1 Renal Unit and 2 Department of Histopathology, Kings College Hospital, London, UK
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Abstract |
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Methods. Since 1995, we have identified a number of patients with biopsy-proven granulomatous interstitial nephritis. Patients were excluded if they had (i) evidence of extrarenal sarcoid, (ii) infections that may have contributed to pathogenesis or (iii) an obvious drug-related aetiology.
Results. Seven patients were identified, of whom five were male and two female, with a median age of 69. Median calculated creatinine clearance at presentation was 14 ml/min. Two had raised serum calcium at presentation and three had a raised serum angiotensin-converting enzyme. All patients were treated with steroids and five out of seven had an improvement in their renal function. Two patients progressed to end-stage renal failure despite treatment with steroids.
Conclusions. Idiopathic granulomatous interstitial nephritis may represent a renal-limited form of sarcoid. It may be associated with hypercalcaemia and a raised serum angiotensin-converting enzyme and usually responds to treatment with corticosteroids.
Keywords: granuloma; interstitial; nephritis; renal; sarcoid; steroids
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Introduction |
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Methods |
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Results |
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Case 2
A 70-year-old Caucasian male presented with confusion, nausea and lethargy and was clinically hypovolaemic. There was no history of hypertension, although he was diabetic and had been taking gliclazide. He was on no other medication. Corrected calcium was 3.47 mmol/l, calculated creatinine clearance 10 ml/min (serum creatinine 435 µmol/l) and serum ACE was raised at 195 U/l. Chest X-ray was normal and proteinuria was 772 mg/day. Liver function tests were normal. His volume depletion and hypercalcaemia were treated with intravenous fluids, frusemide and bisphosphonates. His calculated creatinine clearance improved temporarily to 15 ml/min (serum creatinine 300 µmol/l), but then deteriorated to 10 ml/min (serum creatinine 435 µmol/l) and he underwent renal biopsy. This showed GIN. He was treated with prednisolone at 40 mg a day and 1 month later his calculated creatinine clearance had risen to 20 ml/min and his calcium was normal. At 9 months his calculated creatinine clearance was 21 ml/min (serum creatinine 213 µmol/l).
Case 3
A 66-year-old Caucasian female presented with unexplained renal impairment and a calculated creatinine clearance of 14 ml/min (serum creatinine 296 µmol/l). She had no systemic symptoms and no other significant symptoms or clinical findings. She had been hypertensive for 2 years, treated with enalapril and also took aspirin. She was known to have had an abnormal urea (11.2 mmol/l) 5 years previously, although creatinine was not measured. Renal ultrasound showed 9.4 and 9 cm kidneys with reduced cortical thickness and renal angiography was normal. The 24 h protein excretion was not raised and there was no haematuria. She had a renal biopsy which showed GIN. Chest X-ray, serum ACE and serum calcium were normal. Serum ACE may, however, have been lowered by the ACE inhibitor. Liver function tests showed a mildly elevated alkaline phosphatase of 128 IU/l, a raised GGT of IU/l, with a normal bilirubin. Enalapril was discontinued due to hyperkalaemia, but aspirin was continued. She was treated with prednisolone starting at 30 mg a day. Despite this, her renal function deteriorated and 3 months later she started renal replacement therapy.
Case 4
This 64-year-old Caucasian female presented with systemic symptoms including fevers and weight loss. She had long standing hypertension and had had dermatomyositis 20 years previously but had needed no treatment for 7 years. She had also had a duodenal carcinoid tumour. She was taking oxprenolol, lorazepam, zopiclone, ibuprofen and ciprofloxacin on admission. She was found to have advanced renal failure with a calculated creatinine of clearance of 14 ml/min (serum creatinine 436 µmol/l). Ibuprofen had been started at a time when her calculated creatinine clearance was already 20 ml/min (serum creatinine 300 µmol/l). She had 0.42 g/day of proteinuria. Chest X-ray, serum ACE and calcium were normal. Liver function tests were normal. She had a renal biopsy that showed GIN and was treated with prednisolone starting at 40 mg a day. Oxprenolol and lorazepam were continued, but the other medication she had been taking on admission was stopped. Her calculated creatinine clearance improved rapidly; at 2 months it was 56 ml/min (serum creatinine 129 µmol/l) and has stayed at this level (5356 ml/min, with serum creatinine 125135 µmol/l) after 4 years of treatment.
Case 5
A 69-year-old Caucasian male was admitted with a 12 month history of lethargy and anorexia. He was seen with right upper quadrant pain and gall stones and incidentally found to have a calculated creatinine clearance of 16 ml/min (serum creatinine 493 µmol/l). He was known to have had a normal serum creatinine 1 year previously. Blood pressure was normal. He had been taking ibuprofen for back pain, although this was stopped 2 months prior to his renal biopsy. During this time there was continued deterioration in his renal function. Corrected calcium was 2.63 mmol/l, serum ACE was raised at 160 U/l. Chest X-ray was normal and urine culture for tuberculosis was negative. Liver function tests were normal. The 24 h proteinuria was 230 mg/day with no haematuria. His only medication on admission was paracetamol. Renal biopsy showed GIN. He was treated with prednisolone starting at 40 mg a day and after 3 months his calculated creatinine clearance was 29 ml/min (serum creatinine 264 µmol/l).
Case 6
A 70-year-old Caucasian male presented with unexplained renal failure. He had a 3 week history of vomiting, anorexia and lethargy which was attributed to his uraemia. On admission he was taking atenolol, ibuprofen and omeprazole. Initial calculated creatinine clearance was 6 ml/min (serum creatinine 1243 µmol/l) and he required dialysis for several days. Chest X-ray, serum calcium and serum ACE were normal. Liver function tests were normal. He had 0.9 g/day of proteinuria. Renal ultrasound was normal and biopsy showed GIN. He was treated with intravenous methylprednisolone at 500 mg a day for 3 days followed by prednisolone at 40 mg a day and was able to discontinue dialysis. Atenolol was continued but ibuprofen and omeprazole were not. His creatinine improved very gradually over several years and after 56 months he had a calculated creatinine clearance of 22 ml/min (serum creatinine 356 µmol/l).
Case 7
A 72-year-old Caucasian male presented with unexplained renal impairment. There were no systemic symptoms or other remarkable clinical findings. He was known to have had a normal serum creatinine 18 months previously. His calculated creatinine clearance was 26 ml/min (serum creatinine 400 µmol/l) 4 months earlier when he had a transurethral resection of the prostate. He had no evidence of renal tract obstruction at this point. There was no haematuria and 24 h urinary protein excretion was normal. He was taking allopurinol, bumetanide and omeprazole at presentation. Calculated creatinine clearance was 29 ml/min (serum creatinine 357 µmol/l). Chest X-ray and calcium were normal, serum ACE was marginally raised at 55 U/l but calcium was normal. Liver function tests were normal. Ultrasound showed two normal-sized kidneys with no obstruction. He was not previously known to be hypertensive but required treatment for hypertension before renal biopsy. Renal biopsy showed GIN. He was given prednisolone starting at 20 mg a day and the medication he was taking at presentation was continued. At 4 months his calculated creatinine clearance had risen to 44 ml/min (serum creatinine 235 µmol/l) but fell at 7 months to 31 ml/min (serum creatinine 328 µmol/l).
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Discussion |
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We have identified four reports of single cases of idiopathic GIN in the literature [1114]. In these reports, there were no features of sarcoid in organs other than the kidney and there were no other causes of GIN apparent. Serum ACE was commented on in one of these cases and was normal. Serum calcium was commented on in two cases and was normal. In addition, a recent paper documents five cases of idiopathic GIN [15]. Only one had a raised serum ACE and serum calcium was normal in all cases. Our series of seven patients represents the largest series of idiopathic GIN reported. In contrast to the above series, we found a raised serum ACE in three out of seven patients and high corrected calcium in two of these cases. Two patients had mildly abnormal liver function tests, with liver function tests normal in the remainder. Chest X-ray was normal in all patients. We did not perform further invasive tests, such as bronchoscopy, computerized tomography scan or salivary gland biopsies.
Before making a diagnosis of idiopathic GIN, it is important to consider other causes of GIN. GIN has been attributed to a variety of drugs, although proof that a particular drug is responsible is often circumstantial [16]. Supportive evidence may include a temporal relation between starting the drug and the development of renal failure or cessation of the drug and an improvement in renal function. In two patients (cases 1 and 3), abnormal renal function was noted at a time when no medication was taken. In none of the other cases was there a clear relation between starting a drug and the development of disease. However, it is impossible to exclude a drug-induced aetiology in these patients.
A variety of infections may also cause a granulomatous inflammation in organs including the kidney [17]. In all of our patients, staining of histological sections for mycobacteria and fungi were negative, as were urine cultures for tuberculosis. There was no evidence of any other infection that may have caused the granulomatous inflammation. The response to long-term steroid treatment in five of our seven patients is also against an infectious aetiology.
Interstitial nephritis associated with extrarenal sarcoid responds to treatment with corticosteroids. In a series of 22 patients with interstitial nephritis, of whom 10 also had renal granulomas, 61% of patients showed an improvement in renal function with steroid therapy [10]. A further observation in this report was that patients may show a relapse after withdrawal of steroids. This was seen in five patients and four improved on restarting steroid treatment. This suggests that long-term treatment with steroids may be necessary. Other reports confirm that GIN associated with sarcoid is steroid-sensitive. For example, all six patients reported in Hannedouche et al. [9] showed a response to steroids. However, serum creatinine does not generally return to normal, reflecting the irreversible renal damage commonly seen on biopsy. Even patients with severe chronic damage on renal biopsy may respond to steroids. For example, case 2 had 100% chronic tubular atrophy on biopsy but responded well to steroids. Although this suggests that even a chronically damaged kidney may respond to treatment, there may also be an element of sampling error in the biopsy obtained. Eight of the nine cases of renal-limited sarcoidosis referred to above were treated with steroids and seven showed an improvement in renal function, suggesting that renal-limited sarcoid responds in a similar manner to systemic sarcoid with renal involvement [1115]. Our series of patients confirms that most patients with renal-limited sarcoid respond to steroids, although renal function does not usually return to normal. In five out of seven of our patients, serum creatinine fell in response to steroids, although the serum creatinine then returned to its previous level in one (case 7). As described above for GIN with extrarenal sarcoid, we have found that prolonged steroid treatment may be needed and we recommend continuing for at least 1 year. Two patients progressed to end-stage renal failure despite treatment, necessitating renal replacement therapy. However, one of these patients was known to have had advanced renal failure for several months prior to treatment and in addition may not have complied with treatment.
In conclusion, we have presented a series of seven patients with idiopathic GIN. None of the patients had evidence of sarcoid affecting other organs or another cause for GIN. Three had a raised serum ACE and/or hypercalcaemia, with five out of seven showing a response to steroid treatment.
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Notes |
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References |
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