Gout, Bradycardia, and Hypercholesterolemia After Renal Transplantation.

ABSTRACT: Approximately 17,000 solid organ transplantations are done annually in the United States. Increasingly, care of these patients will be provided by primary care physicians. In this report, we illustrate the complexity of common medical problems in a patient who had cellulitis and who had had a cadaveric renal transplantation 10 years earlier.

Immunosuppressive therapy was cyclosporine (100 mg twice a day) and prednisone (10 mg once a day). The patient's hospital course was complicated by acute gout and symptomatic bradycardia. In both instances, usual treatment--full-dose indomethacin for gout and withholding verapamil for bradycardia--could have had significant interaction with the cyclosporine. At the time of discharge, a therapeutic plan for long-term management of hypercholesterolemia included possible drug interactions with cyclosporine. The potential for drug toxicity in the transplant patient necessitates careful monitoring of immunosuppressive drug levels. Ongoing communication with the transplant center is also needed.

APPROXIMATELY 11,000 renal transplantations, 4,000 liver transplantations, and 2,500 heart transplantations are done annually in the United States. [1-3] Primary care physicians, especially in rural areas, are increasingly likely to be involved in the care of these patients. In this report, we illustrate the complexity of treating common medical problems in a patient receiving immunosuppressive therapy.

CASE REPORT

A 61-year-old white woman was seen in September 1999 after 3 days of pain and swelling in the left lower extremity She had a history of systemic lupus erythematosus, hypertension, hypothyroidism, hypercholesterolemia, podagra, and cadaveric renal transplantation in 1989. Her medications on admission included cyclosporine (100 mg twice a day), azathioprine (150 mg once a day), prednisone (10 mg once a day), verapamil (240 mg each morning and 120 mg each evening), furosemide (80 mg once a day), potassium chloride (10 mEq once a day), clonidine (0.2 mg once a day), and levothyroxine (0.125 mg once a day). The patient weighed 80 kg (176 lb). Physical examination showed bilateral edema up to the knees (greater in the left lower extremity). The left leg was red and warm with a lymphangitic streak. Movement of the left foot was limited in all directions because of pain. The remainder of the physical examination was unremarkable.

Initial laboratory studies included a white blood cell count of 9,400/[mm.sup.3] with 70% segmented neutrophils and 26% lymphocytes. The chemistry profile on admission was normal except for a markedly decreased potassium level of 2.8 mEq/L. Serum creatinine value was 1.2 mg/dL. A radiograph of the left leg and foot showed only soft tissue swelling. Results of venous Doppler studies of the lower extremities were negative. The patient was treated with intravenous cefazolin and received potassium supplementation in addition to her regular medications. Lymphangitis and erythema receded, but the ankle pain worsened. Because of the history of podagra and a uric acid level of 10.6 mg/dL, a clinical diagnosis of gout was made. Steroid therapy for crystalline arthritis was recommended, but the paient declined; thus, a brief course of indomethacin was given, and joint pain quickly resolved.

Symptomatic bradycardia (40 beats/min) developed on day 3 of the hospital stay. The patient recalled similar episodic dizziness before admission. To avoid rapid reduction of the cyclosporine level, verapamil was decreased from 360 to 240 mg/day, and clonidine therapy was discontinued. The patient's heart rate stabilized in the range of 55 to 65 beats/mm. No ill effects occurred from cessation of clonidine therapy, and the creatinine value was unchanged.

At the time of discharge, colchcine therapy was instituted for gout prophylaxis rather than allopurinol because of the azathioprine. Additionally, treatment with low-dose simvastatin (no more than 20 mg/day) was recommended for hyperlipidemia (low-density lipoprotein cholesterol level of 193 mg/dL). Plasma cyclosporine level 1 week after discharge was 81 ng/mL, compared with the previous level of 86 ng/mL.

DISCUSSION

This case illustrates the complex nature of drug interactions that must be considered in the medical treatment of patients receiving immunosuppressive therapy. Hyperuricemia due to decreased uric acid clearance and gout is common in patients taking cyclosporine. [4] Indomethacin, frequently used to treat gout, may potentiate cyclosporine nephrotoxicity. Judicious use of brief courses of indomethacin with careful monitoring of serum creatinine may be acceptable, but consideration of alternative treatment such as steroids is worthwhile in acute gout. Allopurinol, commonly used for gout prophylaxis, is a xanthine oxidase inhibitor. Azathioprime is metabolized by this enzyme; thus, concomitant use may lead to severe bone marrow suppression. [5] Low-dose coichicine is the drug of choice for long-term treatment in this situation.

Hypertension is another common medical problem in patients receiving cyclosporine therapy. Cyclosporine-induced hypertension can cause significant target organ damage after transplantation. [6] Calcium channel antagonists are used at the time of transplantation to improve graft survival; they are usually continued for blood pressure control and because they increase cyclosporine levels by approximately 40%, with significant cost reduction.[7] Our patient was receiving 2.5 mg/kg/day of cyclosporine, which is lower than the usual maintenance dose of 3 to 5 mg/kg/day. Although symptomatic bradycardia led to consideration of withholding verapamil, a more conservative approach was successful, and the need for change in cyclosporine dosage was avoided.

Cardiovascular disease is the major cause of mortality after successful transplantation, and hypercholesterolemia is extremely common with immunosuppressive therapy. [8] Caution should be used with lipid-lowering agents in patients taking cyclosporine, since myositis and rhabdomyolysis may occur. Current recommendations are to use no more than 20 mg of simvastatin daily. [9] Presumably, the same recommendations apply to other agents in this class of drugs. Cholestyramine should be avoided, since it may interfere with cyclosporine absorption.

Monitoring of immunosuppressive drug levels is crucial, and cyclosporine levels should be measured once a week for 4 weeks after any medication change to ascertain that a stable therapeutic level is achieved. The transplant center must be provided with this detailed information, both for the safety of the individual patient and for accuracy of long-term cumulative data.

CONCLUSION

Seemingly straightforward medical problems can become complicated in patients receiving immunosuppressive therapy. Whether as a result of managed care guidelines or limited access to specialty care in rural areas, management of the transplant recipient is increasingly failing under the realm of primary care. Familiarity with immunosuppressive agents is a requisite for all physicians dealing with the burgeoning population of transplant patients. The Table lists the most common categories of drug interactions that may occur with cyclosporine. This information and this illustrative case may help to sensitize the primary care physician to the need for meticulous attention to detail when choosing drug therapy for patients taking immunosuppressive medications.

References

(1.) Chan L, Kam I: Outcomes and complications of renal transplantation. Diseases of the Kidney. Schrier R, Gottschalk C (eds). Boston, Little Brown and Co, 6th Ed, 1997, pp 2713-2769

(2.) Gordon R, Van Thiel D, Starzl T: Orthotopic liver transplantation. Gastroenterology. Haubrick C, Shaffner F, Berk J (eds). Philadelphia, WB Saunders Go, 4th Ed, 1995, pp 2509-2544

(3.)Periroth M, Reitz B: Heart and heart-lung transplantation. Heart Disease. Braunworld E (ed). Philadelphia, WB Saunders Go, 5th Ed, 1997, pp 515-530

(4.) Kahan B: Cyclosporine. N Engl J Med 1989; 321:1725-1738

(5.) Waid TW: Presentation and treatment of renal transplant rejection. Current Therapy in Nephrology and Hypertension. Glassock R (ed). St. Louis, CV Mosby Year Book Inc, 4th Ed, 1998, pp 356-367

(6.) Taler SH, Textor SC, Eanzanello VJ, et al: Cyclosporine-induced hypertension: incidence, pathogenisis, and management. Drug Safety 1999; 20:437-444

(7.) Danovitch G: Immunosuppressive Medications and Protocols for Kidney Transplantation. Danovitch G (ed). Boston, Little Brown and Go, 1st Ed, 1992, pp 437-444

(8.) Drueke TB, Abdulmussh Z, LaCour B, et al: Atherosclerosis and lipid disorders after renal transplantation. Kidney Int 1991; 39:524-528.

(9.) Meyer M, Norman D, Danovitch G: Long-term posttransplant management and complications. Handbook of Kidney Transplantation. Danovitch G (ed). Boston, Little Brown and Co, 1st Ed, 1992, pp 173-207

KEY POINTS

* Hyperuricemia due to decreased uric acid clearance and gout is common in patients taking cyclosporine.

* Indomethacin, often used to treat gout, may potentiate cyclosporine nephrotoxicity.

* Hypertension is another common medical problem in patients receiving cyclosporine therapy.

* Cardiovascular disease is the major cause of mortality after successful transplantation, and hypercholesterolemia is extremely common with immunosuppressive therapy.

* Seemingly straightforward medical problems can become complicated in patients receiving immunosuppressive therapy.

* Management of the transplant recipient is increasingly falling under the realm of primary care.

TABLE. Cyclosporine Interactions

Drugs that increase cyclosporine levels

Calcium channel blockers (except nifedipine)

Macrolide antibiotics

Azole antifungal agents

Cimetidine

Drugs that decrease cyclosporine levels

Phenytoin (Dilantin)

Phenobarbital 

Carbamazepine (Tegretol)

Rifampin

Drugs that increase cyclosporine toxicity

Hyperkalemia 

Potassium-sparing diuretics

Angiotensin-converting enzyme inhibitors 

Nephrotoxicity

Nonsteroidal anti-inflammatory agents

Aminoglycoside antibiotics

Neurotoxicity

Acyclovir

Imipenem

Drugs whose toxicity is increased by cyclosporine

Lovastatin