UNDERSTANDING THE BASICS OF PRIMARY HYPEROXALURIA

Dr.Nageswara Reddy.Pamidi, M.D, D.M(Nephro)

Consultant Nephrologist, PREETI Kidney Hospital, Hyderabad

Mayo Clinic Hyperoxaluria Center

1. Inherited Causes of pediatric stone disease 1.Adenine phosphoribosyltransferase(APRT) deficiency 2.Cystinuria 3.Dent disease 4.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), 5.Primary hyperoxaluria (PH)

CP1167399-5

- O

C

O

C

O O -

Oxalate

What is oxalate?

• A naturally occurring substance found in plants and animals

• Two sources of oxalate in humans:

• Made in liver during metabolism

• Dietary intake

• Not needed for any human body process

• Majority excreted by healthy kidneys into the urine

CP1167399-1

Ox

Ox

Glycine glyoxylate oxalate

Liver cell

Glyoxylate

Oxalate

Glycolate

What is primary hyperoxaluria?

Hyper - oxal - uria

(too much) (oxalate) (in the urine)

Primary (comes from within)

Hyper - oxal - uria (too much) (oxalate) (in the urine)

Primary hyperoxaluria

• A condition in which the liver makes too much oxalate

• Genetic mutations result in defective enzymes

• Three types of primary hyperoxaluria based on which enzyme is defective

Primary hyperoxaluria

• Increased oxalate excreted in the urine

• Oxalate combines with urine calcium forming a salt

• Calcium oxalate damages the kidneys

Oxalate + calcium = CaOx stones

CP1167399-5

- O

C

O

C

O O -

crystals

Ox= + Ca++ CaOx

Cell & tissue damage Obstruction Infection

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Kidney failure

Deposits of CaOx

in body tissues

(oxalosis)

blood oxalate

Kidney Stones Primary Hyperoxaluria

1 to 3 per million people

How many people have this problem?

Types of primary hyperoxaluria

PH1 AGT enzyme

PH2 GR/HPR enzyme

PH3 HOGA1 enzyme

Unclassified ?? cause

CP1167399-2

Glycine glyoxylate oxalate

Liver cell

Glyoxylate

Oxalate

Glycolate

PH1

AGT

CP1167399-3

Glycine glyoxylate oxalate

Liver cell

Glyoxylate

Oxalate

Glycolate

PH2

GR

CP1167399-3

Glycine glyoxylate oxalate

Liver cell

Hydroxyproline

Oxalate

Glyoxalate

PH3

HOGA

RKSC Primary Hyperoxaluria Registry 379 Patients

73%

10%

9% 7%

Clinical Manifestations

Heterogeneity of disease expression

Five clinical presentations of PH type 1 based on age at

presentation/renal manifestations

1.Infantile Oxalosis(26%): nephrocalcinosis and renal dysfunction(

failure to grow,UTI)

2.Childhood with recurrent kidney stones & rapid decline in kidney

function(30%): symptoms of renal colic,UTI, obstuction

3.Occasional stone formation in adults(30%)

4.Diagnosis after failed transplant(10%)

5.Diagnosis after family screening(13%): including those who are

asymptomatic

0

1

2

3

4

5

Normal range

CP1273355-3

Oxala

te (

mm

ol/1

.73

m2/2

4 h

r)

PH type I PH type II Non-PHI/PHII

Urine Oxalate at Diagnosis

Hyperoxaluria

Urine Oxalate mmol/24 hrs

Normal < 0.45

Idiopathic stone disease 0.46 - 0.6

Enteric hyperoxaluria 0.7 - 1.0

Primary hyperoxaluria 1.0 - 4.0

Plasma Oxalate Measurement

Plasma oxalate levels elevated (>6.3 μM) with

normal renal function

Significantly higher (>80 to 100 μM) in ESRD due

to Oxalosis

Without PH1 (40 to 60 μM)

Systemic Oxalosis

• Oxalate overproduction + decreased urinary oxalate excretion = systemic oxalosis

• Deposition in heart: conduction defects, heart failure

• Joints/ bone: pain, resistant anemia, spontaneous fractures

• Hypothyroidism/ /gangrene

• Peripheral neuropathy

‘White Kidney’ on USG

Nephrocalcinosis

Multiple Renal Calculi & and

early bone changes in

femoral heads

Pitch Black foci of multiple CaOx

crystals in inner retina

Primary Hyperoxaluria I

transplant

renal failure

urolithiasis dialysis

oxalosis

death

hyperoxaluria

birth 10 yrs 20 yrs 30 yrs 40 yrs

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80

CP1273215-12

International PH Registry, Renal Survival

Age, years

Number at risk

Renal survival

(%)

P=0.007

PH type II

PH type I

Group PH type I 114 84 55 31 20 11 3 1 0 PH type II 11 8 8 7 6 2 2 1 0 Non-PH/PHI 9 9 3 1 1 0 0 0 0

Non-PHI/PHI I

Clinical metabolic screening (24 hr urinary oxalate by oxidase method,

increased urinary glycolate)

Confirmation by molecular genetic testing: mutation in AGXT gene

Targeted mutational analysis-50-70%

Whole gene sequencing-100%

Diagnosis

GENETICS

4 mutations

Gly170Arg(30-40%)

33_34insC(10-13%)

Phe152Ile(1-5%)

Ile244Thr(3-9%)

Account for 50% of the known 90 mutations of PH typeI disease

Oppurtunity to focus on these to save costs

Caveat: no Indian studies

What can be done to prevent oxalate damage to kidneys?

• Decrease oxalate in the diet?

• Decrease oxalate concentration in urine

• Decrease calcium oxalate crystal formation

• Increase oxalate elimination by the intestines

• Reduce oxalate production by the liver

0

50

100

150

200

Usual Primary

hyperoxaluria

Effect of Diet on Oxalate in Urine

Oxalate/ 24 hours

(mgm)

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30 mgm

180 mgm

Diet

What can be done to prevent oxalate damage to kidneys?

• Decrease oxalate in the diet?

Little effect

• Decrease oxalate concentration in urine

Drink lots of water

• Reduce calcium oxalate crystal formation

Citrate or phosphate medication

CP1131733-28

Calcium oxalate supersaturation

Pre-Rx 15

10

5

0

Rx

P<0.001

Calcium oxalate inhibition

Pre-Rx 160

120

80

40

0

Rx

P<0.001

Crystalluria score

Pre-Rx 5

4

3

2

1

0

Rx

P<0.001

Neutral Phosphate Treatment in PH

What can be done to prevent oxalate damage to kidneys?

• Increase oxalate elimination by the intestines

Oxalobacter formigenes

Oxalate degrading enzymes

• Reduce oxalate production by the liver

What can be done to prevent oxalate damage to kidneys?

• Increase oxalate elimination by the intestines

Oxalobacter formigenes

Oxalate degrading enzymes

• Reduce oxalate production by the liver

Pyridoxine (vitamin B6) p.Gly170Arg, c.33_34insC

Liver transplant

0

1

2

3

4

Primary Hyperoxaluria Type I U

rin

e o

xala

te

(mm

ol/

1.7

3 m

2/d

ay)

CP968803-18

Baseline Pyridoxine

Primary Hyperoxaluria Current Treatment Strategies

By 60 yrs of age, more than 80% of patients with type I PH will have renal failure

Dialysis is not an acceptable option

• Simultaneous/ sequential hepatic & Kidney transplantation

• Restore enzyme activity by liver transplantation

Knowledge of the spectrum of disease expression,

early diagnosis, and initiation of treatment before

renal failure are essential to realize a benefit for

patients.

History of PH at Mayo

• 1967 First PH patient diagnosed at Mayo

• 1974 Research studies with PH patients started in Rochester

• 2003 OHF funded and established the Mayo Clinic Hyperoxaluria Center in Rochester

• 2004 International PH Workshop and first PH Patient meeting in Rochester

The PH Center and the Registry share the same staff of physicians and Study Coordinators

Mayo Clinic Hyperoxaluria

Center

Primary Hyperoxaluria

Registry

Resource to Physicians: •Consulting •Education •Testing •Research

Resource to PH Patients + Families: •Education Referrals •Testing •Support

Research Studies

& Clinical Trials

Mayo Clinic Hyperoxaluria Center

Inquiries to Center

Post transplant recurrence study presenting at

Mayo Clinic, Rochester, Minnesota, USA