Acute interstitial nephritis: clinical features and response to corticosteroid therapy

Michael R. Clarkson1, Louise Giblin2, Fionnuala P. O'Connell1, Patrick O'Kelly2, Joseph J. Walshe2, Peter Conlon2, Yvonne O'Meara3, Anthony Dormon2, Eileen Campbell2 and John Donohoe2

1 Brigham and Women's Hospital, Renal Division, Boston, MA, USA, 2 Beaumont Hospital, Department of Nephrology and Transplantation and 3 Mater Misericordiae Hospital, Department of Medicine and Therapeutics, Dublin, Ireland

Correspondence and offprint requests to: Michael R. Clarkson, Renal Division, Brigham and Women's Hospital, 75 Frances Street, Boston, MA 02115, USA. Email: mrclarkson{at}partners.org



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Acute interstitial nephritis (AIN) is a recognized cause of reversible acute renal failure characterized by the presence of an interstitial inflammatory cell infiltrate.

Methods. In order to evaluate the clinical characteristics and management of this disorder, we performed a retrospective study of all cases of AIN found by reviewing 2598 native renal biopsies received at our institution over a 12 year period. Presenting clinical, laboratory and histological features were identified, as was clinical outcome with specific regard to corticosteroid therapy response.

Results. AIN was found in 2.6% of native biopsies, and 10.3% of all biopsies performed in the setting of acute renal failure during the period analysed (n = 60). The incidence of AIN increased progressively over the period observed from 1 to 4% per annum. AIN was drug related in 92% of cases and appeared to be idiopathic in the remainder. The presenting symptoms included oliguria (51%), arthralgia (45%), fever (30%), rash (21%) and loin pain (21%). Median serum creatinine at presentation was 670 µmol/l [interquartile range (IQR) 431–1031] and 58% of cases required acute renal replacement therapy. Corticosteroid therapy was administered in 60% of cases. Serum creatinine at baseline was similar in the corticosteroid-treated and conservatively managed groups; 700 µmol/l (IQR 449–1031) vs 545 µmol/l (IQR 339–1110) P = 0.4. In this, the largest retrospective series to date, we did not detect a statistically significant difference in outcome, as determined by serum creatinine, between those patients who received corticosteroid therapy and those who did not, at 1, 6 and 12 months following presentation.

Conclusion. The results of this study do not support the routine administration of corticosteroid therapy in the management of AIN.

Keywords: acute interstitial nephritis; acute renal failure; corticosteroids



   Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Acute interstitial nephritis (AIN) is an immune-mediated cause of acute renal failure (ARF) characterized by the presence of an inflammatory cell infiltrate in the interstitium of the kidney. First described by Councilman in 1898, it is now recognized as a major cause of drug-induced ARF and accounts for ~15% of patients undergoing renal biopsy for the investigation of unexplained ARF [1,2]. The mechanism of injury is postulated to involve cell-mediated immunity, and the syndrome is often associated with extra-renal manifestations of hypersensitivity such as rash, fever and eosinophilia [3–5]. Given the hypothesis that this is an immune-mediated disorder, therapy aimed at modulating the immune response has been the mainstay of treatment for AIN for over four decades. This has consisted primarily of the administration of high dose oral and intravenous (i.v.) corticosteroid therapy [2,6]. Despite the relative frequency of AIN as a cause of ARF, and the routine use of corticosteroids in this disorder, relatively few clinical papers have addressed the efficacy of this therapy. We therefore performed a chart review of all cases of biopsy-proven AIN at Beaumont Hospital (Dublin, Ireland). The specific aims of this study were to identify the incidence of AIN as a proportion of all cases of ARF, to examine the clinical features, morbidity and mortality associated with the condition, to identify risk factors for disease progression, and to define the role, if any, of corticosteroids in the management of this disorder.



   Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
We carried out a retrospective study of all adult cases of AIN reviewed at a tertiary nephrology referral centre for the period 1988–2001. Patients >15 years of age at presentation were considered adults. All patients had biopsy-proven AIN in the setting of unexplained ARF. All patients had at least 12 months of follow-up from initial presentation. Exclusion criteria included clinical features or laboratory findings consistent with acute bacterial pyelonephritis, documented evidence of a connective tissue disorder and clinical or serological (serum angiotensin-converting enzyme) evidence of sarcoidosis. This study was performed in accordance with the guidelines of the Hospital Ethics Committee.

Parameters investigated
Patient records were analysed to determine the presenting demographic, clinical, laboratory and renal biopsy characteristics. Possible trigger factors for the development of AIN were identified, as was the use of, and response to, corticosteroid therapy. Patients were considered dialysis dependent if they required renal replacement within 7 days of renal biopsy.

Histological evaluation
The histological diagnosis was based on the presence of an inflammatory interstitial infiltrate with or without interstitial fibrosis and the absence of coincident acute glomerular disease. For light microscopy, biopsy material was fixed in 0.1 M phosphate-buffered 10% formalin. Paraffin sections (3 µm) were stained with haematoxylin and eosin (H+E), periodic acid–Schiff, Masson trichrome and methenamine silver. All tissues were also examined using electron microscopy (EM) and standard immunofluorescence techniques.

Patients were excluded if they had a co-existent glomerular pathology (except minimal change disease) on EM. The presence of large numbers of polymorphonuclear leukocytes, as may be seen in acute pyelonephritis, was also considered an exclusion criterion. All specimens were analysed with respect to the percentage glomerulosclerosis and tubulointerstitial fibrosis, and the presence or absence of eosinophils or interstitial oedema. The severity of the interstitial infiltrate was scored as mild (1+), moderate (2+) or severe (3+). All biopsies were reviewed by one of two histopathologists with a special interest in renal pathology.

Corticosteroid therapy
The decision to use or withhold corticosteroid therapy had been that of the nephrologist caring for the patient at the time of the biopsy. While there was some variation in the dosage and length of steroid treatment, the typical regimen was methyprednisolone 500 mg i.v. for 2–4 days followed by oral prednisone at a dose of 0.75 mg/kg tapered over 3–6 weeks. In all patients who received steroids, therapy was initiated within 4 days of renal biopsy.

Statistical analysis
Non-parametric methods were used to compare the baseline features and clinical outcomes. Median and interquartile ranges (IQRs) are shown. Wilcoxon rank sum test was used to compare differences between the conservatively managed and steroid-treated groups. {chi}2 testing was used to analyse non-continuous variables.



   Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Incidence of acute interstitial nephritis
Sixty cases of AIN were identified over the 12 year period, constituting 2.4% of all native renal biopsies performed over the same period (n = 2598). AIN was the predominant lesion in 10.3% of all biopsies performed for unexplained ARF. The annual incidence increased over the time period analysed from 1 to 4% of all native renal biopsies.

Clinical features
The clinical and demographic features in the patient group are summarized in Table 1. The median age at presentation was 65 years (IQR 49–71) and the sex distribution was equal. The median time from symptom onset to biopsy was 3 weeks (IQR 2.4–4). The most common presenting clinical feature in our series was oliguria (51%). Systemic features of hypersensitivity were common but not invariable. Of these, arthralgia was the most frequent (45%), followed by fever (30%) and skin rash (21%). This ‘classic triad’ of features was seen in <10% of cases. Interstitial oedema leading to painful stretching of the renal capsule has been postulated to occur in AIN, and loin pain was a prominent clinical feature in 15% of patients. Four cases of tubulo-interstitial nephritis and uveitis syndrome were identified. In two cases, uveitis was the presenting feature; the other cases presented with interstitial nephritis in the first instance.


View this table:
[in this window]
[in a new window]
 
Table 1. Clinical and laboratory features at presentation in patients with acute interstitial nephritis

 
Peripheral eosinophilia is widely regarded as a frequent clinical correlate of AIN; however, in our series, it was noted in only 36% of cases at the time of biopsy. The erythrocyte sedimentation rate (ESR) was elevated in all cases. Proteinuria was typically modest, median 0.7 g/24 h (IQR 0.39–1.0); however, the median serum creatinine at presentation was 670 µmol/l (IQR 431–1031). The severity of renal dysfunction at presentation is reflected in the finding that 58% of cases were dialysis dependent at the time of biopsy or required dialytic support within 1 week of biopsy (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Clinical outcomes in patients with biopsy-proven acute interstitial nephritis

 
Histological characteristics
All cases were characterized by a prominent tubulointerstitial inflammatory cell infiltrate of varying composition. The infiltrate was typically lymphocyte-predominant, though eosinophils were noted in 94% of cases. The median percentage of interstitial fibrosis grading was 30% (range 20–40) and the percentage glomerulosclerosis noted was 8% (range 0–20). Interstitial oedema was a prominent finding in 55% of cases. No granulomata were noted.

Aetiology
The most common aetiological trigger factor identified was prior use of non-steroidal anti-inflammatory drugs (NSAIDs), which was documented in 44% of cases (Table 3). There was no statistically significant difference in the presenting serum creatinine between the NSAID-induced cases of AIN and cases unrelated to NSAID usage [673 µmol/l (IQR 266–918) vs 601 µmol/l (IQR 316–1000)], nor was there any appreciable difference noted in outcome at 12 months [123 µmol/l (IQR 110–228) vs 122 µmmol/l (IQR 107–181), P = 0.8]. Antibiotic-associated cases constituted the next largest cohort of patients at 33%. In later years, AIN secondary to proton pump inhibitors constituted a significant proportion of cases.


View this table:
[in this window]
[in a new window]
 
Table 3. Aetiological factors in acute interstitial nephritis

 
Outcome
Two patients died within 12 months of diagnosis (4%). Both died of illnesses unrelated to their renal disease. The first was an 80-year-old male who died of a coincidental bronchial carcinoma several months after diagnosis. The second was an 82-year-old male with a history of severe coronary artery disease who died of sudden cardiac arrest several weeks after renal biopsy. Of the patients who were dialysis dependent at the time of biopsy (n = 35), only two remained dialysis dependent at 12 months. In both cases, moderate to severe tubulointerstitial fibrosis was noted on renal biopsy at presentation. Excluding those patients who died or remained haemodialysis dependent, the short- to medium-term outcome was good. The median serum creatinine at 1, 6 and 12 months was 181 µmol/l (range 143–279), 123 µmol/l (range 112–201) and 141 µmol/l (range 110–206 µmol/l), respectively. At a mean follow-up interval of >5 years, no patient who was dialysis independent within 12 months of presentation had developed end-stage renal disease (ESRD).

Role of corticosteroid therapy
Of those patients in whom complete follow-up data were available (n = 42), 60% received corticosteroid therapy while the remainder received supportive care only. The baseline characteristics of both groups are outlined in Table 4. The two groups were well matched with regard to age, baseline creatinine, tubulointerstitial infiltrate score, baseline haemoglobin, period of time from symptom onset until biopsy, percentage of interstitial fibrosis or glomerulosclerosis noted, and treating physician (steroid treated, n = 26; conservative management, n = 16). No difference in outcome was observed between the two groups with respect to the median serum creatinine at time points of 1, 6 and 12 months following diagnosis (Figure 1, Table 5). Several papers have suggested that corticosteroid therapy accelerates time to recovery without actually affecting eventual outcome as measured by serum creatinine [7]. Whilst this variable was not specifically addressed in our study, time to dialysis independence was similar in the conservatively managed group as compared with the steroid-treated group [1 week (IQR 1–1.5) vs 2 weeks (IQR 1–2) P = 0.6], as was the outcome at 1 month (Table 5). Subgroup analysis of the NSAID-induced AIN cohort revealed similar findings, albeit that the number of patients in both groups was small (n = 9 for both) (Table 6). Of note, there was no difference between the NSAID and non-NSAID groups with respect to systemic eosinophilia or presence of eosinophils in the biopsy specimen (95 vs 93%, P = 0.9). No adverse events leading to prolongation of hospital stay were attributed to corticosteroid-induced complications.


View this table:
[in this window]
[in a new window]
 
Table 4. Baseline characteristics of the conservatively managed vs corticosteroid-treated group

 


View larger version (14K):
[in this window]
[in a new window]
 
Fig. 1. Effect of corticosteroid therapy in AIN compared with conservative management. Values for serum creatinine (µmol/l) are given as median±interquartile range.

 

View this table:
[in this window]
[in a new window]
 
Table 5. Serum creatinine over a 1 year period in the conservatively managed vs the corticosteroid-treated group

 

View this table:
[in this window]
[in a new window]
 
Table 6. NSAID subgroup analysis: serum creatinine over a 1 year period in the conservatively managed vs the corticosteroid-treated group

 


   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Councilman first described AIN in association with diphtheria and scarlet fever in the late 19th century [1]. Since that time, the spectrum of aetiological factors implicated in the development of AIN has evolved such that drug-induced AIN is now the most commonly recognized form of the disease [2,7,8]. The majority of cases are linked to commonly prescribed medications such as NSAIDs and ß-lactam antibiotics. Often included in the differential diagnosis of ARF, AIN accounts for <5% of all cases, and there is a paucity of data in the literature regarding optimal management of the condition. Several small retrospective studies have suggested that corticosteroid therapy improves clinical outcome; however, no prospective studies exist [7,9,10].

In this study, we present the largest published series to date specifically addressing the role of corticosteroid therapy in the management of patients with AIN. In this series, >90% of cases had historical evidence suggestive of a drug-related aetiology. As in other studies, NSAIDs were prominent amongst the causative agents, accounting for 44% of cases. It is unclear whether NSAIDs are specifically more immunogenic than other drug classes or whether the preponderance of NSAID-induced AIN simply reflects their widespread usage especially in older patients. Interestingly, no cases of AIN in association with minimal change disease were noted, a syndrome typically associated with NSAID usage.

The incidence of AIN as a percentage of all renal biopsies in our study is similar to that published in previous reports [2]. Interestingly there appeared to be a sustained rise in the incidence of AIN over the time period analysed. Changes in biopsy practice are unlikely to explain this finding given that the typical presentation was that of rapid-onset azotaemia in association with modest proteinuria and varying degrees of haematuria/pyuria. In this clinical setting, conservative management without recourse to renal biopsy would not have been considered appropriate during the time period of the study. The observed increase in incidence may be associated with changes in prescribing practices such as the greater use of NSAIDs and/or antibiotics by primary care physicians.

AIN can be seen in any age group, but the wider use of prescription medication in the elderly combined with reduced renal drug clearance places this age group at greater risk of adverse events including AIN [11,12]. This is reflected in the median age at presentation in our series of 65 years.

AIN is often suspected in cases of unexplained ARF. However, precise diagnosis is hampered by a combination of the rapid clinical course in most cases and an absence of specific clinical features or laboratory findings. In our series, the median creatinine at presentation was 670 µmol/l, and over half of the patients required dialysis within days of presentation. The median time from onset of any symptoms to biopsy was 3.5 weeks. Most of the signs and symptoms of hypersensitivity such as skin rash, fever and arthralgia are non-specific and unlikely to provoke an immediate assessment of renal function by non-nephrologists within the time frame of presentation.

By the time oliguria has supervened, the need for renal replacement therapy is imminent. The ‘classic triad’ of fever, skin rash and arthralgia characteristic of a generalized systemic allergic reaction was an uncommon presentation and of little use as a discriminatory factor in diagnosis. Laboratory findings were similarly unhelpful. The incidence of eosiniophilia varies greatly in previously published studies [13–15]. In our series, only 36% of patients had documented eosinophilia at the time of biopsy, a finding consistent with studies in the post-methicillin era. While 100% of the patients had an abnormal urinalysis and modest proteinuria, no specific pattern of urinalysis was observed and patients displayed varying levels of pyuria and haematuria. Of note, the incidence of eosinophiliuria was not specifically addressed in this study; however, previous studies have questioned its predictive value in ARF. Thus, while the diagnosis of AIN may be strongly suspected on clinical grounds, renal biopsy is essential for accurate diagnosis.

In contradistinction to patients with ARF in the setting of critical illness in general, the outcome of drug-induced AIN is good and recovery of renal function has been the norm in previous studies [7,15,16]. In our study, the mortality rate was <5%, a remarkably low figure given the high median age of the patients and the fact that >50% were haemodialysis dependent at some stage during their hospitalization. The long-term renal outcome in our series was also encouraging. The median creatinine at 1 year in those patients who did not develop ESRD was 141 µmol/l, a reflection of relatively modest residual renal injury. Progressive renal dysfunction thereafter was unusual, and most patients maintained a stable glomerular filtration rate on subsequent follow-up. In the two patients who developed ESRD, advanced tubulo-interstitial injury was present at the time of diagnosis, possibly reflecting silent renal inflammatory injury and scarring over the preceding months and years.

AIN is a relatively uncommon disorder and treatment in largely empiric. Given the evidence suggesting an allergic aetiology, the mainstay of treatment has been the removal of the offending agent and in many cases the administration of corticosteroid therapy. The issue of corticosteroid therapy is a controversial one, and the available studies are all retrospective and not controlled [6,7,17,18]. The widespread use of corticosteroid therapy in this disorder is largely based on the outcome of two studies involving <25 cases each, in which corticosteroid therapy was found to accelerate renal recovery and improve the final baseline serum creatinine [7,19]. In the larger of these studies, eight of 14 patients with methicillin-induced AIN were treated with oral prednisolone and experienced a more rapid and complete restoration of renal function than those patients managed by discontinuation of the methicillin alone [19]. In the later study by Pusey et al., seven of nine patients with AIN received methylprednisolone with a prompt recovery of renal function, and in the two untreated patients the recovery was either delayed or incomplete [7]. Although other studies have contradicted these findings, most critical reviews continue to advocate the use of corticosteroid therapy [6,17].

The suggestion that corticosteroid therapy accelerates renal recovery in AIN is an important one, but evidence suggesting that corticosteroid therapy effects such a change is lacking from our studies. We were unable to discern any benefit from early corticosteroid therapy in terms of either the rate of renal recovery or final baseline serum creatinine. This was also true for the most severely affected patients, those on haemodialysis, in whom there was no significant difference in time to dialysis independence (as measured in weeks) between those who received corticosteroid treatment and those who did not. The degree of renal dysfunction observed in patients included in this series was similar to previous series by Pusey et al. and Galpin et al. [7,19]. Thus a failure to demonstrate a beneficial effect cannot be ascribed to differences in renal function at presentation.

Several reports have suggested qualitative differences in NSAID-induced AIN as opposed to AIN secondary to infection or other pharmacological agents [17,20]. These differences have been stated to include heavier proteinuria, absence of systemic eosinophilia and a lymphocyte-predominant infiltrate as opposed to an eosinophilic infiltrate on biopsy, and a worse clinical outcome. We were unable to corroborate these findings. The degree of proteinuria and eosinophilia was similar in both groups. There was no difference observed between NSAID-associated AIN in terms of either presenting or final baseline creatinine. Subgroup analysis of the NSAID group in terms of response to corticosteroid therapy was no different from that of the overall series, suggesting that in the absence of a minimal change-like lesion, there is no substantive difference between the subgroup of patients with NSAID-induced AIN and AIN patients with other trigger factors.

In summary, in this series, AIN was seen in a significant minority of renal biopsy cases. It was most frequently associated with prescription medication, typically NSAIDs or commonly prescribed antibiotics. The clinical presentation can be dramatic with life-threatening complications of acute azotaemia; however, with appropriate supportive care, the long-term prognosis is good. We were unable to show a beneficial effect of corticosteroid therapy in terms of either the rate or extent of renal recovery. The limitations of this study include its retrospective nature and relatively small size. A larger multicentre prospective and controlled study is clearly needed to determine the appropriate role of corticosteroid therapy in the management of AIN. In the interim, steroid therapy should be reserved for those patients in whom renal recovery is delayed for >10–14 days following removal of the offending trigger factor or in those patients with a coincident minimal change lesion [21].

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Councilman WT. Acute interstitial nephritis. J Exp Med 1898; III: 27–422
  2. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001; 60: 804–817[CrossRef][ISI][Medline]
  3. Ooi BS, Jao W, First MR, Mancilla R, Pollak VE. Acute interstitial nephritis. a clinical and pathological study based on renal biopsies. Am J Med 1975; 59: 614–629[CrossRef][ISI][Medline]
  4. Magil AB, Ballon HS, Cameron EC, Rae A. Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathologic observations in three cases. Am J Med 1980; 69: 939–943[ISI][Medline]
  5. D’Agati VD, Theise ND, Pirani CL, Knowles DM, Appel GB. Interstitial nephritis related to nonsteroidal anti-inflammatory agents and beta-lactam antibiotics: a comparative study of the interstitial infiltrates using monoclonal antibodies. Mod Pathol 1989; 2: 390–396[ISI][Medline]
  6. Reddy S, Salant DJ. Treatment of acute interstitial nephritis. Ren Fail 1998; 20: 829–838[ISI][Medline]
  7. Pusey CD, Saltissi D, Bloodworth L, Rainford DJ, Christie JL. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med 1983; 52: 194–211[ISI][Medline]
  8. Linton AL, Clark WF, Driedger AA, Turnbull I, Lindsay RM. Acute interstitial nephritis due to drugs. Ann Intern Med 1980; 93: 735–741[ISI][Medline]
  9. Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990; 5: 94–99[Abstract]
  10. Enriquez R, Gonzalez C, Cabezuelo JB et al. Relapsing steroid-responsive idiopathic acute interstitial nephritis. Nephron 1993; 63: 462–465[ISI][Medline]
  11. Gurwitx JH, Field TS, Harold LR et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. J Am Med Assoc 2003; 289: 1107–1116[Abstract/Free Full Text]
  12. Buchanan WW. Implications of NSAID therapy in elderly patients. J Rheumatol Suppl 1990; 20: 29–32[Medline]
  13. Corwin HL, Korbet SM, Schwartz MM. Clinical correlates of eosinophiluria. Arch Intern Med 1985; 145: 1097–1099[Abstract]
  14. Nolan CR 3rd, Anger MS, Kelleher SP. Eosinophiluriaµa new method of detection and definition of the clinical spectrum. N Engl J Med 1986; 315: 1516–1519[Abstract]
  15. Joh K, Aizawa S, Yamaguchi Y et al. Drug-induced hypersensitivity nephritis: lymphocyte stimulation testing and renal biopsy in 10 cases. Am J Nephrol 1990; 10: 222–230[ISI][Medline]
  16. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. J Am Med Assoc 1996; 275: 1489–1494[Abstract]
  17. Porile JL, Bakris GL, Garella S. Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: a review of its clinical spectrum and effects of steroid therapy. J Clin Pharmacol 1990; 30: 468–475[Abstract/Free Full Text]
  18. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M. Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 1996; 27: 209–215.[ISI][Medline]
  19. Galpin JE, Sinaberger JH, Stanley TM et al. Acute interstitial nephritis due to methicillin. Am J Med 1978; 65: 756–765[ISI][Medline]
  20. Schwarz A, Krause PH, Kunzendorf U, Keller F, Distler A. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2000; 54: 170–190
  21. Furuya R, Kumagai H, Ikegaya N et al. Reversible acute renal failure in idiopathic nephrotic syndrome. Intern Med 1993; 32: 31–35[ISI][Medline]
Received for publication: 4. 2.04
Accepted in revised form: 30. 7.04





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
19/11/2778    most recent
gfh485v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (5)
Disclaimer
Request Permissions
Google Scholar
Articles by Clarkson, M. R.
Articles by Donohoe, J.
PubMed
PubMed Citation
Articles by Clarkson, M. R.
Articles by Donohoe, J.