Primary hyperoxaluria and the Kidney

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How to treat using Dialysis? and transplantation

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Primary hyperoxaluria and the Kidney

  1. 1. Primary Hyperoxaluria and Renal Disease Shailaja Chidella, MD Louis Spiegel,MD Hofstra North Shore LIJ School of Medicine
  2. 2. 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
  3. 3. 2nd phase of damage GFR<30-45mL/min Plasma levels rise and surpass saturation threshold systemic oxalosis
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. Dialysis Modalities Hemodialysis Daily HD Intermittent HD Nocturnal HD Peritoneal dialysis Continuous renal replacement therapy
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21.  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)
  22. 22. 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
  23. 23. Results
  24. 24. 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
  25. 25. 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
  26. 26. Conclusion At least 8 hours of daily dialysis with high flux membrane
  27. 27. 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.
  28. 28.  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
  29. 29. PD regimen 10 cycles/night 1-2 additional daytime exchanges Dwell time of 60 min
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. Future therapies Cell therapy to repopulate liver with normal hepatocytes Gene transfer Inhibition of glycolate oxidase Manipulation of chaperone proteins

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