Download - Primary hyperoxaluria and the Kidney
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