Nephrol Dial Transplant (1990) 5: 18-24 © 1990 European Dialysis and Transplant Association-European Renal Association

Nephrology Dialysis Transplantation

Original Article

Renal Granulomatous Sarcoidosis: Report of Six Cases T. Hannedouche1, G. Grateau1, L. H. Noel1, M. Godin2, J. P. Fillastre2, J. P. Griinfeld1 and P. Jungers1 1

Department of Nephrology, Necker Hospital, Paris, 2Nephrology Unit, Hopital de Boisguillaume, France

Abstract. Six cases of chronic renal failure related to granulomatous renal sarcoidosis are reported and compared with data in the literature. The particular features of sarcoidosis granulomatous interstitial nephritis should be emphasised because presentation may be misleading. Renal failure usually presents with a rapidly progressive course, either isolated or associated with mild proteinuria and sterile leukocyturia, while extrarenal localisations may be absent. Diagnosis should be suspected on the basis of elevated or paradoxically normal serum calcium concentrations, due to increased plasma concentrations of calcitriol, while immunoreactive circulating parathormone concentrations are depressed. Calcitriol as well as angiotensinconverting enzyme could represent unregulated secretion products from granulomatous tissue and their plasma concentrations may roughly reflect activity of the disease. Early corticosteroid treatment dramatically improves renal function but long-term renal prognosis may be oblitered due to progressive chronic renal failure related to fibrosis scarring.

Introduction Renal impairment in sarcoidosis usually results from dehydration, nephrocalcinosis and/or nephrolithiasis related to hypercalciuria and hypercalcaemia [1]. Much less common are glomerular disease or granulomatous interstitial nephritis. Despite a 7%-27% prevalence of renal granuloma at autopsy [2,3], review of the literature revealed only 51 reported cases of renal failure attributed to sarcoidosic isolated granulomatous interstitial nephritis [4-42]. We report here six additional cases of isolated granulomatous interstitial nephritis with renal failure related to sarcoidosis, and analyse them with special emphasis on converting-enzyme activity, hydroxylated vitamin D derivatives, and response to long-term corticosteroid therapy. Case 1

In May 1972 a 61-year-old white woman was investigated for persistent fever and weight loss. Physical examination disclosed subclavicular adenopathy, hepatomegaly and Key words: Kidney disease; Sarcoidosis; Granulomatosis; splenomegaly. Laboratory tests revealed renal failure Calcitriol; Angiotensin-converting enzyme with plasma creatinine (Per) 380 umol/1 (4.18 mg/dl) and mild hypercalcaemia 2.62 mmol/1 (10.5 mg/dl). Chest Xray showed unilateral laterotracheal adenopathy. Sarcoma was suspected and splenectomy and hepatic biopsy were performed. Both hepatic and splenic tissues revealed non-caseous epithelioid and giant-cell granulomas characteristic of sarcoidosis. The patient was not given corticosteroid treatment. Correspondence and offprint requests to: Dr T. Hannedouche, DepartIn February 1973, the patient was referred for dement of Nephrology, Necker Hospital, 161 rue de Sevres, 75743 Paris Cedex 15, France. terioration of renal function. Examination revealed

Renal Granulomatous Sarcoidosis

hepatomegaly and moderately elevated blood pressure (170/110 mmHg). Per was 550 umol/1 (6.05mg/dl), plasma calcium concentration (Pea) was 2.51 mmol/1 (10.04mg/dl), proteinuria was 0.7g/24h, with microhaematuria (70 000/mn) and sterile leukocyturia. IVP revealed two enlarged kidneys (15 cm each). A percutaneous renal biopsy was performed. Light microscopy revealed numerous non-necrotic epithelial and giant-cell granulomas, mild diffuse interstitial fibrosis without nephrocalcinosis, normal glomeruli, and prominent arteriolar lesions with fibrous endarteritis of interlobular arterioles. Corticosteroid therapy (prednisolone 1 mg/kg per day) was started. Hepatomegaly disappeared and renal failure dramatically improved (Per 160umol/l or 1.76mg/dl within 2 months) and remained stable with long-term steroid therapy at 10 mg per day. In December 1976 corticosteroid therapy was stopped and Per increased to 310umol/l (3.41 mg/dl). A second renal biopsy showed diffuse interstitial fibrosis without granulomas; most of the glomeruli were hyalinised. Since that time and without corticosteroid therapy, renal function exhibited slow progressive deterioration. In June 1989, Per was 650 umol/1 (7.15 mg/dl) and Pea 2.20 mmol/1 (8.80 mg/dl).

Case 2 A 63-year-old white man was referred in December 1979 for rapidly progressive renal failure and weight loss. Six months previously he had experienced renal colic. At that time Per was 180 umol/1 (1.98 mg/dl) and IVP disclosed two normal-sized kidneys. Physical examination revealed signs of extracellular dehydration and latent bilateral uveitis. Laboratory results showed Per 760 umol/1 (8.36 mg/dl); mild proteinuria, lg/24h; microhaematuria; sterile leukocyturia; hyperchloraemic metabolic acidosis with plasma chloride, 112 mmol/1 (11.2 mEq/dl) and plasma bicarbonate, 19 mmol/1 (1.9 mEq/dl); and plasma calcium concentration, 2.42 mmol/1 (9.68 mg/dl). Chest X-ray was normal and tuberculin tests and culture for M. tuberculosis were negative. Percutaneous renal biopsy revealed non-necrotic interstitial granulomas with giant cells but no glomerular lesion. Corticosteroid therapy (prednisolone 1 mg/kg per day) was started. Uveitis and renal function dramatically improved. Per decreased to 170 umol/1 (1.87 mg/dl) and remained stable when corticosteroid therapy was slowly tapered off. In December 1980, when prednisolone dosage was 7.5 mg/d, sarcoidosis flared up with uveitis, meningoradiculoneuritis and impairment of renal function with Per 350 umol/1 (3.85 mg/dl). No granulomas were found on sural nerve biopsy. Following prednisolone 1 mg/kg per day, both radiculoneuritis and renal function

19

improved. Per remained stable at 160 umol/1 (1.76 mg/dl) with a maintenance dose of prednisolone 10 mg per day. In January 1982 dysuria led to the diagnosis of a highgrade vesical carcinoma, and radiotherapy was instituted. The patient died 1 year later of haemorrhagic colitis and septicaemia unrelated to granulomatosis.

Case 3 A 57-year-old white woman without significant medical history was referred in July 1981 for rapidly progressive renal failure. Two months earlier she had experienced asthenia, weight loss, and anorexia, and Per was 210 umol/1 (2.31 mg/dl). Physical examination disclosed sicca syndrome, splenomegaly, and inguinal adenopathy, and blood pressure was 110/80 mmHg. Laboratory results showed Per 450 umol/1 (4.95 mg/dl); proteinuria 0.5g/24h; sterile leukocyturia (30000/ml) without haematuria; mild hyperchloraemic metabolic acidosis with plasma bicarbonate, 18 mmol/1 (1.8 mEq/dl) and plasma chloride 108 mmol/1 (10.8 mEq/dl); serum calcium concentration, 2.46 mmol/1 (9.84 mg/dl); plasma immunoreactive parathormone (iPTH), 46 pg/ml (N= 15-60); plasma 25(OH)D3 (calcifediol) concentration, 25 ng/ml (N = 5-30); plasma l-25-di(OH)D3 (calcitriol), 44.0 pg/ml (N = 15-50); and plasma angiotensin-converting enzyme (ACE) 45.3nmol/mn per ml (normal range 13.4-29.0). Hepatic and immunological tests were normal or negative. M. tuberculosis was absent from sputum and urine and tuberculin tests were negative. Fundoscopy showed cotton-like exudates. Chest X-ray was normal but gallium scintigraphy revealed mediastinal hyperfixation. Functional respiratory tests were normal except for a mild reduction in pulmonary carbon monoxide uptake. Renal tomographies revealed two normal-sized kidneys (12 cm each). Renal percutaneous biopsy was performed and showed mild arteriosclerosis but no glomerular lesion. Tubulointerstitial lesions were prominent with large strips of fibrosis and non-caseous granulomas with giant cells and epithelioid cells. Corticosteroid therapy (prednisolone 1 mg/kg per day) was started. Within two months Per and ACE fell to 180 |imol/l (1.90 mg/dl) and 22 mmol/mn per ml respectively and subsequently remained stable while prednisolone was progressively tapered off to 5 mg/day. In November 1983, Per rose to 260 umol/1 (2.86 mg/dl), calcaemia to 2.47 mmol/1 (9.88 mg/dl) and ACE to 30 mmol/mn per ml. Corticosteroid therapy was increased and Per returned to baseline values. In December 1988 the patient was in good general condition, with stable Per 210 umol/1 (2.31 mg/dl) on maintenance therapy.

20

T. Hannedouche et al

and numerous non-caseating epithelioid granulomas. No calcium deposits were identified. Giant cells and In October 1982, a 79-year-old white man was admitted epithelioid granulomas were found on liver biopsy. for nausea, vomiting and acute renal failure. Physical Corticosteroid therapy (prednisolone 40 mg/d) was examination was normal except for mild dehydration, and instituted. Within 3 months, the patient had gained weight blood pressure was 120/80 mmHg. Significant investi- and Per had declined to 300 umol/1 (3.3 mg/dl) and plasma gations were: Per 880 umol/1 (9.68 mg/dl); proteinuria calcium concentration to 2.36 mmol/1 (9.44 mg/dl). Three 0.70 g/24 h; absence of haematuria but mild sterile months later, when prednisolone had been tapered to leukocyturia (250/mm3); serum calcium 2.14 mmol/1 20 mg/d, Per increased to 800 umol/1 (8.8 ug/dl) and Pea (8.56 mg/dl); albuminaemia 3.7g/dl; alkaline phospha- to 2.51 mmol/1 (10.4 mg/dl). Methylprednisolone pulses tase 137 UI/1 (N = 40-120) and ACE 32 nmol/mn per ml. (1 g x 3 days) were given, and 2 weeks later Per decreased Chest X-ray, tuberculin tests, and cultures for M. to 400 umol/1 (4.4 mg/dl) and Pea to 2.01 mmol/1 tuberculosis were normal or negative. Bronchioloalveolar (8.04 mg/dl). With maintenance corticosteroid therapy lavage showed no M. tuberculosis, and 25% lymphocytes (prednisolone 30 mg/d), renal function showed a stable including 52% of CD4 + cells. Bronchial granulomas were course until December 1984, when the patient died found on biopsied tissue. Renal ultrasonography revealed suddenly. An autopsy was not performed. two enlarged kidneys without urinary-tract obstruction. Percutaneous renal biopsy was performed. On light microscopy, numerous non-caseous interstitial granulo- Case 6 mas were found but there were no significant glomerular, tubular or vascular lesions. Immunofluorescence study In 1970 a 41 -year-old white woman received isoniazid and was negative. PAS for genital tuberculosis. She was in good general Corticosteroid therapy (prednisone 30 mg/d) was condition until 1983 when she experienced anterior started and 1 month later Per decreased to 360 umol/1 uveitis, papulonodular rash on her legs, and arterial (3.96 mg/dl). With maintenance corticosteroid therapy hypertension. Per was 170 umol/1 (1.87 mg/dl) and (15 mg/d), renal function further improved. In November plasma calcium concentration 3.07 mmol/1 (12.28 mg/dl). 1984, Per was 180 umol/1 (1.98 mg/dl) and plasma calcium In 1985 the patient was referred for deterioration of concentration 2.28 mmol/1 (9.12 mg/dl) with prednisone renal function. Physical examination was normal therapy 10 mg/d. except for obesity, and blood pressure was 130/80 mmHg. Significant biological tests showed Per 280 umol/1 (3.08 mg/dl); mild hyperchloraemic metabolic acidosis; mild proteinuria, 0.50 g/24 h; no haematuria or leukoCase 5 cyturia; plasma calcium, 2.70 mmol/1 (10.8 mg/dl); serum In June 1983, a 71-year-old white man was admitted for phosphate, 1.35 mmol/1 (4.05 mg/dl); iPTH, 53 pg/ml asthenia, anorexia, polydipsia, weight loss, and renal (N= 15-60); calcifediol, 22ng/ml (N = 5-3O); calcitriol, failure. Blood pressure was 150/94 mmHg and physical 35 pg/ml (N= 15-50); and ACE, 24.8 nmol/mn per ml; examination was unremarkable. Significant investi- hepatic tests were normal. Chest X-rays revealed stellar gations were: Per 420 umol/1 (4.62 mg/dl); proteinuria, calcification of the left lower pulmonary field but no 0.40 g/24 h; no significant haematuria or leukocyturia; adenopathy or interstitial syndrome. Bronchioloalveolar albuminaemia, 34 g/1, plasma alkaline phosphatase lavage showed 47% lymphocytes, including 75% CD4 + 204 UI/1 (N = 40-120); normal values of aminotransfer- cells. ases; serum calcium, 2.70 mmol/1 (10.8 mg/dl); iPTH, IVP disclosed two normal-sized irregular kidneys 2.3 UI/1; and ACE, 24.0 nmol/mm per ml. Chest X-ray (12 cm). Percutaneous renal biopsy was performed. was normal but gallium scintigraphy showed hyper- Pathological findings: no glomerular or arteriolar fixation of the two pulmonary bases, and functional pul- lesions, numerous interstitial granulomas with epithelioid monary tests revealed mild restrictive syndrome with and giant cells containing characteristic asteroid body reduced pulmonary carbon monoxide uptake. Tuberculin of Schaumann. There was no caseous necrosis tests and cultures for M. tuberculosis were negative. or nephrocalcinosis. Immunofluorescence study was Bronchioloalveolar lavage showed absence of M. negative. tuberculosis, 86% lymphocytes including 37% CD4 + Corticosteroid therapy (prednisone 1 mg/kg) was insticells. Bronchial endoscopy and biopsies were normal. tuted. One month later, Per decreased to 160 umol/1 IVP revealed two normal-sized kidneys and percu- (1.76 mg/dl), calcaemia to 2.40 mmol/1 (9.6 mg/dl) and taneous renal biopsy was performed. On light microscopy ACE to 14mmol/mn per ml. On maintenance corticothe renal cortex was markedly infiltrated by interstitial steriod therapy (25 mg/dl), renal function and serum mononuclear cells and distorted by an extensive fibrosis calcium remained stable. At last follow-up in December Case 4

Renal Granulomatous Sarcoidosis

1986 results were Per 170umol/l (1.87mg/dl), plasma calcium concentration, 2.43 mmol/1 (9.72 mg/dl); ACE, 14.6 nmol/mn per ml; calcifediol, 13 ng/ml; and calcitriol, 20pg/ml.

Discussion Renal failure in sarcoidosis may occur as a consequence of hypercalcaemia or hypercalciuria, glomerular disease, or granulomatous interstitial nephritis [1]. In two large series, 7%-27% of patients with sarcoidosis were found at autopsy to have granulomatous renal involvement [2,3]. Despite this high anatomical prevalence, only 51 cases of renal failure secondary to sarcoidosic isolated granulomatous interstitial nephritis have been reported to date [4-^2] [Table 1]. In the six additional patients reported here, there was no evidence of nephrocalcinosis or glomerulonephritis on renal biopsy, and renal failure was presumably a consequence of granulomatous interstitial renal involvement. In all but one patient, weight loss or polyuria was the presenting symptom of sarcoidosis. In case 1, weight loss and organomegaly were prominent and simulated lymphosarcoma. However, infivepatients, renal impairment led to the diagnosis of sarcoidosis. In a few cases in the literature, isolated renal failure had eventually led to the diagnosis of sarcoidosis [16,17,25,26,28,30,32]. In these five cases and in many in the literature, renal disease presented as rapidly progressive renal failure, either isolated or associated with mild proteinuria, microhaematuria and sterile leukocyturia, all features that are suggestive of interstitial nephritis. Renal failure may be severe enough to require dialysis at least transiently. Occasional tubular dysfunction including hyperchloraemic metabolic acidosis, orthoglycaemic glycosuria, aminoaciduria and hyperphosphaturia, which may result in a full-blown Fanconi syndrome, have been reported. Tubular dysfunction is generally thought to be related to nephrocalcinosis or diffuse tubular atrophy but may also be associated with hyperglobulinaemia [27]. Only hyperchoraemic acidosis was observed in our patients. As in most cases cited in the literature, our patients presented with advanced renal failure. Patient 1, who received no treatment for at least one year, exhibited slow but significant deterioration of renal function. In the other five patients the course of renal failure was rapidly progressive. Following corticosteroid therapy, renal function dramatically improved in all six patients. However, in none did plasma creatinine return to normal values. Most patients reported in the literature responded to corticosteroid treatment and six regained normal renal function [7,11,20,26,34,37], but the majority had residual renal impairment after up to 30 months of maintenance lowdose prednisolone treatment. As in patient 3, relapse

21

occurred in seven of the previously published cases [4,11,12,16,19,32,35]; all were receiving doses of 7.5 mg/d or less. The occurrence of relapse did not seem to be associated with reduced initial dosage and each case of relapse, as in ours, responded to a further course of corticosteroid. In patient 1, plasma creatinine increased when corticosteroids were stopped. A second renal biopsy performed 4 years after the first pathological examination showed prominent diffuse interstitial fibrosis but no granulomas. Conflicting data have been reported on repeated renal biopsies. Most authors found residual interstitial fibrosis and no granulomas, suggesting that corticosteroid therapy was not accompanied by complete reversal of changes [7,11,13,38]. Others found persisting interstitial granulomas generally associated with increased interstitial fibrosis [4,12,16,20]. Despite advanced renal failure, patients were either mildly hypercalcaemic [patients 4, 6] or normocalcaemic [patients 1-3] but at the upper limit of normal range and with disproportionately elevated concentrations for the degree of renal impairment. In patients 3 and 4 elevated or paradoxically normal plasma calcium concentration could be related to normal plasma calcidiol and calcitriol, despite coexistence of advanced renal failure. In hypercalcaemic patients 4 and 6, normal plasma immunoreactive PTH is suggestive of suppressed parathyroid function, since iPTH is generally found to be elevated in renal failure because of hypocalcaemia and a reduced clearance rate of the hormone by the kidney. Hypercalcaemia is found in approximately 10% of patients with sarcoidosis and is due to increased intestinal absorption of calcium related to increased concentrations of l-25-di(OH)D3 or calcitriol [43,44]. As in patients 3 and 4, Sandier et al found a strong positive correlation between calcidiol and calcitriol concentrations in patients with sarcoidosis [44]. Elevated serum calcitriol was found in an anephric patient with sarcoidosis and hypercalcaemia, providing thefirstevidence of extrarenal synthesis of calcitriol in this disorder [45,46]. Studies by Singer and Adams [47] and Mason et al [48] pointed to the sarcoid macrophage as the source of excessive synthesis of a metabolite indistinguishable from calcitriol. Macrophage la-hydroxylation is very susceptible to inhibition by glucocorticoids, which promptly decreased serum calcium concentration in patients with sarcoidosis [47]. With corticosteroid therapy, patient 4, who was hypercalcaemic, exhibited a moderate decrease in serum calcium concentration whenever renal failure improved. In patient 3, plasma creatinine increased as corticosteroids were tapered to less than 5 mg/d and calcium concentration increased mildly from the lower to the upper limit of normal range. Both were reversible with increased doses of corticosteroids. These findings agree with reports by Falls et al [12] that serum calcium

22

T. Hannedouche et al

Table 1. Renal granulomatous sarcoidosis Ref. Authors

Year

Sex

Age

Extrarenal localisations

Ca (mmol/1)

PCr(umol/l) Before CS

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Berger Cameron Sorger Ogilvie Panitz Leng-Levy

1955 1956 1961 1964 1965 1965

M

Guedon Coburn Falls Bourke Ravindranath Kohout King Bolton Vanhille Turner Aubia Ford Wanbergue

1967 1967 1972 1973 1975 1975 1976 1976 1977 1977 1978 1978 1978

F M M M F F

F M M F M M M

37 19 46 21 21 42 51 60 34 13 15 60 ?

M M M M F

52 60 21 54 12

F M M M M M M F F M M M

58 21 48 53 34 75 44 68 56 26 26 45

F M F

58 66 68 57 19 26 47 30 57 13 46 26 22 74 54 61 63 57 79 71 41

23

MacSearraigh

1978

24

Martini

1980

25 26 27 28 29 30 31 32 33 34

Belgioso Allegri Muther Alcazar Boer Hagege Tomino Williams Korzeto Laurentjoye

1980 1980 1980 1981 1982 1983 1983 1984 1985 1985

35

Simonsen

1985

M

M M

M M

F 36 37

Michelsen Singer

1985 1986

38

Farge

1986

39 40

Shen van Dorp

1986 1987

M

F M M M F M

F 41 42

Mery Marti

1988 1988

M M M

Personal series

1 2 3 4 5 6

F M

F M M F

37 52 35 27 25 56

HLN, PLN, E, skin* HLN, L, E, skin HLN, IF, L, PLN, spleen PLN,* E HLN, IF, L,* E IF, PLN,* facial palsy, parotitis IF, E, osteitis HLN, IF, L,* E, rhinitis* HLN,* IF, E HLN, PLN,* E L,* PLN, bone marrow* Locomotor system HLN* HTA IF, PLN,* L* HLN, L,* E HLN

2.33 1.50

2.62 2.62 2.37 2.25 2.52

1.65 PLN,* L, E, arthritis, splenomegaly IF, PLN* (Daniels), L* E HLN, PLN* (Daniels) IF,L* IF, L, E, erythema nodosum L HLN, HTA E HLN, L, HTA IF, L E, rectum* HLN, PLN* (scalen) HLN, IF, PLN,* testis HLN,* IF, HTA HLN, IF, PLN* (Daniels), E IF, HLN, muscle,* skin* IF, L, osteitis, muscle* IF, L,* osteitis L, E, CNS IF, skin* HLN, IF, PLN L* PLN,* muscle* HLN, L* E, HLN, PLN E HLN L* PLN, splenomegaly HLN, PLN, L* E PLN, splenomegaly Bronchus* L*

E*

2.05 2.5 1.8

2.5 2.62 2.1 2.39 2.45 2.30 3.79 3.31

3.5 2.72 2.51 2.51 7 Normal Normal 3.12 3.5 2.4 2.51 2.42 2.46 2.14 2.70 2.70

180 474 484 82 (Ccr) 148 (Ccr) 42 (Curea) 35 185 194 246 299 475 1135 625 484 510 182 1400

Relapse

2nd renal pathol.

+

Granulomas

0(died) 0(died) 0 0

Fibrosis

After CS 100 1443 124 184 40 35 88 150 158 132 123 299 114 264 264 'N'

0 0

+ + 0 0 0

+ 0 0

+

Fibrosis Granulomas Fibrosis Granulomas Fibrosis

0 Died

Granulomas

502 150 484 220 132 185 45 (Ccr) >45 5,4 (Ccr) >5,4

0 0 0 0 0

Fibrosis

25 (Ccr) 830 299 704 924 399 950 440 380 390 340 335

0 0 0 0 0 7 7 ?

185 830 1435 67 (Ccr) 228 885 258 1434 720 320 Dialysis 240 340 229 619 137 550 760 450 880 420 280

>25 352 88 352 510 154 180 300 160 180 160 80 ? 352 240 81 208 Dialysis 94 400 550 125 115 110 130 380 106 160 170 180 180 300 160

+

Granulomas

0 0 0 0(died) 0 0 0

+ 0 0 0 0 0 + (transplant)

Fibrosis

0 Fibrosis 0 0

+ + +

Fibrosis

0

+ 0

Ca, serum calcium concentration; Per, plasma creatinine concentration; Ccr, creatinine clearance; Curea, Urea clearance; CS, corticosteroid treatment; HLN, Hilar lymph node; PLN, peripheral lymph node; E, eye involvement; L, liver involvement; IF, pulmonary interstitial fibrosis; HTA, arterial hypertension; CNS, central nervous system involvement; *biopsy-proven granuloma

Renal Granulomatous Sarcoidosis

concentration increased from the upper limit of normal at presentation to become significantly elevated on relapse of renal impairment. Although DeRemee and Rohrbach [49] found elevated serum angiotensin-converting enzyme to be an indicator of activity in sarcoidosis, serum angiotensin-converting enzyme was elevated in only two of four of our patients in whom it was studied, despite evidence of extensive renal granulomatosis. Such conflicting results have been reported by others [38,50] and may be related to the influence of renal failure on serum angiotensin-converting enzyme [51]. In patient 6, serum angiotensin-converting enzyme was initially normal but decreased during the evolution and roughly paralleled plasma creatinine and calcium concentrations. These results agree with DeRemee's findings that serum angiotensin-converting enzyme values were more useful in following up the clinical course than in establishing sarcoidosis as the cause of hypercalcaemia [49,52]. The epithelioid and giant cells have been implicated as the source of increased serum angiotensin-converting enzyme activity in sarcoidosis [53]. However, there is at present no evidence directly linking increased angiotensin-converting enzyme production with increased la-hydroxylase activity that may lead to increased production of calcitriol. The parallel decline of serum angiotensin-converting enzyme and calcaemia following treatment with prenisolone suggests that these enzymatic activities should reflect the metabolic aberrations of monocytic cells.

References 1. Glassock RJ. Sarcoidosis. In: Massry SG, Glassocks RJ, eds. Textbook of Nephrology. Williams and Wilkins. Baltimore 1983; 6.176-6.178 2. Longcope WT, Freiman DG. A study of sarcoidosis based on combined investigation of 160 cases including 30 autopsies from Johns Hopkins Hospital and Massachusetts General Hospital. Medicine 1952; 31: 1-132 3. Ricker W, Clark M. Sarcoidosis, a clinico-pathologic review of 300 cases including 22 autopsies. Am J Clin Path 1959; 19: 725-749 4. Berger K.W, Relman AS. Renal impairment due to sarcoid infiltration of the kidney. N EnglJ Med 1955; 252:44-49 5. Cameron HM. Renal sarcoidosis. J Clin Palhol 1956; 9: 136 6. Sorger K, Taylor WA. Generalized sarcoidosis. Arch Palhol 1961; 71:35-43 7. Ogilvie RI, Kaye M, Moore S. Granulomatous sarcoid disease of the kidney. Ann Intern Med 1964; 61:711-715 8. Panitz F, Shinaberger JH. Nephrogenic diabetes insidipidus due to sarcoidosis without hypercalcemia. Ann Intern Med 1965; 62: 113-120 9. Leng-Levy J, David-Chausse J, Martin-Dupont C. Maladie de Besnier-Boeck-Schaumann a localisation renale. Bull Mens Soc Med Hop Paris 1965; 116:907-909 10. Guedon J, Mathieu F, Chome J et al. Sarcoidose renale a forme pseudo-tumorale revelatrice de l'affection. Presse Med 1967; 75: 265-268 11. Coburn JW, Hobbs C, Johnston GS et al. Granulomatous sarcoid nephritis. Am J Med 1967; 42: 273-283 12. Falls WF, Randall RE, Sommers SC et al. Nonhypercalcemic sarcoid nephropathy. Arch Intern Med 1972; 130: 285-291

23 13. Bourke E, Barniville H. Granulomatous sarcoid nephritis. Ir J Med Sc/1973;42: 127-131 14. Ravindranath C, Jain VK, Kirmani N. Sarcoid infiltration leading to reversible renal impairment. Kidney Int 1975; 8: 417 15. Kohout J. Sarkoidose der Niere. Med Klin 1975; 8: 332-336 16. King BP, Esparza AR, Kahn SI, Garella S. Sarcoid granulomatous nephritis occurring as isolated renal failure. Arch Intern Med 1976; 136:241-245 17. Bolton WK, Atuk NO, Rametta C et al. Reversible renal failure from isolated granulomatous renal sarcoidosis. Clin Nephrol 1976; 5: 88-92 18. Vanhille P, Dequiedt P, Raviart B, Lelievre G, Tacquet A. Insuffisance renale par nephrite granulomateuse au cours d'une sarcoidose. Lille Med 1977; 22: 778-782 19. Turner MC, Shin ML, Ruley EJ. Renal failure as a presenting sign of diffuse sarcoidosis in an adolescent girl. Am J Dis Child 1977; 131: 997-1000 20. Aubia J, Torras A, Darnell A et al. Nefropatia por granulomas sarcoideos. Rev Clin Esp 1978; 148: 631-634 21. Ford MJ, Anderton JL, MacLean N. Granulomatous sarcoid nephropathy. Postgrad Med J 1978; 54: 416-417 22. Wambergue FP, Duchatelle P, Riberi P et al. Localisation renale specifique de la sarcoidose (A propos de 4 observations). J Urol Nephrol 1978; 84: 859-865 23. MacSerraigh ET, Doyle CT, Twomey M, O'SuIlivan DJ. Sarcoidosis with renal involvement. Postgrad Med J 1978; 54: 528-532 24. Martini A, Serenella Scotta M, Magrini U. Sarcoidose granulomateuse des reins avec insuffisance renale chez une fille de douze ans. Nephrologie 1980; 1: 117-119 25. Barbiano di Belgiojoso GB, Bertoli S, Confalonieri R et al. Granulomatous interstitial nephritis as a possible isolated manifestation of sarcoidosis: report of a case EDTA Proc Eur Dial Transplant Assoc 1980; 27 26. Allegri L, Olivetti G, David S et al. Sarcoid granulomatous nephritis with isolated and reversible renal failure. Nephron 1980; 25:207-208 27. Muther RS, McCarron DA, Bennett WM. Granulomatous sarcoid nephritis: A cause of multiple renal tubular abnormalities. Clin Nephrol 1980; 14: 190-197 28. Alcazar JM, Bello I, Arteaga J, Ruilope L, Barrientos A, Rodicio JL. Sarcoidosis and renal failure. Nephron 1981; 29: 281 29. Boer PCAM, Knaassen CHL. A patient with deranged renal function from sarcoidosis with interstitial nephritis. Ned Tijdschr Geneeskd 1982; 126:2150-2153 30. Hagege A, Baglin A, Prinseau J et al. Sarcoidose revelee par une insuffisance renale (trois cas). Sem Hop Paris 1983; 59: 2823-2826 31. Tomino Y, Shiina Y, Nishizawa K et al. A case of granulomatous renal sarcoidosis with a dramatic response to corticosteroid and urokinase therapy. TokaiJExp Clin Med 1983; 8: 149-153 32. Williams PF, Thomson D, Anderton JL. Reversible renal failure due to isolated renal sarcoidosis. Nephron 1984; 37: 246-249 33. Korzets Z, Schneider M, Taragan R et al. Acute renal failure due to sarcoid granulomatous infiltration of the renal parenchyma. Am J Kidney Dis 1985; 4: 250-253 34. Laurentjoye P, Martin-Dupont P, Dupuy-Braud E et al. Nephrites granulomateuses au cours de la sarcoidose de Besnier-BoeckSchaumann. Sem Hop Paris 1985; 61: 723-727 35. Simonsen O, Thysell H. Sarcoidosis with normocalcemic granulomatous nephritis. Nephron 1985; 40: 411-417 36. Michelsen P, Van Damme, Hauglustaine D, Waer M, Verberckmoes R, Vanrenterghem Y. Insuffisance renale aigue: premiere revalation d'une sarcoidose familiale. Nephrologie 1985; 6: 151-152 37. Singer RJ, Evans J. Renal impairment in sarcoidosis: Granulomatous nephritis as an isolated cause (two case reports and review of the literature). Clin Nephrol 1986; 26: 250-256 38. Farge D, Liote F, Turner M et al. Granulomatous nephritis and chronic renal failure in sarcoidosis. Am J Nephrol 1986; 6: 21-27 39. Shen SY, Hall-Craggs M, Posner JN, Shabazz B. Recurrent sarcoid granulomatous nephritis and reactive tuberculin test in a renal transplant recipient. Am J Med 1986; 80: 699-702 40. van Dorp WT, Jie K, Lobatto S, Weening JJ, Valentin RM. Renal failure due to granulomatous interstitial nephritis after pulmonary sarcoidosis. Nephrol Dial Transplant 1987; 2: 573-575

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41. Mery JP, Kenouch S. Les atteintes de l'interstitium renal au cours des maladies systemiques. Seminairesd'Urologie-Nephrologie 1988; 57-89 42. Marti HP, Laissue J, Mihatsch M, Cottier H, Truniger B. Renale Manifestationen der Sarkoidose. Schweiz Med Wochenschr 1988; 118:416-^21 43. Papapoulos SE, Clemens TL, Fraher LJ, Lewin IG, Sandier LM, O'Riordan JLH. 1,25-dihydroxy cholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis. Lancet 1979; I: 627-630 44. Sandier LM, Winearls CG, Fraher LJ, Clemens TL, Smith R, O'Riordan JLH. Studies on the hypercalcemia of sarcoidosis: effects of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3. Q J Med 1984; 53: 165 45. Barbour GL, Coburn JW, Slatopolsky E et al. Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981; 305: 440-443 46. Maesaka JK, Batuman V, Pablo NC, Shakamuri S. Elevated 1,25dihydroxyvitamin D levels. Arch Intern Med 1982; 142: 1206-1207

T. Hannedouche et al 47. Singer FR, Adams JS. Abnormal calcium homeostasis in sarcoidosis. N Engl J Med 1986; 315: 755-757 48. Mason RS, Frankel T, Chan YL, Lissner D, Posen S. Vitamin D conversion by sarcoid lymph node homogenate. Ann Intern Med 1984; 100:59-61 49. DeRemee RA, Rohrbach MS. Serum angiotensin-converting enzyme activity in evaluating the clinical course of sarcoidosis. Ann Intern Med 1980; 92: 361-365 50. Romer FK, Faber V, Koch C et al. Serum angiotensin-converting enzyme in chronic granulomatous disease. Lancet 1979; 1: 1237 51. Patel R, Ansari A. Serum angiotensin-converting enzyme activity in patients with chronic renal failure on long-term hemodialysis. Clin Chim Acta 1979; 92: 491-495 52. Lufkin EG, DeRemee RA, Rohrbach MS. The predictive value of serum angiotensin-converting enzyme activity in the differential diagnosis of hypercalcemia. Mayo Clin Proc 1983; 58: 447-451 53. Pertschuk LP, Silverstein E, Friedland J. Immunohistologic diagnosis of sarcoidosis. Detection of angiotensin-converting enzyme in sarcoid granulomas. Am J Clin Pathol 1981; 75: 350-354 Receivedfor publication 25.7.89 Accepted in revisedform 29.8.89