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AHCPR Health Technology Reviews. Rockville (MD): Agency for Health Care Policy and Research (US); 1992-1995. 

                        - This publication is provided for historical reference only and the information may be out of date.

**This publication is provided for historical reference only and the information may be out of date.**

## AHCPR Health Technology Reviews.

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Agency for Health Care Policy and Research (US)

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#  9Combined Liver-Kidney Transplantation

Martin Erlichman and Thomas V Holohan, MD.

Published: March 1995.

## Report

In 1984, Margreiter et al(1). performed the                first combined liver-kidney transplantation (CLKT). This procedure has recently been                considered a therapeutic option for those patients suffering from concomitant liver                and kidney disease.(2,3). Multiple organ transplantation is                performed in order to improve long-term allograft function by correcting the                coexisting dysfunction of other organ systems. Renal and hepatic failure may result                from the same disease process (e.g., polycystic disease), one disease may be a                result of the other (e.g., postviral hepatic cirrhosis in a dialysis patient) or                they may be unrelated but concomitant.(2).

Weir et al(4). reported that hepatic                disease was the leading cause of late mortality among their renal transplant                recipients with grafts functioning for more than 5 years. Moreover, a number of                potential liver transplant candidates may have preexisting renal dysfunction. Where                correction of such renal dysfunction is not expected, the post-liver transplant                management of the patient with chronic kidney failure is problematic. Impaired renal                function has been considered by some to be a contraindication for liver                transplantation. (2,5). Normal kidney function would allow the use of                therapeutic levels of cyclosporine to ensure adequate immunosuppression, without                fear of further damage to compromised kidneys. Therefore, when irreversible and                severe chronic renal disease is documented before hepatic transplantation, CLKT has                been considered with the intent of also providing normal kidney function.(2).

Liver transplantation has been performed in cases of inborn errors of liver                metabolism resulting from genetically determined enzyme deficiencies where                destruction of the host liver is certain (e.g., [alpha]-1-antitrypsin deficiency,                tyrosinemia). (6). CKLT have been reported                for two cases of hepatorenal tyrosinemia (a heterogeneous hereditary disorder) with                severe renal involvement.(7).

Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism resulting                in renal failure. There is no satisfactory treatment for this condition; typically,                patients develop renal insufficiency early in life and succumb to uremia before age                    20.(8). Scheinman(9). estimates that 10 to 15 new patients per                year in the United States will be recognized with end-stage renal failure due to                PH1. CLKT for the treatment of PH1 was reported in 1985 and again in 1987 by Watts                et al(10,11). and has been proposed as a way of replacing the                destroyed kidney, correcting the enzyme deficiency, and normalising oxalate                production and excretion. Rosenberg(8).                and Hillman(12). recommend clinical                studies with long-term followup to evaluate this potentially promising therapy.                Presently, there are no published reports of United States experience with CLKT for                PH1. However, there is European experience;(13). a 1-year graft survival rate of 77 percent for both organs was                achieved in 13 of 17 patients. Currently, the role of CLKT in patients with oxalosis                is not clearly defined.

There have been a total 273 CLKTs performed in the United States since 1987, with                followup data available on 268 patients. More than 80 percent of the procedures have                been performed since 1990. In the first 6 months of 1993, there were 19 CLKT                procedures reported. The number of separate liver and kidney transplants continues                to rise: since 1987, there have been almost 17,000 livers transplanted, increasing                from a little more than 1,000 in 1987 to over 3,000 in 199. Kidney transplants                averaged about 8,700 in 1988 and 1989 and have increased to almost 10,000 in 1992,                according to a Federal Report on organ transplantation(14). and the United Network for Organ Sharing (UNOS)                (written communication, November 2, 1994).

A paucity of published data exists on patient outcomes after CLKT Experience for CLKT                is reported in only a few studies with small series of patients                    (Table                    1). Most patients receive organs from the same donor,                with the liver transplanted first. Patients selected had various combinations of                liver and kidney disease and were monitored for periods ranging from 1 month to 7                years posttransplant. Clinical outcomes for specific disease combinations were                either not provided or represented the experience of only a few patients.

#### Table

Table 1. Outcome data for studies of CLKT. 

Seventy-nine patients have been reported in the medical literature as recipients of                CLKT. Thirty-one (39 percent) of these had end-stage liver disease due to hepatitis                and/or postnecrotic cirrhosis, and 18 (23 percent) with chronic kidney failure                receiving a CLKT, presented with glomerulonephritis or chronic graft rejection. In                10 percent of the patients, the cause of renal failure was unknown. The 25 patients                (32 percent) receiving a CLKT for primary hyperoxaluria (oxalosis) constituted the                largest single category.

Additional patient outcome data regarding liver-kidney recipients are available from                the United States UNOS data base. UNOS operates the national Scientific Registry for                Organ. Transplantation, which collects data from member transplant programs;                transplant recipients are monitored from the time of transplant until 2 years after                the failure of the graft or until the death of the recipient. The estimated                percentage of survivors to 1 year is approximately 73 percent, with a 95 percent                confidence interval of 66.8 to 78.2 percent, for 268 of thes transplant patients for                whom followup data were available (Table 1) (UNOS written                communication, November 2, 1994. Forty-five of the 79 patients in the medical                literature are from U.S. studies and are probably included as part of thee UNOS                registry. Data regarding patient outcomes for specific combinations of liver and                kidney disease are limited.

The relationship between tissue typing and the outcome of transplant procedures                remains equivocal and appears to be organ specific.(17,18). In CLKT                studies, ABO blood group typing was typically performed to provide identical or                compatible donors. Human leukocyte antigen (HLA) tissue typing indicated generally                poor matches. The cytotoxic cross-matches reported in most studies were usually                negative. However, ABO compatibility and organ size were the only criteria used for                selecting donors. Improvements in immunosuppressive therapy appear to have                diminished greatly the effects of HLA mismatching on graft survival.(19). Under current UNOS policy, only kidney                allocations address the degree of antigen mismatches. Current UNOS policy does not                directly address CLKT. Data are insufficient to determine the effect of HLA                matching, particularly at the DR locus, on graft survival for CLKT.

A review of the transplantation history of patients receiving CLKT revealed that some                patients had received kidney or liver transplants before the CLKT, and that some                required subsequent retransplantation of the liver and/or kidney                    (Table                    2). For example, in the largest series, 34 percent of                the patients had a previous transplant, and for all five studies reported in Table                2, approximately 39 percent of the CLKT patients had a previous transplant.                Twenty-seven percent of the 268 patients in the UNOS CLKT registry had a prior                transplant. In contrast, approximately 15 percent of recipients of isolated kidney                (cadaveric) or liver transplants had previous transplants.(14). Patients receiving CLKT (UNOS) were almost twice as                likely to have had a previous transplant than were single-organ recipients. In the                largest single study,(2). 102 organs were                expended by 38 patients. Regarding retransplantation, there is insufficient                information to determine any trends in the CLKT population.

#### Table

Table 2. Transplant history of patients receiving CLKT's. 

At present, it is not possible to determine confidently the most appropriate role for                CLKT, because case series total 79 patients, and overall, only 268 CLKT appear in                the UNOS registry. However, even this limited information may permit several                preliminary observations. The data comprise relatively short-term followup in a                small number of presumably carefully selected patients; moreover, the wide spectrum                of kidney and liver diseases in the recipients makes it impractical to frame                specific and rational patient selection criteria aside from simultaneously observed                (or expected, in the case of certain metabolic diseases) kidney and liver failure.                It is unclear whether the more widespread use of the technique with longer followup                will continue to provide similar results.

Notwithstanding, the information reported by UNOS  (Table 3)                indicates that the 1-year survival rate after CLKT in those patients not previously                transplanted (79.7 percent) is comparable to that for primary liver transplant alone                (81.7 percent). Because liver function is very likely to be the primary determinant                of patient survival, it appears that simultaneous kidney transplant does not                adversely affect the transplanted liver. However, the results differ markedly for                those patients who received a transplant prior to the CLKT (27 percent of the                total). In the letter group, a 1-year survival rate of 56.4 percent was reported for                patients with any prior transplant, and only 40.9 percent for those having had prior                liver transplant. The 1-year survival rate for patients receiving a liver transplant                (first transplant) was reported as 81.7 percent, and only 57.8 percent for those                patients having had a prior liver transplant.

#### Table

Table 3. Survival of patients and grafts [a]. 

It would appear that, at least for the first year after transplant, CLKT performed as                the initial procedure for patients with both liver and kidney failure is of equal                effectiveness regarding survival as is isolated liver transplantation in patients                with liver failure alone. CLKT after prior liver transplant appears to be associated                with a significant decrement in survival, not unlike the decrement in the survival                rate of liver transplant patients who had received a prior transplant. This is not a                trivial issue, because donor organs represent a scarce resource. Retransplantation                is therefore problematic, because in 1993, 500 (8.0 percent) of those awaiting liver                transplant died. This observation may require careful evaluation by those charged                with the establishment of organ distribution policies.

The National Institutes of Health finds that CLKT is a beneficial procedure and                acknowledges that patients who have had a prior liver transplant are less likely to                benefit from a CLKT.

## References

                        - 1.
                        - Margreiter R, Reinhard K, Christoph H, et al. Kramar R, Huber C, et. al.  Combined liver and kidney transplantation.  Lancet.  1984; ; 1: 1077–1078. [PubMed: 6144007]
                        - 2.
                        - Saidman SL, Duquesnoy RJ, Demetris AJ, et al. Simultaneous liver-kidney transplantation: The influence of                        performed lymphocytotoxic antibodies.  Transplant Immunol, in press.  [PMC free article: PMC2956073] [PubMed: 8081794]
                        - 3.
                        - Gil-Vernets, Prieto JM, Grino O. Combined liver-kidney transplantation.  Transplant Proc.  1992; ; 24: 128–129. [PubMed: 1539207]
                        - 4.
                        - Weir MR, Kirkman RL, Strom TB, et al. Liver disease in recipients of long-functioning renal                        allografts.  Kidney Int.  1985; 28: 839–844. [PubMed: 3910917]
                        - 5.
                        - Gonwa TA, Nery JR, Husberg BS, et al. Simultaneous liver and renal transplantation in                        man.  Transplantation.  1988; 46: 690–693. [PubMed: 3057691]
                        - 6.
                        - McDonald JC, Landreneau MD, Rohr MS, et al. Reversal by liver transplantation of the complications of primary                        hyperoxaluria as well as the metabolic defect.  N Engl J Med.  1989; 321: 1100–1103. [PubMed: 2797068]
                        - 7.
                        - Paradis K, Weber A, Seidman EG, et al. Liver transplantation for hereditary tyrosinemia: The Quebec                        experience.  Am J Hum Genet.  1990; 47: 338–342. [PMC free article: PMC1683709] [PubMed: 2378360]
                        - 8.
                        - Rosenberg LE. Inherited disorders of                        amino acid metabolism  in Wilson JD, Braunwald                        E, Isselbacher KJ, et al (Eds): Harrison's Principles of Internal Medicine                        (12th ed), New York: McGraw-Hill, Inc,                         1991 pp 1876–1877.
                        - 9.
                        - Scheinman JI. Editorial review. Primary hyperoxaluria: Therapeutic strategies                        for the 90's.  Kidney Int.  1991; 40: 389–399. [PubMed: 1787639]
                        - 10.
                        - Watts RWE, Caline Calne RY, Williams R, et al. Primary hyperoxaluria (Type I): Attempted treatment by combined                        hepatic and renal transplantation.  Q J Med.  1985; 57: 697–703. [PubMed: 3909198]
                        - 11.
                        - Watts RWE, Rolles K, Morgan SH, et al.  Successful treatment of primary hyperoxaluria type I by combined                        hepatic and renal transplantation.  Lancet.  1987; 2: 474–475. [PubMed: 2887776]
                        - 12.
                        - Hillman RE. Primary                        hyperoxalurias  in Scriver CR, Beaudet AL, SLy                        WS, et al. (Eds): The Metabolic Basis of Inherited Disease (6th                        ed), New York: McGraw-Hill, Inc, 1989 pp                        933–941.
                        - 13.
                        - Watts RWE, Danpure CJ, DePaul L, et al. Combined liver-kidney and isolated liver transplantations for                        primary hyperoxaluria type I: The European experience.  Nephrol Dial Transplant.  1991; 6: 502–511. [PubMed: 1922912]
                        - 14.
                        - U.S. Department of Health and Human Services  Annual Report of the U.S.                        Scientific Registry for Organ Transplantation and the Organ Procurement and                        transplantation Network, Washington, DC: U.S.                        Department of Health and Human Services, Public Health Service, Health                        Resources and Services Administration, Bureau of Health Resources                        Development, Division of Organ Transplant                     1990.
                        - 15.
                        - Vogel W, Steiner E, Kornberger R, et al. Preliminary results with combined hepatorenal                        allografting.  Transplantation.  1988; 45: 491–493. [PubMed: 3278443]
                        - 16.
                        - Kaplan EL, Meier P. Nonparametric estimation from incomplete                        observations.  J Am Stat Assoc.  1958; 53: 457–481.
                        - 17.
                        - Roitt I.                         Transplantation in: Essential                        Immunology, Oxford: Blackwell Scientific Publications,                         1991 pp 277–304.
                        - 18.
                        - Sachs DH. The major                        histocompatibility complex in Paul WE (Ed):                        Fundamental Immunology, New York: Raven Press,                        1984 pp 303–346.
                        - 19.
                        - Perkins HA. Transplantation                        immunology in Fudenberg HIH, Stites DP,                        Calwell JL, et al (Eds): Basic and Clinical Immunology, Los                    Altos, CA: LANGE Medical Publications,  1976,  pp                        160–169.

                        - 
AHCPR Pub. No. 95-0012

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