Nephrologists

Chronic kidney disease is common among Fabry disease patients. Screening studies in cohorts of chronic hemodialysis patients have revealed prevalences of Fabry disease up to 1.2% in males and 0.34% in females.1-7

Progressive endothelial GL-3 accumulation is thought to promote an inflammatory state, which reduces blood flow to tubules and glomeruli, leading eventually to irreparable nephron damage. Because of compensatory mechanisms and the vast reserve in normal kidney function, patients can remain relatively asymptomatic despite significant loss of function.8 However, after a critical number of nephrons are damaged, adequate glomerular filtration cannot be maintained and there is rapid onset of kidney failure.


Light micrograph of end-stage renal disease in Fabry patient. Note that the glomeruli are atrophic and hyalinized, typical of end-stage disease.

Glycosphingolipid-engorged renal cells. Light microscopy of renal capillary endothelium. Arrows indicate areas of GL-3 accumulation.

 

In clinical trials, the primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions). A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated with Fabrazyme compared to 0 of 29 treated with placebo (p<0.001). The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

While renal disease and renal failure in Fabry disease has historically been associated with adult male patients, studies show that females and children also have significant renal manifestations:

  • A review of kidney biopsies of four affected females revealed podocyte effacement only in proteinuric patients. Glomerular sclerosis and tubulointerstitial fibrosis were predictors of proteinuria and CKD stage. Overall findings were not significantly different from those described in males.9
  • Renal biopsies were performed in 9 symptomatic pediatric Fabry patients (7 males, 2 females; age 7 to 18 years).
    • Light microscopy showed changes in glomerular, tubulointerstitial, or vascular compartments in 7 patients. Electron microscopy showed lesions in all patients. Glomerular and vascular changes are present before progression to overt proteinuria and decreased GFR. The combination of acroparesthesia and mild albuminuria, glomerular endothelial cell deposits and arteriopathy may constitute a clinical and morphological combination heralding a potentially progressive renal disease.10

If you suspect Fabry disease in a patient, renal biopsy can demonstrate deposits of the lipid substrate globotriaosylceramide (GL-3), which is characteristic of Fabry disease and can be a useful screening tool. A geneticist can help provide a definitive diagnosis. Learn more about Diagnosing Fabry Disease.

Indication and Usage

Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

Important Safety Information

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. In clinical trials and postmarketing safety experience, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids. If severe allergic or anaphylactic reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

  • In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.
  • Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.
  • If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
  • If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.
  • Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated.
  • Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

Re-administration of Fabrazyme to patients who have previously experienced severe or serious allergic reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel and with appropriate medical support measures readily available.

The most common adverse reactions reported are infusion reactions, some of which were severe. Infusion reactions occurred in approximately 50-55% of patients during Fabrazyme administration in clinical trials. Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, fever, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence.

  • Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.
  • Other serious adverse events reported in clinical studies included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.
  • Severe and serious infusion related reactions have been reported in postmarketing experience, some of which were life threatening including anaphylactic shock. In addition to the above adverse reactions, the following have been reported during postmarketing use of Fabrazyme: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased and hypoxia.
  • Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.

The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients.

In clinical trials, a few patients developed IgE or skin test reactivity specific to Fabrazyme. Physicians should consider testing for IgE in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies.

Fabrazyme is available by prescription only. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1‑800‑FDA‑1088. You may also contact Sanofi Genzyme at 1-800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Sanofi Genzyme at 1-800-745-4447.

References

  1. Merta M, Reiterova J, Ledvinova J, et al. A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population. Nephrol Dial Transplant 2007;22(1):179-186.
  2. Tanaka M, Ohashi T, Kobayashi M, et al. Identification of Fabry’s disease by the screening of alpha-galactosidase A activity in male and female hemodialysis patients. Clin Nephrol 2005;64(4):281-287.
  3. Kotanko P, Kramar R, Devrnja D, et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol 2004;15(5):1323-1329.
  4. Linthorst GE, Hollak CE, Korevaar JC, et al. alpha-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant 2003;18(8):1581-1584.
  5. Nakao S, Kodama C, Takenaka T, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int 2003;64(3):801-807.
  6. Spada M, Pagliardini S. Screening for Fabry disease in end-stage nephropathies. J Inherit Metab Dis 2002;25:113.
  7. Utsumi K, Kase R, Takata T, et al. Fabry disease in patients receiving maintenance dialysis. Clin Exp Nephrol 2000;4:49-51.
  8. Obrador GT, Pereira BJG. Systemic complications of chronic kidney disease. Pinpointing clinical manifestations and best management. Postgrad Med 2002;111:115-22.
  9. Valbuena C, Carvalho E, Bustorff M, et al. Kidney biopsy findings in heterozygous Fabry disease females with early nephropathy. Virchows Arch 2008;453:329-338.
  10. Tondel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal Albuminuria. Am J Kidney Dis 2008;51:767-776.