Prior to 1990 outcomes of transplantation in primary hyperoxaluria were poor, to the extent that the appropriateness of transplantation for patients with PH was questioned (14, 26). Loss of function due to oxalate deposition in the transplanted kidney and death related to systemic oxalosis were particular problems. However, there has been substantial improvement in transplantation outcome among PH patients over the past several decades (27–29). For the cohort of patients in our study of the IPHR who received their first kidney transplant in the year 2000 or later, graft outcome now compares favorably with kidney allograft survival rates for all US recipients of kidney transplants for kidney failure of any cause (Figure 3). Greater use over time of combined liver and kidney transplantation as well as management strategies specific to primary hyperoxaluria appear important in the progress reflected in our experience and that of others (9, 29). Wider availability of definitive diagnostic testing for PH (23), the intensive dialysis needs of PH patients (13,17,27,36,37) and the critical need to minimize the time between ESKD and transplantation have been increasingly appreciated (6,27,29). However, there is as yet no standard approach to transplantation of patients with PH.
The AGT enzyme defect that is the cause of PH type 3, is specific to hepatocytes. Complete removal of the native liver and orthotopic transplantation is required to correct the metabolic defect (16), because any remaining native liver cells with reduced or absent AGT enzyme activity would produce large amounts of oxalate. Thus, the benefits of correcting the metabolic defect must be weighed against the added morbidity and mortality associated with hepatectomy and orthotopic liver transplantation. Early reports from Europe suggested better outcomes with combined K + L transplantation (15,30) whereas those from the United States suggested equally good or better outcomes with K-alone transplantation (18,31). Interestingly, our data, although showing better death-censored kidney allograft outcomes in K + L transplantation (p = 0.011), did not show a difference in uncensored kidney allograft survival (p = 0.14), where death is considered a graft loss. The difference is accounted for by three deaths in patients with functioning kidney grafts among the K + L recipients. Two of the deaths were related to posttransplant immune suppression (one due to PTLD and one to Nocardia sepsis). The remaining death was due to trauma resulting from an automobile accident. Overall patient survival at 5 years was 100% in K (n = 32) versus 67% in K + L (n = 26, p = 0.035), though has improved in more recent K + L transplants.
Oxalosis of the transplanted kidney represents an important challenge to long-term allograft survival in patients with PH (9,13,27). In the IPHR, 38% of first kidney allograft failures were caused by recurrent oxalosis. Though liver transplantation can provide correction of the metabolic deficiency that is the cause of PH type I, it appears no more effective than kidney transplantation alone in reduction of plasma oxalate during the first year after transplantation. There is a prompt fall in plasma oxalate concentrations following either K or K + L transplantation (Figure 5A,B). Nonetheless, urine oxalate remains markedly elevated for many months or even years after successful liver transplantation (Figure 6). This is due to tissue stores of calcium oxalate that are only slowly mobilized with subsequent kidney excretion (13,27). Thus the kidney allograft remains at risk for oxalosis long after correction of the underlying PHI metabolic defect (13,27). The kidney allograft is especially vulnerable to the injurious effects of high urine oxalate and deposition of calcium oxalate crystals in the renal parenchyma (32,33).
The time required for resolution of hyperoxaluria following liver transplantation varies widely, occurring most rapidly in those who undergo transplantation within 6 months after reaching ESKD and who have undergone intensive (daily) dialysis (29). Time on dialysis did not correlate with transplant outcome in our series, unlike that of Jamieson (29). This is perhaps related to the intensive dialysis that a number of our patients received before transplantation or alternatively to the relatively small number of patients dialyzed in our study who were on dialysis for a year or more (Table 2). Nevertheless, in our cohort 36% still had hyperoxaluria during the third year following transplantation.
What can be done to further improve outcomes of transplantation in PH? The large proportion (19%) of patients in whom the diagnosis of PH was not recognized until there was compromise or failure of a first kidney allograft is particularly alarming. Among such patients early graft loss predominated, with renal graft survival of only 62% at 1 year following transplantation, compared with 86% in those whose PH diagnosis was known prior to transplant. With availability of current diagnostic capabilities (22,23,34), most delays in diagnosis are now related to lack of familiarity with the disease. Recognition of PH before transplantation is important in identifying those patients at the outset who will have improved outcomes with K + L transplantation. In addition, it affords the opportunity to better preserve native renal function (5,35), minimize systemic oxalosis with intensive dialysis after renal failure ensues (36) and better protect the kidney allograft from oxalate injury by maintaining a high volume diuresis and inhibition of calcium oxalate crystallization with phosphate or citrate medication (17,27,37). PH should be considered as a potential cause of renal failure in all transplant candidates with a history of recurrent calcium oxalate kidney stones, nephrocalcinosis or interstitial renal disease of undetermined etiology. With this approach, harmful delays in diagnosis that continue to be reported both in the United States and Europe (9,38) can be avoided.
Strategies for individual patients with type 1 PH based on molecular genotyping may be important in achieving the best outcome (9,19). Patients who are fully responsive to pharmacologic doses of pyridoxine, usually those homozygous for the G170R mutation of AGXT, can maintain normal or near normal urine oxalate excretion rates for many years while on pyridoxine treatment (39). Though beyond the scope of the present report, whether native hepatectomy and liver transplantation is indicated in such patients will benefit from further study.
For patients with type 2 disease, which account for approximately 10% of PH patients, kidney-alone transplantation has been the recommended approach (6,27). Unlike AGT, which resides almost entirely within hepatocytes, the GRHPR enzyme deficient in PH type 2 is found in multiple body tissues (40). There has been no evidence to date to confirm that liver transplantation corrects this metabolic defect. Our single patient who required transplantation for PH type 2 maintained good allograft function and was free of stone disease and nephrocalcinosis for 31 years following kidney-alone transplantation despite ongoing hyperoxaluria. This is in keeping with the natural history of PH 2 in which many patients maintain native kidney function into their fifth to sixth decade of life (6,41).
Limitations of our study include the voluntary nature of the registry, and therefore a potentially biased sampling of patients, and lack of randomization in comparing K versus K + L. Though adjusted for in the analysis, the much longer follow-up in patients with K-only versus K + L transplantation must also be considered in interpretation of the results. Relatively small sample size and small numbers of events, due to the rarity of primary hyperoxaluria, limits the ability to perform multivariate analyses adjusting for multiple confounders.
We thank the patients and families who participated. We also greatly thank the IPHR Investigators who so generously provided clinical data: D Adey (San Francisco, California, USA), S Ahmed, M Aigbe (Las Vegas, Nevada, USA), S Alexander, M Anders (Buenos Aires, Argentina), N Amin (Los Angeles, California, USA), Dr. Ashette (New York, NY, USA), JR Asplin (Chicago, Illinois, USA), N Azam (Houston, Texas, USA), N Balakrishnan (Coimbatore Tamilivadu, India), S Bhandare, M Baum (Boston, Massachusetts, USA), B Becker (Wisconsin, USA), David Beckman (Faribault, Minnesota, USA), Dr. Beiken (New York, NY, USA), S Belani (Petaluma, California, USA), A Bellucci (Lake Success, New York, USA), R Berkseth (Minneapolis, MN, USA), P Berry (Austin, Texas, USA), N Bhakta (Los Angeles, California, USA), A Bhat (Roseville, California, USA), S Bhupalam (East Lansing, Michigan, USA), M Bia (New Haven, Connecticut, USA), T Blydt-Hansen (Winnipeg, Manitoba, Canada), R Bousquet (Whitehorse, Yukon, Canada), M Braun (Houston, Texas, USA), E Brewer (Houston, Texas, USA), C Brueggmeyer (Jacksonville, Florida, USA), T Bunchman (Grand Rapids, Michigan, USA), L Butani (Sacramento, California, USA), M Cadnapaphornchai (Aurora, Colorado, USA), E Castillo-Velarde Lima, Peru), MJ Choi (Baltimore, Maryland, USA), F Chybowski (Appleton, Wisconsin, USA), F Ciuitarese (Carneigie, Pennsylvania, USA), L Copelovitch (Philadelphia, Pennsylvania, USA), F Corbin (Quebec, Canada), H Corey (Morristown, New Jersey, USA), D Creemers (Netherlands), R Cunningham (Cleveland, Ohio, USA), K Dalinghaus (Whitehorse, Yukon, Canada), I Davis (Cleveland, Ohio, USA), C de Souza (Uruguay), M DeBeukelaer (Toledo, Ohio, USA), V Delaney (Hawthorne, New York, USA), P Devarajan (Cincinnatti, Ohio, USA), Z Dolezel (Czech Republic), HA Doll (Tallahasse, Florida, USA), P Douville (Quebec, Canada), S Ecklund (Sioux Falls, South Dakota, USA), K Eidman (Minneapolis, Minnesota, USA), M Emmett (Alvardo, Texas, USA), D Ford (Aurora, Colorado, USA), J Foreman (Durham, North Carolina, USA), C Fritsche (Milwaukee, Wisconsin, USA), S Garcia (Barcelona, Spain), D Geary (Toronto, Ontario, Canada), D Gipson (Chapel Hill, North Carolina, USA), D Goldfarb (Cleveland, Ohio, USA), B Greco (Springfield, Massachusetts, USA), L Greenbaum (Atlanta, Georgia, USA), W Haley (Jacksonville, Florida, USA), P Hall (Cleveland, Ohio, USA), M Hames (Greenville, North Carolina, USA), CD Hanevold (Seattle, Washington, USA), F Harris (Metairle, Louisiana, USA), G Hart (Charlotte, North Carolina, USA), E Harvey (Toronto, Ontario, Canada), RL Heilman (Scottsdale, Arizona, USA), R Helman (Duluth, Minnesota, USA), A Herndon (Birmingham, Alabama, USA), J Herrin (Boston, Massachusetts, USA), M Hertl (Boston, Massachusetts, USA), G Hidalgo (Chicago, Illinois, USA), S Hmiel (St. Louis, Missouri, USA), B Hoppe (Cologne, Germany), H Hotchkiss (New Brunswick, NJ, USA), T Hunley (Nashville, Tennessee, USA), Dr. Husmann (Tennessee, USA), J Johnston (Pittsburgh, Pennsylvania, USA), B Kaiser, U Kannapadi (Pittsburgh, Pennsylvania, USA), C Kashani (Minneapolis, Minnesota, USA), F Kaskel (Bronx, New York, USA), E Kendrick (Seattle, Washington, USA), O Khan (Chicago, Illinois, USA), S Knohl (Syracuse, New York, USA), R Kossman (Santa Fe, New Mexico, USA), A Krambeck (Indianapolis, IN, USA), C Langman (Chicago, Illinois, USA), L Larch (Clarksville, IN, USA), J Leiser (Indianapolis, IN, USA), S Lerman (Los Angeles, California, USA), DL Levy (Bangor, Maine, USA), J Lingeman (Indianapolis, IN, USA), DS Lirenman (Vancouver, British Columbia, Canada), N Maalouf (Chattanooga, Tennessee, USA), M Maddy (Duluth, Minnesota, USA), MA Mansell (London, United Kingdom), M Martin (Worcester, Massachusetts, USA), R Mathias (San Francisco, California, USA), M Mauer (Minneapolis, MN, USA), M May (Jacksonville, Florida, USA), M McHugh (Columbus, OH, USA), P Metcalfe (Edmonton, Alberta, Canada), B Morgenstern (Phoenix, Arizona, USA), G Murphy (Greenville, North Carolina, USA), M Narkewicz (Denver, Colorado, USA), M Navarro (Madrid, Spain), HG Pohl (Washington, DC, USA), H Powell (Parkville, Victoria, Australia), I Randeree (Umhlanga Rocks, South Africa), V Rao (Omaha, Nebraska, USA), D Raskin (Phoenix, Arizona, USA), Dr. Ravichandran (India), L Restall (Dallas, Texas, USA), C Richardson (Tacoma, Washington, USA), M Rocklin (Denver, Colorado, USA), P Sacks (Phoenix, Arizona, USA), M Sanderson (Saint Paul, Minnesota, USA), JD Scandling (Palo Alto, California, USA), J Sharma (Bangalore, India), M Sheehan (Denver, Colorado, USA), K Sievers (Rolla, Missouri, USA), E Simon (Boston, Massachusetts, USA), R Sirota (Willow Grove, Pennsylvania, USA), C Smith (Minneapolis, Minnesota, USA), M Sobel (Westerville, OH, USA), Dr. Somasundaram (Indianapolis, IN, USA), T Starzl (Pittsburgh, Pennsylvania, USA), J Steinke (Minneapolis, Minnesota, USA), D Steward, M Suarez (Houston, Texas, USA), JM Symons (Seattle, Washington, USA), IYS Tang (Chicago, Illinois, USA), J Tariq (Pakistan), M Teruel (Fort Collins, Colorado, USA), A Tolaymat (Jacksonville, Florida, USA), MM Tomsho (Summersville, West Virginia, USA), A Torres (La Laguna, Tenerife, Spain), S Tuchman (Washington, DC, USA), MA Turman (Oklahoma City, Oklahoma, USA), R Unwin (London, United Kingdom), R Venick (Los Angeles, California, USA), S Venkatesh (Nashville, Tennessee, USA), A Vera (Bogota, Columbia), H Viko (Oslo, Norway), R Villa (Lubbock, Texas, USA), J Wang (Minneapolis, Minnesota, USA), B Warady (Kansas City, Kansas, USA), B Warshaw (Atlanta, Georgia, USA), C Weimer (Thibodaux, Louisiana, USA), J Weinstein (Dallas, Texas, USA), RA Weiss (Valhalla, New York, USA), P Wertsch (Madison, Wisconsin, USA), J Wesson (Milwaukee, Wisconsin, USA), C Wong (Albuquerque, New Mexico, USA), W Wong (Boston, Massachusetts, USA), E Worcester (Chicago, Illinois, USA), O Yadin (Los Angeles, California, USA), V Yiu (Edmonton, Alberta, Canada).
Our appreciation goes to Julie B. Olson, R.N., Barb Seide, Chuck Madsen, Mark Manneman and Susan Rogers, coordinators of the Mayo Clinic Hyperoxaluria Center and the Rare Kidney Stone Consortium for their tireless efforts.
Funding Sources: This work would not have been possible without funding from the Oxalosis and Hyperoxaluria Foundation and the NIDDK (DK73354).
The Rare Kidney Stone Consortium is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by U54KD083908 from the NIDDK and the NIH Office of Rare Diseases Research (ORDR). The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
This material was presented, in part, at the American Society of Nephrology in 2008. J Am Soc Nephrol 19:101A, 2008.