Systemic hypertension and renal function in long-term liver transplant recipients on cyclosporine

Systemic Hypertension and Renal Function in Long-Term Liver Transplant Recipients on Cyclosporine S. Semhoun-Ducloux, D. Ducloux, S. Bresson-Hadni, M.-C. Becker, C. Vanlemmens, G. Mantion, J.-M. Chalopin, and J.-P. Miguet

T

HE natural history of chronic cyclosporine (CyA) nephrotoxicity is a matter of debate. The issue of whether or not treatment with CyA causes progressive renal failure is important, particularly because the drug is a very potent immunosuppressive agent when high blood levels are maintained. Both the length of follow-up and CyA dose are important parameters to consider in interpreting the available data in the literature. Progressive renal failure has been reported in cardiac allograft recipients given high-dose or low-dose CyA for more than 1 year,1 and actuarial analysis revealed that only 90% of cardiac transplant recipients remained free of end-stage renal failure after 8 years of CyA therapy.1 It has also been documented in renal transplant recipients that renal histological lesions can appear after only 6 months of high-dose CyA therapy2 with progression over time even after CyA dose reduction.3 Finally, experimental findings also suggest the progressive nature of CyA nephropathy.4 Nevertheless, the assumption that CyA causes progressive nephropathy has recently been questioned. Some investigators have reported that transplant patients receiving CyA seem to have impaired but stable renal function.5,6 Although chronic renal failure has become a topic of interest in the field of liver transplantation, there are still few data to address this question in liver transplant patients. Some studies have been reported in which renal function has been monitored in liver transplant patients.7–11 Most of them have concluded that after an initial decrease in glomerular filtration rate (GFR), renal function remained stable over time. Still, none of the studies have examined the course of renal failure after a long-term follow-up beyond 5 years. We report here the first study on renal function in long-term liver transplant survivors (⬎5 years). We also describe the prevalence of hypertension and retrospectively studied factors that might be associated with the evolution of renal function. PATIENTS AND METHODS From March 1986 to June 1993, a total of 157 liver transplantations were performed in our unit. One hundred and thirty-five patients had a complete follow-up in our center. Fifty-one of them survived more than 5 years. © 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 449–452 (2000)

Table 1. Characteristics of the Study Population Before Transplantation

N

Age (years)

Serum Creatinine Concentration (␮mol/L)

51

50 ⫾ 12

84 ⫾ 30

Creatinine Clearance (mL/min)

Hypertension (%)

88 ⫾ 30

5.8%

Primary liver disease was alcoholic cirrhosis in 15 patients, alveolar echinococcosis in 10, hepatocellular carcinoma in 8, primary biliary cirrhosis in 7, posthepatitic cirrhosis in 3, Wilson disease in 2, fulminant hepatitis in 2, cryptogenetic cirrhosis in 2, sclerosis cholangitis in 1, and congenital hepatic fibrosis in 1. Two patients had type 1 hepato-renal syndrome. Immunosuppressive regimens consisted of CyA, prednisolone, and azathioprine for all the patients. In most cases, azathioprine was withdrawn after 3 months’ posttransplant. The CyA dosage was adjusted to achieve serum trough levels of about 300, 200, and 150 ng/mL at 3, 12, and 24 months’ posttransplant, respectively. After the second year posttransplant, serum CyA through levels were maintained between 75 and 100 ng/mL. The CyA dose was also adjusted according to renal function. Serum creatinine concentrations were obtained before transplantation, at 6 months’ posttransplant, and then every year thereafter. Creatinine clearance was calculated according to the Cockcroft and Gault formula.12 Hypertension was defined by the use of antihypertensive therapy, or systolic blood pressure ⬎ 140 mm Hg and/or diastolic blood pressure ⬎ 90 mm Hg in patients not receiving antihypertensive drugs. The number of antihypertensive drugs was recorded each year. Clinical (blood pressure, antihypertensive therapy, weight, acute rejection, death) and biological (serum CyA concentration) correlates were obtained through medical records. First, we described the natural history of renal function in this population and studied the influence of different parameters on renal function. From the Department of Hepatology and Liver Transplantation (S.S.-D., S.B.-H, M.-C.B., C.V., J.P.-M.), Jean Minjoz Hospital; Department of Nephrology and Renal Transplantation (D.D., M.C.), Saint Jacques Hospital; and Department of Surgery and Liver Transplantation (G.M.), Besanc¸on, France. Address reprint requests to Dr Sylvie Semhoun-Ducloux, Department of Hepatology and Liver Transplantation, Jean Minjoz University Hospital, 25000 Besanc¸on, France. 0041-1345/00/$–see front matter PII S0041-1345(00)00844-7 449

450

SEMHOUN-DUCLOUX, DUCLOUX, BRESSON-HADNI ET AL Table 2. Evolution of Renal Function Time

Pre-Tx

6 Months

1 Year

2 Years

3 Years

4 Years

5 Years

6 Years

7 Years

8 Years

9 Years

10 Years

Serum 84 ⫾ 30 142 ⫾ 40*140 ⫾ 31* 149 ⫾ 46* 146 ⫾ 38* 147 ⫾ 45* 142 ⫾ 35* 144 ⫾ 41* 154 ⫾ 62*172 ⫾ 157* 135 ⫾ 54* 138 ⫾ 64* Creatinine Concentration (␮mol/L) 88 ⫾ 30 49 ⫾ 18† 51 ⫾ 17† 51 ⫾ 19† 52 ⫾ 18† 51 ⫾ 17† 51 ⫾ 17† 51 ⫾ 19† 50 ⫾ 18† 55 ⫾ 20† 53 ⫾ 20†55 ⫾ 20† Creatinine Clearance (mL/min) *⬍.005 vs preoperative serum creatinine concentration. † ⬍.005 vs preoperative creatinine clearance.

Second, patients with creatinine clearance ⬎ 40 mL/min at 5 years’ posttransplant were placed in group 1, whereas patients with creatinine clearance ⬍ 40 mL/min at 5 years’ posttransplant were placed in group 2. Comparisons were performed between the two groups. Student’s t test was used for comparing differences between groups and linear regression for estimating the relationships between variables. The ordinal data were analyzed using the chisquare test. Multivariate logistic regression analysis assessed the independent effects of selected risk factors. Results are expressed as means ⫾ SD.

RESULTS

Characteristics of the study population before transplantation are summarized in Table 1. Follow-up reached 10 years in 6 patients, 9 years in 17 patients, 8 years in 4 patients, 7 years in 11 patients, 6 years in 8 patients, and 5 years in 5 patients. The mean follow-up was 7.68 ⫾ 1.7 years. Five patients experienced postoperative acute renal failure requiring hemodialysis. Eight patients died during follow-up. One patient was placed on regular hemodialysis because of end-stage renal failure due to CyA nephropathy at 8 years’ posttransplant. Cyclosporine was replaced by tacrolimus in three patients because of cortico-resistant acute rejection. Three patients with severe renal impairment underwent renal biopsy. Histologic findings were always consistent with CyA nephrotoxicity. Evolution of renal function is described in Table 2. Mean preoperative creatinine clearance was 88 ⫾ 30 mL/min. Mean creatinine clearance decreased to 48 ⫾ 18 mL/min at

6 months’ posttransplant (P ⬍ .0005) and remained stable until 10 years. The evolution of serum creatinine concentration was similar (Table 2). Six months’ posttransplant creatinine clearance was correlated with preoperative creatinine clearance (R-sq ⫽ 0.274; P ⬍ .005). There was no relationship between preoperative serum creatinine concentration and posttransplant serum creatinine concentrations at any time. Neither was there a correlation between serum CyA concentrations and creatinine clearance, nor between these concentrations and the variations in creatinine clearance. The prevalence of hypertension is reported in Table 3. The proportion of hypertensive patients increased each year until 5 years and then remained stable. There was an upward trend in the number of antihypertensive drugs (Table 2). Nevertheless, probably because of the small number of patients, the difference was significant only between 6 months and 3, 4, 5, 6, and 7 years’ posttransplant, respectively. A positive correlation was seen between preoperative creatinine clearance and the rate of decrease in creatinine clearance at 6 months (R-sq ⫽ 0.214; P ⬍ .005). By multivariate logistic regression, age and preoperative creatinine clearance were independently associated with creatinine clearance at 5 years’ posttransplant. At 5 years’ posttransplant, creatinine clearance was above 40 mL/min in 36 patients (group 1) and below 40 mL/min in 15 patients (group 2). Group 2 patients were significantly older (56 ⫾ 8 vs 47 ⫾ 12 years; P ⬍ .01). Preoperative renal

Table 3. Prevalence of Hypertension After Liver Transplantation Time

Pre-Tx

Percent Hypertension Number of Antihypertensive Drugs/Number of Hypertensive Patients

5.8

*⬍.01 vs t 0. † ⬍.01 vs 6 months. ‡ ⬍.01 vs 1 year. § ⬍.01 vs 2 years.

1

6 Months

1 Year

2 Years

3 Years

4 Years

5 Years

6 Years

39.2*

58.8†

68.6‡

76.5§

80.4

82.4

81.2

1.18

1.22

1.51

1.58

1.69

1.71

1.75

7 Years

80.4 1.7

8 Years

9 Years

10 Years

80.4

81.4

81.4

1.44

1.62

2

HYPERTENSION AND RENAL FUNCTION IN LIVER TX

function in group 2 patients was worse than that of group 1 patients (69 ⫾ 27 vs 95 ⫾ 30 mL/min; P ⬍ .005). However, preoperative serum creatinine concentrations did not differ between the two groups (86 ⫾ 37 vs 85 ⫾ 32 ␮mol/L; P ⫽ NS). Mean serum CyA concentrations were similar between the two groups at any time posttransplant. The prevalence of hypertension was greater in group 2 than in group 1 (68.8% vs 58.8% at 1 year; P ⬍ .001 and, 93.8% vs 76.5% at 5 years; P ⬍ .001). DISCUSSION

Few series have been reported in which renal function has been assessed in liver transplant patients.7–11 In most studies, while GFR decreased soon after transplantation, renal dysfunction was seldom progressive, at least in the first years of follow-up. Indeed, Gonwa et al11 recently reported the evolution of renal function in 572 liver transplant recipients and showed that GFR decreased from 94 ⫾ 37 mL/min to 57 ⫾ 32 mL/min in the first postoperative month and then remained stable until 4 years. Nevertheless, such a follow-up is probably too short to assess the real consequences of CyA on renal function. In fact, Goldstein et al13 reported the incidence and progression of CyAassociated end-stage nephropathy after cardiac transplantation. The time lapse between transplantation and hemodialysis ranged from 3.7 to 9.5 years, with a mean duration of 6.4 years. Moreover, it is well known that CyA causes a doserelated decrease in renal function in experimental animals and humans. As CyA doses are traditionally greater in heart transplantation than in liver transplantation, a longer follow-up seems to be required to determine the effects of CyA on renal function in liver transplant patients. To our knowledge, our study is the first report examining renal function in liver transplant recipients after 5 years of follow-up. We found that renal function dramatically decreased in the first 6 months from 88 ⫾ 30 to 49 ⫾ 18 mL/min and then remained stable after a mean follow-up of almost 8 years. Only one patient (2%) developed end-stage renal failure 8 years after transplantation. Our incidence of chronic renal failure requiring dialysis is therefore comparable to previous reports with shorter follow-up, suggesting a stability of renal function over time. The use of a low-dose CyA protocol may also partly explain this result as well as the stability of renal function over time. Whether low-dose CyA protocol promotes chronic rejection cannot be assessed by this study. However, other studies have previously reported a low incidence of rejection in liver transplant recipients with a low-dose CyA protocol, as long as serum CyA levels remained above 75 ng/mL.14 It is interesting to note that patients with the lowest preoperative GFR do not seem to be more sensitive to the effects of CyA than those with the highest GFR. On the contrary, we found that the decrease in GFR was proportionally greater in patients with high GFR. Nevertheless,

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this result must be interpreted with caution. First, we can speculate that the patients with the lowest GFR were placed on renal-sparing protocol including the use of lower CyA dosage. However, we could show no difference in serum CyA levels in the two groups, and we did not find any correlation between renal function and serum CyA levels at any time. Second, it is obvious that the patients with the lowest GFR have some degree of hepato-renal syndrome that was corrected by liver transplantation. Finally, the choice of method used to assess GFR may partly explain this result. Serum creatinine is the most common method of estimating GFR and monitoring GFR on a long-term basis. Serum creatinine is not sensitive enough to detect renal insufficiency in cirrhotic patients.15 Serum creatinine is dependent not only on GFR but also on muscle mass, which is related to age, body weight, and sex. The most common formula used to control for these factors is that of Cockcroft and Gault.12 Several studies have shown correlations between this formula and inulin clearance,16 but few studies have assessed the accuracy of predicted GFR in patients with liver disease.15 Predicted GFR is better correlated to true GFR than serum creatinine concentration and remains the best indicator of renal function in clinical practice.15 Predicted GFR may overestimate true GFR in cirrhotic patients with renal insufficiency. Indeed, any increase in body weight related to ascites increases predicted GFR because body weight is taken into account when calculating predicted GFR. Consequently, the decrease in renal function may have been underestimated in patients with ascites and low preoperative predicted GFR. Nevertheless, there is some evidence to support the use of predicted GFR to assess renal function in this population. First, we found preoperative and posttransplant GFR levels using the Cockcroft formula that were similar to Gonwa et al11 using the I125-iothalamate method. Second, we showed that 6-month-posttransplant predicted creatinine clearance was closely linked to preoperative-predicted creatinine clearance, suggesting the validity of this method to follow renal function before and after liver transplantation. Such a correlation was not found when using serum creatinine concentration. Increased systemic blood pressure is the most frequently encountered adverse effect observed when using CyA.17 In the literature, the prevalence of hypertension in liver transplant patients varied from 45% to 82%.18 –21 We also observed a high prevalence of systemic hypertension in our liver transplant recipients receiving CyA and found that hypertension was closely associated with renal failure. It has been reported that hypertension develops in the first few months following liver transplantation and continues indefinitely.20 In our study, even though most hypertension developed in the first 6 months, the percentage of hypertensive patients clearly increased until 5 years’ posttransplant despite low CyA dosage. Moreover, the number of antihypertensive drugs progressively increases, showing the progression of hypertension with time. This result is of particular importance when considering the other cardio-

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vascular risk factors frequently found in the liver transplant population.18 Our study identifies some risk factors for developing posttransplant chronic renal failure. Age and lower preoperative creatinine clearance were both associated with poor long-term renal function. Such patients should be managed with a renal-sparing immunosuppressive protocol. The use of induction therapy with antilymphocyte globulins and mycophenolate mofetil needs to be defined for these types of patients. In conclusion, our study shows that after an initial decrease in GFR, renal function remains stable in most liver transplant recipients placed on a low-dose CyA protocol. Renal-sparing protocols should be used for patients with risk factors for developing chronic renal failure. REFERENCES 1. Myers BD, Newton L: J Am Soc Nephrol 2:S45, 1995 2. Ruiz P, Kolbeck PC, Scroggs MW, et al: Transplantation 45:91, 1988 3. Fioretto P, Steffes MW, Mihatsch MJ, et al: Kidney Int 48:489, 1995 4. Perico N, Rossini M, Imberti O, et al: J Am Soc Nephrol 2:1398, 1992 5. Ben-Maimon CS, Burke JF, Besarab A, et al: Transplant Proc 23:1260, 1991 6. Lewis R, Janney R, Goldel D, et al: Transplantation 47:266, 1989

SEMHOUN-DUCLOUX, DUCLOUX, BRESSON-HADNI ET AL 7. Platz KP, Mueller AR, Blumhardt G, et al: Transplantation 58:170, 1994 8. Wheatley HC, Datzman M, Williams JW, et al: Transplantation 43:641, 1987 9. Dische FE, Neuberger J, Keating J, et al: Lab Invest 58:395, 1988 10. Monsour HPJ, Wood RP, Dyer CH, et al: Semin Liver Dis 15:123, 1995 11. Gonwa TA, Klintmalm GB, Levy M, et al: Transplantation 59:361, 1995 12. Cockcroft DW, Gault MH: Nephron 16:31, 1976 13. Goldstein DJ, Zuech N, Sehgal V, et al: Transplantation 63:664, 1997 14. Yasutomi M, Arora A, Wiesner RH, et al: Presented at the 16th annual meeting of the American Society of Transplant Physicians, May 1997 15. Caregaro L, Menon F, Angeli P, et al: Arch Intern Med 154:201, 1994 16. Gault MH, Longerich LL, Harnett JD, et al: Nephron 62:249, 1992 17. Haas M, Mayer G: Nephrol Dial Transplant 12:395, 1997 18. Guckelberger O, Bechstein WO, Neuhaus R, et al: Clin Transplant 11:60, 1997 19. Canzanello VJ, Schwartz L, Taler SJ, et al: Transplant Surg 3:1, 1997 20. Schwartz L, Augustine J, Raymer J, et al: J Transpl Coord 6:139, 1996 21. Munoz SJ, Vlasses PH, Boullata JI, et al: Transplant Proc 20:623, 1988