The Use of Indomethacin in Nephropathic Cystinosis in Children: A Tale of Two Cities?

The following information is provided in response to questions which have arisen on the support group regarding the use of indomethacin and other non-steroidal anti-inflammatory drugs (like ibuprofen) in patients with cystinosis. Dr. Craig Langman is a pediatric nephrologist and member of our Medical Advisory Committee. We are grateful for his dedication to the cystinosis community and his time taken to provide us with the following information.

Best Regards,
Christy Greeley
VP, Research
Cystinosis Research Network

Craig B. Langman, MD
Isaac A. Abt, MD Professor of Kidney Diseases
Feinberg School of Medicine, Northwestern University
Head, Kidney Diseases
Children’s Memorial Hospital, Chicago IL USA

Indomethacin is a drug of the non-steroidal anti-inflammatory class, and has been available for four decades at least. It inhibits the action of an enzyme, cyclo-oxygenase (COX), which is responsible for the production of a class of hormones called prostaglandins. The inhibition is not specific to the several different subclasses of cyclo-oxygenase found in the human (COX-1, COX-2). Prostaglandins have important roles in maintaining normal kidney function in humans.

In 1979, there was a report of two patients, one with nephropathic cystinosis, in which the loss of electrolytes by the kidneys was reduced, and the subsequent course of the patient improved.[1] In 1982, in an account by the esteemed London group headed by Sir Cyril Chantler, three children with cystinosis were reported to have treatment with indomethacin for 9-18 months in a dose of 3 mg/kg/day, with an improvement in the symptoms of polyuria, polydipsia, and general well-being.[2] Since at that time phosphocysteamine therapy was not
available (the patients were studied in the late 1970’s), kidney function deteriorated. However, the authors believed that there was no worsening with the drug, compared to other patients who did not receive it. From that time onward, the European continent has been in favor of the use of Indomethacin in the care of children with nephropathic cystinosis. To date, there have been no further studies to demonstrate its safety or efficacy.

Should there be concern in the use of indomethacin in children with cystinosis? Loss of the function with indomethacin therapy that prostaglandins have within the kidney may have serious consequences for kidney function in all ages from infancy through adulthood. Such functions include alterations of the processes that maintain normal glomerular filtration rates and many functions of the proximal and distal tubules. Reports abound of small series of infants and children who have received indomethacin for other purposes than cystinosis,
such as for congenital heart disease[3] . The mechanism of the toxicity has been examined in experimental animals, and seems to be from changes produced in glomerular filtration.[4] Long-term use of the non-steroidal
anti-inflammatory class of drugs, including indomethacin, produces an unique form of damage to the kidney, involving the renal medulla and papillae, where urinary concentrating mechanisms reside.[5]

A recent review concluded that when kidney function was normal, there were no important side-effects of non-steroidal anti-inflammatory drugs in adults.[6] However, it should be remembered that most if not all patients with nephropathic cystinosis have alterations of kidney function, including reductions in glomerular filtration rates. Under these circumstances, data are not available to guarantee safety. Additionally, drugs used commonly in children with chronic kidney disease, including cystinosis, such as angiotensin-converting enzyme inhibitors for control of hypertension, may have serious adverse consequences to kidney function when combined with non-steroidal anti-inflammatory drugs.[7]

What should you do for your child with cystinosis? As usual, a discussion of the potential benefits and adverse outcomes of using the drug must be held with your child’s kidney diseases specialist. Should the drug be used, as is more common in Europe than in the United States , careful monitoring of kidney function must ensue. There may be many other side-effects of the drug, including those in the gastrointestinal tract, which will make other specialists involved in the care of your child monitor for those too.

In the end, as with most concepts in medicine today, there are good and bad aspects of the use of indomethacin in the care of cystinosis that deserve careful consideration for your child. Given our abilities today to provide nourishment, energy, and correction of many of the disturbing aspects of kidney tubular functions, and promote growth in the disease, I think it is the rare child with nephropathic cystinosis who needs chronic indomethacin therapy.

Craig B. Langman, MD
Isaac A. Abt, MD Professor of Kidney Diseases
Feinberg School of Medicine, Northwestern University
Head, Kidney Diseases
Children’s Memorial Hospital, Chicago IL USA


[1] Betend B, David L, Vincent M, Hermier M, Francois R. Successful indomethacin treatment of two paediatric patients with severe tubulopathies. A boy with unusual hypercalciuria and a girl with cystinosis. Hel Paediatr Acta 1979; 34:339-44.

[2] Haycock GB, Al-Dahhan J, Mak RH, Chantler C. Effect of indomethacin on clinical progress and renal function in cystinosis. Arch Dis Child 1982; 57:934-9.

[3] Cuzzolin L, Dal Cere M, Fanos V. NSAID-induced nephrotoxicity from the fetus to the child. Drug Saf 2001; 24:9-18.

[4] Guignard JP. The adverse effect of prostaglandin-synthesis inhibitors in the newborn rabbit. Semin Perinatol 2002; 26:398-405.

[5] Rocha GM, Michea LF, Peters EM, Kirby M, Xu Y, Ferguson DR , Burg MB. Direct toxicity oof nonsteroidal anti-inflammatory drugs for renal medullary cells. Proc Natl Acad Scie USA 2001; 98:5317-22.

[6] Lee A, Cooper MG, Craig JC, Knight JF, Keneally JP. Effects of non-steroidal anti-inflammatory drugs on post-operative renal function in adults.
Cochrane Database Syst Rev 2000; 4:CD002765.

[7] Pisoni R, Ruggeneti P, Sangalli F, Lepre MS, Remuzzi A, Remuzzi G. Effect of high dose ramipril with or without indomethacin on glomerula selectivity. Kidney Int 2002; 62:1010-19.


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