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British Journal of Radiology (2006) 79, 1009-1010
© 2006 British Institute of Radiology
doi: 10.1259/bjr/47913384
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Correspondence

MRI histopathology correlation of N-phenylanthranilic acid induced nephropathy in rats

Analgesic-associated nephropathy and renal papilla necrosis (RPN) is a common cause of renal failure in humans [1]. It mainly develops as a consequence of chronic consumption or long-term abuse of single or mixed analgesics, especially non-steroid anti-inflammatory drugs (NSAIDs). In Australasia, this cause has been reported to account for between 15% and 20% of patients needing renal transplants [2]. The mechanism of this analgesic-associated nephropathy is poorly understood [3, 4]. It has been suggested that NSAIDs might cause RPN through ischaemic injury through the direct inhibition of cyclo-oxygenase-mediated production of prostaglandins [4]. In the early development of analgesic-associated RPN, there are few clinical symptoms and specific urine or blood biomarkers. The progression of renal damage is insidious and renal function may be severely compromised before the condition becomes obvious. Recently, the combined use of imaging modalities ensured an increased degree of positive diagnosis in human population.

N-phenylanthranilic acid (NPAA) has been used as an inducer of nephropathy and RPN in the rat, causing similar pathology to that seen in human analgesic abusers [5–7]. This study investigated the correlation between histopathology of NPAA induced nephropathy in rats and its ex vivo MRI appearance.

12 male Han/Wistar rats (Charles River, UK) were used. The age at the start of dosing was 6–8 weeks. Animals were housed four to a cage with water from the site drinking supply and pelleted diet. Eight animals were dosed once daily, by oral gavage, of NPAA 700 mg kg–1, for 14 days. Four animals were treated with vehicle (1.25%(w/v) carboxymethyl cellulose in water). All animals were euthanized by halothane overdose prior to necropsy approximately 24 h after receiving the final dose. MRI was performed immediately following euthanasia. Without other intervention, left kidney was removed and placed in a small vial containing 10% formalin. These kidneys were scanned using a Varian horizontal 9.4 T magnet (Varian, Palo Alto, CA; 40 Gauss cm–1 gradient strength; rise time 200 µs), and a 38 mm quadrature birdcage radiofrequency (RF) coil. Kidneys were positioned with their longitudinal axis parallel to B0. MRI included a transverse spin echo multiple slice sequence (repetition time (TR)/echo time (TE) = 1000/13 ms, resolution = 0.078 mm x 0.313 mm), a coronal spin echo multiple slice sequence (TR/TE = 2000/30 ms, resolution = 0.313 mm x 0.313 mm), and a coronal gradient echo multiple slice sequence (TR/TE = 35/6 ms, flip angle = 40°, resolution = 0.313 mm x 0.313 mm). The slice thickness was 0.5 mm for all scans. After the MRI scan, kidneys were processed to haematoxylin-eosin stained sections plus immunohistochemistry for collecting ducts. All procedures were performed in full compliance with licenses issued under the UK Animals (Scientific Procedures) act, 1986.

Histopathology revealed that kidneys of all NPAA treated animals showed various nephropathy changes; these kidneys were also large in size. Microscopically, NPAA induced nephropathy included cortical collecting tubular dilatation, tubular basophilia, corticomedullary interstitial nephritis, intratubular protein casts and papillary collecting tubule dilation. One rat showed a minimal degree of unilateral renal papilla necrosis.

With MRI, the medulla of control animal kidneys showed higher signal than the cortex both on spin echo and gradient echo images, with a clear corticomedullary junction (GoFigures 1a and 2aGo). In kidneys with NPAA induced nephropathy, a loss in the clear demarcation of the corticomedullary junction was seen (GoFigures 1b,c and 2bGo). Additionally, fine radial bands pointing to the renal papilla with alternating high and low signal were observed primarily in the cortex. These radial bands were aligned with the medulla rays seen longitudinally (Figure 1b,cGo). These pathological changes could be observed on both spin echo images and gradient echo images, although spin echo images tended to show richer tissue contrast than gradient echo images with the pulse sequence parameters used. MRI also revealed an increase in overall dimensions of kidney compared with the control kidneys.


Figure 1
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  		Figure 1. (a) Coronal spin echo MR image of a left kidney from a control animal. (b,c) Coronal spin echo image of left kidney from NPAA treated animals. The kidneys in (b,c) show increased size, loss of clear demarcation of corticomedullary junction and fines radial bands with alternating high and low signal. (a) A swollen medulla.

 

Figure 2
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  		Figure 2. (a) Axial spin echo MR image of a left kidney from a control animal. (b) Axial spin echo images of left kidney from a NPAA treated animal showing a loss of the demarcation of corticomedullary junction.

 
There are literature reports of using 1H MR spectroscopy for the analysis of urine sample from NPAA induced rat nephropathy [6, 7]. To our knowledge there is no literature report on MRI study in this nephropathy model. Our study demonstrated that MRI was able to detect NPAA induced nephrotoxic changes in rats ahead of renal papillary necrosis. Besides that, MRI demonstrated the increase in overall dimensions of kidneys; the pre-necrotic histological changes observed in the medulla (increased interstitial matrix, hypertrophy of collecting ducts) were consistent with the swollen medulla as demonstrated by MRI. In particular, it is interesting to observe that grouping of collecting tubular dilatation in medullary rays was reflected on MR images as fine radial bands pointing to the renal papilla, probably due to the increased water content and therefore MR signal intensity. Histopathology showed that the corticomedullary junction region was the site of degenerative and regenerative inflammatory changes. This was shown by MRI as a loss of clear demarcation of the corticomedullary junction. It has long been recognized that the changes in the corticomedullary junction on in vivo MRI is an indicator of kidney diseases [8, 9]. This was believed being partly due to the changed status of the relative hydration of the medulla and cortex.

With the magnetic field and gradient strength used in this study, higher spatial resolution could be achieved. However, this was constrained during the study by the requirement that the MR scan duration needed to be minimized so that the kidney specimens could be processed quickly for further histology. In addition, our results are from ex vivo study with the kidney not being perfused. Further in vivo study is needed to confirm these findings.

In conclusion, our ex vivo MRI preliminary results appear to suggest that non-contrast-enhanced MRI could provide sensitive imaging markers for NPAA induced kidney damage. These findings could potentially be translated to non-invasive in vivo animal studies and clinical studies in humans.

Yi-Xiang J Wang, Graham Betton, Eike Floettmann and Carsten Liess

AstraZeneca Pharmaceuticals Alderley Park Macclesfield Cheshire UK

Received for publication February 15, 2006. Revision received August 16, 2006. Accepted for publication August 25, 2006.

References

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  2. Stewart JH, Gallery ED. Analgesic abuse and kidney disease. Aust N Z J Med 1976;6:498–508.[Medline]
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  5. Hardy TL. N-phenyl anthranilic acid: an agent for inducing and studying renal papillary necrosis in the rat. Br J Exp Pathol 1970;51:348–55.[Medline]
  6. Hardy TL, Bach PH. The effect of N-phenylanthranilic acid-induced renal papillary necrosis on urinary acidification and renal electrolyte handling. Toxicol Appl Pharmacol 1984;75:265–77.[CrossRef][Medline]
  7. Williams RE, Cottrell L, Jacobsen M, Bandara LR, Kelly MD, Kennedy S, et al. 1H-Nuclear magnetic resonance pattern recognition studies with N-phenylanthranilic acid in the rat: time- and dose-related metabolic effects. Biomarkers 2003;8:472–90.[CrossRef][Medline]
  8. Bennett HF, Li D. MR imaging of renal function. Magn Reson Imaging Clin N Am 1997;5:107–26.[Medline]
  9. Lohr J, Mazurchuk RJ, Acara MA, Nickerson PA, Fiel RJ. Magnetic resonance imaging (MRI) and pathophysiology of the rat kidney in streptozotocin-induced diabetes. Magn Reson Imaging 1991;9:93–100.[CrossRef][Medline]



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