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)

Oxalate - O O C C O - O CP1167399-5

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

Liver cell Ox Glycine glyoxylate oxalate Glyoxylate Glycolate Ox Oxalate CP1167399-1

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

- O O C C O - O Oxalate + calcium = CaOx  stones crystals CP1167399-5

Ox = + Ca ++  CaOx  Cell & tissue damage Obstruction Infection

Kidney failure blood oxalate Deposits of CaOx in body tissues (oxalosis) CP1167399-4

How many people have this problem? Kidney Stones Primary Hyperoxaluria 1 to 3 per million people

Types of primary hyperoxaluria  AGT enzyme PH1  GR/HPR enzyme PH2  HOGA1 enzyme PH3 Unclassified ?? cause

PH1 Liver cell AGT Glycine glyoxylate oxalate Glyoxylate Glycolate Oxalate CP1167399-2

PH2 Liver cell Glycine glyoxylate oxalate GR Glyoxylate Glycolate Oxalate CP1167399-3

PH3 Liver cell Glycine glyoxylate oxalate HOGA Glyoxalate Hydroxyproline Oxalate CP1167399-3

RKSC Primary Hyperoxaluria Registry 379 Patients 7% 9% 10% 73%

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

Urine Oxalate at Diagnosis 5 Oxalate (mmol/1.73 m 2 /24 hr) Normal range 4 3 2 1 0 PH type I PH type II Non-PHI/PHII CP1273355-3

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 Multiple Renal Calculi & and early bone changes in Nephrocalcinosis 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

International PH Registry, Renal Survival 100 Non-PHI/PHI I PH type II 80 60 Renal survival (%) 40 PH type I 20 P=0.007 0 0 10 20 30 40 50 60 70 80 Age, years Number at risk 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 0 Non-PH/PHI 9 9 3 1 1 0 0 0 CP1273215-12

Diagnosis 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%

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

Effect of Diet on Oxalate in Urine 180 mgm 200 150 Oxalate/ 100 24 hours 30 mgm (mgm) 50 Diet 0 Usual Primary hyperoxaluria CP1167399-6

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

Neutral Phosphate Treatment in PH Pre-Rx Rx Pre-Rx Rx Pre-Rx Rx 15 160 5 4 120 10 3 80 2 5 40 1 P<0.001 P<0.001 P<0.001 0 0 0 Calcium oxalate Calcium oxalate Crystalluria supersaturation inhibition score CP1131733-28

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

Primary Hyperoxaluria Type I 4 (mmol/1.73 m 2 /day) Urine oxalate 3 2 1 0 Baseline Pyridoxine CP968803-18

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

Mayo Clinic Hyperoxaluria Center Resource to Resource to PH Patients Physicians: Research Primary + Families: • Consulting Studies • Education Hyperoxaluria • Education & Clinical Registry Referrals • Testing Trials • Testing • Research • Support The PH Center and the Registry share the same staff of physicians and Study Coordinators

Mayo Clinic Hyperoxaluria Center Inquiries to Center

Post transplant recurrence study presenting at Mayo Clinic, Rochester, Minnesota, USA