EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The purpose of this study was to evaluate the causes of kidney impairment associated with liver transplant in patients who had kidney biopsy before or after liver transplant.

Materials and Methods: In 408 patients who had liver transplant from January 1990 to December 2012, there were 10 patients who had kidney biopsy (total, 19 kidney biopsies) for evaluation of kidney dysfunction. A retrospective review of clinical records and kidney biopsies was performed.

Results: There were 7 male and 3 female patients (median age at liver transplant, 43 y; range, 10 to 62 y). The most frequent reason for liver transplant were hepatitis B virus cirrhosis (4 patients). There were 3 patients who had a kidney transplant before or concurrent with liver transplant. Increased serum creatinine level was the most common clinical finding at the time of kidney biopsy. The median interval from liver transplant to kidney biopsy was 495 days (mean, 1025 d; range, 10-4980 d). The most common pathology in the kidney biopsies was immune complex glomerulonephritis (total, 7 patients: IgA nephropathy, 4 patients; lupus nephritis, 2 patients; membranoproliferative glomerulonephritis, 1 patient). There were 4 patients who had allergic tubulointerstitial nephritis, 2 patients who had chronic calcineurin inhibitor nephrotoxicity, and 1 patient who had karyomegalic nephropathy. There were 7 patients who died at mean 34 months (range, 1-70 mo) after liver transplant. The other 3 patients were alive at mean 128 months (range, 67-193 mo) after liver transplant and had a functioning liver graft and chronic kidney disease.

Conclusions: Chronic kidney disease after liver transplant has a major effect on mortality. The frequency of immune complex glomerulonephritis associated with liver transplant may be greater than previously recognized.

Key words : Chronic calcineurin inhibitor nephrotoxicity, Chronic kidney disease, End-stage liver disease, Glomerulonephritis, Tubulointerstitial nephritis

Liver transplant is an effective therapy for end-stage liver disease. The increased survival after liver transplant enables evaluation of associated kidney diseases. Studies about kidney pathology before and after liver transplant are few and sample sizes are small.^1-5

Chronic kidney disease affects 30% to 50% nonrenal organ transplant recipients and causes increased morbidity and mortality in these patients.^6-8 Chronic kidney disease also may occur before liver transplant, possibly because of hepatitis C virus-related kidney disease, cirrhotic glomerulonephritis, immunoglobulin A (IgA) nephropathy caused by liver disease, hypertension-related nephropathy, diabetic nephropathy, and other glomerular diseases.^1-11

Kidney injury commonly is attributed to chronic calcineurin inhibitor nephrotoxicity, especially after liver transplant.^3,4,6 However, other studies suggest that kidney impairment may be caused by several interconnected factors.^1,2,5 Chronic kidney disease is a frequent complication of liver transplant, and the 5-year overall cumulative incidence of chronic kidney disease after liver transplant is 21% to 50%.^7,12,13 However, kidney biopsy is not frequently performed in patients after liver transplant. Most patients with liver transplant are diagnosed with chronic kidney disease from clinical and laboratory examinations without biopsy confirmation.

We performed a clinicopathologic study of patients who had kidney biopsy before or after liver transplant. The purpose of this study was to evaluate the causes of kidney impairment associated with liver transplant.

Materials and Methods

A retrospective clinicopathologic evaluation was performed of all kidney biopsies of patients who had liver transplant that were archived at the Department of Pathology, Başkent University Ankara Hospital from January 1990 to December 2012. In these 22 years, 408 patients had liver transplant at the Transplantation Surgery Center of Başkent University. There were 10 patients who had ≥ 1 kidney biopsy before or after liver transplant (7 living-related and 3 deceased-donor transplants). The archived information, including 19 percutaneous kidney biopsies and 18 percutaneous liver biopsies in the 10 patients, were reviewed jointly by 2 transplant and kidney pathologists.

The assessment of kidney biopsies included light microscopy and immunofluorescence microscopy. All kidney biopsy specimens included 2 or 3 tissue cores; 1 core was fixed in 10% formalin for paraffin embedding, 1 core was frozen for immuno-fluorescence studies, and 1 core (when available) was fixed in glutaraldehyde for transmission electron microscopy. Light microscopy was performed with 3-mm sections from paraffin-embedded tissue using hematoxylin-eosin and histochemical staining methods including periodic acid Schiff, Masson trichrome, and Jones methenamine silver stains. Direct immunofluorescence studies were performed on snap-frozen specimens with fluorescein isothiocyanate-conjugated antisera for IgA, IgG, IgM, C3, C1q, and kappa and lambda light chains when indicated. Ultrastructural examination was performed with glutaraldehyde fixed tissue. The presence of electron-dense deposits and abnormalities of the glomerular basement membrane, epithelial cells, and foot processes were evaluated.

Clinical data about presentation and follow-up were retrieved from hospital records. We evaluated the time of kidney biopsy after transplant, indications for kidney biopsy, and parameters of kidney function including serum creatinine and proteinuria. Kidney biopsy was performed when there was proteinuria and/or persistent increase
(> 20%) in serum creatinine from the level before transplant on ≥ 2 samples. Patient survival, liver transplant survival, and kidney survival after liver transplant were recorded.

Clinical characteristics
The 10 patients who had kidney biopsy before or after liver transplant included 7 male and 3 female patients (median age at liver transplant, 43 y; range, 10-62 y). There were 3 patients who had kidney transplant before or at the time of liver transplant, including 1 patient who had combined kidney and liver transplant because of methylmalonic acidemia and 2 patients who had kidney transplant before liver transplant because of kidney failure of unknown cause (Table 1). Before liver transplant, 7 patients had hypertension and 5 patients had diabetes mellitus (Table 1). After liver transplant, 8 patients had hypertension and 7 patients had diabetes mellitus (Table 1). There were 2 patients who did not have hypertension or diabetes mellitus before liver transplant but had either hypertension or diabetes mellitus after liver transplant. All patients had combination immunosuppressive therapy with prednisolone, calcineurin inhibitors (cyclosporine or tacrolimus), and sirolimus after liver transplant (Table 1).

The median interval from liver transplant to kidney biopsy was 495 days (mean, 1025 d; range, 10-4980 d) (Table 2). Most patients had increased serum creatinine level (9 patients), and proteinuria was present in 4 patients (including 1 patient who had only proteinuria) (Table 2). The mean serum creatinine level at liver transplant was 26.4 mmol/L (1.4 mg/dL) and at kidney biopsy was 170.6 mmol/L (1.9 mg/dL).

Liver graft biopsy
The most frequent reasons for liver transplant were hepatitis B virus cirrhosis (4 patients) and cryptogenic cirrhosis (3 patients) (Table 3). There were 7 patients who had liver biopsy to evaluate elevated liver enzymes after liver transplant, and the first liver biopsy was at median 14 days (range, 5-450 d) after liver transplant. In the 18 liver biopsies performed in the 10 patients, the most common pathology was acute cellular rejection in 11 biopsies of 4 patients (Table 3).

Kidney biopsy
The 19 kidney biopsies (10 graft and 9 native kidney biopsies) showed that 7 patients had primary glomerular pathology that was an immune complex glomerulonephritis (IgA nephropathy, 4 patients; lupus nephritis, 2 patients; membranoproliferative glomerulonephritis, 1 patient) (Table 2). The characteristic features of IgA nephropathy included expansion of the mesangial matrix and increase in mesangial cellularity. Immunofluorescence micro-scopy showed heavy deposits of IgA in the mesangium, and ultrastructural study showed electron-dense mesangial and perimesangial immune complex deposits.

In 2 patients who had lupus nephritis, kidney biopsy showed glomeruli that had mesangial proliferative changes associated with a “full-house” immunofluorescence pattern including deposits of IgG, IgM, IgA, C1q, and C3. In the patient who had membranoproliferative glomerulonephritis, all glomeruli had lobular appearance on light microscopy because of global endocapillary proliferation; immunofluorescence microscopy showed global staining of IgG, IgM, IgA, and C3 in an irregular capillary and mesangial distribution.

Diabetic and/or hypertensive changes and arteriolar hyalinosis were noted in 7 patients, and cryoglobulinemia was noted in 1 patient. There were 2 patients who had nodular hyalinosis involving the media and adventitia of renal arterioles, associated with myocyte degeneration, features compatible with vasculopathy-related calcineurin inhibitor nephrotoxicity; 1 patient (patient 2) had received cyclosporine-based immunosuppression for 660 days and 1 patient (patient 9) had received tacrolimus-based immunosuppression for 540 days when kidney biopsy was performed (Tables 1 and 2).

Mild or moderate interstitial fibrosis and tubular atrophy were present in 7 patients (70%). Severe interstitial fibrosis and tubular atrophy were noted on a biopsy at 22 months after combined kidney and liver transplant in the patient who had methylmalonic acidemia (patient 3) because he developed chronic kidney allograft rejection after multiple attacks of acute cellular rejection (Tables 1, 2, and 3).

Karyomegalic nephropathy was noted in an adolescent girl who had liver transplant for cirrhosis caused by Wilson disease (patient 5); cortical tubules were noted with epithelial cells that contained enlarged and pleomorphic nuclei, typically observed in karyomegalic nephropathy.

Allergic tubulointerstitial nephritis associated with a specific type of glomerulonephritis was observed in 3 patients (patients 2, 8, and 9). Another patient (patient 4) had allergic tubulointerstitial nephritis characterized by interstitial infiltration with numerous lymphocytes, macrophages, and eosinophils; this was associated with mild tubular lesions that had been noted on a kidney graft biopsy that had been performed before liver transplant (Table 2).

Survival
There were 3 patients who had progressive dysfunction of the liver graft at mean 6 months (range, 20 d to 15 mo) after liver transplant (Table 3). The other 7 patients had a functioning liver graft at follow-up at mean 75 months (range, 14-193 mo) after liver transplant.

Chronic kidney disease was noted in 6 patients at the time of kidney biopsy, and 2 patients developed chronic kidney disease after kidney biopsy (Table 2). Follow-up at mean 40 months (range, 1-87 mo) after first kidney biopsy showed that 8 patients required hemodialysis and 2 patients had normal allograft kidney function.

Death was not directly related to liver or kidney disease in any patient. There were 7 patients who died at mean 34 months (range, 1-70 mo) after liver transplant (Table 3). The other 3 patients were alive at mean 128 months (range, 67-193 months) after liver transplant (patients 1, 5, and 9) and had a functioning liver graft and chronic kidney disease (Tables 2 and 3).

In present study, there were 19 kidney biopsies in 10 patients (2.5% of all 408 patients who had liver transplant). In contrast with other studies, some of the present patients also had kidney biopsies before liver transplant. We also included 2 patients who had kidney transplant before liver transplant and 1 patient who had kidney and liver transplant at the same time. The interval from liver transplant to kidney biopsy was shorter than previously reported. In a previous study of 105 kidney biopsies from 101 non-kidney transplant recipients, the indications for kidney biopsy included increased creatinine level (83%), heavy proteinuria (22%), protracted acute renal failure (9%), and renal insufficiency before revision transplant (9%).3 The indications for kidney biopsy in the present patients included renal impairment (90%), mild to moderate proteinuria (40%).

Previous studies showed that various factors may cause chronic kidney disease after liver transplant.^{2,4,6,7,13,14} Major risk factors for chronic kidney disease after liver transplant include calcineurin inhibitors (cyclosporine and tacrolimus), diabetes mellitus, nephroangiosclerosis, previous use of hydroxyethyl starch, and the potential risk factors for chronic kidney disease after liver transplant include older age, non-Asian ethnicity, postoperative acute renal failure, and pretransplant obesity, hypertension, diabetes mellitus, low glomerular filtration rate, proteinuria, and renal replacement therapy.^7,13,14 Other possible causes of chronic kidney disease in liver transplant patients include hepatitis C virus-related kidney disease, IgA nephropathy caused by liver disease, and other glomerular diseases.^9-11 Each patient in the present series had ≥ 1 risk factor; 7 of 10 patients (70%) had immune complex glomerulonephritis, 7 patients had hypertension with or without diabetes mellitus before liver transplant, and 3 patients had renal replacement therapy before liver transplant (Table 1).

Some patients may have been adversely affected by metabolic disorders before and/or after liver transplant. Development of metabolic syndrome after liver transplant, which may include impaired glucose tolerance, high blood pressure, dyslipidemia, and obesity, may contribute to renal impairment. The frequency of metabolic syndrome in liver transplant recipients is 2-fold greater than reported for the general population (before liver transplant, 5.4%; after liver transplant, 51.9%).¹⁵ In the present study, 70% patients had ≥ 1 metabolic disorder before liver transplant, and these patients had continued metabolic disorder after liver transplant. In addition, 2 patients who did not have any metabolic disorder before liver transplant developed ≥ 1 metabolic disorder after liver transplant. The most common histopathologic finding in patients who had metabolic disorders was arteriolar hyalinosis (70%).

Immunosuppressive drugs, including calcineurin inhibitors (cyclosporine and tacrolimus) and steroids, are associated with metabolic disorders such as diabetes mellitus after transplant caused by steroids and hyperlipidemia after transplant caused by sirolimus.¹⁶ In the present study, 2 patients developed diabetes mellitus, and 1 patient developed hyperlipidemia after liver transplant (patients 1 and 3) because of immunosuppressive drugs possibly (Table 1).

In some liver transplant recipients, the underlying liver disease may be associated with diabetes mellitus, including hemochromatosis, alcohol abuse, and autoimmune hepatitis. Hepatitis C virus infection also may be associated with insulin resistance in patients with or without liver transplant.^9-11 In the present study, 1 patient who had hepatitis C virus infection developed diabetes mellitus.

There was a high frequency of immune complex glomerulonephritis (70%) in the present patients, higher than reported previously.^1,2,4,5 The most common type of glomerulonephritis was IgA nephropathy (40%) (Table 2), consistent with a previous report.1 Although IgA nephropathy is the most common type of primary chronic glomerulonephritis worldwide, the pathogenesis of this nephropathy is controversial. The IgA nephropathy may be mediated by immune complexes. In addition, hepatitis B virus may contribute to the pathogenesis of IgA nephropathy; in a previous study, hepatitis B surface antigenemia was noted in 18 of 100 patients who had IgA nephropathy, and hepatitis B virus antigens were identified in kidney tissue in 31% patients who had IgA nephropathy.16 In the present study, the 4 patients who had IgA nephropathy also had hepatitis B virus-related cirrhosis (patients 6, 8, 9, and 10) (Tables 2 and 3).

Lupus nephritis was the second most frequent type of glomerulopathy in the present patients. Limited information is available about the association between lupus nephritis and liver transplant. Subclinical liver involvement is frequent in patients who have systemic lupus erythematosus, but end-stage liver disease is a rare manifestation of systemic lupus erythematosus unless there are other causes of liver disease present such as nonalcoholic fatty liver disease, drug-induced hepatitis, viral hepatitis, autoimmune hepatitis, or primary biliary cirrhosis.¹⁷ The cause of cirrhosis in the 2 patients who had lupus nephritis was unknown (patients 1 and 2) (Tables 2 and 3).

In the present patient who had methylmalonic acidemia (patient 3), kidney graft biopsy showed interstitial fibrosis and tubular atrophy and arteriolar hyalinosis at 8 months after kidney and liver transplant (Tables 2 and 3). These chronic changes may be attributed to chronic rejection and/or metabolic damage of the allograft from the primary disease.¹⁸

Allergic tubulointerstitial nephritis was identified in 4 patients (40%) in the present study (patients 2, 4, 8, and 9) (Table 2). This type of nephritis is uncommon in studies of kidney biopsy after liver transplant. In the present study, allergic tubulointerstitial nephritis may be attributed to the high frequency of herbal supplement use in Turkish patients and the large variety of medicines used by liver transplant patients for their various health issues.

Most patients in the present study (90%) had > 1 pathologic finding on kidney biopsy (Table 2), consistent with previous reports.^1,2,4 These findings included diabetic and/or hypertensive changes, arteriolar hyalinosis, cryoglobulinemia, allergic tubulointerstitial nephritis, and interstitial fibrosis and tubular atrophy. Arteriolar hyalinosis and interstitial fibrosis and tubular atrophy were the most frequent pathologic findings, similar to previous studies.^1,2,4,5

Nodular hyalinosis of the renal arterioles, a feature associated with calcineurin inhibitor nephrotoxicity, was observed in native kidney biopsies in 2 patients (20%) in the present study (patients 2 and 9) (Table 2). Previous studies suggested that calcineurin inhibitor nephrotoxicity is major cause of kidney injury after liver transplant.^3,4,6 However, a study of 81 kidney biopsies after liver transplant showed that 16% patients had evidence of calcineurin inhibitor nephrotoxicity.² Another study showed a similar frequency of calcineurin inhibitor nephrotoxicity.¹ The lower frequency of calcineurin inhibitor nephrotoxicity in these studies and the present study may be attributed, in part, to strict diagnostic criteria, because the diagnosis of calcineurin inhibitor nephrotoxicity was made only when nodular hyalinosis was present.

In the present study, 7 patients (70%) died of varied causes at mean 34 months after liver transplant (Table 3). The small number of patients in the study precluded statistical survival analysis. However, 50% patients were alive at 5 years after liver transplant. A previous study of 221 adult liver transplant recipients showed that overall 5-year survival after liver transplant was 74%.¹² Chronic kidney disease may contribute to increased morbidity and early mortality.^7,8 Therefore, the low survival in the present series may be attributed, in part, to the presence of kidney disease.

The present study was limited by the small number of patients. Nevertheless, it was important to evaluate the pathologic kidney lesions in liver transplant recipients. The frequency of immune complex glomerulonephritis associated with liver transplant may be greater than previously recognized. The occurrence of chronic kidney disease before and after liver transplant has a major effect on mortality. Additional studies are needed to better characterize the natural history of chronic kidney disease in liver transplant recipients. Further study may enable the development of strategies for early detection and prevention of chronic kidney disease, including the identification of modifiable preoperative, perioperative, and postoperative factors that may affect kidney function after liver transplant.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

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