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Primary hyperoxaluria and the Kidney
 

Primary hyperoxaluria and the Kidney

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How to treat using Dialysis? and transplantation

How to treat using Dialysis? and transplantation

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    Primary hyperoxaluria and the Kidney Primary hyperoxaluria and the Kidney Presentation Transcript

    • Primary Hyperoxaluria and Renal Disease Shailaja Chidella, MD Louis Spiegel,MD Hofstra 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 damage GFR<30-45mL/min Plasma levels rise and surpass saturation threshold systemic oxalosis
    • Systemic oxalosis Cardiac conduction defects  cardiac arrest Poor peripheral circulationdistal gangrene and difficulties with vascular access for hemodialysis. Bone manifestations Pain, 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
    • Epidemiology Type 1 hyperoxaluria Most common form 1-3 cases / 1 million 1 case / 120,000 live births in Europe 1-2% of pediatric ESRD
    • Clinical Features May 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
    • Facts Pts 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
    • Diagnosis Majority present with symptoms c/w urolithiasis Urinary oxalate, calcium, citrate, sodium, magnesium, urate, pH, volume Usually >95% calcium oxalate monohydrate Oxalate crystals in biopsy specimen Elevated oxalate excretion/day Urinary oxalate:creatinine Genetic testing
    • Management Combined 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 Therapy Long 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 Modalities Hemodialysis Daily HD Intermittent HD Nocturnal HD Peritoneal dialysis Continuous renal replacement therapy
    • Nocturnal Hemodialysis Performed 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 1989 Recurrence 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 HDF Explained 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
    • Conclusion At 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 50 mol/lμ 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 regimen 10 cycles/night 1-2 additional daytime exchanges Dwell time of 60 min
    • Discussion Promising reports for pre emptive liver transplant, but controversial Unpredictable 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 removal Only occurred when using higher blood flow, larger dialyzer
    • Final suggestions Early start to dialysis Total accumulated body oxalate determines long term outcomes Goal oxalate <50 micromoles/l Intensify PD by adjusting dwell time, volume
    • Transplant Sole 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 therapies Cell therapy to repopulate liver with normal hepatocytes Gene transfer Inhibition of glycolate oxidase Manipulation of chaperone proteins