Renal transplantation in a patient with common variable immunodeficiency

CASE REPORT

Renal Transplantation in a Patient With Common Variable Immunodeficiency Mary Beth Hogan, MD, Nevin W. Wilson, MD, and Dianne G. Muchant, MD ● A 15-year-old girl developed end-stage renal disease requiring renal transplantation. Posttransplantation immunosuppression therapy consisted of antithymocyte globulin, glucocorticosteroids, cyclosporine A, and azathioprine. The patient’s clinical course after transplantation was complicated by several episodes of graft rejection, chronic anemia, oral candidiasis, and numerous infections of the sinopulmonary tract that were recalcitrant to antibiotics and surgical intervention. An immunologic evaluation showed marked immune abnormalities beyond that expected by the transplant immunosuppression. Examination of serum samples taken before the transplant confirmed a diagnosis of common variable immunodeficiency. The difficulties of managing posttransplantation immunosuppression in a patient with a primary immunodeficiency are discussed. Patients with end-stage renal disease and a history of recurrent sinopulmonary infections may require immunologic screening before renal transplantation. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Common variable immunodeficiency; end-stage renal disease; renal transplantation.

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OMMON VARIABLE immunodeficiency is a primary immunodeficiency characterized by hypogammaglobulinemia, defective specific antibody responses, and variable T cell defects.1 This primary immunodeficiency may present at any age and is characterized by recurrent infections of the sinuses, ears, and lungs.1 Autoimmune diseases are very common, with approximately 20% of patients developing this complication.2 Renal disease is quite uncommon in patients with common variable immunodeficiency unless it is secondary to an autoimmune disease. We describe a patient with end-stage renal disease of unknown cause and common variable immunodeficiency and her clinical course after renal transplantation. CASE REPORT A 15-year-old girl initially presented to her local physician with a 3-month history of nausea, fatigue, and progressive shortness of breath. She was diagnosed with pulmonary edema and acute renal failure, with a creatinine of 15.4 mg/dL. She was started on hemodialysis. An extensive evaluation for the cause of her renal failure included complement levels, antinuclear antibody, antineutrophil cytoplasmic antibodies, and serum protein electrophoresis, which were normal. A renal ultrasound showed slightly small kidneys bilaterally. The patient had no history of previous renal problems. Beginning at 6 years of age, she had recurrent episodes of tonsillitis and otitis media. There was no family history of renal disease, immunodeficiency, or autoimmune diseases. The patient remained on hemodialysis. Six months after her initial presentation, she was referred to our facility for consideration of a renal transplant. At that time, she was

found to have severe hypertension and dilated cardiomyopathy. Her cardiac evaluation included a normal cardiac catheterization and muscle biopsy. She underwent bilateral nephrectomies for severe hypertension. Renal pathology showed chronic interstitial changes and nephrosclerosis consistent with end-stage renal disease. Immunofluorescence and electron microscopy did not show evidence of immune deposits. Her dialysis modality was changed to peritoneal dialysis. Her blood pressure was aggressively treated, resulting in gradual resolution of her cardiomyopathy. Six months later, she received a living related, onehaplotype kidney from her father. The patient underwent sequential immunosuppressant therapy consisting of antithymocyte globulin, azathioprine, cyclosporin A, and methylprednisolone. Despite prophylaxis against candidiasis with a topical antifungal agent, she developed severe oral candidiasis in the immediate posttransplantation period. She had two episodes of steroid-responsive rejection in the first 6 months posttransplantation. Renal biopsies were performed in both episodes before starting treatment. Biopsy specimens showed mild to moderate acute cellular rejection. Each rejection episode was also associated with severe oral candidiasis, which was treated with topical amphotericin B. Five months after her transplantation, she developed sinusitis that responded to 1 month of oral antibiotics. At 8 and 10 months posttransplantation, she had two more episodes of steroid-

From the Department of Pediatrics, West Virginia University School of Medicine, Morgantown, WV. Received December 3, 1998; accepted in revised form February 26, 1999. Address reprint requests to Dianne G. Muchant, MD, West Virginia University School of Medicine, Department of Pediatrics, Box 9214, Morgantown, WV 26506-9214. E-mail: [email protected]

娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3306-0039$3.00/0

American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: E7

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responsive rejection associated with severe oral candidiasis that responded to topical amphotericin B. Once again renal biopsy specimens showed mild acute cellular rejection. In addition, mild chronic rejection was also present. At that time, azathioprine was discontinued, and the patient was started on mycophenolate mofetil. Because of drug toxicity problems and recurrent oral candidiasis, the mycophenolate mofetil dose was reduced by 50%. Despite this reduction in T cell suppression, no further rejection episodes occurred. One year after her transplantation, the patient developed severe anemia, with a hemoglobin of 6.5 mg/dL. An extensive hematologic evaluation showed zinc deficiency, with a zinc level of 50 µg/dL (normal, 57 to 113). She was started on oral zinc supplementation, with improvement in her anemia to a hemoglobin of 9 mg/dL and a zinc level of 80 µg/dL. Fifteen months posttransplantation, she developed sinusitis that did not clear with prolonged therapy with broadspectrum oral antibiotics. Because of her worsening health status, which included significant weight loss and fever, she was admitted to the hospital, and intravenous antibiotic therapy was initiated. Sinus surgery was performed when intravenous antibiotics failed to treat her sinusitis. She did well for 3 months and redeveloped sinusitis, which required additional surgery.

Because of the history of recalcitrant sinusitis and a pretransplantation history of multiple infections consistent with a humoral immunodeficiency, an immunologic evaluation was performed. Immunologic studies obtained from stored sera taken before transplantation showed the presence of common variable immunodeficiency (Table 1). The patient was started on monthly 400-mg/kg intravenous immunoglobulin infusions. Because of ongoing difficulties secondary to her recalcitrant sinusitis, her intravenous immunoglobulin dose was increased to 500 mg/kg. Her sinusitis has healed, and she has had no other opportunistic infections. Results of pulmonary function tests remain normal. She is now 24 months posttransplantation, with a stable creatinine of 1.8 mg/dL.

DISCUSSION

Sera from our patient obtained before transplantation clearly showed that she had common variable immunodeficiency. Her total immunoglobulin G (IgG) was low, and more importantly, she was unable to mount a specific antibody response to the pneumococcal vaccine given before immunosuppression (Table 1). Not surpris-

Table 1. Humoral Immunologic Studies Before Transplantation

IgG (650-1500 mg/dL) IgA (70-390 mg/dL) IgM (40-345 mg/dL) IgE Diphtheria (⬎0.09 IU/mL) Tetanus (⬎0.09 IU/mL) H influenzae (⬎500 ng/mL) Isohemagluttins (⬎1:16)

442 37 67 4.3

8 Months After Transplantation

301 15 41 ⬍0.01 0.44 392 Anti-B 1:64

9 Months After Transplantation

259 14 53 ⬍2.0 1.09 0.32 4590

Pneumococcal Antibody Titers* (ng Ab N/mL)

Before Transplantation

1 Month After 1st Immunization. Before Transplantation

Before 2nd Immunization. Posttransplantation

1 Month After 2nd Immunization. Posttransplantation

Isotype 1 3 4 6B 7F 8 9N 12F 14 18C 19F 23F

310 1710 2940 570 520 320 580 300 790 2490 4180 820

290 5920 600 340 550 230 410 320 520 940 4330 720

110 2130 110 60 120 70 90 170 860 170 530 470

80 1260 1490 90 170 170 260 190 220 190 560 350

*A good serotype response consists of a post-vaccination concentration ⬎500 ng Ab N/mL and the post/pre ratio is ⬎3. A patient is considered to have a normal response to the vaccine if nine or more serotypes show a good response.

RENAL TRANSPLANTATION IN A PATIENT WITH CVID

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ingly, her immunoglobulin levels declined even further after transplantation immunosuppression was initiated. Pneumococcal responses indicated that the patient was no longer even protected against sepsis, because several of her titers had fallen below 200 ng/dL despite booster immunization. Her hospitalizations and surgical procedures after her transplantation were predominately related to her sinus disease. This further decline in her humoral immunity undoubtedly contributed to her frequent and recalcitrant sinopulmonary infections posttransplantation. Before transplantation, our patient had problems with recurrent infections, including otitis media. Recurrent ear infections during the second decade of life are very unusual and suggest the possibility of a humoral immunodeficiency. Common variable immunodeficiency may occur at any age, but most frequently presents between 10 and 29 years of age.1 The most common organisms infecting these patients are Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus and occur predominately in the sinopulmonary tract. Immunologic deficiencies include hypogammaglobulinemia, IgA deficiency, depressed levels of IgM, and, in half of these patients, a T cell deficiency also exists.1,3 Autoimmune diseases occur with increased frequency in patients with common variable immunodeficiency. Among these are Henoch Scho¨nlein purpura,4 systemic lupus erythematosus,5 and chronic glomerulonephritis.6 Associated autoimmune diseases may spontaneously go into remission without overt medical therapy. Although it is tempting to speculate that our patient’s kidney disease may have been a complication of common variable immunodeficiency and autoimmune disease, there were no serological or pathological data to support this hypothesis at the time of our patient’s initial presentation. Patients with common variable immunodeficiency may have an associated anemia from causes as varied as autoimmune hemolytic anemia, pernicious anemia, anemia of chronic disease, or gastrointestinal malabsorption.4 Evaluation of our patient’s anemia indicated a low zinc level, which is often associated with malabsorption. Zinc supplementation was instituted, her zinc level normalized, and her anemia improved.

T cells function broadly across three areas of immunologic responsibility: recognition of self versus nonself, tumor surveillance, and resistance to infection. Patients with primary immunodeficiency have variable T cell number and function. This accounts for their variability in presentation, with some patients presenting with autoimmune disease, some with neoplastic disease, and some with recurrent infections and eventual difficulty with all three problems. In addition, T cell helper number and function, and T cell suppressor number and function may be affected to differing degrees. This variability in T cell helper and T cell suppression is commonly seen in such diseases as Wiskott-Aldrich syndrome7 and common variable immunodeficiency.1 There are no current data on precisely how secondary immunosuppression during transplantation effects the previously existing T cell milieu in patients with a primary immunodeficiency. However, it seems intuitive that if T cell recognition of self versus nonself remains intact at the time of transplantation, the patient will still be capable of rejecting the allograft. In addition, those patients with a preexisting immunodeficiency may have a markedly turbulent posttransplantation course, with multiple infections. This most likely accounts for our patient’s ability to reject her allograft while having a more profound problem with infections after her renal transplantation. Renal transplantation in patients known to have a primary immunodeficiency has been previously attempted.8-10 These patients had WiskottAldrich syndrome that is noted to have specific B and T cell defects in addition to thrombocytopenia. Despite the presence of a primary T cell immunodeficiency, these patients were capable of allograft rejection much like our patient with common variable immunodeficiency.8,10 Standard posttransplantation immunosuppression in patients with underlying immunodeficiencies may lead to both marked difficulties clearing infection and rapidly fatal lymphoproliferative cancer.10 Investigators attempting renal transplantation in these patients have recommended reductions in azathioprine and eliminating the use of antithymocyte immunoglobulin because of these difficulties.8,10 Although the diagnosis of common

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variable immunodeficiency was not apparent at the time of our patient’s transplantation, infectious complications have led us to discontinue azathioprine and decrease the dose of mycophenolate mofetil by 50% without incurring rejection thus far. Standard therapy for common variable immunodeficiency includes monitoring for infections and monthly intravenous infusions of immunoglobulin.11 In addition, pulmonary function tests are monitored, because bronchiectasis is a common complication of the frequent sinopulmonary infections.11 Last, these patients are at increased risk of cancer even without medically induced immunosuppression. In conclusion, this patient presented with endstage renal disease of unknown origin and underwent renal transplantation. After the procedure, she developed severe oral candidiasis, chronic anemia, weight loss, and recalcitrant sinusitis that required hospitalization. Immune studies showed that she had common variable immunodeficiency, and stored serum samples confirmed that it had been present before transplantation. Adjustment of her immunosuppression therapy and intravenous gamma-globulin infusions greatly decreased her infections without leading to subsequent allograft rejection. Patients with end-stage renal disease and a history of recurrent sinopulmonary infections may require immunologic screening before renal transplantation. Identifying a preexisting immunodeficiency may allow for pretransplantation planning of appropriate

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immunosuppression and immunoglobulin supplementation. REFERENCES 1. Cunningham-Rundles C: Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 9:22-33, 1989 2. Hermans PE, Diaz-Buxo JA, Stobo JD: Idiopathic late-onset immunoglobulin deficiency: Clinical observations in 50 patients. Am J Med 61:221-236, 1976 3. Sneller MC: Clinical spectrum of common variable immunodeficiency, in Sneller MC, moderator: New insights into common variable immunodeficiency. Ann Intern Med 118:720-730, 1993 4. Hermaszewski RA, Webster ADB: Primary hypogammaglobulinaemia: A survey of clinical manifestations and complications. Q J Med 86:31-42, 1993 5. Eisenstein EM, Sneller MC: Common variable immunodeficiency: Diagnosis and management. Ann Allergy 73: 285-294, 1994 6. Fasth A: Primary immunodeficiency disorders in Sweden: Cases among children, 1974-1979. J Clin Immunol 2:86-92, 1982 7. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA: A multiinstitutional survey of the Wiskott-Aldrich Syndrome. Pediatrics 125:876-885, 1994 8. Meisels IS, Strom TB: Renal allograft rejection in a patient with Wiskott-Aldrich syndrome. Transplantation 59: 1214-1215, 1995 9. Webb MC, Andrew PA, Koffman CG, Cameron JS: Renal transplantation in Wiskott-Aldrich syndrome. Transplantation 56:747-748, 1993 10. Fischer A, Binet I, Oertli D, Bock A, Thiel G: Fatal outcome of renal transplantation in a patient with the WiskottAldrich syndrome. Nephrol Dial Transplant 11:2077-2079, 1996 11. Weissman D, Landreth KL, Wilson NW: Antibody mediated lung defenses and humoral immunodeficiency (chap 23), in Fishman AP (ed): Pulmonary Diseases and Disorders (ed 3). New York, NY, McGraw Hill, 1998, pp 303-314