Aisling E. Courtney1, Declan M. O’Rourke2 and Alexander Peter Maxwell1
Nephrol Dial Transplant (2007) 22: 621–623
Case # 2 – 55 year old, female
Chief complaint: Recurrent episodes of hypoglycemia over 4 weeks
Clinical history:
- Known type 1 diabetec for 35 yearsTx: 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)
Other Medications:
Statin Six anti-hypertensive agents Warfarin Orlistat had been commenced 5 months previously with a subsequent 12 kg weight reduction
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 - 141 mmol/l and eGFR - 66 ml/min/1.73m2
(5 months before presentation)
Physical Examination:
BMI - 35 kg/m2 BP - 176/86 mmHg UNREMARKABLE
Laboratory Results:
Creatinine - 626 mmol/leGFR 12 ml/min/1.73m2Metabolic acidosis Hyperkalaemia (6.8 mmol/l).
Urinalysis – proteinuriaUltrasound - both kidneys were non-obstructed
and anatomically normal. The bladder was empty.Inflammatory markers – normalImmunological investigations – negative
Laboratory Results:
- 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:
2-weeks course of oral steroid therapy NO objective improvement NO recovery of renal function
Management:
24 months later….
OBESITYAS ADISEASE
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.
Classification of Obesity based on BMI (Caucasians)
Asia-Pacific Classification of Obesity based on BMI
The metabolic syndromeThe metabolic syndrome
Metabolic syndrome (MS) is the clustering of Metabolic syndrome (MS) is the clustering of cardiovascular risk factorscardiovascular risk factors
Most common definition (NCEP ATPIIIMost common definition (NCEP ATPIII11) is ) is 3 of:3 of: Abdominal obesity, waist >102 cm Abdominal obesity, waist >102 cm ♂♂ or >88 cm or >88 cm ♀♀ Blood pressure Blood pressure 130/85 mmHg130/85 mmHg Triglycerides Triglycerides 1.7 mmol/L1.7 mmol/L HDL cholesterol <1 mmol/L HDL cholesterol <1 mmol/L ♂♂ or <1.3 mmol/L or <1.3 mmol/L ♀♀ Fasting plasma glucose Fasting plasma glucose 6.1 mmol/L6.1 mmol/L
Patients with MS are more likely to have Patients with MS are more likely to have comorbidities such as type 2 diabetes and comorbidities such as type 2 diabetes and cardiovascular diseasecardiovascular disease2, 32, 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
Mortality, especially Mortality, especially cardiovascular mortality, is cardiovascular mortality, is
increased in subjects with MSincreased in subjects with MS
Isomaa et al. Diabetes Care 2001; 24: 683–9Results of a 7-year follow-up*p<0.001 vs. subjects without MS
20
15
10
5
0
Subjects (%)
12.2%*
18.0%*
2.2%
4.6%
No MSMS
Cardiovascular mortality Total mortality
Prevalence of MS (ATP III)Prevalence of MS (ATP III)in a non-diabetic population – St. in a non-diabetic population – St.
Georgen StudyGeorgen Study
70
60
50
40
30
20
10
0
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
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. 1998.
Litonjua, Sy et al: PASOO
The burden of overweight and obesity in the Asia-Pacific region
Obesity Reviews, Volume 8, Number 3, May 2007 , pp. 191-196(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
TREATMENTTREATMENT
1. Hunger or overt hyperphagia are recognised factors contributing to weight gain
2. There are associated co-morbidities including impaired glucose tolerance, dyslipidaemia and hypertension3. 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
I. Acting on the central nervous system to influence appetite
A. Drugs acting via serotoninergic (5HT) pathways Fenfluramine and Dexfenfluramine
FluoxiteneB. Drugs acting via noradrenergic pathways
Ephedrine and CaffeinePhentermine 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
51
Xenical binds to the lipase Xenical binds to the lipase active site...active site...
……inhibiting lipaseinhibiting lipase
Triglycerides remain intact
53
Xenical prevents the Xenical prevents the absorption of up to 30% of absorption of up to 30% of
dietary fat...dietary fat...
……which pass through the which pass through the body undigested and are body undigested and are
excreted.excreted.
30% of triglycerides
pass undigested and are excreted.
Pharmacokinetics:Pharmacokinetics:
AbsorptionAbsorption::Systemic absorption is minimalSystemic absorption is minimalPlasma concentrations of intact Orlistat were near Plasma concentrations of intact Orlistat were near the limits the limits of detection (<5ng/ml)of detection (<5ng/ml)No evidence of accumulationNo evidence of accumulation
Bioavailability:Bioavailability:male ratsmale rats - 150 mg/kg/day (0.12%) - 150 mg/kg/day (0.12%) -1000 mg/kg/day (0.59%)-1000 mg/kg/day (0.59%)male dogsmale dogs -100 mg/kg/day (0.7%) -100 mg/kg/day (0.7%) - 1000 mg/kg/day (1.9%)- 1000 mg/kg/day (1.9%)
Pharmacokinetics:Pharmacokinetics:
Distribution:Distribution:In vitro - >99% bound to plasma proteinsIn vitro - >99% bound to plasma proteins
Metabolism:Metabolism:- occurs mainly in the gastrointestinal wall- occurs mainly in the gastrointestinal wall
- the metabolites (M1 & M3 moiety) are - the metabolites (M1 & M3 moiety) are pharmacologically pharmacologically
inconsequentialinconsequential
Pharmacokinetics:Pharmacokinetics:
Elimination:Elimination:FFecal excretion (97%) , 87% - unchanged ecal excretion (97%) , 87% - unchanged
OrlistatOrlistatRenal excretion <2%Renal excretion <2%Time to reach complete excretionTime 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)
Xenical is safe in obese Xenical is safe in obese patients with co-morbiditiespatients with co-morbidities
Xenical is safe in overweight and obese patients with:Xenical is safe in overweight and obese patients with:
type 2 diabetestype 2 diabetes1,2,31,2,3
hypertensionhypertension4,54,5
dyslipidaemiadyslipidaemia6,7,86,7,8
multimorbiditiesmultimorbidities88
Xenical is safe in obese adolescent patientsXenical is safe in obese adolescent patients99..
1Hollander et al. Diabetes Care 1998; 21: 1288-1294; 2Kelley et al. Diabetes Care 2002; 25: 1033-1041; 3Miles et al. Diabetes Care 2002; 25: 1123-1128; 4Sharma & Golay. J Hypertens 2002; 20: 1873-1878; 5Zavoral. J Hypertens 1998; 16: 2013-2017; 6Muls et al. Int J Obes Relat Metab Disord 2001; 25: 1713-1721; 7Broom I et al, on behalf of the Orlistat UK Study Group. Br J Cardiol 2002; 9: 460-468; 8Broom et al, on behalf of the UK Multimorbidity Study Group. Int J Clin Pract 2002; 56: 494-499 9Chanoine et al,. JAMA 2005. In press
Xenical has a similar safety Xenical has a similar safety profile to placeboprofile to placebo
Respiratory
Infections
Musculo-skeletal
Nervous system
Cardiac
Skin / subcutaneous
Gastrointestinal
General
0 20
60 100Patients (%)40
80
Torgerson et al. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 1): S124. Toplak et al. Diabet Obes Metabol 2005, in
8%8%
66%
Adverse events reported in year
four36%
12%11%
23%
9%9%
6%6%
15%13%
45%43%
63%
Placebo + lifestyle (n=1655)
Xenical + lifestyle (n=1649)
Most patients on Xenical Most patients on Xenical experience experience
only 1 or 2 gastrointestinal only 1 or 2 gastrointestinal eventsevents
Xenical + diet 20
15
10
5
0
Pati
ents
experi
en
cing f
att
y/o
ily
stools
(%
)
1 >22Overall
Number of episodes
Data on file, F. Hoffmann-La Roche Ltd
20.0%
14.5%
3.6%
1.9%
Gastrointestinal 32 (2) 32 (2)Infections 25 (2) 30 (2)Musculoskeletal 19 (1) 23 (1)Nervous system 11(<1) 21 (1)General 18 (1) 12(<1)Respiratory 4(<1) 4(<1)Metabolism/nutrition 3(<1) 1(<1)Cardiac 22 (1) 40 (2)Skin/subcutaneous 3(<1) 2(<1)Neoplasms 17 (1) 22 (1)Death 7(<1) 2(<1)
Fraction of patients with Fraction of patients with serious adverse events during serious adverse events during
years 1years 1––44Placebo + lifestyle
n (%)Xenical + lifestyle
n (%)
XENDOS; Torgerson et al. Diabetes Care 27: 155-161
Zhaoping Li et al; 5 April 2005 Annals of Internal Medicine Volume 142 • Number 7
Zhaoping Li et al; 5 April 2005 Annals of Internal Medicine Volume 142 • Number 7
Xenical acts locally in the gut Xenical acts locally in the gut and is minimally absorbedand is minimally absorbed
Xenical does not act on thecentral nervous system
Xenical inhibits gastrointestinal lipaseaction
Xenical acts locally
30% of dietary fatis not absorbed
• Non-systemic1
• Minimal drug-drug interactions1
• >96% drug elimination in the faeces1
• Safe with concomitant medications1
• Suitable for overweight/obese patients with co-morbidities2,3
• Side effects are transient and mild41Guerciolini. Int J Obes Relat Metab Disord 1997; 21 (Suppl. 3): S12-S23
2Hollander et al. Diabetes Care 1998; 21: 1288-1294 3Muls et al. Int J Obes Metab Disord 2001; 25: 1713-17214Hauptman. Int J Obes Relat Metab Disord 1998; 22 (Suppl. 3): P678
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