HYPERURICEMIA AND GOUT IN RENAL TRANSPLANT RECIPIENTS

Abstract

Hyperuricemia, unlike clinical gout, is extremely common in renal transplant patients. The high prevalence of hyperuricemia is related to prolonged exposure to cyclosporine rather than to its dose or serum concentration. Serum creatinine levels do not show significant correlation with hyperuricemia, behaving more like a surrogate marker for cyclosporine dose and trough level. The low incidence of gout in renal transplant patients, despite the hyperuricemia, may be related to the prolonged immunosuppression effect.

• Cyclosporine
• Gout
• Hyperuricemia
• Renal transplantation

INTRODUCTION

Gout and hyperuricemia are common problems in renal transplant patients.[[1]], [[2]], [[3]], [[4]], [[5]], [[6]], [[7]] This association is important because (1) gout is a disabling disease and may complicate the rehabilitation of a renal transplant patient, (2) gout and hyperuricemia may adversely affect renal function, and (3) management of hyperuricemia and gout in a renal allograft recipient poses more pitfall than in the general population. Several factors may contribute to the high prevalence of hyperuricemia and gout in renal transplant patients. These include hypertension, impaired graft function, use of diuretics and cyclosporine. Cyclosporine is the most important factor causing hyperuricemia, however it is not clearly known what other additional factors might modify the hyperuricemic effect of cyclosporine in the setting. Gout in renal transplant patients behaves similarly to gout in other settings. It follows a variable period of asymptomatic hyperuricemia, though its incidence is much less than that of hyperuricemia. It is possible that the patient's threshold for manifesting clinical gout may be modified by the immunosuppressive therapy, but this remains to be proven.[[8]] In this retrospective study, we have studied the clinical characteristics of hyperuricemia in 45 renal transplant recipients followed over a period of 8.9 years. Prevalence of hyperuricemia, its onset and relationship with various predisposing factors are discussed.

METHODS

Forty-five renal transplant recipients were studied with respect to gout and hyperuricemia. Patients with graft duration of one year or more were included. All patients were on regular follow up. On each visit, patients underwent physical examination and biochemical evaluation including cyclosporine trough levels. Hyperuricemia was defined as serum uric acid level of >6 mg/dL in females, and >8 mg/dL in males. Clinical gout was defined as hyperuricemia with gouty arthritis, tophi or uric acid nephrolithiasis. Statistical tests used were student's t-test and Pearson's product—moment correlation coefficient.

RESULTS

Of the 45 patients 37 were males and 8 were females. Mean age was 41 ± 11 years. Mean duration of renal transplant was 8.9 ± 4 years. Immunosuppressive regimen used were cyclosporine, prednisolone and azathioprine (28 patients), cyclosporine and prednisolone (2 patients), cyclosporine and azathioprine (4 patients) and cyclosporine, prednisolone and mycophenolate mofetil (2 patients).

Hyperuricemia was seen in 25 patients (55%). However none of these patients showed evidence of clinical gout during the follow up period. Hyperuricemia occurred 3.8 ± 3 years after renal transplantation. Mean serum uric acid level in hyperuricemic patients (n = 25) was 9.6 ± 1.4 mg/dL, while in normouricemic patients (n = 20) 6.5 ± 0.9 mg/dL.

Cyclosporine trough levels: 43 patients used cyclosporine as one of the immunosuppressive drugs. Mean cyclosporine level of the whole group was 208 ± 44 ng/mL while mean serum uric acid level was 8.3 ± 1.9 mg/dL. No significant correlations were found between cyclosporine trough level and serum uric acid level (Table 1) (r = 0.28, p = 0.10). Cyclosporine level in hyperuricemic patients (n = 25) was 212 ± 45 ng/mL while in normouricemic patients it was 203 ± 41 ng/mL. There was no significant difference between the cyclosporine levels in the two groups (p>0.10, Table 2).

Table 1. Correlation Between Serum Uric Acid and Various Predisposing Factors for Hyperuricemia in Renal Transplant Patients

S. No.	Clinical and Biochemical Parameters	Values	Correlation Coefficient (r)
1	No. of Patients	45
2	Serum uric acid ng/dL.
	All patients (n = 45)	8.2 ± 1.95
	Patients on cyclosporine (n = 43)	8.3 ± 1.94
3	Cyclosporine trough level (ng/mL)	2.1 ± 44	0.28
4	Cyclosporine dose (mg/kg)	3.1 ± 0.95	+ 0.01
5	Serum creatinine (mg/dL)	1.3 ± 0.32	+ 0.02
6	Duration of transplant (Years)	8.9 ± 4.6	0.01

Table 2. Comparison of Various Predisposing Factors Causing Hyperuricemia Between Hyperuricemic and Normouricemic Renal Transplant Patients

Clinical and Biochemical Parameters	Patients with Hyperuricemia (n = 25)	Patients with Normal Uric Acid Levels (n = 20)	p Value
Cyclosporine level (ng/mL)	212±45	203±41	>0.1
Cyclosporine dose (mg/kg)	3.1±0.9	3.1±1.1	>0.1
Serum creatinine (mg/dL)	1.41±0.3	1.1±0.2	>0.1
Duration of transplant (Years)	9.0±3.9	8.9±5.4	>0.1

Dose of cyclosporine: The mean dose of cyclosporine in the whole group was 3.1 ± 0.95 mg/kg. There was no significant correlation between serum uric acid and the dose of cyclosporine (r = + 0.01, Table 1). The dose of cyclosporine was 3.1 ± 1 mg/kg in patients with hyperuricemia as well as in patients with normouricemia (3.1 ± 1 mg/kg, Table 2). There was no significant difference between the two groups (Table 2).

Serum creatinine level: Mean serum creatinine level of the whole group was 1.3 ± 0.3 mg/dL. There was no significant correlation between serum creatinine level and serum uric acid level (r = + 0.02, Table 1). Serum creatinine in patients with hyperuricemia was 1.43 ± 0.34 mg/dL while in patients with normouricemia 1.1 ± 0.2 mg/dL. There was no significant difference between the serum creatinine in two groups (p>0.10, Table 2).

The mean duration of renal transplant in the whole study group was 8.9 ± 4.6 years. There was no significant correlation between the duration of renal transplant and serum uric acid (r = + 0.01, Table 1). In patients with hyperuricemia the mean duration of renal transplant was 9 ± 3.9 years while in patients with normal uric acid level, it was 8.9 ± 5.4 years. There was no significant difference between the duration of renal transplant and hyperuricemia (p>0.10, Table 2).

DISCUSSION

Gout and hyperuricemia are common problems among renal transplant patients. Gout has a prevalence of 2-13% whereas hyperuricemia has higher prevalence of 19–84%.[[1]], [[2]], [[3]], [[4]], [[5]], [[6]], [[7]] In this study, hyperuricemia was seen in 55% of patients while none of the patients developed clinical gout.

Several factors contribute to the high prevalence of hyperuricemia in renal transplant patients. Hypertension and edema are common in renal transplant patients where diuretics are frequently used. Diuretics impair excretion of uric acid, possibly because of poor graft function. Cyclosporine adversely affects the renal excretion of uric acid and it is the most important factor responsible for hyperuricemia in renal transplant patients. In this study 43 out of the 45 patients were on cyclosporine as one of the immunosuppressive drugs, and this may explain the high prevalence of hyperuricemia (55%).

The adverse effects of cyclosporine on renal excretion of uric acid were recognized soon after the drug came into clinical use. The mechanism by which it causes impaired excretion of uric acid has been the subject of considerable investigation. Cohen and coworkers[[10]] noted a reduction in uric acid clearance among cyclosporine treated patients. This was attributed to enhanced tubular secretion and reabsorption of uric acid along with reduced glomerular filtration. In another study by Hansen,[[11]] the antiuricosuric effect of cyclosporine was attributed to reduction in the filtered load. Majority of the studies has tended to implicate impaired tubular handing of uric acid in the hyperuricemia of adult and pediatric transplant patients receiving cyclosporine.[[9]], [[12]], [[13]], [[14]], [[15]], [[16]]

Cyclosporine induced hyperuricemia is seen in patients with cardiac allografts,[[20]] as well as in patients receiving cyclosporine for autoimmune diseases.[[21]] Gout and hyperuricemia also show higher prevalence in renal transplant patients treated with azathioprine and prednisolone,[[17]] but this prevalence is not as high as that seen in patients on cyclosporine. It is therefore possible that in addition to predisposing patients to gout, cyclosporine may accelerate its appearance.

It is unclear whether additional factors may further amplify the risk of hyperuricemia and gout in patients receiving cyclosporine. Diuretics may heighten the risk of gout in cyclosporine treated patients,[[1]], [[12]], [[18]], [[19]] but their contribution has been reported to be small.[[3]], [[5]], [[6]] Few workers have examined the relationship between hyperuricemia and cyclosporine levels.[[1]], [[6]] Serum creatinine levels have shown correlation with hyperuricemia.[[1]], [[2]], [[12]], [[19]] However serum creatinine may be a surrogate for cyclosporine level. Renal transplant recipients develop hyperuricemia and gout months to years after transplantation. This shows that the risk of hyperuricemia depends more upon the total exposure to cyclosporine and its trough levels.

In this study, we have tried to correlate the prevalence of hyperuricemia with various factors including the dose and level of cyclosporine, the serum concentration of creatinine and the total duration of renal allograft. The aim was to find out whether these factors modify hyperuricemic effect of cyclosporine or not. We found no correlation between cyclosporine trough levels and serum uric acid levels. In addition, patients with or without hyperuricemia had almost the same trough levels of cyclosporine. Furthermore, no correlation was found between the dose of cyclosporine and serum uric acid level. This shows that hyperuricemia is more related to the total exposure to cyclosporine rather than to its dose and trough levels. There was no significant correlation between the duration of renal transplant and serum uric acid level. However, most patients developed hyperuricemia after a long period of exposure to cyclosporine (range 1–10 years). This again confirms that prolonged exposure to cyclosporine is the most important predisposing factor for hyperuricemia.

Serum creatinine levels in this study did not differ much in hyperuricemic and normouricemic patients, and thus behaved similar to cyclosporine level and its dose. This shows that serum creatinine behaves more like a surrogate marker for cyclosporine dose and trough level in renal transplant patients.

None of the patients showed any evidence of clinical gout in this study despite the fact that the follow up period after kidney transplantation was rather long (8.9 ± 4.6 years). This finding is in sharp contrast with the high prevalence of clinical gout noted in other studies involving renal transplant patients.[[1]], [[2]], [[3]], [[4]], [[5]], [[6]], [[7]] Immunosuppressive therapy might impair the inflammatory response to hyperuricemia and increase the threshold for manifesting clinical gout, but this has not yet been proven.[[8]]