Mesalazine was discontinued and azathioprine was introduced (2 mg/Kg) in combination with prednisolone (5mg/day). Two months later, serum creatinine decreased to 1.5 mg/dl and urinalysis revealed no white blood cells/field and 2-5 red blood cells/field; proteinuria/creatinine ratio decreased to 0.3 g/g.

Case 2

A man with Crohn’s disease and no other relevant medical history was sent to Nephrology consultation for chronic kidney disease. Inflammatory bowel disease had been diagnosed when he was 35 years old (in 2009). At that moment, he had a serum creatinine of 0.8mg/dl, with no abnormalities in urinalysis. He started oral mesalazine (4g/day) and prednisolone (60 mg/day) with a gradual decrease of doses and clinical remission. One year later he had 1.48 mg/dl serum creatinine. After two years, he had 1.80 mg/dl serum creatinine and leukocyturia (25-50 WBC/field) in urinalysis. Mesalazine was discontinued and he started azathioprine (AZA) (1mg – 2mg/kg/day) with poor control of IBD activity and need to increase the corticosteroids (CT) dose (1mg/kg/day) with a gradual decrease and clinical remission. At Nephrology evaluation, the patient had only gastro-intestinal symptoms (abdominal discomfort and diarrhoea).

Three months after stopping mesalazine, serum creatinine decreased to 1.5 mg/dl and urinalysis revealed no white or red blood cells. Six months after treatment with AZA and lower doses of prednisolone (5 mg/day), the IBD became active. AZA was increased to 2 mg/kg/day and CT to 1 mg/kg/day with clinical remission. AZA was stopped two months later due to pancytopenia. The patient was proposed for further treatment with anti-TNF due to refractory IBD.

DISCUSSION

Aminosalicylates compounds are widely used in acute phase and remission maintenance therapy of IBD¹⁰. Mesalazine also known as 5-aminosalicylic acid (5-ASA), is a derivative of salicylic acid and it is the active moiety of sulfasalazine (without the adverse effects attributed to the latter one). A number of reports have linked oral mesalazine therapy to tubulointersticial nephritis. Although this association is currently well established there are no guidelines for monitoring renal function in patients who are receiving this treatment¹¹.

The first reports were published in 1989, and in 1990 the Committee on Safety of Medicines (CSM) issued a warning of nephrotoxic reactions to mesalazine.

From 1985 to 1997, the CSM had received 35 reports implicating the drug in interstitial nephritis.

In recent editions of nephrology textbooks, mesalazine is one of the drugs that could be associated with acute and chronic interstitial nephritis^9,12,13.

The true incidence of this problem is not really known. Primas et al. showed that renal impairment, defined as any increase in serum creatinine, may occur in up to one in 100 patients treated with this drug¹⁴. The incidence of clinically significant interstitial nephritis was estimated to be less than one in every 500 patients treated, when serum creatinine is monitored regularly. In a larger study of 223 outpatients with IBD, Schreiber et al. found an increased prevalence of tubular proteinuria in patients who were receiving high dosages of 5-ASA¹¹. All reports of interstitial nephritis in IBD patients are associated with drugs used in its treatment⁹.

The nephrotoxicity associated with mesalazine takes the form of an acute or an indolent chronic and progressive interstitial nephritis. It can be severe and lead to chronic kidney disease^14,15. The development of tubulointersticial nephritis is independent of treatment duration. Fifty per cent of patients present within the first 12 months of starting therapy but some are diagnosed within 5 years after beginning treatment¹. It has been suggested that undercurrent steroid therapy used in the IBD treatment may delay presentation.

Signs and symptoms are scanty and non-specific. Patients may be asymptomatic, such as those who presented. A minority of patients have systemic symptoms like fever, myalgia, anorexia and weight loss¹⁶. An increase in serum creatinine is a late event but may be the first evidence of nephrotoxicity.

Reagent strip urinalysis can be normal, or positive to blood and protein. Proteinuria can be mild to heavy and can be influenced by IBD activity. Sterile pyuria may be present. Eosinophilia has been recorded but it is not a specific finding^16-18.

The pathogenic basis of mesalazine associated interstitial nephritis is not completely known. In the acute stage of the disease, there is a mixed inflammatory cell infiltrate composed of B and T lymphocytes and macrophages, with interstitial oedema, which is comparable to that seen in renal allograft acute cellular rejection. It has been suggested that this represents a delayed cell-mediated hypersensitivity response^16-20. Only a minority of patients manifest a systemic type-I hypersensitivity reaction with fever and eosinophilia⁸.

In the chronic stage, the cellular infiltrate is accompanied by interstitial fibrosis and tubular atrophy, as it happened in our second case. The extent of these hallmarks means an irreversible renal impairment and is predictive of progression to chronic renal failure²¹.

Mesalazine is structurally related to salicylic acid; salicylates inhibit the synthesis of intra-renal prostaglandins, which are vasoactive mediators of intra-renal blood flow, uncouple oxidative phosphorylation in mitochondria and inhibit the pentose phosphate shunt rendering the kidney susceptible to oxidative damage^22-25. All of these effects cause a disturbance in intra-renal blood flow and promote local tissue hypoxia.

Direct tubular toxicity in addition to tissue hypoxia is also suggested^20,21. After reperfusion injury, there is an inflammatory response that may contribute to chronic inflammation and interstitial fibrosis^23-26.

Due to the small number of cases described and the inability to determine the degree of systemic absorption, is impossible to say if nephrotoxicity is dose-related. Tubulointersticial nephritis has been reported in patients taking doses of mesalazine as low as 400 mg/day. The systemic bioavailability is determined by the route of administration and by the location and extent of the IBD. Systemic absorption of rectal mesalazine is approximately 50% of oral mesalazine; there is no report of significant nephrotoxicity in patients using only rectal formulation; the nephrotoxicity could be an idiosyncratic effect^20,24.

In the Dutch Pentasa Study, over 150 subjects were screened prospectively for renal toxicity. They were randomized to receive two dosages of oral slow-release mesalazine (1.5 vs. 3.0 g per day), and followed-up for 12 months. There were no differences in toxicity or compliance rate between the high and low dose groups. Two patients (1.3%) developed modest, reversible renal impairment, but only one of them had biopsy proven interstitial nephritis²¹.

Mesalazine should be withdrawn when the renal impairment is not explained by other factors. A renal biopsy provides diagnostic and prognostic information.

It is indicated in subjects with impaired renal function that is not explained by other factors, in which renal function does not recover to baseline following withdrawal of the drug, or in those who present with atypical features such as nephrotic range proteinuria, which may suggest an alternative diagnosis.

The response to drug withdrawal is variable. It leads to recovery of renal function in 85% of cases where the diagnosis is made within 10 months of starting treatment. When the diagnosis is delayed beyond 18 months from the start of treatment only one-third of cases show some recovery of renal function and this is usually only partial^20-23. Active chronic tubulointersticial nephritis was described in biopsies from patients in whom mesalazine has been withdrawn several months prior to biopsy^19,22,26.

Steroids and azathioprine have been used for IBD treatment with a good response, but this depends of level on the established chronicity lesions in renal biopsy. Nevertheless, a trial of high dose steroid (1 mg/day/kg, maximum 60 mg/day for up to 3 months) is recommended in patients whose renal function does not respond to drug withdrawal alone. This may be preceded by pulsed intravenous methylprednisolone in severe cases (0.5 to 1 g on three successive days).

Both our patients had improvement in renal function after discontinuation of the drug and none of them made an intensive course of corticosteroid therapy. In both cases, the low-dose of corticosteroids may have contributed to the improvement of the renal function.

Other manifestations of renal disease in patients with inflammatory bowel disease (IBD)

Extraintestinal manifestations (EIM) of IBD are common. These manifestations can involve nearly any organ system – including the renal but also the musculoskeletal, dermatologic, hepatopancreatobiliary, ocular, and pulmonary systems⁹. Symptoms of renal impairment are not always specific and since the underlying bowel disease is preponderant, renal function deterioration may be underestimated¹⁰.

Renal or urinary complications can occur in 4%-23% of patients; the most common manifestations are kidney stones, enterovesical fistulas and ureteral obstruction. Patients with IBD have a 10 to 100 time higher risk of nephrolithiasis compared with the general population. The risk is higher in adults than in children and in patients with CD. Kidney stones in IBD are composed primarily of calcium oxalate or uric acid²⁶.

Fistulas between the gastrointestinal tract and the urinary system are uncommon, occuring in 1%-8%; they are more common in patients with ileal or ileocecal disease than in patients with colonic disease²⁷.

Morphological changes in the glomeruli – podocyte effacement, mesangial deposition of immunoglobulin and complement have been well described. There are also reported associations with membranous glomerulonephritis, rapidly progressive glomerulonephritis, mesangiocapillary glomerulonephritis, IgA nephropathy (as in our first case), and thin basement membrane disease^1,9,26-31. Glomerulonephritis presenting as nephrotic syndrome in patients with IBD is rare16. Tubular damage was seen in 31% of CD and in 23% of UC patients who were not on ASA therapy. Granulomatous interstitial nephritis, interstitial nephritis with hyperoxalouria and renal tubular acidosis have also been reported^32-35.

Secondary amyloidosis (AA amyloidosis) is a rare but serious complication that may occur in chronic inflammation diseases, including IBD, mainly longstanding Crohn’s disease. The reported prevalence of secondary amyloidosis in IBD patients varies from 0.5 to 29% in CD and from 0 to 0.4% in UC with a higher prevalence at autopsy^16,29.

The majority of patients have renal involvement with asymptomatic proteinuria or manifestations of nephrotic syndrome. Differential diagnosis of primary systemic amyloidosis presenting as regional enteritis should always be considered. The response of IBD-related secondary amyloidosis to treatment is variable. It is reported that medical or surgical treatment has stabilized or improved renal disease but there exist reports suggesting no benefit with them³⁰.

There is only a retrospective review study to date that examined the histopathology of 83 renal biopsies performed in IBD patients. The authors present 45 and 38 cases CD and UC, respectively. IgA nephropathy was the most common finding (24%), followed by interstitial nephritis (19%), arterionephrosclerosis (12%), acute tubular injury (8%), proliferative GN (7%), and minimal-change disease (5%). Of the 16 cases of interstitial nephritis, nine (56%) had current or recent past exposure to aminosalicylates, including all cases of granulomatous interstitial nephritis¹⁷.

There are no specific guidelines for surveillance of renal function. Frandsen et al. recommend measurement of serum creatinine prior to the start of mesalazine treatment and every 6 months thereafter⁴.

CONCLUSIONS

These are the first two cases of TIN associated with mesalazine identified by renal biopsy in our Hospital.

Management of mesalazine-induced interstitial nephritis includes discontinuation of drug and sometimes a trial of corticosteroid therapy. In both cases, the history of inflammatory bowel disease, mesalazine use and the histopathology, support the diagnosis of a drug-associated renal injury.

It is very important to recognize renal impairment early, to prevent the progression to an end-stage renal disease. We suggest regular monitoring of renal function (serum creatinine and urinalysis) in patients treated with mesalazine; it is simple, inexpensive and it is the only way to diagnose new cases early.

Further epidemiological data are needed to clarify the causal mechanisms of nephrotoxicity. Similar data should be reported to estimate the true incidence of this serious adverse effect. These cases show us the need to create some protocols for routine renal function surveillance in IBD patients.

References