HYPEROXALURIA - Dr. Moumit mita a Sama mant nta, , Assis sista - PowerPoint PPT Presentation

HYPEROXALURIA - Dr. Moumit mita a Sama mant nta, , Assis sista tant nt Professor essor, , - Pediatric iatric Medicine cine - Disclaimer: Experience is limited…still in learning curve

AETIOLOGY  Hyperoxaluria – increased urinary excretion of oxalate  Primary & secondary hyperoxaluria are 2 distinct clinical expressions  Primary hyperoxaluria - inherited defect of oxalate metabolism  Secondary/Enteric hyperoxaluria- - increased ingestion of oxalate, its precursors (vit C) - calcium deficiency - fat malabsorption: Crohns disease short bowel syndrome pancreatic insufficiency (cystic fibrosis )

Healthy Plasma Liver Glyoxylate Oxalate AGT [B6] Glycine Glycolate Glycolate Oxalate Urine

Primary Hyperoxaluria 1 Plasma Liver Skeleton Glyoxylate Oxalate Oxalate AGT X [B6] Glycine Glycolate Oxalosis Glycolate Oxalate Urine

MANIFESTATIONS  Ur Urolithi lithiasi sis- obstructive uropathy recurrent hematuria recurrent UTI/sterile pyuria stones contain >95% calcium oxalate monohydrate crystals

MANIFESTATIONS  Nephr phrocal ocalcino cinosi sis-  Chron onic ic kidne dney y disea ease se- HTN, , failure to thrive, non oliguric renal failure

MANIFESTATIONS OF SYSTEMIC OXALOSIS GFR <60 ml/min/1.73m 2 : serial fundoscopy  GFR < 30 ml/min/1.73m 2 : ECG,ECHO, Bone X ray  Others: calcification of arteries, hypothyroidism  myopathy, arthritis

MANAGEMENT GUIDELINES Being a rare disease there is limited ed access to recommen mmendat ation ions for diagnosis and  management due to lack of RCT and meta-analyses An expert group (OxalEu Europe ope) has been established to provide the necessary  recommendations based on peer-reviewed publications in this field.

SCREENING TESTS Screen for hyperoxaluria by more than n one test st  Accurat Ac rate 24 hour urine ne collecti tion on is s corner erstone ne for eva valuati ation  2-3 urine collections are recommended  Avoid urine collection- when receiving parenteral infusions, during UTI, following lithotripsy or  relief of urinary tract obstruction. Reliability of urine collection is estimated by urine creatinine excretion:12-20mg/kg/day 

SCREENING TESTS For primary hyperoxaluria the best screening test is 24-hr urine oxalate or oxalate creatinine  ratio in spot urine sample. The urine for oxalate should be collected in a container containing 2N HCl acid as preservative.  If 24-hr urine oxalate is >40-50 mg/1.73sq. m/day, this is most suspicious.  Most PH1 show more than 100 mg/1.73sq.m There are different age specific cut offs for oxalate/creatinine ratio in spot urine  0-6 mths <288-260mg/g 7-24 mths <110-139 mg/g 2-5 yrs <80mg/g 5-10 yrs <60-65 mg/g > 10 yrs <32 mg/g

DIAGNOSTIC TESTS A firm diagnosis is tough High plasma oxalate (POx) >100µmol/L [ target during HD <30-45µmol/L]  Deficiency of AGT enzyme on frozen liver biopsy tissue (gold d standa ndard d with high  sensitivity) AGXT gene sequencing – indicated in patients with phenotypic characteristics of  PH1, prenatal diagnosis, screening of siblings & parents of index case These assays are to my knowledge not available yet in the country

WHEN TO SUSPECT??  First line work up for recurrent urolithiasis is negative  To complete the work up for rare metabolic disorders causing nephrocalcinosis.  For referral patients who present with reports of oxalate crystals in urine  When primary hyperoxaluria is a differential diagnosis.

INHOUSE EXPERIENCE  5 year old male child with urolithiasis & recurrent hematuria at OPD…… - sent first line investigations, reports awaited.  4 month infant with failure to thrive, polyuria and nephrocalcinosis …. - NOMID syndrome

PRIMARY CONGENITAL HYPEROXALURIA  Inborn error of glyoxylate metabolism  Recessive autosomal inheritance  3 types – PH1 PH3 PH2 • 80% • 5% • 15% • AGXT • GRHPR • HOGA1  Vitamin B 6 dependant liver specific Alanine-glyoxylate aminotransferase deficiency

PREVALANCE  The prevalence of PH1 is approximately 1-3 cases per million population [ Nephrol Dial Transplant 2003 ].  At least 1% of the ESRD in pediatric population is attributable to PH1 in European and Japanese studies [ Clin J Am Soc Nephrol 2012 ; Pediatr Nephrol 2002].  It is more frequently seen in populations where consanguineous marriages are practiced.  A significant delay of diagnosis was seen in 42% of patients and 30% of patients were diagnosed only at end-stage renal disease (ESRD). [ Pediatr Nephrol (2003) 18:986 – 991- US Registry]

INDIAN DATA.. pubmed search Isolated few case reports or case series  Primary hyperoxaluria type1 in three Indian children- 6 month, 18 month & 6 year old with ESRD at presentation [Indian J Nephrol 2012;22:459-61]  Indian family with 2 affected siblings with inherited AGXT mutation [Indian J Pediatr. 2009 Feb;76(2):215-7]  The etiology of nephrocalcinosis in northern Indian children included d-RTA in 50% patients and idiopathic hypercalciuria and hyperoxaluria in 7.5% each. Other causes were Bartter syndrome, primary hypomagnesemia with hypercalciuria, severe hypothyroidism and vitamin D excess. No cause was found in 12.5% patients. [Pediatr Nephrol. 2007 Jun;22(6):829-33] 18 yr old male with history of recurrent abdominal pain & passage of stones in urine . CT Abdomen  revealed bilateral symmetrical nephrocalcinosis with normal sized kidneys suggestive of primary hyperoxaluria. Renal functions were deranged . Liver biopsy confirmed the diagnosis. [Ann Acad Med Singapore. 2010 Jan;39(1):70-1 ]

PRESENTATION Infantile nephrocalcinosis 35% 1. Recurrent stones with progressive CKD 20% 2. Late adulthood onset with sporadic calcium oxalate stone* 15% 3. (50% have ESRD at presentation) Presymptomatic diagnosis from pedigree screening 15% 4. Diagnosis from post-renal Tx recurrence 10% 5.

CONSERVATIVE TREATMENT As soon as a diagnosis of PH1 has been even suggested  Hi High fluid d intake e ≥ 3 L/m² per 24 h  Tube feeding for adequate hydration (infants)  Vitami min B6 (pyridoxine) Starting at 5 mg/kg per day, up to 20 mg/kg per day  Aiming to decrease Uox by < 30% by 3 months of max dose   Calci cium um oxalate e crystal allizati ization on inhibi ibiti tion on Alkalization with oral potassium citrate  0.10 – 0.15 g/kg BW per day as long as GFR is preserved   No special cial diet etar ary interven enti tions ons in the abse sence nce of CKD- spinach, peanuts,cocoa

SURGICAL MANAGEMENT OF UROLITHIASIS Avoid oid any kind nd of su surgica cal l inter erventi ention on in patients with uncomplicated  urinary stone disease, except when there is obstruction, infection or multiple urolithiasis En Endoscop doscopic ic proced cedure ure is the e preferred erred strategy egy in patients who require  intervention

RENAL REPLACEMENT THERAPY Organ transplantation to be planned prior to systemic oxalosis ie, befor ore e CKD stage ge 4  Combine mbined liver er and kidney y transpla splant nt is ideal  If no other option then isolated kidney transplant  Routine HD not very useful  High efficacy dialysis: daily HD, nocturnal dialysis, combined HD with PD 

ENTERIC HYPEROXALURIA Management includes: Intake of diet with low oxalate,  low fat diet with calcium supplements with meals cholestyramine might be helpful probiotics (oxalobacter formigenes) in research stage

IN A NUT SHELL… PH1 is a rare autosomal recessive inborn error of  glyoxylate metabolism due to deficiency of liver specific AGT enzyme. Over production & excessive urinary excretion of oxalate→ urolith thia iasis sis &  nephrocal ocalci cinosis nosis As GFR falls systemic accumulation of oxalate → oxalosis osis  Diagnosis depends on clinical/radiological/urinary oxalate / DNA  analyis/enzymology Early conser servat ativ ive e Rx (high fluid intake/urine alkalination/pyridoxine) helps to  conser serve renal functi ction on In CKD stage 4 and 5 best outcomes seen with combined liver and kidney  transplantation

TAKE HOME MESSAGE Think of Primary hyperoxalurias to find them  Early conservative measures as soon as possible  Patient information regarding lifelong management  Perseverance pays!!