Hyderabad Mayo Clinic Hyperoxaluria Center 1. Inherited Causes of - - PowerPoint PPT Presentation

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

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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

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• 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

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Glycine glyoxylate oxalate

Liver cell

Glyoxylate Oxalate Glycolate

PH1

AGT

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Glycine glyoxylate oxalate

Liver cell

Glyoxylate

Oxalate

Glycolate

PH2

GR

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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

1 2 3 4 5

Normal range

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Oxalate (mmol/1.73 m2/24 hr)

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
• xalate 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

• xalosis

death hyperoxaluria

birth 10 yrs 20 yrs 30 yrs 40 yrs

20 40 60 80 100 10 20 30 40 50 60 70 80

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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 PH type II 11 8 8 7 6 2 2 1 Non-PH/PHI 9 9 3 1 1

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

• xalate 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

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

• xalate 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

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Calcium oxalate supersaturation

Pre-Rx

15 10 5

Rx

P<0.001

Calcium oxalate inhibition

Pre-Rx

160 120 80 40

Rx

P<0.001

Crystalluria score

Pre-Rx

5 4 3 2 1

Rx

P<0.001

Neutral Phosphate Treatment in PH

What can be done to prevent

• xalate 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

• xalate 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

1 2 3 4

Primary Hyperoxaluria Type I

Urine oxalate (mmol/1.73 m2/day)

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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