Combined Hepatic and Renal Transplantation in Primary Hyperoxaluria Type I: Clinical Report of Nine Cases RICHARDW

Home , Glycogen storage disease

Combined Hepatic and Renal Transplantation in Primary Hyperoxaluria Type I: Clinical Report of Nine Cases RICHARDW. E.~ATTs,M.D., D.sc.,P~.D., F.R.c.P.,F.R.s.c., STEPHEN H.MORGAN,M.B., M.R.C.P.,CHRISTOPHERJ. DANPURE, P~.D.,PAULPURKISS,M.SC., M.R.s.c., Harrow,fng/and, RovY. CALNE, M.s., F.R.c.s., F.R.s., KEITH ROLLES,F.R.C.S., Cambridge,England, LAURENCER. I. BAKER,M.D., F.R.c.P., MARTINA.MANSELL,M.D., F.R.C.P.,LOIJ~O~, England, LYNWOODH. SMITH, M.D., Rochester,Minnesota, ROBERTM.MERION,M.D.,MICHAELR.L‘UCEY,M.D.,F.R.C.P.I., Ann Arbor, Michigan

PURPOSEANDPATIENTSANDMETHODS: The may have had. They are either employed or con- purpose of this article is to report the experi- tinuing their education. ence of three centers with combined hepatic and CONCLUSIONS: A prolonged period of end-stage renal transplantation for pyridoxine-resistant renal failure treated by dialysis regimens that primary hyperoxaluria type I (alanine:glyoxy- are suitable for non-hyperoxaluric renal failure late aminotransferase [EC 2.6.1.441 deficiency), and extensive systemic oxalosis, particularly ox- with particular emphasis on the selection crite- alotic osteodystrophy, are poor prognostic fea- ria and timing of the operation. Nine patients tures. We propose that hepatic transplantation with this inherited disease were treated by com- should be considered as definitive treatment be- bined hepatic and renal transplantation. The fore end-stage renal failure develops. This former replaces the enzyme-deficient organ should be supplemented by renal transplantation while the latter replaces the functionally affect- with vigorous pre- and perioperative heinodialy- ed organ. sis to deplete the body stores of oxalate. Al- RESULTS: One patient with gross systemic oxa- though some authorities would reserve hepatic losis died in the immediate postoperative period transplantation for patients in whom renal and another died 8 weeks postoperatively of a transplantation has failed, we suggest that com- generalized cytomegalovirus infection, having bined liver and kidney transplantation is appro- shown evidence of biochemical correction. One priate in patients who have never had a renal patient with particularly severe osteodystrophy graft. F’urthermore, the time has come to consid- at the time of the operation died 14 months post- er hepatic transplantation before any irrevers- operatively from renal failure due to progressive ible renal damage has occurred in these calcium oxalate nephrocalcinosis involving the patients. transplanted kidney, plus thromboembolic disease. He also had very extensive systemic oxalosis. A.n additional patient with severe osteodys- rimary hyperoxaluria type I (PHI) is an autoso- trophy died 9 months postoperatively. One P ma1 recessively inherited inborn error of metab- patient developed hyper-rejection of the kidney olism [l] that is due to alanine:glyoxylate amino- and died later of gastrointestinal hemorrhage. transferase (AGT: EC 2.6.1.44) deficiency in the The four long-term survivors (22 to 38 months) liver [2-41. There is increased synthesis and excre- have remained asymptomatic from the stand- tion of oxalate and glycolate with recurrent calcium point of their renal disease, with resolution of oxalate urolithiasis and irreversible nephiocalcino- any manifestations of systemic oxalosis that they sis, which cause fatal renal failure. Calcium oxalate is deposited in many tissues (oxalosis) when oxalate From the Clinical Research Centre (RWEW, SHM, CJD. PP), Harrow, retention and oxalate over-production combine to England; Department of Surgery (RYC, KR), University of Cambridge, Cambridge, England: Department of Nephrology (LRIB), St. Bartholo- produce greatly increased oxalate ion concentration mews Hospital, London, England; St. Peters Hospital and Institute of in the tissue fluids generally. Except for the treat- Urology (MAM), London, England; Division of Nephrology (LHS), The Mayo Clinic, Rochester, Minnesota; and Departments of Internal Medi- ment of pyridoxine-responsive variants of the dis- cine and Surgery (RMM. MRL), University of Michigan, Ann Arbor, ease with pharmacologic doses of the vitamin [5,6], Michigan. there had been no reports of biochemical correction Requests for reprints should be addressed to Richard W. E. Watts, M.D., Wellington Hospital, Wellington Place, London, NW8 9LR, England. of the disease until Watts et al [7] reported a case Manuscript submitted May 23, 1990, and accepted in revised form treated by combined hepatic and renal transplanta- October 7, 1990. tion (Patient 1 in this communication). Although

February 1991 The American Journal of Medicine Volume 90 179 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL

TABLEI The Patients

Age at Onset of First Episode Age at First of End-Stage Cause of Kidney Symptoms Renal Failure Previous Kidney Kidney Transplant Transplant Patient Sex (years) (years) Transplant Survival Failure Previous Reference

1 M 7.5 17.5 1 cadaveric 10 days Oxalate deposition Patient 2 [41, 421 Single case [7] Patient NA [38]

2 M 1.5 22 1 live related 5 months Oxalate deposition Patient GF [38] Patient F [4] 1 cadaveric 1 month Acute rejection Patient GF [38] 3 F 7 19 0 - -

4 M 6 19 1 cadaveric 8 months Oxalate deposition Patient H [38]

5 M 11 36 1 cadaveric 14 days Oxalate deposition [I61 and rejection 6 M 18 28 1 cadaveric 11 months Oxalate deposition -

7 M 8 15 0 -

8” M 19 23 1 cadaveric Never functioned - 1 live related

91 M 10 26 1 cadaveric 21 months Oxalate deposition Siblings. that patient died of a disseminated cytomegalovi- ed in end-stage oliguric renal failure 8 years before rus infection about 8 weeks after transplantation, liver transplantation. All but one of the livers were the biochemical results encouraged further work by completely, or almost completely (less than 2%), the same group, who were subsequently able to re- lacking in AGT activity (Table II). However, one port a patient in whom combined liver and kidney patient (Patient 7) had a significant residual activi- transplantation led to near-normalization of plas- ty of AGT (9%). There is no evidence that severe ma and urine metabolite levels and who was well chronic renal failure has any effect on hepatic AGT and in regular employment 8 months postopera- activity. In fact, a diagnosis of PHI has been exclud- tively [8] (Patient 2 in this communication). This ed in three patients with end-stage renal disease by was a notable advance in the management of a pre- their completely normal liver AGT levels (Danpure, viously untreatable disease and an example of the unpublished observations). Five patients had no widening scope of liver transplantation as a means detectable immunoreactive AGT protein and three of enzyme replacement in the treatment of the in- had detectable but significantly reduced levels. Pa- born errors of metabolism. We now report experi- tient 4 had normal levels of immunoreactive AGT ence with combined hepatic and renal transplanta- protein despite having almost no AGT enzyme action for PHI from three centers with particular tivity (Table II). reference to the selection criteria and timing of the operation. We also discuss some aspects of pre- and Methods perioperative management, the relative merits of a The analytical methods were derived from the one- or two-stage operation, and evidence that the following references: urine and plasma oxalate [9- successfully treated patients gradually mobilize 111; urine and plasma glycolate [12]; glomerular fil- their systemic oxalate deposits. tration rate (GFR) by a standard isotopic EDTA- or DTPA-chelate technique, liver AGT (EC 2.6.1.44) PATIENTS AND METHODS and glutamate:glyoxylate aminotransferase (GGT; The case histories of the patients were all typical EC 2.6.1.4) enzyme activities [3]; and immunoreac- of PHI (Table I). All of these patients had had tive AGT protein [13]. The surgical procedures used recurrent urinary stones and were in end-stage re- are those described by Calne [14,15], and consist of nal failure. In five patients, renal transplantation orthotopic grafting of the liver to the hepatic fossa had failed, and one patient (Patient 4) had present- with anatomic anastomoses of the vessels and renal

180 February 1991 The American Journal of Medicine Volume 90 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL transplantation to the right iliac fossa together with TABLE11 ureteric drainage into the bladder. liver Enzyme Activities (rmol l hour-l l mg protein-l) RESULTS Patient AGT GGT AGT” CRM Table III shows the condition of the patients Native liver when they underwent transplanation and the out- : 0.700.42 0.581.01 0.030.04 - come in each case. Patients 2,4, 5,6, and 7 all had good postoperative outcomes with satisfactory re- i 0.440.54 0.650.69 0.010.08 +++ covery of liver function and adequate residual renal ; 0.540.51 0.900.68 i.06 +/-- function. Patient 6 underwent combined liver and ; 0.980.62 0.900.87 0.390.05 + kidney transplantation despite systemic manifesta- 9 0.53 0.72 0.05 +/- tions of oxalosis that included congestive cardiomy- Donor liver opathy due to myocardial oxalosis (confirmed by myocardial biopsy), complete heart block, and pe- i 4.016.26 0.820.38 3.765.72 +ttttt ripheral neuropathy plus end-stage renal failure. Controls Mean 5.00 0.65 4.50 He had been treated by continuous ambulatory Ranget 3.25-8.99 0.38-0.92 2.75-8.38 peritoneal dialysis and one renal allograft for 18 Number 16 12 12 I months. Since combined transplantation, his car- AGT = alanine:glyoxylate aminotransferase; GTT = glutamate:glyoxylate aminotransferase; CRM = immunologically cross-reacting AGT (+++ = normal, - = not detectable). diomyopathy has resolved. Patient 4, who had un- * AGT corrected for crossover [3] from GGT (AGT* = AGT - [GGT X 0.661). dergone chronic hemodialysis for 7 years preopera- t From [3]. tively, presented in end-stage renal failure with very painful oxalotic osteodystrophy, which persist- postoperative day. The kidney was removed and ed and prevented normal activities. Postoperative- hemodialysis was reinstituted. The liver continued ly, he lost kidney function progressively because of to function well. His general condition, particularly calcium oxalate nephrocalcinosis in the grafted kid- the bone and joint pain, improved. However, he ney and died 14 months later with extensive throm- died of a massive gastrointestinal hemorrhage boembolic disease (multiple pulmonary infarcts, about 3 months postoperatively. cerebrovascular disease, inferior vena cava obstruc- “High-resolution x-ray powder diffraction analy- tion) and heart failure. However, Patients 2, 5, 6, sis of bone and kidney tissue from Patients 8 and 9 and 7 have been able to resume their regular em- yielded x-ray diffraction maxima for calcium oxa- ployment. Patient 3 had been in end-stage renal late monohydrate only. The widths of the diffrac- failure for 5 years. This had been treated initially by tion maxima for the bone calcium oxalate were nar- continuous ambulatory peritoneal dialysis and sub- rower than for most calcium oxalate stone patterns. sequently by hemodialysis regimens suitable for This implies that the calcium oxalate crystals non-hyperoxaluric renal failure. Neither of these [were] highly crystallized” (Dr. Neil S. Mandel). In regimens was sufficient to prevent very severe sys- oxalotic osteodystrophy, calcium oxalate replaces temic oxalosis, which showed as gangrenous toes, the bone calcium phosphates, and its high crystal- right bundle branch block, arterial calcification, os- linity weakens the bones. teosclerosis, and synovitis. She became septicemic Figure 1 shows the long-term changes in the and died during the immediate postoperative plasma oxalate concentration, the urinary oxalate period. excretion, and the GFR in two of the patients (Pa- Patient 8 had very severe osteodystrophy. He tients 2 and 7) who have made good long-term re- sustained bilateral pathologic fractures of the femo- coveries and in Patient 4 who had advanced osteo- ral necks and effusions into his right knee about 3 dystrophy when he received his transplant and who months before the orthotopic liver transplantation. died after about 14 months. The changes in Patient His postoperative course included cardiopulmo- 5, who also had a good long-term outcome, were nary complications, recurrent pleural effusions, a similar to those in Patients 2 and 7, with the plasma liver abscess, gastric ulcers, and generalized debility oxalate concentration decreasing toward normality and wasting. He died 9 months after the liver over the course of several months and the urinary transplantation. oxalate excretion values declining more slowly. The Patient 9 made a good immediate recovery from urinary glycolate values decreased immediately af- the hepatic and renal transplantation. The kidney ter the transplantation as shown in Table IV. The functioned well and removed about 13,000 mmol of available data for Patient 6 are more limited. His oxalate in 6 days. However, he developed hypera- highest recorded plasma oxalate concentration was cute rejection of the grafted kidney on the eighth 170 pmol/L 1 month before transplantation and 100

February 1991 The American Journal of Medicine Volume 90 181 TABLEIll Stateof the Patientsat Time of Transplantationand the OutcomeAfter Combined Hepaticand RenalTransplantation

Plasma Oxalate Age at Hepatic (pm) at Time Follow*Up Most Recent Values Serum Transplantation Clinical State at Duration of last of liver Period Plasma Oxalate Urine Oxalate GFR Creatinine Patient (years) Time of Operation Episode of ESRD Transplantation Clinical Outcome (months) (PM) (pmo1/24 hours) (mL/minute/l.73 m*) (pM) 1 18 Anuric. Intensivehemodialysis. 4 months 249 Died from generalized 2 - - No clinical evidence of cytomegalovirus infection 2 systemicoxalosis. months postoperatively. Progressivearterial Biochemical correction calcification observed during f;ronstrated antemortem operations to obtain vascular access. Microscopicarteriolar calcification on a skeletal muscle biopsy.

2 24 Anuric. Intensivehemodial sis. 11 months 168 Asymptomatic. In full-time 50 4, 5% 550, 509* 101,720” 120 Renal transplants failed Y1 clerical employment. cadaveric, 1 live related). No clinical evrdence of systemic oxalosis.

3 24 Anuric. Conventional 5 years 27 Died in the immediate 0 - peritoneal/hemodialysis perioperative period. regimen for 5 years before referral, perioperative intensive hemodialysisonly. Malnourished. Arterial calcification (radiologic). Peripheral gangrene. Osteosclerosis.Synovitis. Right bundle branch block. Myocardial ischemia on thallium scanning.

4t 28 Anuric. Home hemodialysisfor 9 years 56 (49)* Initially improved. Lived at 14 § 5 5 § 7 years. Cadaveric renal home independently for 6 transplant failed. Only months. Bone pain. tolerated limited Progressive lossof renal perioperative intensive function due to calcium hemodialysis. Extensive oxalate deposition in arterial calcification trans lanted kidney. Died 14 (radiologic). Painful montR s postoperatively due osteodystrophy. Vertebral to extensive thromboembolic collapse. Pulmonary disease with multiple calcification. Synovitis. pulmonary infarcts. Inferior vena canal obstruction. Heart failure. TABLE III (Cont.) State of the Patients at Time of Transplantation and the Outcome After Combined Hepatic and Renal Transplantation

Plasma Oxalate Age at Hepatic (pm) at Time Follow-Up Most Recent Values Serum Transplantation Clinical State at Duration of Last of Liver Period Plasma Oxalate Urine Oxalate GFR Creatinine Patient (years). Time of Operation Episode of ESRD Transplantation Clinical Outcome (months) (PM) (pmol/24 hours) (mL/minute/l.73 m2) (pM) 5 36 Polyuric. GFR = 13 mL/ 5 months 90-97 Asymptomatic. In full-time 43 3.2 280 48 132 minute/ 1.73 m* on intensive (20-40)* employment as automobile hemodialysis to remove salesman. oxalate. No clinical evidence of oxalosis.

6 29 ESRF. Intensive hemodialysis to 5 months Asymptomatic. Part-time work. 43 10 690 124 remove oxalate. Congestive Full activity at home. cardiomyopathy, complete heart block, peripheral neuropathy.

7 15 ESRF. Intensive hemodialysis to 5 months 33-41 Living independently at home. 36 2.6 470 175 remove oxalate. No clinical In full-time education. evidence of systemic oxalosis.

8 29 ESRF. Conventional 7 years Postoperative cardiovascular 9 - - - hemodialysis 7 years. Two complications. Recurrent renal transplants failed (1 pleural effusions. Liver cadaveric, 1 live related), abscess. Gastric ulcers. rejection, and calcium oxalate Ascites. Wasting. Died 9 nephrocalcinosis. Extensive months postoperatively. osteodystrophy, arterial and subcutaneous calcification, digital gangrene. Parathyroidectomy (high PTH).

9 32 ESRF. Conventional 6 years 39” Hyperacute rejection of kidney 3 - - hemodialysis for 6 years. 8 days postoperatively. Cadaveric renal transplant Immediate nephrectomy. failed. Hemodialysis. Died from massive gastrointestinal hemorrhage 3 months postoperatively. ;PD = end-stage renal disease;,ESRF = end-stage renal failure: PTH = parathyroid hormone. * Results ot two separate aetermrnatrons. t Renal transplantation about 1 month after the liver transplant. r The values in parentheses were obtained immedrately after a period of hemodialysis. 5 No data available for the period immediately before death. See Figure 1 for earlier data HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL

TABLE IV Comparative Values for the Urinary Excretion of Oxalate and Patient 2 Glycolate Before and After Hepatorenal Transplantation 601 (Patient 5)

Urinary Excretion (mmol/24 hours) Oxalate Glycolate

Before transplant 8.88 3.86

After transplant Day 2 2.9 0.12 3.0 0.32 6 3.0 0.32 -- _ -=~ -___ --.--CT9 I I J-l-0 2: 2.02.7 0.360.82 b Id0 260 360 460 560 8&O Days post liver + kidney transplant El 1.11.0 0.460.78 _--- upper limit of normal ranges 1;; 0.40.6 0.480.5 191 0.5 0.54

Patient 7 GFR 1.3 38 23 507” ’ pmol/L and 28 pmol/L immediately before and af- z ter hemodialysis, respectively, before the trans- 0 40 a E i plantation. Six months after transplantation, the . /LOX plasma oxalate concentration and urinary oxalate excretion were 13 pmol/L and 2.9 mmo1/24 hours, respectively. Some of the data for Patient 2 have been pub- 2 10 - ‘\ l \ \ \*----L 5 lished previously [8]. Data on Patient 5 have also 0j,i---- / - I ---5- ,! 0 been presented in preliminary form [16]. 0 100 200 300 Days post liver + kidney transplant - --- upper limit of normal ranges COMMENTS The development of cyclosporine for the control of graft rejection has encouraged organ transplan- Patient 4 tation as a means of enzyme replacement therapy. 15 I In PHI, liver transplantation provides the missing - 2.4 enzyme (AGT) in the normal cellular and subcellular locations. Because of the central role of the liver in intermediary metabolism, liver transplantation merits particular attention as a means of enzyme replacement for inborn errors of metabolism in which the metabolic lesion is specifically expressed in the liver. Hepatic failure, as in Wilson’s disease [17] and tyrosinemia type I [18], has heretofore - 0.4 3

oJ+we------Lo been the main indication for the operation in this

I I I field. However, there is an expanding range of in- 0 100 200 300 born errors of metabolism in which liver transplan- Days post liver transplant - --- upper limit af normal ranges tation is becoming the preferred method of treatment because the allograft either synthesizes a factor for export to another organ, (e.g., cq-antitrypsin deficiency) [19-211, or protects another or- Figure 1. The short- and long-term changes in the urinary gan from damage by a toxic metabolite as in the oxalate excretion (Uo,), plasma oxalate concentration (Pox), Crigler-Najjar syndrome [22]. Liver transplanta- and glomerular filtration rate (GFR) in Patients 2 and 7 who had good postoperative recoveries and in Patient 4 who died tion can correct multiple secondary metabolic de- about 14 months postoperatively. Horizontal lines -- and rangements as in glycogen storage disease type I ___--- show the upper limits of the reference ranges for Pox [23]. Starzl and colleagues [20,21,24] have also suc- and U,,, respectively. cessfully treated a child with familial hypercholes-

184 February 1991 The American Journal of Medicine Volume 90 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL terolemia by a combined liver and heart transplantation [25]. NORMAL The data presented in this paper support and Soluble pool amplify our previous conclusion that liver transplantation is potentially curative in PHI [7,8]. AGT is almost entirely liver-specific [26]. Therefore, transplantation of this organ should reintroduce nearly all of the body’s requirement for the enzyme. Liver transplantation lowered the glycolate levels Urine immediately, whereas plasma and urinary oxalate I Y levels reverted toward normal much more slowly in GLYCOtiTE OXALATE, our patients. The metabolic fluxes of glyoxylate, oxalate, and glycoiate before and after liver transplantation are shown diagramatically in Figure 2. PRIMARY HYPEROXALURIA (PHI Glycolate does not form a highly insoluble calcium salt, so that once excessive synthesis is corrected, Soluble pool insoluble pool 1 Liver I I I only the contents of the expanded soluble glycolate metabolic pool have to be excreted. Conversely, calcium oxalate is highly insoluble and is deposited in many tissues when oxalate retention due to advanced renal failure is added to oxalate overproduc- tion. We interpret the more gradual decrease in the plasma and urine oxalate levels, with the urine lev- ~;LYc~L*TE oxtibw 1 els lagging behind the plasma levels, to mobilization of the extrarenal oxalotic deposits. Cochat et aE [27] have shown that if the liver is transplanted when PH AFTER LIVER TRANSPLANTATION renal function is still good and before there is any systemic oxalosis, the plasma oxalate also normal- Soluble DOOI Insoluble pool izes on the first postoperative day. The final extent to which calcium oxalate can be removed from the tissues remains to be assessed, but the results in Patient 6 show that cardiac oxalosis is potentially reversible. Better methods than those currently available for measuring the amount of oxalate in tissues in uiuo are needed. Patients with pyridoxine-resistant PHI who are treated by long-term hemodialysis or peritoneal dialysis die from the effects of their systemic oxalosis Figure 2. The metabolic fluxes of glyoxylate and its metabolic because treatment regimens that control the ure- products in a normal subject and in a patient with PHI before mia are not sufficient to keep up with the rate of and after liver transplantation. The thickness of the arrows oxalate production, at least in the long term [28]. represents the magnitude of the flux in the direction indicat- This situation is exemplified by Patients 3 and 4 in ed. Note that oxalate translocation from the soluble pool into the urine is still greater than normal after the liver transplan- the present study. The only definitive treatment tation while the oxalotic deposits are being mobilized. options, unless the patient is highly responsive to pyridoxine, are either renal transplantation, which replaces the damaged target organ but leaves it ex- posed to the risk of further stone formation and/or been exceptions [33-351. We have recently reviewed nephrocalcinosis, or liver transplantation or a com- the existing literature and found that of 46 patients bined liver and kidney transplant. The last of these (not all of whom were specified as being either type both normalizes the rate of oxalate production by I or type II) reported to have received 55 renal allo- correcting the metabolic lesion and replaces the grafts between them, only 20 survived 2 to 5 years, damaged target organ. The results of renal trans- five for 5 to 10 years, and only one patient, who was plantation alone have usually been poor, if it has shown to be pyridoxine responsive, for more than 10 been performed when the patient was already in years. This contrasts sharply with the greater than end-stage renal failure [29-321, although there have 75% l-year survival after renal transplantation for

February 1991 The American Journal of Medicine Volume 90 185 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL other types of chronic renal failure [36]. Morgan et tion less daunting in these patients than in many al [37] concluded from their studies of oxalate re- severely ill patients who require liver tention in hyperoxaluric and non-hyperoxaluric re- transplantation. nal failure that, in primary hyperoxaluria, plans for It could be argued that a renal allograft should be renal transplantation should be ready by the time tried first and combined liver and kidney trans- the GFR has decreased to about 20 to 25 plantation reserved until one renal transplantation mL.min-l-1.73 rnm2, and Watts et al [38] have has been destroyed by calculi and nephrocalcinosis shown that early renal transplantation, preferably or fails for some other reason. This proposition ig- while the patient still has appreciable renal func- nores the morbidity of recurrent stone disease, the tion, plus very vigorous pre- and perioperative he- risks of urinary tract infections, and, in particular, modialysis to deplete the miscible oxalate metabol- the risk of progressive potentially irreversible and ic pool, improves graft survival. lethal intrarenal crystallization of calcium oxalate To date, our experience has shown us that the and systemic oxalosis during episodes of obstruc- main complications after combined liver and kid- tive uropathy. Furthermore, since compromised re- ney transplantation are infections, biliary leaks, nal function has been assessed as a poor prognostic and poor function of the grafted kidney, but not indicator of outcome in liver transplantation [39], irreversible rejection of the .grafted liver. The out- we favor either liver transplantation alone when come was excellent in Patients 2, 5, and 7, who there is stable and well-preserved renal function or underwent prompt and vigorous dialysis after the the combined operation with vigorous periopera- onset of their terminal illness and who received tive hemodialysis as the definitive procedure when transplants as soon as possible, particularly before the patient is approaching end-stage renal disease. there was evidence of gross systemic oxalosis with Patients whose GFR is in the range of 25 to 60 severe bone disease and/or peripheral vascular in- mL.min-l-1.73 m-2 should be followed up closely sufficiency. The improved outlook for isolated renal with sequential assessment based on the rate of grafts in PHI with early transplantation and vigor- stone formation and the rate of loss of overall renal ous perioperative dialysis [38] suggests that similar function as judged by serum creatinine and GFR considerations should apply to the management of measurements, along with plasma and urinary oxa- patients undergoing either hepatic transplantation late levels. The plasma oxalate concentration is a or the combined operation. The grafted kidney is particularly valuable guide with which to assess the particularly at risk of damage from the high levels imminence of the oxalotic phase of the illness. If the of plasma oxalate, as well as cyclosporine toxicity patient is to be treated by elective liver transplanta- and immunologic rejection. Very large amounts of tion alone, this should be done as soon as the disease calcium oxalate can accumulate in the skeleton, in- has been shown to be acting aggressively. It should creasing its crystallinity, thereby making it more be stressed that renal failure progresses very slowly fragile and producing bone pain. Three of the pain some of these individuals, but the terminal phase tients who did poorly (Patients 3,4, and 8) because is characteristically brief. Planning for a combined of postoperative renal failure had extensive oxalotic liver-kidney transplant should begin while the pa- osteodystrophy. Further experience is needed to tient still has appreciable renal function (GFR at provide guidelines as to the degree of oxalotic osteo- least 20 to 25 mL.min-1~1.73 me2). This approach dystrophy that should be a contraindication to usually means that the liver and kidneys can be transplantation. However, the successful outcome obtained from the same donor. However, it is uncer- to combined hepatorenal transplantation plus in- tain whether this theoretic advantage is offset by tensive perioperative dialysis in a patient with car- possibly improved kidney graft survival after a two- diomyopathy and peripheral neuropathy as the sys- stage procedure in which the metabolic lesion is temic manifestations of oxalosis (Patient 61 shows corrected by liver transplantation, with renal trans- that these patients should be considered for dual plantation after a period of vigorous hemodialysis organ transplantation. The fact that the plasma ox- to deplete the oxalate pool. McDonald et al [40] alate concentration returns to normal before the reported the use of a well-functioning renal allo- urinary oxalate excretion (which, however, ulti- graft in a severely oxalotic patient to off-load oxa- mately normalizes) indicates that oxalotic deposits late and improve the patient’s general condition are mobilized from the tissues when excessive oxa- before orthotopic liver transplantation. Given that late synthesis is corrected by liver transplantation. some oxalate can be removed by very vigorous he- It should be noted that the absence of chronic hepa- modialysis and the high probability that the renal tobiliary disease and portal hypertension makes the graft will fail if the excessive oxalate production is technical demands of orthotopic liver transplanta- not terminated, we do not regard this as the appro-

186 February 1991 The American Journal of Medicine Volume 90 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL priate strategy in most cases. Both extensive oxalo- Ine on oxalate dynamics in three cases of primary hyperoxaluria (with glycolic tic osteodystrophy with bone pain and prolonged aciduria). Clin Sci 1985; 69: 87-90. 7. Watts RWE, Calne RY. Williams R, et ai. Primary hyperoxaluria (type I): at- dialysis using conventional regimens worsen the tempted treatment by combined hepatic and renal transplantation. Q J Med prognosis after liver-kidney transplantation. 1985; 57: 697-703. It is important to diagnose primary hyperoxa- 8. Watts RWE. Caine RY, Rolles K. ei al. Successful treatment of primary hyper- luria early, to explore the possibility of pyridoxine oxaluria type I by combined hepatic and renal transplantation. Lancet 1987; 2: 474-5. sensitivity, and to institute vigorous medical man- 9. Chalmers RA. The enzymatic spectrophotometricdetermtnation of oxalate in agement and a conservative surgical policy that uti- blood and urine. In: Rose GA, Robertson WG, Watts RWE, eds. Oxalate in human lizes modern endoscopic and stone fragmentation biochemistry and clinical pathology. London: The Wellcome Foundation, 1979: techniques fully. 61-6. 10. Kasidas GP, Rose GA. Continuous flow assay for urinary oxalate using Immo- The present studies establish PHI as a member of bilised oxalate oxidase. Ann Clin Biochem 1985; 22: 412-9. the group of inborn errors of metabolism in which 11. Kasidas GP, Rose GA. Measurement of plasma oxalate in healthy subjects liver transplantation is recommended to normalize and in patients with chronic renal failure using immobilised oxalate oxidase. Clin a metabolic pathway and prevent damage to remote Chim Acta 1986; 154: 49-58. 12. Chalmers RA, Tracey BM. Mistry J, Griffiths KD, Green A, Winterborn MH. L- organs by a metabolite that accumulates behind a glyceric aciduria (primary hyperoxaluria type II) in siblings in two unrelated metabolic block in the patient’s own, otherwise nor- families. J Inherited Metab Dis 1984; 7 (Suppl 2): 133-4. mal, liver. The patients in this series have all been 13. Wise PJ, Danpure CJ, Jennings PR. Immunological heterogeneity of hepatic in end-stage renal failure and hence in need of renal alanine:glyoxylate aminotransferase in primary hyperoxaluria type I, FEBS Lett 1987;222: 17-30. replacement. Most patients with PHI have rapidly 14. Caine RY. A new technique for biliary drainage in orthotopic liver transplan- progressive urolithiasis, and kidney transplanta- tation utilising the gallbladder as a pedicle graft conduit between the donor and tion could be avoided if the liver was transplanted recipient common bile ducts. Ann Surg 1976; 184: 605-9. 15. Calne RY. Recipient operation. In: Calne RY. ed. Liver transplantation, the as soon as the enzymologic diagnosis had been made Cambridge and Kings College Hospital experience. New York: Grune and Strat- and it was clear that the patient’s disease was fol- ton, 1983: 155-73. lowing an aggressive clinical course. Alternative 16. Smith L, Perkins J, Wilson D, McCarthy J, Wiesner R. Biochemical correction strategies, i.e., heterotopic auxiliary liver trans- of type I primary hyperoxaluria with combined liver-kidney transplant. Kidney Int 1988; 33: 209. plantation and the implantation of hepatocytes, are 17. Groth CG, Dubois RG, Corman J, et a/. Metabolic effects of hepatic replace- not considered to be viable alternatives to orthoto- ment in Wilson’s disease. Transplant Proc 1973; 5: 829-33. pit liver transplantation because of competition 18. Kvittingen EA. Hereditary tyrosinaemia type l-an overview. Stand J Clin from the patient’s own liver, which functions nor- Lab Invest 1986; 46 (Suppl 184): 27-34. 19. Hood JM, Keop LJ, Peter RF, eta/. Liver transplantation for advanced liver mally except for the AGT deficiency. disease with al-antitrypsin deficiency. N Engl J Med 1980; 302: 272-5. 20. Starzl TE, Bilheimer DW, Bahnsen HT, et al. Heart-liver transplantation in a ADDENDUM patient with familial hypercholesterolaemia. Lancet 1984; 1: 1382-3. More prolonged follow-up of the surviving pa- 21. Zitelli BJ, MalatakJJ. Gartner JC Jr, Shaw BW, lwatsuki S, Starzl TE. Orthoto- pit liver transplantation in children with hepatic based metabolic disease. Trans- tients in this series and of other patients has shown plant Proc 1983; 15: 1284-7. that the urinary oxalate excretion, as well as the 22. Wolff H, Otto G. Giest H. Liver transplantation in Crigler-Najjar syndrome. A plasma oxalate concentration, becomes completely case report. Transplantation 1986; 42: 84. 23. Malatak JJ. Finegold DN. lwatsuki S, et a/. Liver transplantation for type I normal after a successful liver graft. glycogen storage disease. Lancet 1983; 1: 1073-5. 24. Hoeg JM, Starzl TE, Brewer HB. Liver transplantation for treatment of car- ACKNOWLEDGMENT diovascular disease: comparison with medication and plasma exchange in ho- The hepatic enzyme activities were measured by Mrs. P. R. Jennings. mozygous familial hypercholesterolemia. Am J Cardiol 1987; 59: 785-7. 25. Bilheimer DW, Goldstein JL, Grundy SM. Starzl TE, Brown MS. Liver transplantation to provide low-density lipoprotein receptors and lower plasma choles- terol in a child with homozygous familial hypercholesterolaemia. N Engl J Med 1984; 311: 1658-64. 26. Kamoda N. Minatogawa Y, Nakamura M, Nakanishi J. Okuno E, Kido R. The REFERENCES organ distribution of human alanine:2-oxogluterate aminotransferase and alan- 1. Archer HE, Dormer AE, Scowen EF, Watts RWE. Primary hyperoxaluria. Lan- ine:glyoxylate aminotransferase. 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February 1991 The American Journal of Medicine Volume 90 187 HEPATORENAL TRANSPLANTATION IN PRIMARY HYPEROXALURIA I / WATTS ET AL complications in oxalosis after successful cadaveric kidney transplantation. 38. Watts RWE, Morgan SH. Purkiss P, Mansell MA, Baker LRI, Brown CB. Timing Transplantation 1984; 38: 93-5. of renal transplantation in the management of pyridoxine resistant type I pri- 33. David DS, Cheigh JS, Stenzel KH, Rubin AL. Successful renal transplantation mary hyperoxaluria. Transplantation 1988; 45: 1143-4. in a patient with primary hyperoxaluria. Transplant Proc 1983; 15: 2168-71. 39. Cuervas-Mons V. An analysis of the early causes of death in 40 consecutive 34. Whelchel JD, Alison DV. Luke RG, Curtis J. Dietheim AG. Successful renal cases. Hepatology 1986; 6: 495-501. transplantation in hyperoxaluria. A report of two cases. Transplantation 1983; 40. McDonald JC, Landreneau MD, Rohr MS, Devault GA. Reversal by liver 35: 161-4. transplantation of the complications of primary hyperoxaluria as well as the 35. Scheinman J, Najarian JS, Mauer SM. Successful strategies for renal trans- metabolic defect. N Engl J Med 1989; 321: 1100-3. plantation in primary oxalosis. Kidney Int 1984; 25: 804-11. 41. Watts RWE. Chalmers RA, Gibbs DA, Lawson AM, Purkiss P, Spellacy E. 36. Leading article. Cyclosporin for ever. Lancet 1986; 1: 419-20. Studies on some possible biochemical treatments of primary hyperoxaluria. Q J 37. Morgan SH. Purkiss P, Watts RWE. Mansell MA. Oxalate dynamics in Fhronic Med 1979; 48: 259-72. renal failure. Comparison with normal subjects and patients with primary hyper- 42. Watts RWE, Veal1 N, Purkiss P. Sequential studies of oxalate dynamics in oxaluria. Nephron 1987; 46: 253-7. primary hyperoxaluria. Clin Sci 1983; 65: 627-33.

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