Combined liver-kidney and kidney-alone transplantation in primary hyperoxaluria

Combined Liver-Kidney and Kidney-Alone Transplantation in Primary Hyperoxaluria Carla G. Monico and Dawn S. Milliner Combined liver-kidney and kidney-only transplantation outcomes in primary hyperoxaluria (PH) are described. Strategies for the selection of type and timing of transplantation and pretransplantation and posttransplantation management are reviewed. Records were reviewed for 16 patients with PH who received 9 liver-kidney and 10 kidney-only transplants. Plasma oxalate values declined from 61 ⴞ 42 ␮mol/L pretransplantation to 9 ⴞ 6 ␮mol/L 1 month after transplantation in liver-kidney transplant recipients and 92 ⴞ 19 to 9 ⴞ 5 ␮mol/L in kidney-only transplant recipients. In most liver-kidney transplant recipients, hyperoxaluria persisted for 6 to 18 months after transplantation. Follow-up was 3.5 ⴞ 4.1 years in liver-kidney and 4.5 ⴞ 6.3 years in kidney-alone transplant recipients. Patient survival rates were 78% for liver-kidney and 89% for kidney-only transplant recipients. No hepatic allografts were lost. Three of 9 liverkidney and 6 of 10 kidney-alone transplants lost renal allograft function. In those with functioning kidneys, renal clearance was 45.1 ⴞ 19.5 mL/min/1.73 m2 in liverkidney transplant recipients and 49.5 ⴞ 26.1 mL/min/ 1.73 m2 in kidney-only transplant recipients at last follow-up. Kaplan-Meier 1-, 2-, 3-, and 5-year renal allograft survival rates for patients undergoing transplantation after 1984 were 78%, 78%, 52%, and 52% in liver-kidney transplant recipients and 86%, 71%, 54%, and 36% in kidney-only transplant recipients. Simultaneous grafting of liver and kidney after the development of renal insufficiency is recommended for the majority of patients with PH type I (PH-I). Kidney-alone transplantation is recommended for those with pyridoxine-responsive type I disease because pharmacological therapy allows favorable management of oxalate production in this situation. Kidney-alone transplantation also is recommended for PH type II (PH-II). This disease is less severe than PH-I, and it is currently unknown whether liver transplantation will correct the metabolic defect responsible for PH-II. (Liver Transpl 2001;7:954-963.)

T

ransplantation in hepatic-based inborn errors of metabolism is most often indicated because of hepatic insufficiency or hepatic failure.1 In type I primary hyperoxaluria (PH-I), extrahepatic manifestations provide a basis for orthotopic liver transplantation. In From the Division of Nephrology, Mayo Clinic, Rochester, MN. Address reprint requests to Dawn S. Milliner, MD, Division of Nephrology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Telephone: 507-266-1045; FAX: 507-266-7891; E-mail: [email protected] Copyright © 2001 by the American Association for the Study of Liver Diseases 1527-6465/01/0711-0006$35.00/0 doi:10.1053/jlts.2001.28741

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PH-I, deficiency and/or subcellular mistargeting from peroxisomes to mitochondria of the hepatic enzyme alanine:glyoxylate aminotransferase (AGT) result in markedly increased production of oxalate by the liver.2 Because oxalate is eliminated primarily by renal excretion and there are no known metabolic pathways for its degradation, marked hyperoxaluria ensues. Calcium oxalate deposition causing urolithiasis or nephrocalcinosis occurs early in the course of the disease. Renal failure typically develops later, followed by calcium oxalate deposition in bone, blood vessels, myocardium, and other organs.3 Systemic oxalosis results in severe morbidity and death. Clinical expression in PH-I is variable. A slow progressive decline in renal function exacerbated by episodes of obstructive uropathy and urinary tract infections is observed in the majority of patients. A smaller number present initially with renal failure, some as early as during infancy. The median age of end-stage renal failure is 25 years. Eighty percent of patients require renal replacement by the third decade.4,5 A less common variant, primary hyperoxaluria type II (PH-II), also characterized by hyperoxaluria and urolithiasis, but less frequently by renal failure, is caused by a different hepatic enzyme defect (glyoxylate/hydroxypyruvate reductase [GR/HPR]).6,7 Aside from increased oxalate production, hepatic function remains normal in both these disorders, even in late stages of disease progression. In 1975, it was the conclusion of the American College of Surgeons and The National Institutes of Health that primary hyperoxaluria (PH) was “unsuitable for treatment by renal transplantation.”8 In a review of 14 transplantations performed in 10 patients, the committee reported seven deaths. Oxalate deposition in single or multiple allografts resulted in death from uremia in 4 patients, ranging from 49 days to 2.5 years after transplantation. Similarly disappointing results with isolated renal transplantation caused by disease recurrence and the inefficiency of oxalate removal by standard modes of dialysis9 were noted by other investigators.10,11 Nonetheless, with advances in transplantation and increasing understanding of the pathophysiological course of PH over the past two decades, improved outcomes have been obtained in PH-I.12,13 Enhanced awareness of the toxic effects and distribution of oxalate

Liver Transplantation, Vol 7, No 11 (November), 2001: pp 954-963

Transplantation in Primary Hyperoxaluria

launched therapeutic tactics designed to minimize oxalate-related tissue damage. These include initiation of renal replacement therapy earlier in the course of renal failure and specific approaches to the management of hyperoxalemia and hyperoxaluria both before and after transplantation. Identification and isolation of the causative enzyme to liver in the 1980s2 opened a new avenue of treatment. Simultaneous correction of the hepatic metabolic defect and renal failure by combined liver-kidney transplantation (LKT) in PH-I was first attempted in 1984 in an adolescent with a cadaveric renal allograft failing because of oxalate deposition.14 Results of oxalate dynamic studies performed in this patient confirmed correction of the metabolic defect by the orthotopic hepatic allograft.15 Although LKT for correction of the metabolic defect and renal failure is now widely adopted for the treatment of PH-I, controversy remains regarding specific indications for and timing of hepatic transplantation.16 In PH-II, characterized by a more benign clinical course17 and localization of the enzyme defect to organs other than liver,18,19 experience has been limited to kidney-alone transplantation. To date, published reports of transplant outcomes in PH are derived predominantly from registry sources. Little information is available with respect to urine oxalate excretion rates, plasma oxalate concentrations, and renal clearance after transplantation. In view of the wide phenotypic spectrum of PH, such knowledge is relevant to transplantation recommendations. We review our single-center experience with 19 renal and hepatic transplantations in 16 patients with PH.

Methods Patients We retrospectively reviewed medical records of all patients with PH who underwent transplantation at the Mayo Clinic (Rochester, MN). Of 15 patients with PH-I, the diagnosis was confirmed by hepatic enzyme analysis of the patient or an affected sibling in 13 patients and complete pyridoxine responsiveness in 1 patient. In the patient who underwent transplantation in the 1960s, hepatic enzyme analysis for AGT was not yet available, and a clinical diagnosis of PH was inferred from marked hyperoxaluria, a history of nephrolithiasis, and an affected sibling who died of the disease at 8 years of age. In the patient with PH-II, hepatic GR/HPR deficiency was established by both liver biopsy and elevated urine oxalate and L-glycerate levels. Since 1990, we have used a standard perioperative transplantation protocol for patients with PH. To minimize the likelihood of delayed graft function, donor organs with less than 24 hours of ischemia time and a negative cross-match

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were sought. The protocol includes intensive dialysis to reduce plasma oxalate concentrations pretransplantation, high-volume diuresis posttransplantation, and hemodialysis or continuous venovenous hemodiafiltration (CVVHDF) until the posttransplantation plasma oxalate concentration is less than 20 ␮mol/L. The goal for urine output in the perioperative period is 4 to 7 L/24 h. If intravascular volume expansion alone does not suffice, diuretic agents are added. Daily hemodialysis or CVVHDF is initiated within 24 hours of transplantation and continued until renal function is sufficient to maintain a plasma oxalate concentration less than 20 umol/L. Dialysis removal of oxalate is most efficient with hemodialysis and CVVHDF, with oxalate clearances of 52 to 185 mL/min reported.9,20 The specific dialysis prescription is determined by the patient’s plasma oxalate concentrations and renal allograft function. In both kidney-alone and liver-kidney transplant recipients, therapy with neutral phosphate, an inhibitor of calcium oxalate crystal formation in urine,21 is initiated at 30 mg/kg/d of phosphorus in divided doses on achievement of satisfactory renal allograft function (serum creatinine ⬍ 2.0 mg/dL). Neutral phosphate therapy and oral fluid intake to maintain urine output greater than 4 L/24 h are sustained indefinitely in kidney-alone transplant recipients and until normalization of urine oxalate levels in recipients of hepatic allografts. In patients unable to maintain sufficient oral intake, supplemental intravenous or nasogastric fluid is administered. In kidneyonly transplant recipients who are pyridoxine responsive, pharmacological doses of 5 to 8 mg/kg/d are continued posttransplantation. Renal function is monitored closely in all patients, with prompt imaging or biopsy of the allograft as indicated. Imaging of the transplanted kidney also is performed at 6- to 12-month intervals to assess the degree of metabolic stone-forming activity for as long as hyperoxaluria is present.

Analytic Methods Until 1988, urine oxalate was measured using the method of Olthuis et al22 (normal reference range, 0.23 to 0.68 mmol/24 h). The immobilized oxalate oxidase method has been used since to determine oxalate concentrations in both urine and plasma, with a normal reference range of 0.11 to 0.46 mmol/24 h in urine and 0.4 to 3.0 ␮mol/L in plasma.23 Urine samples for oxalate determination were collected for 24 hours and acidified with hydrochloric acid to prevent oxalate crystal formation and in vitro conversion of ascorbate to oxalate. Glomerular filtration rate was measured by 2-hour clearance of iothalamate, administered subcutaneously.24 Hepatic enzyme analyses were completed in the laboratories of Drs C. Danpure and G. Rumsby.19,25-27

Statistical Methods The Kaplan-Meier method was used to determine renal allograft survival. Primary end points for renal allograft survival were return to dialysis, retransplantation, or death.

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Results From 1968 to the present time, 15 patients with PH-I and 1 patient with PH-II underwent LKT or kidneyalone transplantation. A total of 10 isolated renal transplantations were performed in 8 patients with PH-I and 1 patient with PH-II. Four allografts were cadaveric; two allografts were transplanted in the 1960s in the same patient; one allograft, 1970s; and one allograft, 1980s. Six living donor allografts were transplanted in the 1990s. Nine cadaveric LKTs were performed in 9 patients with PH-I from 1987 to 2000. Two pairs of siblings (patients 3 and 16 and 7 and 13) received transplants. Clinical information is listed in Table 1. Kidney-alone transplant and liver-kidney transplant recipients were of similar age at the onset of endstage renal disease (means age, 32.4 ⫾ 11.4 [SD] and 37.7 ⫾ 14.1 years, respectively; P ⫽ .19) and transplantation (32.9 ⫾ 11.7 and 40.6 ⫾ 13.2 years; P ⫽ .10), but liver-kidney transplant recipients underwent dialysis for a longer time before transplantation (2.1 ⫾ 2.0 v 0.51 ⫾ 0.6 years in kidney-alone transplant recipients; P ⫽ .014). None of the nine kidney-alone transplant recipients and four of nine liver-kidney transplant recipients had clinical evidence of severe systemic oxalosis before transplantation. Patients 3 and 8 had received an isolated renal allograft (one graft, cadaveric donor; one graft, living related donor, respectively) before LKT at our institution. Patients 10, 12, 13, and 14 had received an isolated renal allograft (three grafts, cadaveric donors; one graft, living unrelated donor, respectively) elsewhere before LKT. All patients had experienced loss of renal allograft function by the time of LKT. After transplantation, plasma oxalate concentrations improved promptly in all patients from 92 ⫾ 19 and 61 ⫾ 42 ␮mol/L pretransplantation (P ⫽ .16) to 9 ⫾ 5 and 9 ⫾ 6 ␮mol/L at 1 month posttransplantation in kidney-alone and liver-kidney transplant recipients, respectively (Fig. 1). Urine oxalate levels improved more slowly, decreasing gradually to pretransplantation values in kidney-alone transplant recipients and normalizing over several months to years in liver-kidney transplant recipients (Fig. 2). In one liver-kidney transplant recipient with extensive tissue oxalosis pretransplantation, marked hyperoxaluria of 2.26 mmol/24 h was still present 4.75 years after transplantation. During the course of follow-up, urinary tract stone formation occurred in three kidney-alone transplant recipients and one liver-kidney transplant recipient. Duration of follow-up was 4.5 ⫾ 6.3 years (median, 1.8 years; range, 0.08 to 20.2 years) for kidney-alone

transplant recipients and 3.5 ⫾ 4.1 years (median, 2.1 years; range, 0.25 to 13.9 years) for liver-kidney transplant recipients. Acute hepatic allograft rejection unresponsive to methylprednisolone, but successfully treated with OKT3, was observed in two hepatic allograft recipients. No patient experienced hepatic allograft loss, and at last follow-up, hepatic function was excellent in all surviving patients, with the following values: total bilirubin, 0.6 ⫾ 0.5 mg/dL; direct bilirubin, 0.2 ⫾ 0.1 mg/dL; and aspartate aminotransferase, 23.4 ⫾ 7.6 U/L. At last follow-up, four of eight surviving kidneyalone transplant recipients and six of seven surviving liver-kidney transplant recipients had functioning kidney grafts. Serum creatinine levels at last follow-up were 1.7 ⫾ 0.6 mg/dL (median, 1.8 mg/dL) for kidneyalone transplant recipients and 1.2 ⫾ 0.3 mg/dL (median, 1.2 mg/dL) for liver-kidney transplant recipients. Renal clearances were 49.5 ⫾ 26.1 mL/min/1.73 m2 (median, 46 mL/min/1.73 m2; range, 23 to 83 mL/min/1.73 m2) and 45.1 ⫾ 19.5 mL/min/1.73 m2 (median, 45 mL/min/1.73 m2; range, 20 to 74 mL/min/1.73 m2), respectively. Renal clearance as a function of time from transplantation in kidney-alone and liver-kidney transplant recipients is shown in Figure 3. In patients with functioning allografts, renal clearances were similar in kidney-alone and liver-kidney transplant recipients at 6 months (65.0 ⫾ 4.2 and 63.4 ⫾ 19.9 mL/min/1.73 m2, respectively) and 1 year (52.8 ⫾ 18.0 and 52.2 ⫾ 18.2 mL/min/1.73 m2, respectively) after transplantation. Renal graft loss was observed in 6 of 10 kidney-alone and 3 of 9 liver-kidney transplants (P ⫽ .24). One kidney-alone cadaver transplant in 1969 failed to function from the time of transplantation because of acute tubular necrosis. Five kidney-alone allografts were lost at 16 days to 4.7 years after transplantation (Table 1). Acute or chronic rejection was the primary cause of allograft failure in patients 5 and 6. Oxalate deposits in the allograft appeared primarily responsible for graft loss in patients 1 and 3. In patient 8, transient obstruction of the allograft ureter caused by stones contributed to loss of function. In all kidney-alone transplant recipients with graft loss, oxalate deposits were noted in renal tubules and interstitium and appeared to have at least a partial role in renal allograft dysfunction. In liver-kidney transplant recipients, acute or chronic rejection was primarily responsible for graft loss at 5 days, 7 days, and 3.2 years. Patient 10, in addition to delayed hyperacute rejection in the renal allograft, had acute obstruction caused by oxalate deposits in the renal pelvis and ureter. For patients receiving transplants after 1984, when cyclosporine-based immunosuppression regimens began

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Table 1. Clinical Characteristics of Transplant Recipients With PH-I and PH-II Age at Dialysis Duration Age at Patient Type of PH ESRD Pretransplantation Transplantation Year of No./Sex Transplant Type (yr) (mo) (yr) Transplantation

Transplantation in Primary Hyperoxaluria

1/F

I

27

2/F 3/M 4/F 5/F

K, CAD K, CAD K, CAD K, CAD K, LRD K, LRD

21 36 26 17

0 11.2 4.1 0 2.1 2.8

27 29 22 36 27 18

1968 1969 1977 1986 1990 1992

II I I I

6/M

K, LRD

I

23

5.1

24

1994

7/F 8/F 9/F 3/M 10/M 11/F 12/M 13/M

K, LRD K, LRD K, LURD L/K, CAD L/K, CAD L/K, CAD L/K, CAD L/K, CAD

I I I I I I I I

42 50 47 36 29 19 33 31

6.6 24.5 4.5 6.2 mo 4.1 yr 5.7 yr 4.1 yr 1.2 yr

42 52 48 37 33 25 38 34

1994 1996 1999 1987 1988 1995 1995 1997

8/F 14/M 15/F 16/F

L/K, CAD L/K, CAD L/K, CAD L/K, CAD

I I I I

50 23 53 60

None 1.6 yr 9.1 mo 11.9 mo

55 25 54 61

1998 1999 1999 2000

Immune Suppression Pred/Aza Pred/Aza Pred/Aza Pred/Aza/CsA ALG/Pred/Aza/CsA ALG/OKT3 ⫻ 2/ATG/ Pred/Aza/CsA ATG/OKT3/Pred/Aza/ CsA ATG/Pred/Aza/CsA Pred/MMF/CsA Pred/MMF/Tac Pred/Aza/CsA 3 Tac ALG/Pred/Aza/CsA ALG/Pred/MMF/Tac OKT3/Pred/MMF/Tac ATG/Pred/MMF/CsA 3 Tac Pred/MMF/Tac OKT3/Pred/MMF/Tac Pred/MMF/Tac Pred/MMF/Tac

S Creat at Iothal Clearance Last F/U at Last F/U (mg/dL) (mL/min/1.73 m2)

Duration of F/U

Functional Renal Allograft at Last F/U

1 mo 0 mo 20.2 yr 16 d 8.6 yr 1.2 yr

Graft loss 1 mo Graft loss 0 mo, died Yes Graft loss 16 d Yes Graft loss 1.2 yr

— — 1.0 — 2.2 —

— — 83 — 36 —

Graft loss 4.7 yr

—

—

Yes Graft loss 2.3 yr Yes Yes Graft loss 7 d, died Graft loss 5 d, died Yes Graft loss 3.2 yr

2.2 — 1.4 1.6 — — 1.4 —

23 — 56 20 — — 38 —

Yes Yes Yes Yes

0.9 1.2 0.9 1.2

74 45 56 59

4.7 yr 7.2 yr 2.3 yr 1 yr 13.9 yr 2.9 mo 3.1 yr 4.8 yr 3.2 yr 2.1 yr 1.9 yr 1 yr 1 yr

Abbreviations: F/U, follow-up; ESRD, end-stage renal disease; L/K, combined liver-kidney transplant; K, kidney-alone transplant; CAD, cadaver; LRD, living related donor; LURD, living unrelated donor; Pred, prednisone; Aza, azathioprine; ATG, antithymoglobulin; CsA, cyclosporine A; ALG, antilymphocyte globulin; MMF, mycophenolate mofetil; Tac, tacrolimus; S Creat, serum creatinine; Iothal, iothalamate.

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Figure 1. Plasma oxalate concentrations before and after LKT (circles) and kidney-alone (squares) transplantation in PH. (TX, transplantation.)

to be used, 1-, 2-, 3-, and 5-year allograft survival rates were 86%, 71%, 54%, and 36% in kidney-alone and 78%, 78%, 52%, 52% in liver-kidney transplant recipients, respectively. At last follow-up, eight of nine kidney-alone (89%) and seven of nine liver-kidney (78%) transplant recipients were alive. All three deaths occurred in patients with extensive systemic oxalosis present at the time of transplantation. Patient 1 received two unsuccessful cadaver renal allografts in 1968 and 1969, was maintained on dialysis therapy thereafter, and died of uremia and severe oxalosis 91⁄2 years after the first transplantation. Two liver-kidney transplant recipients had successful liver transplants, but lost renal allograft function

Figure 2. Urine oxalate excretion rates after LKT in patients with type I PH. Each line represents one patient. Normal range is less than 0.46 mmol/24 h. Time required for normalization of urine oxalate levels depends on tissue oxalate stores at the time of transplantation and is often longer than 1 year.

within days of transplantation. One of these patients (patient 10) died of a gastrointestinal bleed with a functioning hepatic allograft 3 months after transplantation. Patient 11 remained on dialysis therapy with a functioning liver transplant and died 3.1 years later of sepsis in a setting of severe oxalosis.

Discussion Patient and allograft outcomes in PH have improved over time.12,13,28 European registry data from 1984 to 1997 for 87 liver transplantations in 80 patients with PH-I showed 1-, 2-, and 5-year patient survival rates of 88%, 80%, and 72%.12 Registry data for 1984 to 1996 in the United States showed overall patient survival rates of 74% in 62 kidney-alone transplant recipients and 69% in 42 combined liver-kidney transplant recipients.13 We found similarly encouraging overall survival rates in patients receiving transplants since 1984 of 100% in kidney-alone and 78% in liver-kidney transplant recipients. The renal allograft survival rate in liver-kidney transplant recipients was 62% at 5 years in the European data. In the American experience, lifetable 6-year renal allograft survival rates were similar in kidney-alone (50%) and liver-kidney transplant recipients (56%; P ⫽ .91),13 as observed in our patients. Strategies for optimum patient and allograft outcomes must take into account the specific pathophysiological characteristics of PH. Important considerations include patient selection for type of transplantation, appropriate timing of transplantation, and clinical management, both at the time of transplantation and long term. Time

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Figure 3. Renal allograft clearance measured by iothalamate after LKT (F) and kidney-alone ( ■ ) transplantation in patients with PH. (— – —) Represents the patient with PH-II who underwent kidney-only transplantation.

awaiting transplantation after reaching renal failure should be kept to a minimum because of the accompanying risk for progressive systemic oxalosis. The majority of patients with PH-I will benefit most from an LKT. LKT is suggested for patients with a high daily production of oxalate that is resistant to pyridoxine, dialysis therapy duration of more than 1 year, clinical evidence of systemic oxalosis, or previous renal allograft failure caused by oxalate deposition. Combined LKT also should be considered in patients without available living donor options in whom waiting times of more than 1 year are expected for cadaveric organs. In PH-II, deficiency of glyoxylate reductase is shown not only in liver, but also in other body tissues.18,19,29 It is not known whether this metabolic deficiency is sufficiently corrected by liver transplantation to justify the risks of the procedure. The degree of hyperoxaluria is lower and the clinical course more favorable than in PH-I.17 For these reasons, kidney-alone transplantation is recommended for patients with PH-II. At last followup, our cadaveric kidney transplant recipient with PH-II remained free of stone formation, with a renal allograft clearance rate of 83 mL/min/1.73 m2 nearly 21 years posttransplantation. Although the degree of hyperoxaluria is usually lower and the clinical course more favorable in PH-II, there is sufficient overlap in clinical findings in individual patients that PH-I and PH-II cannot be reliably distinguished from one another based on plasma oxalate concentrations or other clinical parameters.17 For this reason, it is essential that the diagnosis of PH-I

be confirmed by hepatic enzyme analysis before liver transplantation is recommended (Table 2). In the future, analysis of DNA for known mutations may provide an alternative means of diagnostic confirmation. However, the large number of mutations and polymorphisms of the gene coding for AGT recognized to date complicate the use of this approach. In PH-I, the predictive value of this technique for the two most common mutations is less than 50% at present.30 The molecular understanding of PH-II is less complete.31,32 Sequential liver transplantation followed by kidney transplantation in PH-I has been reported in young infants in whom physical limitations prohibited simultaneous grafting of the two organs.33,34 In PH-I, this

Table 2. Diagnosis of PH-I and PH-II Hepatic Enzyme Analysis* PH-I

PH-II

Deficiency/ mistargeting of peroxisomal AGT GR/HPR deficiency

Urinary Parameters

Clinical Criteria

1Urine oxalate 1or normal urine glycolate

Pyridoxine response†

1Urine oxalate, 1urine L-glycerate

No response to pyridoxine

*Neither clinical criteria nor urine parameters allow definitive differentiation between PH-I and PH-II. Hepatic enzyme analysis is required. †Pyridoxine responsiveness is defined as significant improvement or normalization of urine oxalate excretion after pharmacological doses of pyridoxine and is seen in approximately 30% of patients with PH-I.

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approach is rarely indicated for circumstances other than an infant who has already developed end-stage renal disease. When a liver is transplanted in the absence of a functioning kidney, hyperoxalemia and continued risk for calcium oxalate precipitation persists and is disadvantageous for the transplant recipient. Oxalate removal by dialysis alone is inefficient and does not keep pace with even normal daily oxalate production.9 Therefore, improvement in established tissue oxalate deposition is not permitted by correction of the metabolic defect and dialysis alone. Auxiliary liver transplantation as a means of enzyme replacement is not appropriate in PH. Because of the presence of increased oxalate production, rather than decreased catabolism, oxalate overproduction would continue in any remaining native liver tissue.35 For the same reason, the application of gene therapy techniques in PH would require transfection of a significant proportion of hepatocytes (⬎75%) to counteract the increased oxalate synthesis of neighboring nontransfected cells.36 Kidney-only transplantation is appropriate for patients with pyridoxine-responsive PH-I, those with PH-II, and as an interim step preceding cadaveric liver transplantation in patients with pyridoxine-resistant PH-I when a living donor kidney is available and waiting time for a donor liver is expected to be greater than 12 months. Combined living donor kidney and living donor liver transplantation may be an alternative in such patients with PH-I.37 Normalization or marked reduction in oxalate production with the oral administration of pharmacological doses of pyridoxine is seen in approximately 30% of patients with PH-I.36,38 Among patients with partial or complete pyridoxine responsiveness, excellent posttransplantation outcomes can be obtained with kidney-only grafts.16,39 For most pyridoxine-responsive patients with PH-I, dosages of 400 to 800 mg/d are effective. Pharmacological doses of pyridoxine greater than 1,000 mg/d in adult patients have been associated with the development of a peripheral sensory neuropathy in a small number of case reports.40 No other clinically adverse effects have been observed. Timing of transplantation is influenced by several factors. The extent of systemic calcium oxalate tissue deposition (oxalosis) is a primary determinant of patient morbidity and mortality and outcomes in transplantation.12,41 Accordingly, early transplantation before the development of a significant oxalate tissue burden is of importance. Because oxalate elimination from blood and body tissues is dependent on renal excretion, hyperoxalemia is observed in all patients with

markedly reduced renal function. Supersaturation of plasma with respect to calcium and oxalate is a risk factor for calcium oxalate deposition in tissues.42-44 The risk becomes significant when plasma oxalate concentrations exceed 28 to 50 ␮mol/L. This degree of hyperoxalemia develops at renal clearances of 24 to 34 mL/min/1.73 m2 in patients with PH and 8 to 11 mL/min/1.73 m2 in patients with other causes of renal disease.42,45 Oxalate dynamic studies suggest that an increase in the oxalate metabolic pool size and, by inference, tissue oxalate accumulation may occur earlier in PH when renal clearance is 40 to 60 mL/min/1.73 m2.3,46 In agreement with these observations, early introduction of transplantation or dialysis is recommended for plasma oxalate concentrations greater than 30 ␮mol/L and/or glomerular filtration rates of 25 to 30 mL/min/ 1.73 m2 or less. Early preemptive hepatic transplantation for correction of the metabolic defect and as a mode of preventing end-stage renal disease remains controversial. Proponents support the deterrence of renal failure and avoidance of systemic oxalosis. However, with currently available knowledge, it is not possible to predict the clinical course of an individual patient with PH-I. Patients with symptom onset in the first 5 years of life may have well-preserved renal function for several decades5 and may maintain reduced but stable renal function for many years.5,47 Affected siblings often follow very different time courses with respect to renal function, as evident in our patients 3 and 16 and patients 7 and 13. In this context, the 2- and 5-year mortality rates of 10% to 12% observed in children receiving hepatic allografts for metabolic disorders must be weighed carefully and generally are not acceptable.48 It also is difficult to justify the effects of early and long-term immune suppression in young growing children with an unpredictable time course to renal failure. Of the patients in our series, mean age at end-stage renal failure was 34.3 ⫾ 13.1 years (median, 30.8 years), only 5 of 16 patients (31.3%) reached renal failure before the age of 25 years, and none reached renal failure before the age of 15 years. In our opinion, given current transplantation limitations, the preferred approach to management is close clinical follow-up with careful monitoring of plasma oxalate levels and renal function and appropriate timing of transplantation or initiation of dialysis therapy as renal function declines to levels associated with hyperoxalemia. Careful management specific to PH includes reduction of plasma oxalate concentrations with intensive dialysis pretransplantation, maintenance of high-vol-

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Table 3. Management Guidelines for Patients With PH Renal Clearance Pretransplantation ⬍ 25 mL/min/1.73 m2

Perioperative Variable

Stone prevention

Hydration as tolerated by renal function Pyridoxine

Goal is urine output of 4-7 L/24 h with IV fluid, diuretics as needed Pyridoxine in kidney-only recipients Neutral phosphate if serum creatinine ⱕ 2 mg/dL

Prevent systemic oxalosis

Intensive hemodialysis or combined hemodialysis and peritoneal dialysis

Monitor

Urine volume Urine oxalate excretion rate and concentration Renal function Plasma oxalate

Hemodialysis or CVVHDF pretransplantation and daily posttransplantation until plasma oxalate is ⬍20 umol/L Pyridoxine in kidney-only recipient Daily urine volume Urine oxalate excretion rate and concentration CaOx crystalluria Daily plasma oxalate and serum phosphorus

Posttransplantation ⬎ 30 mL/min/1.73 m2 Fluid intake to maintain urine output ⬎ 4 L/24 h Pyridoxine in kidney-only recipient Neutral phosphate Magnesium or citrate in selected patients Maintain hydration Minimize nephrotoxic agents Pyridoxine in kidney-only recipient Renal function Plasma oxalate Urine volume Urine oxalate excretion rate and concentration CaOx crystalluria Serum P, PTH Renal imaging for stones, nephrocalcinosis

NOTE. Pyridoxine dose is 5 to 8 mg/kg/d in pyridoxine-responsive patients; maximum dose, 1,000 mg/d. Pyridoxine is not needed after liver transplantation. Neutral phosphate dose is 30 mg/kg/d of elemental P (divided three or four times daily); maximum dose, 2,000 mg/d. Abbreviations: CaOx, calcium oxalate; P, phosphorus; PTH, parathyroid hormone; IV, intravenous.

ume diuresis posttransplantation, and, as soon as renal allograft function permits, initiation of neutral phosphate therapy to reduce calcium oxalate crystallization and supersaturation21 (Table 3). Close monitoring is recommended to maintain plasma oxalate levels at less than 20 to 30 ␮mol/L, with dialysis as needed, and urine oxalate concentration at less than 0.3 mmol/L, with hydration as needed. Attention to the presence of calcium oxalate crystals in urine and stone formation also is important, as is prompt adjustment of doses of cyclosporine A, tacrolimus, and other potentially nephrotoxic agents. It should be kept in mind that not all renal allograft loss in kidney-alone transplantation is caused by oxalate deposition, and renal allografts in liver-kidney transplant recipients remain at risk for loss caused by recurrent oxalosis until urine oxalate excretion rates approach normal. Although plasma oxalate concentrations appear to decrease promptly with replacement of renal function, hyperoxaluria may persist for years after hepatic transplantation. This is caused by the length of time required for the mobilization and excretion of tissue oxalate

stores. For patients with residual renal function less than 10 mL/min/1.73 m2 who are pyridoxine resistant, hemodialysis 6 days weekly or combined hemodialysis and continuous peritoneal dialysis are required. In our experience, patients who have undergone intensive individualized dialysis (hemodialysis 6 days weekly or combined hemodialysis and peritoneal dialysis) for up to 12 months before transplantation and who do not have extensive systemic oxalosis often are able to mobilize and excrete tissue stores in the first 9 to 12 months after transplantation. In patients with extensive tissue stores and those who have undergone dialysis therapy for longer periods before transplantation, many years may be required before marked hyperoxaluria resolves. Until normal urine oxalate excretion rates are achieved, maintenance of high-volume urine output daily and neutral phosphate therapy are recommended to minimize stone formation20 and preserve renal allograft function. With this approach, our patients showed little formation of calcium oxalate stones and none developed nephrocalcinosis. With early diagnosis and recognition of renal insuf-

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ficiency in PH, attentive medical management, and current approaches to transplantation, continued improvement in patient and renal allograft survival can be expected for patients with this inborn error of metabolism. In the future, advances in gene therapy techniques and increased insight into the pathophysiological course of PH, particularly in regard to mechanisms of oxalate-related renal injury, will hopefully obviate the need for kidney and orthotopic liver transplantation.

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