Sequential Liver-kidney Transplantation Research Articles

Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria.

Primary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who do progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five of whom received a simultaneous transplantation, and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8months (range 4-20). Among the patients, 5 were from medium-lowincome countries. Median follow up was 3.2years (range 1.6-11). Median estimated glomerular filtration rate at 6 and 12months was 81.2 (range: 45.7-108.8) and 79.3ml/min/1.73m2 (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5-86.7) and 38.3ml/min/1.73m2 (range 29.9-77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12months showed precipitation of calcium oxalate crystals in 7 patients, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitation were observed between patients that underwent bilateral nephrectomy and those who did not. As of their most recent follow up, none of the patients has lost their kidney graft. Our study shows that by adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated.

The clinical outcome of sequential liver-kidney transplantation

The clinical outcome of sequential liver-kidney transplantation

MO096: Chronic Liver Disease and Hepatic Calcium-Oxalate Deposition in Patients with Primary Hyperoxaluria Type I

Abstract BACKGROUND AND AIMS Patients with primary hyperoxaluria type I (PH I) are prone to develop early end-stage kidney failure (ESKF). Systemic deposition of calcium-oxalate (CaOx) crystals starts when renal function declines and plasma oxalate (Pox) increases >30 µmol/L. It is anticipated that all parenchymal organs, but also bone (marrow), retina and the central nervous system can be involved. However, liver involvement, either as CaOx deposition or as chronic hepatitis/fibrosis, was never reported. METHOD We now examined liver involvement in 19 patients with PH I aged 1.5–52 years. Liver specimen was obtained by biopsy for diagnostic purposes (1), at autopsy (1) or at the time of combined or sequential liver kidney transplantation (17). RESULTS With polarization microscopy, crystals with the typical star-like appearance of CaOx were found in 3/19 patients. The crystals were located in small arteries but not within hepatocytes. Cirrhosis was seen in one patient. Fibrosis was seen in 10/19 patients, with porto-portal and nodular fibrosis (n = 1), and a limitation of fibrosis to the portal field in eight and/or to central areas in five patients. Unspecific hepatitis features were observed in seven patients. Fiber proliferations were detectable in 10 cases, and in one sample, transformed Ito-cells (myofibroblasts) were found. Iron deposition but also megakaryocytes as a sign of extramedullary erythropoiesis were found in nine and three patients, respectively. CONCLUSION Overall, liver involvement in patients with PH I was more pronounced, as previously described. However, compared with CaOx deposition in other organs/tissue, such crystal accumulations were only minimal in the liver, although the oxalate concentration must be the highest.

Sequential Liver-Kidney Transplantation for Recurrent Liver Cysts Infection in a Patient With Autosomal Dominant Polycystic Kidney Disease: A Case Report

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Liver cysts are the most common extrarenal manifestation of the disease and usually remain asymptomatic. Liver cyst infection is rare, and its treatment is challenging. Liver transplantation (LT) is the only curative therapeutic option in symptomatic polycystic liver disease associated with ADPKD. Only a few cases of LT for recurrent liver cyst infection have been published. To our knowledge, we report the first case of sequential liver-kidney transplantation for recurrent liver cysts infection in a patient with ADPKD. A 55-year-old woman with ADPKD who had a kidney transplantation (KT) presented with multiple liver cysts infection 9 months after her KT. These episodes started after biliary tract complications due to an ampullary adenoma necessitating multiple endoscopic interventions. Her general status gradually degraded because antibiotic treatment was not effective, and she underwent LT for recurrent liver cysts infection 1 year and 9 months after her KT. LT in this setting turned out to be challenging but was possible. We think that better biliary tract workup before KT may prompt better care in these patients.

Combined liver and kidney transplantation in children and long-term outcome.

Combined liver-kidney transplantation (CLKT) is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual (usually a cadaver) to the same recipient during a single surgical procedure. Most common indications for CLKT in children are autosomal recessive polycystic kidney disease and primary hyperoxaluria type 1. Atypical haemolytic uremic syndrome, methylmalonic academia, and conditions where liver and renal failure co-exists may be indications for CLKT. CLKT is often preferred over sequential liver-kidney transplantation due to immunoprotective effects of transplanted liver on renal allograft; however, liver survival has no significant impact. Since CLKT is a major surgical procedure which involves multiple and complex anastomosis surgeries, acute complications are not uncommon. Bleeding, thrombosis, haemodynamic instability, infections, acute cellular rejections, renal and liver dysfunction are acute complications. The long-term outlook is promising with over 80% 5-year survival rates among those children who survive the initial six-month postoperative period.

Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end-stage renal disease.

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end-stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver-kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver-kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4-11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9-14.7) years in all patients. Overwhelming post-splenectomy infections and cholangitis did not occur during the median follow-up period of 6.3 (range, 1.0-13.2) years. The estimated glomerular filtration rate at the last follow-up was 53 (range, 35-107) mL/min/1.73m2 . No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation.

SUN-331 COMBINED LIVER KIDNEY TRANSPLANTATION FOR PRIMARY HYPEROXALURIA: SINGLE CENTRE EXPERIENCE IN SOUTH INDIA

Type 1 primary hyperoxaluria is a rare inherited autosomal recessive disorder, characterized by deficiency of the hepatic enzyme alanine glyoxylate aminotransferase, leading to increased oxalate production, nephrocalcinosis, urolithiasis, and systemic oxalosis. Early diagnosis and management is pivotal as medical management and definitive treatment in the form of combined or sequential liver-kidney transplantation, isolated liver or kidney transplantation have been studied to transform disease outcomes. Here, we review the experience from our institution of combined liver-kidney transplantation among patients with primary hyperoxaluria from February, 2014 to October, 2019. Among three children with primary hyperoxaluria, two underwent deceased donor liver-kidney transplantation, and the third live related donor sequential liver-kidney transplantation. Case 1 was that of a 17 year old boy, who had been on intensive daily dialysis for two years prior to deceased donor sequential liver-kidney transplantation, with a history of bladder calculus in childhood. He had a relatively uneventful post -transplant period and is doing well on follow up five years following transplantation. Case 2 was a 4 year old boy, diagnosed to have oxalosis two years prior to transplant, on dialysis five days a week through tunnelled catheter, prior to deceased donor liver-kidney transplantation, with a history of tonic-clonic seizures. Post-operatively, he had a stormy course with cytomegalovirus infection of the hepatic allograft, and hepatic artery thrombosis, and expired a month following transplantation. Case 3 was that of a 13 year old girl, diagnosed at 10 years of age with primary hyperoxaluria, who underwent live related donor sequential liver-kidney transplantation. She developed obstructive jaundice following liver transplantation, owing to biliary stricture, and underwent ERCP and biliary stenting. She also had an upper gastro -intestinal bleed, and profound anaemia, and later developed sepsis and cholangitis, which were conservatively managed. Subsequently, she underwent renal transplantation and later developed gram negative septicemia, and recurrent proximal bile duct stricture, which was subjected to biliary stenting. Presently, she has stable graft function, and is clinically stable. The experience from our institution re-emphasises the significance of early diagnosis, and pre-transplant intensive dialysis in reducing oxalate load if planning for sequential liver-kidney transplantation to improve outcomes in primary hyperoxaluria. Isolated liver or kidney transplantation have not been adopted in our centre. In all patients, Scheinman protocol was followed in the immediate post-transplant period. Renal biopsies in the recipient showed only mild oxalate deposits which did not affect graft survival.

Liver transplantation in transthyretin amyloidosis: Characteristics and management related to kidney disease.

Orthotopic liver transplantation (LT) was implemented as the inaugural disease-modifying therapy for hereditary transthyretin (ATTR) amyloidosis, a systemic amyloidosis mainly affecting the peripheral nervous system and heart. The first approach to pharmacologic therapy was focused on the stabilization of the TTR tetramer; following that new advent LT was assumed as the second step of treatment, for those patients whose neuropathy becomes worse after a course of pharmacologic therapy. The renal disease has been ignored in hereditary ATTR amyloidosis. The low level of proteinuria or slight renal impairment does not suppose such a heavy glomerular and vascular amyloid deposition. Moreover, severity of renal deposits does not consistently parallel that of myelinated nerve fiber loss. These are pitfalls that limit the success of LT and suggest troublesome criteria for pharmacological therapy or LT. An algorithm of evaluation concerning renal disease and treatment options is presented and some bridges-to-decision are exposed. In stage 4 or 5 kidney disease, the approach remains to deliver combined or sequential liver-kidney transplantation in eligible patients. However, in the majority, hemodialysis is the only option even in the presence of a well-functioning liver graft. In this review, we highlight useful information to aid the transplant hepatologist in the clinical practice.

The landscape of treatment of chronic kidney disease in hereditary ATTR amyloidosis

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease, caused by mutations in the TTR gene, the most prevalent being V30M. Although each TTR variant has a different involvement, peripheral neuropathy and cardiomyopathy are predominant. Kidney deposits are well recognized since the original description of the disease as well as a renal phenotype is also likely. Kidney involvement with proteinuria and progressive renal failure is a major cause of morbidity and mortality in ATTR amyloidosis. However, kidney impairment is not as common as in AA or AL amyloidosis. Epidemiological studies from Portugal and Sweden reveal that approximately one third of the patients display varying degrees of albuminuria and renal dysfunction. Dialysis improves the prognosis and survival, but morbidity and mortality are higher than in other populations given this treatment. The low level of proteinuria or slight renal impairment does not suppose a so heavy glomerular and vascular deposition of amyloid as in ATTR, particularly in V30M mutation. Moreover, severity of renal amyloid deposition did not consistently parallel that of myelinated nerve fiber loss, with dissociation between kidney and neurological involvement. These are pitfalls that motive troublesome criteria for therapy in ATTR nephropathy. Twenty five years ago, liver transplantation (LT) was introduced as a treatment of ATTR, since this suppresses the production of circulating mutant TTR and theoretically stops the amyloid formation and disease progression, but uncertainties remain about its role on kidney deposits. Renal dysfunction pre LT and acute renal injury post LT are risk factors for chronic renal disease development after LT. The approach for stage 4 or 5 kidney disease remains the combined or sequential liver-kidney transplantation in eligible patients. However, in the majority of patients, hemodialysis is the unique option even in the presence of a well-functioning liver graft. Tafamidis, a TTR stabilizing drug, was described as having a benefit effect on albuminuria and renal function. Non-steroidal anti-inflammatory drugs showed efficacy stabilizing ATTR in early forms of amyloid neuropathy. However, studies with diflunisal noted decline in eGFR even with exclusion of patients with significant renal impairment. RNA interference (RNAi) is an endogenous cellular mechanism for controlling gene expression with application to ATTR neuropathy. The therapeutic value in kidney disease with successfully silenced intraglomerular genes in mouse models was proved, raising the possibility of a future role for renal ATTR amyloidosis. Antisense oligonucleotides are also under clinical trials; renal epithelial cells efficiently take up oligonucleotides without apparent degradation, rendering the kidney an excellent target for site-directed antisense therapy, but also a site of antisense toxicity. Other several natural products that inhibit TTR amyloid fibril formation where progressively investigated to stop neuropathy, but the specificity for renal disease was never evaluated. Until now, doubts remain about the role of new therapies in nephropathy, if there are preferential indications for a specific one and if dialysis patients should be included in a particular treatment.

Pediatric combined liver-kidney transplantation: a 2015 update.

The experience of combined liver-kidney transplantation (CLKT) is limited in pediatric populations. This strategy is, however, required in specific diseases such as metabolic diseases (namely primary hyperoxaluria type one and methylmalonic acidemia), autosomal recessive polycystic kidney disease, miscellaneous ciliopathies and atypical hemolytic uremic syndrome. Different series and registry studies have confirmed the feasibility of pediatric CLKT with encouraging results in the long term, even in the youngest and smallest patients, provided that highly trained multidisciplinary teams are involved in this global management. As such, the long-term outcomes after CLKT are currently comparable to that of isolated liver or kidney transplantations, even though the immediate postoperative period remains challenging. Some questions remain nevertheless unanswered, such as the respective place of combined versus sequential liver-kidney transplantation, especially in primary hyperoxaluria and autosomal recessive polycystic kidney disease. The aim of this review was therefore to provide a 2015 update on pediatric CLKT. In the future, international collaborative studies and registries may help to improve our knowledge of this rare and still highly challenging technique.

Liver cell transplantation in severe infantile oxalosis--a potential bridging procedure to orthotopic liver transplantation?

The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. Pox decreased from 104.3±8.4 prior to 70.0±15.0 μmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 μmol/L) and after Day 14 of LCT until LKTx (77.3 μmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient's clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Sequential liver–kidney transplantation in a boy with congenital hepatic fibrosis and nephronophthisis from a living donor

A five-yr-old boy developed chronic liver failure and ESKD because of CHF and juvenile NPHP. He underwent sequential liver and kidney transplantation with a compatible blood type from his father, at five yr, seven months and five yr, 11 months old, respectively. Because the patient was not in ESKD, we initially performed LDLT because of significant portal hypertension. Even after LDLT, his ascites was not ameliorated, and he needed continuous drainage of ascites and daily albumin and gamma globulin infusion. Thereafter, he progressed to ESKD and needed hemodialysis for one month before LDKT. CDC crossmatch for donor B cells in the warm test, FCXM for B cell IgG, and flow PRA for donor class II were positive before LDKT. After pretreatment of three courses of plasma exchange and intravenous gamma globulin, LDKT was performed. Two weeks after LDKT, AIHA concomitant with autoimmune thrombocytopenia, also called Evans syndrome, occurred because of passenger lymphocytes from the donor; however, the patient was successfully treated with intravenous methylprednisolone. Eighteen months have passed since LDKT, and liver and kidney function in both the recipient and donor are normal.

A novel approach to severe acute pancreatitis in sequential liver-kidney transplantation: the first report on the application of VAC therapy

This work is the first report of vacuum-assisted closure (VAC) therapy applied as a life-saving surgical treatment for severe acute pancreatitis occurring in a sequential liver- and kidney-transplanted patient who had percutaneous biliary drainage for obstructive "late-onset" jaundice. Surgical exploration with necrosectomy and sequential laparotomies was performed because of increasing intra-abdominal pressure with hemodynamic instability and intra-abdominal multidrug-resistant sepsis, with increasingly difficult abdominal closure. Repeated laparotomies with VAC therapy (applying a continuous negative abdominal pressure) enabled a progressive, successful abdominal decompression, with the clearance of infection and definitive abdominal wound closure. The application of a negative pressure is a novel approach to severe abdominal sepsis and laparostomy management with a view to preventing compartment syndrome and fatal sepsis, and it can lead to complete abdominal wound closure.

Combined Liver-Kidney Transplantation in Polycystic Disease: Case Reports

Polycystic disease causes a progressive decrease in renal function and liver degeneration. The progression of the disease evolves separately between organs and transplantation options vary: simultaneous or sequential liver-kidney transplantation or single-organ transplantation. From September 2006 to June 2007 3 combined liver kidney transplantations (CLKT) were performed for polycystic disease with end-stage renal disease: 2 with polycystic liver disease, and 1 with hepatic failure due to congenital hepatic fibrosis. The widest dimensions of the polycystic liver of 50 and 60 cm diameter were due to extensive cystic degeneration. We performed 1 simultaneous CLKT and 2 sequential transplantations: 1 liver after kidney, and 1 kidney after liver. At present all patients are alive with 100% graft function. Median creatinine level at discharge was 0.9 mg/dL (ranges, ±0.2). Good liver graft function was reported in all 3 cases. Transplant benefit in polycystic liver-kidney disease has been already demonstrated; conservative surgical options may result in a high incidence of complications in highly involved polycystic livers. Delaying transplantation results in a more difficult surgical technique, a higher rate of postoperative complications, and a disturbance of optimal graft retrieval because of the worse preoperative condition of the patients.

Sequential liver–kidney transplantation

The indications for sequential liver and kidney transplantation have not been well defined. Two categories of patients may benefit from this procedure: patients with primary renal disease associated with hepatic disorders (glomerulonephritis, tubulointerstitial nephritis, metabolic diseases, and structural diseases) and patients who develop renal failure after liver transplantation. Chronic renal failure is a frequent long-term complication after liver transplantation. End-stage renal disease develops in 2% to 10% of cases by 10 years after transplantation. Kidney transplantation appears to be a better option than dialysis for the treatment of end-stage renal disease after liver transplantation. In contrast, survival rates, after kidney transplantation are significantly lower among liver transplant patients than primary-only kidney transplant recipients. Considering the donor shortage, kidney transplantation should be cautiously considered in liver transplantation patients. New immunosuppressive drugs and protocols are needed to reduce chronic renal failure after liver transplantation.

Results of combined and sequential liver-kidney transplantation

Experience with combined liver-kidney transplantation (L-KTx) has increased, but controversy regarding this procedure continues because the indications are not clearly defined yet. Between 1984 and 2000, 38 patients underwent simultaneous L-KTx and 9 patients underwent sequential transplantation, receiving either a liver before a kidney or a kidney before a liver. Main indications for a simultaneous procedure were polycystic liver-kidney disease with cirrhosis and coincidental renal failure. The main indications for sequential procedure were cirrhosis caused by viral infection for the liver and glomerulonephritis for the kidneys. Outcomes in these patients were evaluated retrospectively. Regarding simultaneous transplantation, 28 (73.7%) long-term survivors were followed up for 0.7 to 12.5 years. Currently, 24 (63.2%) patients are alive with good liver function. Fourteen patients died; 10 patients died in the early postoperative phase because of septic complications, and most of them were cirrhotic with a poor preoperative clinical status. Currently, 2 of the surviving patients (8%) have returned to dialysis, 4 (17%) have reduced renal function, and 18 (75%) have good renal function. Five liver and 2 kidney retransplantations were performed during the follow-up. In cases of sequential grafting, patients undergoing kidney transplantation in the presence of a previously transplanted stable liver did better than those who underwent liver transplantation after kidney transplantation. When liver transplantation was performed early and electively before substantial worsening, combined L-KTx is a safe procedure offering excellent long-term palliation. (Liver Transpl 2003;9:1067-1078.)

Sequential liver–kidney transplantation from a living-related donor in primary hyperoxaluria type 1 (oxalosis)

Sequential liver–kidney transplantation from a living-related donor in primary hyperoxaluria type 1 (oxalosis)

Success of sequential liver-kidney transplantation in a patient with preformed lymphocytotoxic antibodies : Marian Griffin, John Fung, Thomas Starzl, Byers Shaw Jr., and Rene Duquesnoy; Department of Surgery and Division of Immunopathology, University of Pittsburgh, Pittsburgh, PA

Success of sequential liver-kidney transplantation in a patient with preformed lymphocytotoxic antibodies : Marian Griffin, John Fung, Thomas Starzl, Byers Shaw Jr., and Rene Duquesnoy; Department of Surgery and Division of Immunopathology, University of Pittsburgh, Pittsburgh, PA