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Keywords:

  • Crohn's disease;
  • ulcerative colitis;
  • inflammatory bowel disease;
  • 5-aminosalicylic acid;
  • mesalazine;
  • mesalamine;
  • nephrotoxicity;
  • interstitial nephritis

Abstract

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Nephrotoxicity has been described in some patients with inflammatory bowel disease (IBD) treated with 5-aminosalicylic acid (5-ASA). Studies with 5-ASA treatment in which serum creatinine or creatinine clearance was measured regularly show that nephrotoxicity is exceptional (mean rate of only 0.26% per patient-year). There have been several case reports, including 46 patients, of renal disease associated with 5-ASA treatment in patients with IBD. 5-ASA treatment-related nephrotoxicity is reported most often within the first 12 months, but also delayed presentation after several years has been shown. The absence of a clear relationship between 5-ASA dose and the risk of nephrotoxicity suggests that this complication is idiosyncratic rather than dose-related. Most of the patients with renal disease associated with 5-ASA treatment suffered interstitial nephritis, with symptoms and signs being nonspecific, which may delay detection for many months. The nephrotoxicity potential of mesalazine and sulfasalazine seems to be similar. The risk with different oral preparations of 5-ASA is probably too small to influence the choice of agent. Mesalazine should be withdrawn when renal impairment manifests in a patient with IBD; if this does not result in a fall in serum creatinine, then renal biopsy should be considered. A trial of high-dose steroid may be recommended in patients whose renal function does not respond to drug withdrawal. The optimal monitoring schedule of serum creatinine in patients receiving 5-ASA treatment remains to be established, as there is no evidence to date that either the test, or the frequency of testing, improves patient outcomes.

(Inflamm Bowel Dis 2007)

Sulfasalazine has been used in the treatment of inflammatory bowel disease (IBD), both for ulcerative colitis (UC) and for Crohn's disease (CD), for more than 50 years.1 In 1977, Azad Khan et al2 studied the therapeutic activity of the component parts of sulfasalazine and found that 5-aminosacicylic acid (5-ASA, mesalazine, mesalamine) was the therapeutically active component of the drug. As mesalazine is believed to act locally from within the gut lumen in patients with IBD, 3 methods have been widely used for delivering this drug to the colon: linking the mesalazine molecule with an azo bond to either another mesalazine molecule or an inert carrier, so that it is activated by colonic bacterial azoreductase, enteric coating, or prolonged release of the drug through a semipermeable membrane.1

In mild to moderate active UC, both sulfasalazine and 5-ASA have proven efficacy in inducing and maintaining clinical remission.1, 3 Considerations of long-term toxicity are important as lifetime maintenance treatment is usually recommended for UC. The introduction of 5-ASA into the treatment of patients with IBD has offered the opportunity of increasing dosages much further than had been possible with sulfonamide carrier compounds such as sulfasalazine, as a major advantage of 5-ASA agents is the safety profile.1 However, a number of cases have been reported with 5-ASA-related toxicity.4, 5 In particular, nephrotoxicity, which may be potentially irreversible, has been described in some patients with IBD treated with 5-ASA.4, 5 In this respect, both acetylsalicylic acid and phenacetin, which have been implicated in the occurrence of nonsteroidal antiinflammatory drug-induced nephropathy, share structural similarities with 5-ASA.6, 7 Furthermore, it has been demonstrated that 5-ASA may cause lesions to kidney tubular epithelial cells in animals when fed in high doses.6, 7

While the incidence of nephrotoxicity in the population of patients with IBD treated with 5-ASA is low, the morbidity in an affected individual is high, with some cases progressing to end-stage renal disease.4 The actual incidence of nephrotoxicity in IBD patients receiving 5-ASA therapy has not been determined, but it has been suggested that renal impairment may occur in up to 1 in 100 patients treated with 5-ASA, although clinically important interstitial nephritis (an interstitial inflammatory response with edema and possible tubular cell damage) would occur in only 1 in 500 patients.8 However, data regarding potential of renal impairment by 5-ASA therapy are contradictory, with some studies reporting an incidence >1% of interstitial nephritis, and others suggesting that 5-ASA treatment has no effect on renal function. Nevertheless, these data are based on a relatively low number of patients and with a limited follow-up. Furthermore, the effect of the type or the dose of 5-ASA prescribed on renal function has been insufficiently evaluated. Consequently, despite increasing recognition of the potential for this serious adverse event, nephrotoxicity, guidelines for monitoring renal function in patients prescribed 5-ASA preparations are not widely employed.4

Therefore, our aim was to conduct a systematic review of the effect of 5-ASA treatment on renal function in patients with IBD. We will review the following aspects or questions about the potential relationship between 5-ASA treatment and nephrotoxicity: 1) Is renal impairment in IBD patients an extraintestinal manifestation or a toxic side effect of 5-ASA? 2) Proteinuria frequency and significance in patients with IBD. 3) Epidemiological studies evaluating nephrotoxicity in IBD patients treated with 5-ASA. 4) Case reports of nephrotoxicity in IBD patients treated with 5-ASA. 5) Chronological aspects of 5-ASA nephrotoxicity. 6) Renal markers of nephrotoxicity. 7) Is there a relationship between dose of 5-ASA and nephrotoxicity? 8) Type of nephrotoxicity related to 5-ASA treatment. 9) Is there any difference in the nephrotoxicity potential of mesalazine and sulfasalazine? 10) Type of 5-ASA compound and nephrotoxicity. 11) Safety of 5-ASA treatment in patients with IBD and chronic renal failure. 12) Management of renal impairment due to 5-ASA treatment. 13) Is renal impairment due to 5-ASA treatment reversible? and, finally, 14) Recommendations for renal function monitoring in IBD patients treated with 5-ASA.

REVIEW METHODS

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

To perform this review, bibliographical searches were performed in MEDLINE electronic database from January 1966 to July 2006 looking for the following words (all fields): (“inflammatory bowel disease” OR “Crohn's disease” OR “ulcerative colitis”) AND (“5-aminosalicylic acid” OR aminosalicylate OR 5-aminosalicylate OR aminosalicylates OR 5-ASA OR mesalazine OR mesalamine OR sulfasalazine) AND (renal OR kidney OR nephrotoxicity OR “renal function” OR “renal dysfunction” OR “tubular dysfunction” OR “glomerular dysfunction” OR “renal damage” OR “tubular damage” OR “glomerular damage” OR nephritis OR “interstitial nephritis” OR proteinuria OR creatinine OR glomerular). The main outcome considered in this study was “nephrotoxicity.” References from the articles selected for the study were also examined in search of articles meeting inclusion criteria, that is, those studies dealing with the nephrotoxicity of 5-ASA therapy. Articles published in any language were included.

Case reports of patients with IBD and renal disease associated with 5-ASA treatment were specifically reviewed. For each case of nephrotoxicity the following variables were extracted in a predefined data extraction form (see Table 1): author, IBD type (UC or CD), 5-ASA dose, duration of 5-ASA treatment, and type of nephrotoxicity.

Table 1. Case Reports of Patients with Inflammatory Bowel Disease and Renal Disease Associated with 5-Aminosalicylic Acid (5-ASA) Treatment
Author (Reference)Inflammatory Bowel DiseaseDose (g/day)Duration (mo)aType of Nephrotoxicity
  • UC, ulcerative colitis; CD, Crohn's disease.

  • a

    From starting 5-ASA treatment to nephrotoxicity development.

  • b

    The patient had already impaired renal function before starting treatment with 5-ASA.

Agharazii et al51UC3.6Interstitial nephritis
Agharazii et al51UC6.0Interstitial nephritis
Arend et al52UC1.218Interstitial nephritis
Behrens et al53CDInterstitial nephritis
Bonet et al54UC1.636Interstitial nephritis
Brouillard et al55CDInterstitial nephritis
Brouillard et al55CDInterstitial nephritis
Brouillard et al55UCInterstitial nephritis
Calvino et al56CD1.212Interstitial nephritis
Colombel et al57CD46Interstitial nephritis
De Broe et al58UC1.528Interstitial nephritis
Fornaciari et al59UCMinimal change nephropathy
Frandsen et al60UC10Interstitial nephritis
Garcia-Diaz et al61CD1Interstitial nephritis
Haas et al62CD2.412Interstitial nephritis
Hamling et al63CD372Interstitial nephritis
Henning et al64UC0.536Interstitial nephritis
Howard et al65UC36Interstitial nephritis
Laboudi et al66CD84Interstitial nephritis
Maeda et al67UCInterstitial nephritis
Manenti et al68UC12Interstitial nephritis
Margetts et al69UC24Interstitial nephritis
Margetts et al69CD36Interstitial nephritis
Masson et al70UC1.210No renal biopsy
Mehta et al71UC2.47Interstitial nephritis
Musil et al72UC1Interstitial nephritis
Novis et al73UC2.45Minimal change nephropathy
Ohya et al74UC12Interstitial nephritis
Popoola et al75UC1.612Interstitial nephritis
Popoola et al75UC1.6-2.460Interstitial nephritis
Ruf-Ballauf et al76UC1.57Interstitial nephritis
Smilde et al77bUC324Interstitial nephritis
Smilde et al77bUC1.5-210Interstitial nephritis
Smilde et al77UC1.536Interstitial nephritis
Smilde et al77CD1.56Interstitial nephritis
Smilde et al77CD1.58Interstitial nephritis
Tadic et al78UC1.548Interstitial nephritis
Thuluvath et al79UC1.224Interstitial nephritis
Thuluvath et al79UC2.436Interstitial nephritis
von Muhlendahl et al80UC0.7536No renal biopsy
Wilcox et al81CD10Interstitial nephritis
Witte et al82CD24Interstitial nephritis
World et al8UC2.42Interstitial nephritis
World et al88Interstitial nephritis
World et al8UC1.63Interstitial nephritis
World et al8CD4.242Interstitial nephritis

Moreover, studies with 5-ASA treatment in which serum creatinine or creatinine clearance was measured regularly were also reviewed and the following variables were extracted (see Table 2): author, number of patients treated with 5-ASA, duration of 5-ASA treatment, and percentage of cases with nephrotoxicity. The mean percentage of patients with renal impairment was calculated and expressed as weighed mean (and corresponding 95% confidence interval [CI]) to make due allowance for the number of patients included in each study. As the follow-up time markedly varies among studies, the risk of renal impairment is better expressed as the incidence of nephrotoxicity per patient-years of follow-up, and therefore the annual nephrotoxicity rate (per patient-year) was also calculated.

Table 2. Studies with 5-Aminosalicylic Acid (5-ASA) Treatment in Which Serum Creatinine or Creatinine Clearance was Measured Regularly
Author (Reference)No. PatientsDuration of 5-ASA Treatment (mo)Patients with Nephrotoxicity (%)
Birdetvedt et al2532282 (6%)
Birdetvedt et al2559383 (5%)
Courtney et al2649120 (0%)
Courtney et al2650120 (0%)
de Jong et al2756460 (0%)
Diener et al2890 (0%)
Fockens et al18150121 (0.7%)
Fraser et al1321120 (0%)
Gendre et al2980240 (0%)
Giaffer et al3065120 (0%)
Green et al31108120 (0%)
Green et al3249120 (0%)
Green et al3246120 (0%)
Hawkey et al339960 (0%)
Ireland et al348260 (0%)
Kiilerich et al35114120 (0%)
Kruis et al3610860 (0%)
Mahmud et al374090 (0%)
McIntyre et al384160 (0%)
Mesalamine Study Group3912660 (0%)
Monteleone et al40360 (0%)
Mulder et al4141120 (0%)
Poulou et al1486290 (0%)
Rachmilewitz et al4211520 (0%)
Rijk et al4323480 (0%)
Riley et al4440482 (5%)
Riley et al4550120 (0%)
Riley et al934350 (0%)
Rutgeerts et al46131120 (0%)
Sandberg-Gertzen et al4716060 (0%)
Schreiber et al15185320 (0%)
Schroeder et al48491.50 (0%)
Singleton et al4923040 (0%)
Siveke et al5039>60 (0%)
Thomson et al9568120 (0%)

PROTEINURIA IN PATIENTS WITH IBD

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Normal subjects excrete less than 15 mcg/min during overnight urine collections; values of 20 mcg/min or higher are considered to represent abnormal microalbuminuria. Microalbuminuria has been demonstrated to be present in the majority of IBD patients, and it seems to be related to disease activity rather than to 5-ASA treatment.9–14 Furthermore, it has been shown that there is no positive relationship between the cumulative dose of 5-ASA and the severity of tubular proteinuria.11 However, other studies—although a minority—have found that microalbuminuria is not present in patients with IBD,9, 13 either at diagnosis or following treatment with 5-ASA. Finally, some authors have concluded that an increased prevalence of tubular proteinuria may be attributed to high doses of 5-ASA.15 Nevertheless, differences between results reported in these studies may relate to differences in disease activity of IBD. In this respect, microalbuminuria values have been shown to fall when the disease is quiescent,9, 10 even though the patients were receiving 5-ASA treatment.14

A recent observational prospective study revealed that renal impairment was observed in 2.2% of 1529 IBD patients followed for 1 year, both including patients with and without concomitant 5-ASA treatment.16 More recently, a case-control analysis found that IBD patients who were 5-ASA users had an increased risk of renal disease.17 However, after adjustment for several variables (including diabetes mellitus, heart disease, hypertensive disease, other renal diseases, or drug intake), the risk of 5-ASA users was comparable to controls; furthermore, this study found that IBD patients not using 5-ASA also had increased risk of renal disease (the most frequent were renal failure, followed by nephritis or nephropathy and nephrotic syndrome). Therefore, these data suggest that, although users of 5-ASA may have an increased risk of renal disease, it may be partly attributable to the underlying disease.17

EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Several studies investigated the epidemiology of nephrotoxicity associated with 5-ASA use in patients with IBD. As an example, in the Dutch Pentasa study performed in 1995 2 patients (1.3%) developed modest, reversible renal impairment, only 1 of whom had biopsy proven interstitial nephritis; a rate of clinically significant interstitial nephritis rate of ≈1 in 150 was observed.18 In 1996 a review of 8 published clinical trials of 5-ASA therapy in IBD concluded that renal impairment, defined as any increase in serum creatinine, may occur in up to 1 in 100 patients treated with this drug; clinically significant renal impairment did not occur in any of the 500 patients for whom data were available; therefore, the incidence of clinically significant interstitial nephritis was estimated to be less than 1 in every 500 patients treated when serum creatinine is monitored regularly.8 That same year, Marteau et al19 presented the safety reports on the use of Pentasa in France: spontaneous reports of adverse effects, submitted to a pharmaceutical manufacturer over a 2-year period, included 2 cases of renal impairment in ≈45,000 patient-years of therapy.19 One year later, Walker et al20 reviewed a large computerized database drawn from general practices in the UK: records of 2894 patients in whom general practitioners had diagnosed UC, and who were receiving ongoing medical therapy specific to that disease, were identified, and the authors found that renal complications of 5-ASA therapy were extremely rare (0 and 0.2 cases per 100 patient-years for high-dose users of sulfasalazine and 5-ASA, respectively). In 2002, Ransford and Langman21 evaluated serious adverse reactions reported to the Committee on Safety of Medicines of the UK in 1991–1998, noting 11.1 reports/1 million prescriptions of interstitial nephritis associated with 5-ASA. That same year, a recent review of the literature including 18 clinical trials assessing the efficacy of 5-ASA preparations in the treatment of IBD for 6 months or more, where serum creatinine was regularly monitored, detected only 1 case with deterioration in renal function among 1638 patients, which gives a prevalence of only 0.06%.22 In 2003, Logan and van Staa,23 in a large epidemiological study in the UK including almost 40,000 patients, found that the overall incidence of renal damage was rare in patients taking 5-ASA drugs, but was increased relative to control patients (general population). More recently, data from the UK General Practice Research Database were used to estimate the incidence of renal disease in patients with IBD in a nested case-control analysis17: among the 19,025 5-ASA users with IBD, 130 patients developed renal disease (incidence rate of 0.17 cases per 100 patients per year), while the incidence among patients with IBD but without 5-ASA use was 0.25 and among patients without IBD was 0.08. Also in 2004, in a large European registry containing more than 1500 patients with IBD, reported during a follow-up of 1 year that the incidence of renal failure was not increased in patients using 5-ASA16 (decreased creatinine clearance was observed in 34 patients, among them 13 with chronic renal impairment; comparing patients with and without renal impairment, no difference could be observed in 5-ASA consumption). Finally, a detailed postal questionnaire was sent in 2004 to all 1298 names in the British Society of Gastroenterology database and 290 consultant members of the Renal Association24: the authors estimated that the incidence of clinical nephrotoxicity in patients taking 5-ASA therapy was ≈1 in 4000 patients/year only.

Studies with 5-ASA treatment in which serum creatinine or creatinine clearance was measured regularly are summarized in Table 2,9, 13–15, 18, 25–50 where it is shown that nephrotoxicity was exceptional, being reported in few studies.18, 25, 44 Thus, when all the studies were considered 2671 patients received 5-ASA treatment during a total of 3070 years of follow-up. The mean overall risk of nephrotoxicity calculated from the studies included in Table 2 was 0.3% (95% CI: 0.15%–0.6%), and mean annual nephrotoxicity rate (per patient-year) was only 0.26% (95% CI: 0.13%–0.5%). In summary, the incidence of nephrotoxicity in IBD patients receiving 5-ASA therapy seems to be less than 0.5%.

CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

There have been several case reports of renal disease associated with 5-ASA treatment in patients with IBD (Table 1).8, 51–82 The actual development of 5-ASA-related renal disease seems rare, as only 46 patients with this complication have been reported. Nevertheless, this adverse drug reaction may be underrecognized and underreported. From these 46 patients, 15 had CD and 30 UC (the IBD type was unknown in 1 patient). Nevertheless, the apparent higher frequency of 5-ASA nephrotoxicity in UC may merely indicate that 5-ASA has proven efficacy in inducing and maintaining clinical remission and that lifetime maintenance treatment is usually recommended for UC,1, 3 in contrast to CD, where the role of 5-ASA is more debatable.83

CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

The renal impairment associated to 5-ASA use may be diagnosed at any interval after starting treatment. Thus, several studies have concluded that there is no relationship between duration of 5-ASA treatment and the risk of renal disease.9, 21 Nevertheless, it has been suggested that ≈50% of reported cases of 5-ASA-induced interstitial nephritis present within 1 year of treatment initiation, but the reported time range for presentation has been very wide.4, 8, 22 From the data summarized in Table 1 it can be observed that nephrotoxicity may appear from less than 1 month to more than 80 months after starting 5-ASA treatment. Nevertheless, in 20 cases (that is, in approximately half of the patients), renal impairment was described within the first 12 months of starting 5-ASA treatment. In summary, 5-ASA treatment-related nephrotoxicity is reported most often within the first 12 months, but also delayed presentation after several years has been observed. Thus, in case analytical control is recommended in patients taking 5-ASA treatment (see below), regular monitoring of renal function should be performed for the duration of therapy.

RENAL MARKERS OF NEPHROTOXICITY

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

The adequate early urinary marker of renal damage is not yet available. Leukocyturia and low-density urine gravity are common features of interstitial nephritis, but they are nonspecific for immunoallergic interstitial nephritis. The presence of white blood cells on urine microscopy is only noted in a minority of patients with 5-ASA-related nephrotoxicity.8 Low-grade proteinuria is present but its value as an early marker of renal damage is unreliable due to its variations as an acute phase response in relapses of IBD.

Several attempts have been made to measure early signs of renal impairment in patients with IBD treated with 5-ASA using sensitive markers of glomerular and tubular dysfunction. Tubular enzymuria is a more sensitive and specific marker of renal damage but it is not yet available as a screening method. Minor tubular and glomerular renal damage apparently exist in patients treated with 5-ASA.25 However, we do not know if these changes represent progressive renal disease. On the other hand, some authors have been unable to establish a correlation between several urinary markers of renal damage and 5-ASA treatment.40, 84 Furthermore, Riley et al9 found that the incidence of elevated urinary markers (such as β-N-acetyl-D-glucosamidase) is low in patients with quiescent UC, which is independent of the dose and duration of 5-ASA treatment.

In summary, when renal damage does occur, its presence is unlikely to be detected by urinalysis (leukocyturia, low-grade proteinuria, etc.) in its early remediable stages. Although tubular enzymuria may be a more sensitive and specific marker of renal damage, it is not yet available as a screening method and the correlation between the several urinary markers of renal damage and 5-ASA treatment remains unproven. These limitations emphasize the importance of monitoring serum creatinine in patients with IBD treated with 5-ASA.78

IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

In preclinical studies in animals nephrotoxicity appeared to be dose-related.4 However, interstitial nephritis has been reported in patients taking doses of 5-ASA as low as 0.75 g/day80 or even 0.5 g/day.64 Most of the cases of nephrotoxicity reported in the literature occurred in patients taking doses of 1.2–2.4 g/day; that is, relatively low doses (Table 1). Furthermore, several studies have concluded that there is no relationship between 5-ASA dose and the risk of renal disease.9, 16, 17, 21, 27 Finally, some authors have evaluated urinary enzymes as markers of renal tubular damage in patients with IBD and could not demonstrate a correlation between the enzymuria and the cumulative doses of 5-ASA.11 Moreover, they showed normalization of these urinary enzymes with successful medical therapy (directed to IBD) despite increasing cumulative doses of 5-ASA.11 In this respect, in a point prevalence study no clear distinction between the influence of disease activity and drug treatment can be made, if increased dosage of the antiinflammatory drug used correlated highly with disease activity.15

In summary, the low overall incidence of renal disease during 5-ASA treatment reported in the literature, and the absence of a clear relationship between 5-ASA dose and the risk of nephrotoxicity, suggest that the renal reactions may be idiosyncratic rather than dose-related in nature (see next section).

TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

The exact mechanism of nephrotoxicity described in IBD patients is not fully understood, but there would appear to be at least 2 means of induction of renal disease: first, a hypersensitivity or idiosyncratic etiology, independent of intake dose85; and second, a pharmacologically explainable dose-dependent nephrotoxicity.

Although in previous animal studies 5-ASA-related nephrotoxicity was dose-dependent, nephrotoxicity was only apparent at doses that were much higher compared with doses used in humans with IBD (ranging from 40–320 mg/kg of body weight; evidence of renal papillary necrosis was found at 60 or 100 mg/kg in dogs and 320 mg/kg in rats).7, 28 As previously mentioned, it has been suggested that in most cases renal failure was caused by an acute or chronic interstitial nephritis, which may be an idiosyncratic and dose-unrelated adverse event.

Clinical presentation of 5-ASA-related nephrotoxicity has been typically with enzymuria or microalbuminuria, interstitial nephritis, glomerulonephritis, hypersensitivity reaction involving liver and kidney, and acute renal failure. In rats, high-dose intravenous 5-ASA does cause renal papillary necrosis4, 6; in contrast, this lesion has only been reported once in the published reports of 5-ASA nephrotoxicity in patients with IBD.68, 86 As summarized in Table 1, most of the case reports of patients with IBD and renal disease associated with 5-ASA treatment suffered interstitial nephritis. In the particular case of this lesion, it seems probable that 5-ASA is causative and this is given credence by cases of partial or complete resolution of interstitial nephritis following drug withdrawal (see corresponding section). Furthermore, the cause–effect relationship between 5-ASA treatment and nephrotoxicity is strengthened by a report in which 5-ASA was associated with azotemia, which resolved with withdrawal of the drug but recurred when 5-ASA was reinstituted.68

The most frequent form of interstitial nephritis is severe, chronic, and progressive. Unlike classic drug-induced interstitial nephritis, symptoms and signs are scanty and nonspecific. Thus, 5-ASA-associated nephrotoxicity most frequently takes the form of an indolent, severe, chronic, and progressive interstitial nephritis.4, 52 The generally insidious onset and the lack of specific symptoms may delay detection for many months.22 The exact mechanism of the induction of interstitial nephritis is unknown. However, the prime mechanism is unlikely to be a type 1 hypersensitivity reaction, as in only a few cases have patients been noted to have fever, arthralgia, eosinophilia, or skin rashes.8, 75, 78 A delayed, cell-mediated response, resembling that described for other nonsteroidal antiinflammatory drugs, is the most likely mechanism.4, 8, 52, 75

IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

It has been suggested that mesalazine may induce renal impairment more frequently than sulfasalazine.25 In an analysis of spontaneous reports of adverse events in the UK, 5-ASA-related nephrotoxicity seemed more frequent in mesalazine-treated patients compared with sulfasalazine-treated patients.21 Thus, a total of 4.7 million prescriptions were dispensed for sulfasalazine compared with 2.8 million for mesalazine. Interstitial nephritis was only described for mesalazine, with 11.1 reports/1 million prescriptions.21 However, there are several important limitations of spontaneous reporting systems.87 In this respect, the results of another large epidemiological study, including almost 40,000 patients, showed no differences in renal toxicity between mesalazine and sulfasalazine (1.2 versus 1.7 rate per 1000 person years, respectively),23 in agreement with previous retrospective20 and case-control studies.9 More recently, data from the UK General Practice Research Database were used to estimate the incidence of renal disease in adult patients with IBD, and mesalazine and sulfasalazine users had comparable risks of nephrotoxicity (0.17 versus 0.29 cases per 100 person-years, respectively).17 In summary, the nephrotoxicity potential of mesalazine and sulfasalazine seems to be similar, and, if differences exist, they are probably minor.

TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Several authors have been unable to find differences between the nephrotoxicity potential of the several 5-ASA compounds.20, 21 Others have pointed out that mesalazine-associated interstitial nephritis has been reported most frequently with Asacol, but has also occurred with Dipentum (olsalazine).81 In 2 previous reports, serum concentrations of 5-ASA were higher in the mesalazine group compared with the olsalazine group.88, 89 In patients with IBD receiving maintenance 5-ASA therapy there was greater absorption and less acetylation of 5-ASA from mesalazine (Asacol) compared with sulfasalazine or olsalazine; however, this has not been shown to result in increased nephrotoxicity.90 Finally, although it has been suggested that Pentasa may be less frequently associated with interstitial nephritis than other 5-ASAs,8 and it has been noted that Asacol, Claversal, and Salofalk have a relatively higher dose-dumping effect than Pentasa with higher peak serum concentrations, theoretically contributing to potential nephrotoxicity.4, 91 Observation to date suggests that the relative risk with different oral preparations of 5-ASA is probably too small to influence the choice of agent.4, 17

SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Data in the literature about the safety of 5-ASA compounds in patients with IBD and chronic renal failure are lacking. Nevertheless, it has been suggested that more attention may be needed for patients with chronic renal failure and IBD using 5-ASA,92 as it is well known that patients with chronic renal failure are more likely to be affected by prerenal uremia and nephrotoxic agents.92 Furthermore, patients with IBD are more susceptible to renal damage during exacerbations of the illness—during the acute episode of diarrhea—when they may become dehydrated.

MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Mesalazine should be withdrawn when renal impairment manifests in a patient with IBD in whom no other cause can be readily identified. If withdrawal of 5-ASA treatment does not result in a fall in serum creatinine, then the patient should be referred for consideration of renal biopsy, as only this will determine whether interstitial nephritis or glomerulonephritis associated with IBD is the cause of the persistent impaired renal function.8

Steroids and azathioprine have been used in patients with renal impairment due to mesalazine-associated interstitial nephritis, but the evidence for a beneficial role is anecdotal and uncontrolled. Partial improvement or even complete recovery of renal function after steroid administration has been reported by several authors.51–56, 58, 59, 69, 73, 75–78 However, other studies have been unable to demonstrate a beneficial effect of these immunosuppressive drugs.8, 52, 58, 79 Nevertheless, it has been suggested that a trial of high-dose steroid (60 mg/day or 1 mg day/kg for up to 3 months) may be recommended in patients whose renal function does not respond to drug withdrawal alone.4

IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Withdrawal of 5-ASA therapy leads to recovery of renal function in the majority of these patients, with better changes after early withdrawal.8, 18, 52, 59, 61, 63, 64, 70, 71, 73, 76–80, 93 Thus, drug withdrawal leads to restoration of renal function in 40%–85% of cases where the diagnosis is made within 10 months of starting treatment.4, 8, 52 When the diagnosis is delayed beyond 18 months from the start of treatment, only one-third of cases show any recovery of function, and this is usually only partial.4, 8 Time to improvement of renal function after 5-ASA withdrawal, if it occurs, ranges from some weeks to 1 year.8, 18, 52, 59, 61, 63, 64, 70, 71, 73, 76–80, 93 Other authors have reported only partial improvement of renal function after drug withdrawal.21, 51, 53–56, 68, 69, 72, 74, 75, 77, 81, 82 Finally, although most case reports indicate reversibility after cessation of the drug, in some cases permanent clinical kidney dysfunction has been observed.55, 56, 58, 63, 65, 69, 77, 79 Thus, it has been calculated that ≈10% of the patients with 5-ASA nephrotoxicity will develop end-stage renal disease.52

In summary, the important message emerging is the need for timely recognition of renal impairment and prompt discontinuation of 5-ASA treatment of affected patients. By not doing so, patients are placed at risk for developing irreversible kidney damage.94

RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

First, it seems logical to avoid, if possible, 5-ASA preparations in patients with already known renal disease. Moreover, caution is recommended in patients at risk for developing renal disease, such as patients with diabetes mellitus and hypertension. Increased monitoring frequency is warranted in patients receiving concurrent steroid therapy since this may mask the development of significant renal damage.8

Despite a lack of evidence that monitoring of serum creatinine is necessary or effective in patients receiving 5-ASA treatment, it has been suggested that there is a need for this analytical control, as renal impairment is oligo-symptomatic and, if diagnosed at later stage, may result in irreversible chronic end-stage renal disease (on the contrary, prompt withdrawal of the drug could result in restoration of normal renal function if this is depressed as a result of interstitial nephritis in its early stages).

As most reported cases of mesalazine-induced interstitial nephritis present within 1 year of treatment initiation (see above), more frequent serum creatinine measurements are generally recommended during the first 12 months after starting 5-ASA treatment. Thus, many authors agree on performing frequent serum creatinine measurements during the first year of 5-ASA therapy, with gradually less frequent measurements thereafter. However, the optimal monitoring schedule remains to be established. It has been suggested that serum creatinine concentration should be measured each month for the first 3 months of treatment, 3-monthly for the remainder of the first year, and annually thereafter.8, 16, 27 A less “strict” recommendation for renal function monitoring advocate performing routine serum creatinine measurements at 6 and 12 months and then annually.22 As the reported time range for presentation of mesalazine-induced nephrotoxicity is wide and may be delayed several years (see above), regular monitoring of renal function has been suggested to be performed for the duration of therapy.

It should be noted that renal function is typically monitored using serum creatinine, which reflects the glomerular filtration rate; however, the shortcomings of serum creatinine as a marker of renal function are well known. Moreover, significant renal disease may predate increases in creatinine. Therefore, more studies are necessary to determine whether serum creatinine gives sufficient warning of nephrotoxicity or whether more elaborate tests of renal function are required.24

Finally, it should be emphasized that there is no evidence to date that either the test, or the frequency of testing, is effective in identifying these patients at risk of developing 5-ASA-related renal impairment, and therefore there are no firm recommendations, supported by medical evidence, for renal function monitoring (type and frequency) in IBD patients treated with these drugs. Moreover, the aforementioned “recommendations” regarding screening for renal impairment should be considered as “suggestions” and not as medically necessary based on the review of the literature, as there is presently no evidence that such screening or monitoring improves patient outcomes.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES

Nephrotoxicity, which may be potentially irreversible, has been described in some patients with IBD treated with 5-ASA. Microalbuminuria has been demonstrated to be present in the majority of IBD patients, and it seems to be related to disease activity rather than to 5-ASA treatment. Studies with 5-ASA treatment in which serum creatinine or creatinine clearance was measured regularly show that nephrotoxicity is exceptional, with a mean annual nephrotoxicity rate of only 0.26% per patient-year. There have been several case reports, including 46 patients, of renal disease associated with 5-ASA treatment in patients with IBD. 5-ASA treatment-related nephrotoxicity is reported most often within the first 12 months, but also delayed presentation after several years has been reported. The low overall incidence of renal disease during 5-ASA treatment reported in the literature, and the absence of a clear relationship between 5-ASA dose and the risk of nephrotoxicity, suggest that the renal reactions may be idiosyncratic rather than dose-related in nature. Most of the case reports of patients with IBD and renal disease associated with 5-ASA treatment suffered interstitial nephritis, with symptoms and signs being scanty and nonspecific, which may delay detection for many months. The nephrotoxicity potential of mesalazine and sulfasalazine seems to be similar. The relative risk with different oral preparations of 5-ASA is probably too small to influence the choice of agent. Mesalazine should be withdrawn when renal impairment manifests in a patient with IBD. The important message is the need for timely recognition of renal impairment and prompt discontinuation of 5-ASA treatment of affected patients. By not doing so, patients are placed at risk for developing irreversible kidney damage. If withdrawal of 5-ASA treatment does not result in a fall in serum creatinine, then the patient should be referred for consideration of renal biopsy. A trial of high-dose steroid may be recommended in patients whose renal function does not respond to drug withdrawal alone. Despite a lack of evidence that monitoring of serum creatinine is necessary or effective in patients receiving 5-ASA treatment, it has been suggested that there is a need for this analytical control. However, the optimal monitoring schedule remains to be established, as there is no evidence to date that either the test, or the frequency of testing, improves patient outcomes.

REFERENCES

  1. Top of page
  2. Abstract
  3. REVIEW METHODS
  4. PROTEINURIA IN PATIENTS WITH IBD
  5. EPIDEMIOLOGICAL STUDIES EVALUATING NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  6. CASE REPORTS OF NEPHROTOXICITY IN IBD PATIENTS TREATED WITH 5-ASA
  7. CHRONOLOGICAL ASPECTS OF 5-ASA NEPHROTOXICITY
  8. RENAL MARKERS OF NEPHROTOXICITY
  9. IS THERE A RELATIONSHIP BETWEEN DOSE OF 5-ASA AND NEPHROTOXICITY?
  10. TYPE OF NEPHROTOXICITY RELATED WITH 5-ASA TREATMENT
  11. IS THERE ANY DIFFERENCE IN THE NEPHROTOXICITY POTENTIAL OF MESALAZINE AND SULFASALAZINE?
  12. TYPE OF 5-ASA COMPOUND AND NEPHROTOXICITY
  13. SAFETY OF 5-ASA TREATMENT IN PATIENTS WITH IBD AND CHRONIC RENAL FAILURE
  14. MANAGEMENT OF RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT
  15. IS RENAL IMPAIRMENT DUE TO 5-ASA TREATMENT REVERSIBLE?
  16. RECOMMENDATIONS FOR RENAL FUNCTION MONITORING IN IBD PATIENTS TREATED WITH 5-ASA
  17. CONCLUSIONS
  18. REFERENCES