Transcript Joy Duenas and Edgar Lim 04102007

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
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 successful
pharmacotherapy 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.
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
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).
Physical Examination: Unremarkable
Laboratory Results:
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
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.
Laboratory Results
Renal Ultrasound:
Sonogram showed normal-sized nonhydronephrotic kidneys
with slightly increased echogenicity.
Figure: Urinary oxalate concentrations in the patient presented show increased urinary
oxalate excretion with orlistat that decreased after discontinuation of drug.
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.
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.)
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.
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.
Disposition:
Discharged improved
Advised to drink fluids liberally everyday
Orlistat therapy was discontinued
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]).
Second Biopsy:
NO calcium oxalate crystals within tubules or interstitium;
Diffuse chronic interstitial fibrosis
Otherwise, there were no new or acute histopathologic
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]
CASE # 2
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
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
CKD
HTN
Obesity
Gout
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
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)
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).
Laboratory Results:
Urinalysis – proteinuria
Ultrasound - both kidneys were non-obstructed
and anatomically normal. The bladder was empty.
Inflammatory markers – normal
Immunological investigations – negative
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
Management:
2-weeks course of oral steroid therapy
NO objective improvement
NO recovery of renal function
24 months later….
OBESITY
AS A
DISEASE
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.
Classification of Obesity based on BMI (Caucasians)
Asia-Pacific Classification of Obesity based on BMI
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
Mortality, especially cardiovascular
mortality, is increased in subjects with
MS
Subjects (%)
20
No MS
MS
18.0%*
15
12.2%*
10
4.6%
5
2.2%
0
Cardiovascular mortality
Results of a 7-year follow-up
*p<0.001 vs. subjects without MS
Total mortality
Isomaa et al. Diabetes Care 2001; 24: 683–9
Prevalence of MS (ATP III)
in a non-diabetic population – St. Georgen Study
Proportion with MS (%)
70
61.0
60
50
40
30
27.0
20
10
0
7.0
Normal
(48 yr)
Overweight
(54 yr)
Obese
(54 yr)
Mean age
Jacob et al. ADA presentation 2005
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
The burden of overweight and obesity in the
Asia-Pacific region
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)
TREATMENT
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
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
Xenical binds to the lipase active site...
51
…inhibiting lipase
Triglycerides remain intact
Xenical prevents the absorption of up to
30% of dietary fat...
53
…which pass through the body
undigested and are excreted.
30% of
triglycerides
pass
undigested and are excreted.
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 - 150 mg/kg/day (0.12%)
-1000 mg/kg/day (0.59%)
male dogs -100 mg/kg/day (0.7%)
- 1000 mg/kg/day (1.9%)
Pharmacokinetics:
Distribution:
In vitro - >99% bound to plasma proteins
Metabolism:
- occurs mainly in the gastrointestinal wall
- the metabolites (M1 & M3 moiety) are
pharmacologically inconsequential
Pharmacokinetics:
Elimination:
Fecal excretion (97%) , 87% - unchanged Orlistat
Renal excretion <2%
Time to reach complete excretion
(fecal + urinary) = 3 to 5 days
Half-life:
1 to 2 hours (absorbed Orlistat)
Xenical is safe in obese patients with comorbidities
Xenical is safe in overweight and obese patients with:

type 2 diabetes1,2,3

hypertension4,5

dyslipidaemia6,7,8

multimorbidities8

Xenical is safe in obese adolescent patients9.
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 profile to
placebo
0
Respiratory
20
40
Patients (%)
45%
43%
Nervous
system
15%
13%
Placebo + lifestyle (n=1655)
6%
6%
9%
9%
Xenical + lifestyle (n=1649)
23%
Gastrointestinal
General
100
63%
66%
Musculoskeletal
Skin /
subcutaneous
80
8%
8%
Infections
Cardiac
60
36%
12%
11%
Torgerson et al. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 1): S124. Toplak et al. Diabet Obes Metabol
2005, in
Adverse events reported in year
four
Most patients on Xenical experience
only 1 or 2 gastrointestinal events
Patients experiencing fatty/oily stools (%)
20
20.0%
Xenical + diet
14.5%
15
10
3.6%
5
1.9%
0
Overall
1
2
Number of episodes
Data on file, F. Hoffmann-La Roche Ltd
>2
Fraction of patients with serious adverse
events during years 1–4
Placebo + lifestyle
n (%)
Gastrointestinal
Infections
Musculoskeletal
Nervous system
General
Respiratory
Metabolism/nutrition
Cardiac
Skin/subcutaneous
Neoplasms
Death
XENDOS; Torgerson et al. Diabetes Care 27: 155-161
32
25
19
11
18
4
3
22
3
17
7
(2)
(2)
(1)
(<1)
(1)
(<1)
(<1)
(1)
(<1)
(1)
(<1)
Xenical + lifestyle
n (%)
32
30
23
21
12
4
1
40
2
22
2
(2)
(2)
(1)
(1)
(<1)
(<1)
(<1)
(2)
(<1)
(1)
(<1)
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 and is
minimally absorbed
Xenical does not act on the
central nervous system
Xenical inhibits
gastrointestinal lipase
action
30% of dietary fat
is not absorbed
Xenical
acts locally
• Safe with concomitant medications1
• Non-systemic1
• Minimal drug-drug interactions1
• Suitable for overweight/obese patients
with co-morbidities2,3
• >96% drug elimination in the faeces1
• Side effects are transient and mild4
1Guerciolini. 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: 1713-1721
4Hauptman. Int J Obes Relat Metab Disord 1998; 22 (Suppl. 3): P678
Thank You for Your Attention!!