Despite systemic thromboembolic complications being frequent, portal vein thrombosis is a rare complication of nephrotic syndrome. We report here a liver transplant recipient who presented a late extensive portal vein thrombosis related to nephrotic syndrome. During regular follow-up after liver transplant, the patient presented with diabetes, arterial hypertension, hypercholesterolemia, and progressive renal dysfunction. In addition, urine analysis showed isolated proteinuria, and the diagnosis of nephrotic syndrome was made 36 months after liver transplant. Sixty months after liver transplant, the patient presented with mild acute abdominal pain, and the diagnosis of portal vein thrombosis was made from a computed tomography scan. Other causes for portal vein thrombosis were excluded. Histologic examination of a liver biopsy disclosed only mild steatosis. Histologic examination of a kidney biopsy disclosed severe lesions, suggesting a multifactorial, advanced chronic nephropathy probably caused by nephroangiosclerosis, diabetes, and toxicity of calcineurin inhibitors. Anticoagulation therapy led to complete recanalization of the portal and splenic veins, which was maintained thereafter. In conclusion, the case we report here illustrates that portal vein thrombosis can occur after liver transplant in the context of nephrotic syndrome, complicating chronic kidney disease, which is a very frequent and multifactorial complication after liver transplant.
Key words : Abdominal pain, Chronic kidney disease, Diabetes, Renal dysfunction, Thromboembolic complications
Despite systemic thromboembolic complications being frequent, portal vein thrombosis (PVT) is a rare complication of nephrotic syndrome.1 We report here a liver transplant recipient who presented with late PVT related to nephrotic syndrome.
In October 2005, a 51-year-old man underwent a first liver transplant because of decompensated alcoholic cirrhosis. The initial immunosuppressive regimen included tacrolimus, mycophenolate mofetil (MMF), and steroids. Initial outcome was favorable, and the patient was discharged at day 20 after transplant. During regular follow-up, the patient presented with diabetes, arterial hypertension, hypercholesterolemia, and progressive renal dysfunction. A protocol liver biopsy was normal 1 year after liver transplant. Glomerular filtration rate, estimated from the Modification of Diet in Renal Disease formula, was 80 mL/min in October 2006, 58 mL/min in October 2007, 47 mL/min in October 2008, and 36 mL/min in October 2009 (4 years after liver transplant). In parallel, urine analysis showed isolated proteinuria: 24-hour levels were 5750 mg in April 2008 and 6950 mg in October 2009. The diagnosis of nephrotic syndrome was made.
At diagnosis of nephrotic syndrome, the immunosuppressive regimen consisted of tacrolimus and MMF. Trough level of tacrolimus was 2.2 ng/mL. Liver function tests were as follows: aspartate aminotransferase of 25 U/L (normal range, 10-45 U/L), alanine aminotransferase of 32 U/L (reference range, 10-45 U/L), alkaline phosphatase of 234 U/L (reference range, 38-120 U/L), gamma-glutamyltransferase of 220 U/L (reference range, 7-65 U/L), total bilirubin of 7 μmol/L (reference range, 0-20 μmol/L), albumin level of 2.8 g/dL (reference range, 3.5-5.0 g/dL), prothrombin rate 100%, and international normalized ratio of 1.0. Abdominal Doppler ultrasonography results were normal. Histologic examination of liver biopsy disclosed only mild steatosis (25%). Histologic examination of a kidney biopsy disclosed severe interstitial fibrosis and tubular atrophy (> 50%), secondary focal segmental glomerulosclerosis, and 60% of globally sclerotic glomeruli. Vessels showed moderate to severe arteriolosclerosis. Immunofluorescence studies did not show any specific deposits. Altogether, these lesions suggested a multifactorial advanced chronic nephropathy probably caused by nephroangiosclerosis, diabetes, and toxicity of calcineurin inhibitors.
In April 2010, the patient presented with mild acute abdominal pain, and a CT scan was performed, showing thrombosis of the portal vein, with extension to the splenic vein and the proximal part of the superior mesenteric vein, without extension to intrahepatic portal branches (Figure 1). At that time, medications included tacrolimus, MMF, atorvastatin, omeprazole, perindopril, isradipine, irbesartan, aspirin, furosemide, and repaglinide. Laboratory findings were as follows: hemoglobin level of 10.0 g/dL (reference range, 11.5-16.0 g/dL), leukocyte count of 4000/mm3 (reference range, 4,000-10 500), platelet count of 93 000/mm3 (reference range, 150 000-400 000), aspartate aminotransferase of 27 U/L (reference range, 10-45 U/L), alanine aminotransferase of 48 U/L (reference range, 10-45 U/L), alkaline phosphatase of 173 U/L (reference range, 38-120 U/L), gammaglutamyltransferase of 298 U/L (reference range, 7-65 U/L), total bilirubin of 6 μmol/L (reference range, 0-20 μmol/L), albumin of 2.5 g/dL (reference range, 3.5-5.0), globulin level of 11.0 g/L (reference range, 8.0-13.5 g/L), total cholesterol of 5.08 μmol/L (reference level is < 5.18 μmol/L), glomerular filtration rate of 36 mL/min, proteinuria 10 500 mg/24 hour, prothrombin rate of 100%, and international normalized ratio of 1.0. Protein C, protein S, and antithrombin III were within normal ranges. Antiphospholipid antibodies, prothrombin gene, and factor V Leiden mutations were not found. Anticoagulation therapy with low-molecular-weight heparin (for 10 days) and fluindione was started. One month after initial diagnosis, Doppler ultrasonography confirmed complete recanalization of the portal and splenic veins. Anticoagulation therapy with fluindione was maintained thereafter. Because of end-stage renal disease, a kidney transplant was performed in May 2014. In October 2015, at 10 years after liver transplant, liver Doppler ultrasonography was normal and histologic examination of a liver biopsy disclosed again only mild steatosis (20%). Maintenance immunosuppressive regimen consisted of tacrolimus and MMF. Proteinuria was 0.240 mg/24 hour.
Venous thrombosis is a common complication of nephrotic syndrome, occurring in about 25% of patients.1 Nevertheless, PVT is rare in this field, with < 15 cases reported in the literature.2-11 We report here the first case after liver transplant. Portal vein thrombosis is a frequent complication of cirrhosis, especially in severe patients on wait lists for liver transplant. Pretransplant PVT is a risk factor for PVT recurrence in the recipient, which occurs especially in the early period after liver transplant. Posttransplant PVT can therefore significantly reduce both graft and patient survival after liver transplant and can cause limitations or loss of future options for retransplant.12 For our patient, this situation was not applicable, as our patient did not present PVT at the time of liver transplant. In addition, a PVT as a complication of postoperative anastomotic stricture was ruled out by morphologic evaluation and late outcome. Causes other than nephrotic syndrome for acute PVT were excluded from morphologic evaluation and initial clinical presentation, biologic tests, and/or late follow-up, including myeloproliferative disease, JAK2 mutation, antiphospholipid syndrome, protein C deficiency, protein S deficiency, antithrombin deficiency, prothrombin gene mutation, factor V Leiden, connective tissue disease, and local factors.13 Ultimately, a chronic liver graft disease was excluded from liver biopsy.
Thromboembolic complications in patients with nephrotic syndrome could be related to alterations in coagulation factors (especially low levels of antithrombin III related to a urinary leak), fibrinolysis, and platelet function, together with low levels of plasma albumin, dyslipidemia, and use of diuretics and steroids.1 The beneficial effect of primary prophylactic anticoagulation is uncertain, even in patients with “high risk” of thromboembolic complications (advanced age, massive proteinuria, hypovolemia, hypoalbuminemia, and dyslipidemia). As reported in our case, an acute portal/mesenteric venous thrombosis should be suspected in a patient with nephrotic syndrome presenting with abdominal pain, with diagnosis confirmed from Doppler ultrasonography and/or CT scans. Treatment consists of anticoagulation. An immediate surgical intervention is needed in cases of intestinal ischemia.
The development of chronic kidney disease after liver transplant is common, and the risk appears to compound over time, reaching approximately 30% to 50% at 10 years after transplant.14 Chronic kidney disease could be due to preexisting kidney disease, kidney disease associated with initial liver disease (hepatitis C, alcohol, diabetes), and/or posttransplant diabetes, posttransplant hypertension, or posttransplant calcineurin inhibitor toxicity. In a review of 2100 adults who underwent liver transplant, approximately 3% had a subsequent kidney biopsy, with a mean posttransplant renal referral time of 5.3 years.15 On average, there was 39% glomerular sclerosis, 45% interstitial fibrosis, 44% chronic tubular atrophy, and 65% moderate to severe vascular damage shown in the biopsies. Finally, the cause of renal dysfunction was found to be attributable to 1 or more of the following: apparent calcineurin inhibitor toxicity (48%), hypertensive vascular changes (44%), membranoproliferative glomerulonephritis (17%), immunoglobulin A nephropathy (9%), diabetic nephropathy (9%), proliferative glomerulonephritis with crescents (4%), and acute tubular necrosis (4%). Several of these kidney diseases can specifically cause nephrotic syndrome, especially membranoproliferative glomerulonephritis (usually type 1 or type 3, which are commonly associated with cryoglobulinemia and hepatitis C virus infection), immunoglobulin A nephropathy (rare), and diabetic nephropathy. In addition, all of these listed above can lead to chronic destruction of the kidney and favor secondary focal segmental glomerulosclerosis, which is responsible for high-range proteinuria and sometimes nephrotic syndrome. This was the case of the patient that we that report here.
In conclusion, the case we report here illustrates that PVT can occur after liver transplant in context with nephrotic syndrome, complicating chronic kidney disease, which is a very frequent and multifactorial complication after liver transplant.
DOI : 10.6002/ect.2016.0259
From the 1Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de
Transplantation Hépatique, the 2Université Claude Bernard Lyon 1, the
civils de Lyon, Hôpital Edouard Herriot, Service de Néphrologie et
Transplantation, the 4Hospices civils de Lyon, Hôpital Edouard Herriot, Service
de Radiologie Digestive, and the 5Hospices civils de Lyon, Hôpital Edouard
Herriot, Service d’Anatomie Pathologique, Lyon, France
Acknowledgements: The authors have no conflicts of interest or sources of funding to declare. J.D. and A.S. clinically managed the patients and wrote the manuscript; O.G., P.J.V., J.Y.S., and O.B. clinically managed the patients. All authors read and approved the final version of the manuscript.
Corresponding author: Jérôme Dumortier, Pavillon L, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France
Phone: +33 472110111
Figure 1. Computed Tomography Scan (Portal Phase) Showing Extensive Portal Vein Thrombosis