Primary Hyperoxaluria

and Renal DiseaseShailaja Chidella, MD

Louis Spiegel,MDHofstra North Shore LIJ School of Medicine

Overview AR

Overproduction of oxalate◦ Highly insoluble, excreted primarily via kidney◦ Tendency to crystallize in renal tubules

Inherited hyperoxaluria◦ Overproduction by liver increased renal excretion

urolithiasis, nephrocalcinosis CKD◦ Intratubular and interstitial deposits as well as

obstruction secondary to stones

2nd phase of damageGFR<30-45mL/minPlasma levels rise and surpass saturation

threshold systemic oxalosis

Systemic oxalosisCardiac conduction defects cardiac arrest

Poor peripheral circulationdistal gangrene and difficulties with vascular access for

hemodialysis.

Bone manifestationsPain, EPO resistant anemia, increased risk for

spontaneous fracture

Joint deposition synovitis with reduced mobility and pain.

Retinal epithelium and the macula diminished visual acuity

Hypothyroidism, peripheral neuropathy, dental problems

Skin manifestations Livedo reticularis, peripheral gangrene, and

calcinosis cutis metastatica

Forms Type 1

Deficiency of liver specific peroxisomal enzyme alanine glyoxylate aminotransferase accumulation of glyoxylate and excessive production of oxalate and glycolate

Type 2 Lack of glyoxolate reductase-hydroxypyruvate reductase Lactate dehydrogenase metabolizes glyoxolate to oxalate

Type 3 Defects in mitochondrial enzyme 4-hydroxy-2-oxoglutarate

aldolase Unclear why causes elevated oxalate levels

EpidemiologyType 1 hyperoxaluria

Most common form

1-3 cases / 1 million

1 case / 120,000 live births in Europe

1-2% of pediatric ESRD

Clinical FeaturesMay occur at any age

Median age of onset 5.5 years

Infantile nephrocalcinosis and failure to thrive

Stone formation in adulthood

20-50% with advanced CKD/ESRD at time of dx

Median age at dx of ESRD is 24 years old

FactsPts with type 1 hyperoxaluria produce

approximately 5-10 mg/kg/day of oxalate

Removal of oxalate may fall short of daily production and may be insufficient to reverse clinical consequences

Oxalate levels rebound rapidly following HD to ~ 80% of pre dialysis levels within 24 hours

Supersaturation of plasma with Ca oxalate occurs with concentrations as low as 2.7-4.1mg/dl

Volume of distribution of exchangeable oxalate smaller than urea

Poor solubility of oxalate deposits in tissues and limited ability to mobilise the salts during treatment

DiagnosisMajority present with symptoms c/w urolithiasis

Urinary oxalate, calcium, citrate, sodium, magnesium, urate, pH, volume

Usually >95% calcium oxalate monohydrateOxalate crystals in biopsy specimen

Elevated oxalate excretion/day

Urinary oxalate:creatinine

Genetic testing

ManagementCombined Kidney-Liver transplantation is the

best long term treatment for type I hyperoxaluria

Many patients must undergo interval dialysis treatment while awaiting transplant surgery

Medical TherapyLong term adherence can improve prognosis and slow

progression to ESRD

>2-3L/day of fluid intake

K citrate to alkalinize urine

Pyridoxine for type 1 Starting dose of 5mg/kg/day and not to exceed

20mg/kg/day Responsive if decrease in urinary oxalate by >30%

Shock wave lithotripsy NOT recommended for heavy stone burden

Dialysis ModalitiesHemodialysis

Daily HDIntermittent HDNocturnal HD

Peritoneal dialysis

Continuous renal replacement therapy

Nocturnal HemodialysisPerformed 7 nights per week using 60L of

dialysate over 8-10 hours lowered oxalate concentrations.

(Case report in AJKD):

Pre HD oxalate levels 11.4mg/dl. Nocturnal HD decreased pre and post HD oxalate levels to 3.8mg/dl and 1.3mg/dl after 4 wks of therapy.

Pyridoxine added after 6 wks of therapy. Pre HD level decreased to <= 2.8 mg/dl and post HD levels remained <=0.9 mg/dl

Combination of Daily HD (nocturnal) and PD

Substantial additional oxalate removal can be done by adding PD to intensive HD in difficult oxalosis cases.

Study looked at 4 ESRD pts (included 1 pediatric pt)

All pts underwent HD except for 1 adult and the child also underwent CAPD

Oxalate removal during PD estimated by measuring peritoneal effluent after 3 , 4 and 12 hour exchange periods

Oxalate kinetic values for HD estimated using concentration versus time

7year old child on CCPD( 1.5L, 6 exchanges, 2 hours each) removed ~ 500mg oxlalate/wk.

Combined CCPD plus high efficiency HD 6xwk resulted in total oxalate removal of 1480mg/wk with CCPD accounting for approx 10% of total removal

Adult using CAPD (10l/day) and high efficiency HD 4x/wk resulted in weekly oxalate removal of 1200mg with 1/3rd accounted for by PD

CRRT

Literature search showed efficacy in oxalate clearance during peri and post transplant period of combined liver kidney tx

High dose CVVHD effective in controlling

plasma oxalate levels

Use of high dose CVVHD strongly considered in patients with PH1 at risk for DGF as low UOP leads to decreased oxalate clearance and puts the transplant at great risk

Oxalate Removal by daily dialysis

Generally agreed that standard HD does not control hyperoxalemia in type 1

Several reports demonstrating oxalate removal with dialysis

Evaluate oxalate mass removal Daily HD vs standard HD vs Hemodiafiltration

Yamauchi T, Quillard M, Takahashi S, et.al

59 yoF in March 1985 when she was started on standard HD

Renal transplant in October 1985

Renal bx in March 1986 numerous oxalate crystal

April 1989Recurrence of primary disease 4 hour, 3x/week HD

Pyridoxine and vitamin C discontinued

Standard HD 3 weekly sessions 4 hours each session Triacetate membrane with surface area 1.7m2 (1) or

2.1m2(2)

Hemodiafiltration 3 weekly sessions 4 hours each session Triacetate membrane surface area 2.1m2(3)

Daily HD 6 weekly sessions 4 hours each session Triacetate membrane with surface area 1.7m2(4) or

2.1m2(5)

Protocols 1,4,5 for one week

Protocols 2,3 for 2 weeks

BFR 250mL/min

DFR 500mL/min

HDF with post dilution mode with infusion of 50mL/hour

Results

No significant difference in plasma concentration

Only postdialysis oxalate concentations with daily HD with FB 210 were significantly lower than when FB 170 was used

Weekly mass removal during daily HD 2x greater than standard HD or HDFExplained by difference in time of HD

Results No significant difference in mass removal per session

between standard HD and HDF

Prior studies did show difference HD with cuprophan HDF with AN69 (highly permeable) Suggests that removal may be maximized with high flux

dialyzers

Larger membrane or HDF did not improve oxalate removal

Daily HD most effective oxalate removal is time dependent

High G/R ratios Generation rate higher than removal rate

ConclusionAt least 8 hours of daily dialysis with high flux

membrane

Study of plasma oxalate concentration, clearance, removal

6 pediatric patients on RRT while awaiting transplant

Goal to reduce oxalate levels below 50μmol/l

Illies F, Bonzel K-E, Wingen A-M, Latta K, et al.

Six patients between 1997 and 2004

Age of diagnosis 3.3 years

None responsive to pyridoxine

Management Preserving maximal diuresis Adequate nutrition Control of acidosis EPO and HGH

Standard infant dialysis therapy CCPD High flux polysulfone HD Both

PD regimen10 cycles/night

1-2 additional daytime exchanges

Dwell time of 60 min

DiscussionPromising reports for pre emptive liver

transplant, but controversialUnpredictable course of disease, difficult timing,

disappointing survival rates

Neither HD nor PD able to achieve a rate of oxalate removal that matches tissue oxalate accretion rate

HD able to adequately balance removal with production rates, but once HD stopped rebound

HD loses effectiveness during each session

Additional sessions/week rather than increased time/session is advised

Addition of a standard HD regimen to PD did not significantly increase removalOnly occurred when using higher blood flow, larger

dialyzer

Final suggestionsEarly start to dialysis

Total accumulated body oxalate determines long term outcomes

Goal oxalate <50 micromoles/l

Intensify PD by adjusting dwell time, volume

TransplantSole organ responsible for glyoxylate detoxification

Preemptive liver transplant before systemic deposition is goal- before CKD IV

Kidney transplant without liver transplant high risk of recurrence May consider if confirmed response to pyridoxine

5 year survival 64% dual kidney-liver 45% kidney alone

HD during and after transplant for those with heavy systemic oxalate burden or insufficient urine output

Future therapiesCell therapy to repopulate liver with normal

hepatocytes

Gene transfer

Inhibition of glycolate oxidase

Manipulation of chaperone proteins