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Combined liver-kidney transplantation in a 15-year-old boy with alpha1-antitrypsin deficiency
Journal of Hepatology 36 (2002) 565–568 www.elsevier.com/locate/jhep
Case report
Combined liver-kidney transplantation in a 15-year-old boy with alpha1-antitrypsin deficiency Massimiliano Loreno 1, Patrizia Boccagni 1, Paolo Rigotti 2, Remo Naccarato 1, Patrizia Burra 1,* 1
Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani 2, 35122 Padua, Italy 2 Department of Medical and Surgical Sciences, University of Padua, Via Giustiniani 2, 35122 Padua, Italy
Alpha1-antitrypsin (a1-AT) deficiency is the most common genetic cause of liver disease in infants and children. The major clinical manifestations include liver disease (primarily in children) and emphysema in adults. For patients who progress to cirrhosis and liver failure, liver transplantation provides a metabolic cure for the deficiency and presumably prevents the associated complications. Several case reports in the pediatric literature describe glomerulonephritis in the setting of severe a1-AT deficiency, but this association is less well documented in adults. End-stage chronic kidney disease is a rare finding in the literature and kidney transplantation is the treatment of choice. We report on a 15-year-old boy with a1-AT deficiency and consequent end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure, who successfully underwent combined liver-kidney transplantation. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Alpha1-antitrypsin deficiency; Liver disease; Liver transplantation; Glomerulonephritis; Renal failure; Kidney transplantation
1. Introduction Alpha1-antitrypsin (a1-AT) deficiency is the most common genetic cause of liver disease in infants and children and the most common genetic disease for which pediatric liver transplantation is indicated [1]. a1-AT is the most abundant circulating protease inhibitor and is synthesized primarily in the hepatocytes. It inactivates trypsin, neutrophil elastase and other enzymes. a1-AT is encoded by a single gene (PiM) located on the long arm of chromosome 14 and its inheritance is codominant [2]. At present, more than 75 alleles have been recognized and PiZ is the predominant genetic variant [3,4]. Diagnosis is based on diminished serum levels of a1-AT (15–20% of normal values), abnormal a1-AT mobility in isoelectric focusing [5] and the demonstration of PAS-positive, diastase-resistant globules in liver cells [6]. The major clinical manifestations of a1-AT deficiency include liver disease (primarily in children) and emphysema in adults. Clinically-important liver disease only occurs in Received 31 July 2001; received in revised form 12 December 2001; accepted 17 December 2001 * Corresponding author. Tel.: 139-49-821-2892; fax: 139-49-876-0820. E-mail address: [email protected] (P. Burra).
about 10–20% of all homozygous (PiZZ) neonates, though the majority (70%) have abnormal liver function tests. In a minority of homozygous (PiZZ) neonates developing liver disease, this progresses to cirrhosis and liver failure, for which the treatment of choice is liver transplantation [7]. Renal involvement is frequent in patients with severe a1AT deficiency, but clinically goes unnoticed in most cases [8]. Controversy exists as to whether various types of glomerulonephritis [8–16] are specific for a1-AT deficiency or a non-specific manifestation of severe liver disease. End-stage chronic kidney disease associated with a1-AT deficiency is rarely reported in the literature. Elzouki et al. reported on a homozygous patient with renal failure proving reversible after orthotopic liver transplantation [14]. Os et al. described the first case in the literature of kidney transplantation in a 30-year-old man (PiZZ) with cirrhosis in early childhood and renal failure in adult life [17]. The present case report describes a 15-year-old boy with a1-AT deficiency and associated end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure who underwent a successful combined liver-kidney transplantation.
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00012-0
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M. Loreno et al. / Journal of Hepatology 36 (2002) 565–568
2. Case report A 15-year-old boy was admitted to our Gastroenterology Unit for evaluation for combined liver-kidney transplantation. The patient had been born by vaginal delivery to a primiparous woman after an uncomplicated 39-week gestation. His birth weight was 2500 g. He developed prolonged neonatal cholestasis and a1-AT deficiency was diagnosed. He underwent liver biopsy at the age of 3 years and histopathological examination showed marked portal fibrosis, mild inflammatory changes, periportal steatosis, intracellular cholestasis, ductular proliferation without PAS-positive, diastase-resistant globules. Pi typing showed that the patient was homozygous for the PiZ genetic variant. At the age of 13, mild fever, marked fatigue, abdominal swelling, peripheral edema and macroscopic hematuria occurred. On physical examination, the liver was not enlarged and the spleen was palpated 9 cm below the costal margin. Serum albumin was 20.2 g/l (39.9–53.0), total urinary albumin .6 g/24 h (,0.025), serum creatinine 175 mmol/l (62–115), serum urea 19.98 mmol/l (2.5–7.5), prothrombin time 65% (75– 112). Antinuclear antibodies, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies and the Waaler-Rose test were all negative. IgA, IgG, IgM, C4, C3 activator, C1NH and C1q levels were normal, while C3 was low. Gastrointestinal endoscopy showed grade F1 esophageal varices. Chest X-ray and respiratory function tests were normal. A histological diagnosis of membranoproliferative glomerulonephritis was made on kidney biopsy. The patient remained well until February 2000, when fever, arterial hypertension, macroscopic hematuria and oliguria occurred with swelling of the limbs, ascites and right pleural effusion. Serum creatinine was 309 mmol/l (62–115), serum urea 41.24 mmol/l (2.5–7.5), serum albumin 14 g/l (39.9–53.0), total serum bilirubin 35.91 mmol/l (1.7–17), prothrombin time 61% (75–112), and a1-AT 0.21 g/l (0.89–2.00). A blood culture revealed the presence of Streptococcus pneumoniae. Progressive impairment of renal function occurred and the patient underwent hemodialysis. Given the deteriorated liver function and lack of improvement in kidney function, a work-up for combined liver-kidney transplantation was started. The portal vein was thin, with a cavernomatous appearance at the porta hepatis; gastrointestinal endoscopy confirmed grade F1 esophageal varices with mild congestive gastropathy; abundant ascites was confirmed on CT scan. Respiratory function tests revealed a restrictive pattern with mild alveolar distension and reduced CO diffusion capacity; a chest X-ray showed right pleural effusion; a high-resolution CT scan of the chest revealed no sign of obstructive or restrictive lung disease. No pericardial effusion was found on echocardiography. No contraindications to combined liver and kidney transplantation emerged and, on 23 May 2000, the patient underwent successful surgery. Liver transplantation was performed with caval preservation. Arterial and portal recon-
struction involved an end-to-end anastomosis between both recipient and donor hepatic arteries and portal veins. Biliary reconstruction was achieved by a Roux-en-Y hepatic jejunostomy, without stenting. The kidney was transplanted extraperitoneally in the right iliac fossa. Histological examination of the explanted liver revealed portal fibrosis with septa and nodular regeneration, portal lymphocytic infiltrates with piecemeal necrosis and mild steatosis. Immunohistochemical assay showed PAS-positive globules with a1-AT reactivity. No evidence of hepatic tumor was found. Cyclosporine, prednisolone and mycophenolate mofetil were used for immunosuppression but the mycophenolate mofetil was suspended 9 days after surgery because of severe leukopenia. Toxoplasma and CMV infections occurred 1 month after the procedure and were treated with trimethoprim-sulphamethoxazole (960 mg/day), spiramycin (9 MIU/day) and gancyclovir (250 mg/day iv). After 2 months of surgery, moderate arterial hypertension developed, associated with a mild renal function impairment (serum creatinine 159 mmol/l) that was well controlled with transdermal clonidine and manidipine (20 mg/day). At the same time, histologically-proven grade II–III acute liver rejection was treated with pulse steroids (methylprednisolone 1 g. iv for 3 days). The patient was seen 1 year after combined liver-kidney transplantation. He underwent routine liver biopsy and the histological findings were normal, as were the liver and renal function test results.
3. Discussion To the best of our knowledge, this is the first reported case of combined liver and kidney transplantation for end-stage liver and kidney disease associated with a1-AT deficiency. The patient was homozygous for the PiZ variant of a1AT, he had suffered a prolonged episode of neonatal cholestasis and his liver disease had then remained well compensated throughout childhood. At the age of 13 he had developed mild renal failure with nephrotic syndrome. Since his liver disease was already advanced, liver transplantation probably ought to have been considered then to prevent further renal damage (a recent case of membranoproliferative glomerulonephritis and nephrotic syndrome regressing after orthotopic liver transplantation is reported in the literature [14]). Renal involvement in chronic liver disease is quite a frequent finding [18]; the clinical course in this setting is often benign and seldom leads to end-stage kidney disease needing dialysis [19]. Different types of glomerular lesion are described, depending on the etiology of the liver disease. Membranous GN, membranoproliferative GN and mesangioproliferative GN are often associated with chronic hepatitis B infection [20]; membranoproliferative GN is associated with chronic hepatitis C infection and mixed cryoglobulinemia [21–23]. IgA nephropathy is the most
M. Loreno et al. / Journal of Hepatology 36 (2002) 565–568
common finding, primarily in patients with alcoholic liver disease [24,25]. The association of a1-AT deficiency with glomerulonephritis used to be considered unusual. It was first described in 1969 [26], followed by several case reports mainly involving children and based on autoptic findings [12,14]. Davis et al. reported a higher frequency (74%) and a more variable pattern of glomerular changes in homozygous PiZ children than in a control population with chronic liver failure unrelated to a1-AT deficiency. Glomerular lesions were mesangiocapillary GN, mesangial proliferative GN, diffuse endocapillary proliferative GN, and focal segmental mesangial proliferative GN with segmental necrosis [8]. The role of a1-AT deficiency in the onset of glomerular lesions is controversial. Some authors have speculated that, with the loss of balance between protease and antiprotease, ineffective proteolytic enzyme inhibition may cause damage to tissues other than the lungs [27]. Moreover, abnormal a1AT deposits have been found in the subendothelial region of the glomerular basement membrane [9]. It has been suggested that altered PiZ protein released from the injured hepatocytes could act as an antigen, which locally elicits an immunological response with injury of the glomeruli [23], or leads to the formation of circulating immunocomplexes causing diffuse systemic vasculitis, including glomerulonephritis [28]. Our patient showed no signs of cutaneous vasculitis, arthritis or abdominal pain on admission. Unfortunately, immunoreactivity for PiZ a1-AT was not tested in the renal biopsy specimen. However, the finding of membranoproliferative glomerulonephritis is consistent with the pathological spectrum of a1-AT-related nephropathy frequently seen in children [10–13]. Further evidence of the impact of renal disease in a1-AT deficiency comes from experience with liver transplantation. In patients with clinical signs of renal involvement, early orthotopic liver transplantation may represent an optimal therapeutic approach, providing metabolic cure of the genetic defect, consequent normalization of a1-AT serum levels and, presumably, the prevention of associated longterm complications such as emphysema and renal failure. The above-mentioned case of nephrotic syndrome regressing after liver transplantation [14] supports the hypothesis of a role for protease/antiprotease imbalance in the pathogenesis of renal disease and the beneficial effect of restoring normal levels of circulating a1-AT. Nevertheless, NobleJamieson et al. [11] reported on five children with a1-AT deficiency and end-stage liver disease with varying grades of GN histology who developed severe arterial hypertension probably of renal origin after liver transplantation. In our patient, blood pressure before transplantation was well controlled with diuretics. Hepatic insufficiency and concomitant Streptococcus Pneumoniae sepsis are likely to have contributed to the rapid deterioration in renal function and its progression to end-stage renal failure. Our case supports the opinion that the renal disease associated with a1-AT deficiency can occur as a consequence of
567
concomitant hepatic disease and emphasizes the value of early, accurate renal function assessment in these patients to evaluate the immediate and long-term renal prognosis. There is currently no specific therapy for liver disease associated with a1-AT deficiency and the role and efficacy of new therapeutic strategies, e.g. recombinant a1-AT administration, gene therapy and hepatocyte transplantation, remain to be seen. A number of PiZZ individuals with severe liver disease, and even cirrhosis and portal hypertension, may have a relatively low rate of disease progression and lead a normal life for extended periods of time. Progressive liver dysfunction and failure in children have been treated with orthotopic liver transplantation, with survival rates approaching 90% at 1 year and 80% at 5 years [29]. When signs of irreversible renal failure have occurred on top of decompensated cirrhosis, a rapid deterioration in clinical conditions is to be expected in spite of hemodialysis, and combined liver-kidney transplantation should be taken into consideration.
References [1] Gartner JC, Zitelli BJ, Malatack JJ, et al. Orthotopic liver transplantation in children: 2 year experience with 47 patients. Paediatrics 1984;74:140–145. [2] Long GL, Chandra T, Woo SLC, et al. Complete sequence of cDNA for human a1-antitrypsin and the gene for the S variant. Biochemistry 1984;23:4828–4837. [3] Crystal RG. Alpha1-antitrypsin deficiency, emphysema, and liver disease. Genetic bases and strategies for therapy. J Clin Invest 1990;85:1343–1352. [4] Cox DW. Alpha1-antitrypsin deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Basis of Inherited Disease, 6th ed. New York: McGraw-Hill, 2000. pp. 2409–2437. [5] Buffone GJ, Stennis BJ, Schimbor CM. Isoelectric focusing in agarose: classification of genetic variants of a1-antitrypsin. Clin Chem 1983;29:328–331. [6] Hadchouel M, Gautier M. Histopathologic study of the liver in the early cholestatic phase of a1-antitripsin deficiency. J Pediatr 1976;89:211–215. [7] Birrer P, McElvaney NG, Chang-Stroman LM, Crystal RG. Alpha1antitrypsin deficiency and liver disease. J Inherit Metab Dis 1991;14:512–525. [8] Davis ID, Burke B, Freese D, Sharp HL, Kim I. The pathologic spectrum of the nephropathy associated with alpha1-antitrypsin deficiency. Hum Pathol 1992;23:57–62. [9] Levy M, Gubler MC, Hadchouel M, Niaudet P, Habib R, Odievre M. Deficit en alpha1-antitrypsine et atteinte renale. Nephrologie 1985;6:65–70. [10] Moroz SP, Cutz E, Balfe JW, Sass-Kortsak A. Membranoproliferative glomerulonephritis in childhood cirrhosis associated with alpha1antitrypsin deficiency. Pediatrics 1976;57:232–238. [11] Noble-Jamieson G, Barnes ND, Thiru S, Mowat AP. Severe hypertension after liver transplantation in alpha1-antitrypsin deficiency. Arch Dis Child 1990;65:1217–1221. [12] Rodriguez-Soriano J, Fidalgo I, Camarero C, Vallo A, Oliveros R. Juvenile cirrhosis and membranous glomerulonephritis in a child with alpha1-antitrypsin deficiency Pi SZ. Acta Pediatr Scand 1978;67:793–796. [13] Strife CF, Hug G, Chuck G, McAdams AJ, Davis CA, Kline JJ.
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[14]
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[16]
[17]
[18] [19]
[20]
[21]
M. Loreno et al. / Journal of Hepatology 36 (2002) 565–568 Membranoproliferative glomerulonephritis and alpha1-antitrypsin deficiency in children. Pediatrics 1983;71:88–92. Elzouki AN, Lindgren S, Nilsson S, Veress B, Eriksson S. Severe alpha1-antitrypsin deficiency (PiZ homozygosity) with membranoproliferative glomerulonephritis and nephrotic syndrome, reversible after orthotopic liver transplantation. J Hepatol 1997;26(6):1403– 1407. Stauber RE, Horina JH, Trauner M, Krejs GJ, Ratschek M, Klimpfinger M. Glomerulonephritis as later manifestation of severe a1antitrypsin deficiency. Clin Invest 1994;72:404–408. Mazodier P. Association entre deficit en alpha1-antitrypsine et maladie re´ nale: revue de 48 cas dont 17 personnels. Pe´ diatre 1977;60:205– 219. Os I, Skjorten F, Svalander C, Berge E. Alpha1-antitrypsin deficiency associated with hepatic cirrhosis and IgA nephritis. Nephron 1997;77(2):235–237. Newell GC. Cirrhotic glomerulonephritis: incidence, morphology, clinical features, and pathogenesis. Am J Kidney Dis 1987;9:183–190. Strom EH, Gudat F, Mihatsch MJ. Interrelationship between kidney and liver disease. In: Schmid R, Bianchi L, Gerok W, Maier KP, editors. Extrahepatic Manifestations in Liver Diseases, London: Kluver, 1993. pp. 213–230. Johanson RJ, Couser WG, Hepatitis B. infection and renal disease: clinical, immunopathogenetic and therapeutic considerations. Kidney Int 1990;37:663–676. Johanson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P,
[22]
[23] [24] [25]
[26]
[27] [28]
[29]
et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993;328:465–470. Pasquariello A, Ferri C, Moriconi L, La Civita L, Longombardo G, Lombardini F, et al. Cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus. Am J Nephrol 1993;13:300–304. D’Amico G, Fornasieri A. Cryoglobulinemic glomerulonephritis induced by hepatitis C virus. Am J Kidney Dis 1995;25:361–369. Sinniah R. Heterogeneous IgA glomerulonephropathy in liver cirrhosis. Histopathology 1984;8:947–962. Woodroffe AJ, Gormly AA, McKenzie PE, Wootton AM, Thompson AJ, Seymour AE, et al. Immunologic studies in IgA nephropathy. Kidney Int 1980;18:366–374. Miller F, Kuschner M. Alpha1-antitrypsin deficiency, emphysema, necrotizing angiitis and glomerulonephritis. Am J Med 1969;46:615– 623. Morse JO. Alpha1-antitrypsin deficiency. N Engl J Med 1978;299: 1099–1105. Lewis M, Kallenbach J, Zaltzman M, Levy H, Lurie D, Baynes R, et al. Severe deficiency of a1-antitrypsin associated with cutaneous vasculitis, rapidly progressive glomerulonephritis, and colitis. Am J Med 1985;79:489–494. Esquivel CO, Vicente E, Van Thiel D, Gordon R, Marsh W, Makowka L, et al. Orthotopic liver transplantation for alpha1-antitrypsin deficiency: an experience in 29 children and ten adults. Transplant Proc 1987;19:3798–3802.
Case report
Combined liver-kidney transplantation in a 15-year-old boy with alpha1-antitrypsin deficiency Massimiliano Loreno 1, Patrizia Boccagni 1, Paolo Rigotti 2, Remo Naccarato 1, Patrizia Burra 1,* 1
Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani 2, 35122 Padua, Italy 2 Department of Medical and Surgical Sciences, University of Padua, Via Giustiniani 2, 35122 Padua, Italy
Alpha1-antitrypsin (a1-AT) deficiency is the most common genetic cause of liver disease in infants and children. The major clinical manifestations include liver disease (primarily in children) and emphysema in adults. For patients who progress to cirrhosis and liver failure, liver transplantation provides a metabolic cure for the deficiency and presumably prevents the associated complications. Several case reports in the pediatric literature describe glomerulonephritis in the setting of severe a1-AT deficiency, but this association is less well documented in adults. End-stage chronic kidney disease is a rare finding in the literature and kidney transplantation is the treatment of choice. We report on a 15-year-old boy with a1-AT deficiency and consequent end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure, who successfully underwent combined liver-kidney transplantation. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Alpha1-antitrypsin deficiency; Liver disease; Liver transplantation; Glomerulonephritis; Renal failure; Kidney transplantation
1. Introduction Alpha1-antitrypsin (a1-AT) deficiency is the most common genetic cause of liver disease in infants and children and the most common genetic disease for which pediatric liver transplantation is indicated [1]. a1-AT is the most abundant circulating protease inhibitor and is synthesized primarily in the hepatocytes. It inactivates trypsin, neutrophil elastase and other enzymes. a1-AT is encoded by a single gene (PiM) located on the long arm of chromosome 14 and its inheritance is codominant [2]. At present, more than 75 alleles have been recognized and PiZ is the predominant genetic variant [3,4]. Diagnosis is based on diminished serum levels of a1-AT (15–20% of normal values), abnormal a1-AT mobility in isoelectric focusing [5] and the demonstration of PAS-positive, diastase-resistant globules in liver cells [6]. The major clinical manifestations of a1-AT deficiency include liver disease (primarily in children) and emphysema in adults. Clinically-important liver disease only occurs in Received 31 July 2001; received in revised form 12 December 2001; accepted 17 December 2001 * Corresponding author. Tel.: 139-49-821-2892; fax: 139-49-876-0820. E-mail address: [email protected] (P. Burra).
about 10–20% of all homozygous (PiZZ) neonates, though the majority (70%) have abnormal liver function tests. In a minority of homozygous (PiZZ) neonates developing liver disease, this progresses to cirrhosis and liver failure, for which the treatment of choice is liver transplantation [7]. Renal involvement is frequent in patients with severe a1AT deficiency, but clinically goes unnoticed in most cases [8]. Controversy exists as to whether various types of glomerulonephritis [8–16] are specific for a1-AT deficiency or a non-specific manifestation of severe liver disease. End-stage chronic kidney disease associated with a1-AT deficiency is rarely reported in the literature. Elzouki et al. reported on a homozygous patient with renal failure proving reversible after orthotopic liver transplantation [14]. Os et al. described the first case in the literature of kidney transplantation in a 30-year-old man (PiZZ) with cirrhosis in early childhood and renal failure in adult life [17]. The present case report describes a 15-year-old boy with a1-AT deficiency and associated end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure who underwent a successful combined liver-kidney transplantation.
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00012-0
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M. Loreno et al. / Journal of Hepatology 36 (2002) 565–568
2. Case report A 15-year-old boy was admitted to our Gastroenterology Unit for evaluation for combined liver-kidney transplantation. The patient had been born by vaginal delivery to a primiparous woman after an uncomplicated 39-week gestation. His birth weight was 2500 g. He developed prolonged neonatal cholestasis and a1-AT deficiency was diagnosed. He underwent liver biopsy at the age of 3 years and histopathological examination showed marked portal fibrosis, mild inflammatory changes, periportal steatosis, intracellular cholestasis, ductular proliferation without PAS-positive, diastase-resistant globules. Pi typing showed that the patient was homozygous for the PiZ genetic variant. At the age of 13, mild fever, marked fatigue, abdominal swelling, peripheral edema and macroscopic hematuria occurred. On physical examination, the liver was not enlarged and the spleen was palpated 9 cm below the costal margin. Serum albumin was 20.2 g/l (39.9–53.0), total urinary albumin .6 g/24 h (,0.025), serum creatinine 175 mmol/l (62–115), serum urea 19.98 mmol/l (2.5–7.5), prothrombin time 65% (75– 112). Antinuclear antibodies, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies and the Waaler-Rose test were all negative. IgA, IgG, IgM, C4, C3 activator, C1NH and C1q levels were normal, while C3 was low. Gastrointestinal endoscopy showed grade F1 esophageal varices. Chest X-ray and respiratory function tests were normal. A histological diagnosis of membranoproliferative glomerulonephritis was made on kidney biopsy. The patient remained well until February 2000, when fever, arterial hypertension, macroscopic hematuria and oliguria occurred with swelling of the limbs, ascites and right pleural effusion. Serum creatinine was 309 mmol/l (62–115), serum urea 41.24 mmol/l (2.5–7.5), serum albumin 14 g/l (39.9–53.0), total serum bilirubin 35.91 mmol/l (1.7–17), prothrombin time 61% (75–112), and a1-AT 0.21 g/l (0.89–2.00). A blood culture revealed the presence of Streptococcus pneumoniae. Progressive impairment of renal function occurred and the patient underwent hemodialysis. Given the deteriorated liver function and lack of improvement in kidney function, a work-up for combined liver-kidney transplantation was started. The portal vein was thin, with a cavernomatous appearance at the porta hepatis; gastrointestinal endoscopy confirmed grade F1 esophageal varices with mild congestive gastropathy; abundant ascites was confirmed on CT scan. Respiratory function tests revealed a restrictive pattern with mild alveolar distension and reduced CO diffusion capacity; a chest X-ray showed right pleural effusion; a high-resolution CT scan of the chest revealed no sign of obstructive or restrictive lung disease. No pericardial effusion was found on echocardiography. No contraindications to combined liver and kidney transplantation emerged and, on 23 May 2000, the patient underwent successful surgery. Liver transplantation was performed with caval preservation. Arterial and portal recon-
struction involved an end-to-end anastomosis between both recipient and donor hepatic arteries and portal veins. Biliary reconstruction was achieved by a Roux-en-Y hepatic jejunostomy, without stenting. The kidney was transplanted extraperitoneally in the right iliac fossa. Histological examination of the explanted liver revealed portal fibrosis with septa and nodular regeneration, portal lymphocytic infiltrates with piecemeal necrosis and mild steatosis. Immunohistochemical assay showed PAS-positive globules with a1-AT reactivity. No evidence of hepatic tumor was found. Cyclosporine, prednisolone and mycophenolate mofetil were used for immunosuppression but the mycophenolate mofetil was suspended 9 days after surgery because of severe leukopenia. Toxoplasma and CMV infections occurred 1 month after the procedure and were treated with trimethoprim-sulphamethoxazole (960 mg/day), spiramycin (9 MIU/day) and gancyclovir (250 mg/day iv). After 2 months of surgery, moderate arterial hypertension developed, associated with a mild renal function impairment (serum creatinine 159 mmol/l) that was well controlled with transdermal clonidine and manidipine (20 mg/day). At the same time, histologically-proven grade II–III acute liver rejection was treated with pulse steroids (methylprednisolone 1 g. iv for 3 days). The patient was seen 1 year after combined liver-kidney transplantation. He underwent routine liver biopsy and the histological findings were normal, as were the liver and renal function test results.
3. Discussion To the best of our knowledge, this is the first reported case of combined liver and kidney transplantation for end-stage liver and kidney disease associated with a1-AT deficiency. The patient was homozygous for the PiZ variant of a1AT, he had suffered a prolonged episode of neonatal cholestasis and his liver disease had then remained well compensated throughout childhood. At the age of 13 he had developed mild renal failure with nephrotic syndrome. Since his liver disease was already advanced, liver transplantation probably ought to have been considered then to prevent further renal damage (a recent case of membranoproliferative glomerulonephritis and nephrotic syndrome regressing after orthotopic liver transplantation is reported in the literature [14]). Renal involvement in chronic liver disease is quite a frequent finding [18]; the clinical course in this setting is often benign and seldom leads to end-stage kidney disease needing dialysis [19]. Different types of glomerular lesion are described, depending on the etiology of the liver disease. Membranous GN, membranoproliferative GN and mesangioproliferative GN are often associated with chronic hepatitis B infection [20]; membranoproliferative GN is associated with chronic hepatitis C infection and mixed cryoglobulinemia [21–23]. IgA nephropathy is the most
M. Loreno et al. / Journal of Hepatology 36 (2002) 565–568
common finding, primarily in patients with alcoholic liver disease [24,25]. The association of a1-AT deficiency with glomerulonephritis used to be considered unusual. It was first described in 1969 [26], followed by several case reports mainly involving children and based on autoptic findings [12,14]. Davis et al. reported a higher frequency (74%) and a more variable pattern of glomerular changes in homozygous PiZ children than in a control population with chronic liver failure unrelated to a1-AT deficiency. Glomerular lesions were mesangiocapillary GN, mesangial proliferative GN, diffuse endocapillary proliferative GN, and focal segmental mesangial proliferative GN with segmental necrosis [8]. The role of a1-AT deficiency in the onset of glomerular lesions is controversial. Some authors have speculated that, with the loss of balance between protease and antiprotease, ineffective proteolytic enzyme inhibition may cause damage to tissues other than the lungs [27]. Moreover, abnormal a1AT deposits have been found in the subendothelial region of the glomerular basement membrane [9]. It has been suggested that altered PiZ protein released from the injured hepatocytes could act as an antigen, which locally elicits an immunological response with injury of the glomeruli [23], or leads to the formation of circulating immunocomplexes causing diffuse systemic vasculitis, including glomerulonephritis [28]. Our patient showed no signs of cutaneous vasculitis, arthritis or abdominal pain on admission. Unfortunately, immunoreactivity for PiZ a1-AT was not tested in the renal biopsy specimen. However, the finding of membranoproliferative glomerulonephritis is consistent with the pathological spectrum of a1-AT-related nephropathy frequently seen in children [10–13]. Further evidence of the impact of renal disease in a1-AT deficiency comes from experience with liver transplantation. In patients with clinical signs of renal involvement, early orthotopic liver transplantation may represent an optimal therapeutic approach, providing metabolic cure of the genetic defect, consequent normalization of a1-AT serum levels and, presumably, the prevention of associated longterm complications such as emphysema and renal failure. The above-mentioned case of nephrotic syndrome regressing after liver transplantation [14] supports the hypothesis of a role for protease/antiprotease imbalance in the pathogenesis of renal disease and the beneficial effect of restoring normal levels of circulating a1-AT. Nevertheless, NobleJamieson et al. [11] reported on five children with a1-AT deficiency and end-stage liver disease with varying grades of GN histology who developed severe arterial hypertension probably of renal origin after liver transplantation. In our patient, blood pressure before transplantation was well controlled with diuretics. Hepatic insufficiency and concomitant Streptococcus Pneumoniae sepsis are likely to have contributed to the rapid deterioration in renal function and its progression to end-stage renal failure. Our case supports the opinion that the renal disease associated with a1-AT deficiency can occur as a consequence of
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concomitant hepatic disease and emphasizes the value of early, accurate renal function assessment in these patients to evaluate the immediate and long-term renal prognosis. There is currently no specific therapy for liver disease associated with a1-AT deficiency and the role and efficacy of new therapeutic strategies, e.g. recombinant a1-AT administration, gene therapy and hepatocyte transplantation, remain to be seen. A number of PiZZ individuals with severe liver disease, and even cirrhosis and portal hypertension, may have a relatively low rate of disease progression and lead a normal life for extended periods of time. Progressive liver dysfunction and failure in children have been treated with orthotopic liver transplantation, with survival rates approaching 90% at 1 year and 80% at 5 years [29]. When signs of irreversible renal failure have occurred on top of decompensated cirrhosis, a rapid deterioration in clinical conditions is to be expected in spite of hemodialysis, and combined liver-kidney transplantation should be taken into consideration.
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