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Antineutrophil Cytoplasmic Autoantibodies: The Nephrologist's Perspective
Antineutrophil Cytoplasmic Autoantibodies: The Nephrologist's Perspective C. Martin Lockwood, FRCP
• Serologic tests for antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in patients with nephritis and systemic vasculitis. Four case histories are discussed that illustrate ANCA positivity in patients with renal impairment caused by interstitial, rather than glomerular, nephritis. Renal biopsy should continue to be used to diagnose the cause of renal impairment in ANCA-positive patients. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: anti neutrophil cytoplasmic autoantibodies; systemic vasculitis; interstitial nephritis.
T
HERE IS NOW considerable evidence that antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in a variety of systemic vasculitides associated with nephritis. I -3 For nephrologists, this information illuminates an area of clinical practice that has hitherto relied on histological interpretation of renal biopsies, since such noninvasive tests were not previously available. One consequence of this is to raise in the nephrologist's mind the question of whether renal biopsies are really necessary, particularly because renal involvement in systemic vasculitis usually takes the form of a rapidly progressive glomerulonephritis (RPGN). Set in the context of an unexplained decline in renal function, a positive ANCA test might, therefore, indicate a renal limited vasculitis. Since conventional treatment for RPGN is cyclophosphamide and corticosteroid therapy, a decision to treat on the basis of a positive ANCA test carries considerable implications in terms of risk from the side effects of these drugs. Should ANCA positivity be a feature of mechanisms producing renal impairment other than by vasculitic injury to the glomerulus, then the need for renal biopsy would still have high priority. This report documents four patients seen in one renal unit over a 2-year period, where ANCA positivity was a feature of renal impairment produced by an interstitial, rather than a glomerular, nephritis. That these patients merit segregation was justified not only on morphological grounds, but also by evidence deduced from diagnostic imaging and clinical course, since three of the four showed spontaneous remissions. In none of
the four was it possible to identify pharmacological agents as initiators of renal injury. PATIENTS (CASE HISTORIES)
Case 1 This 57-year-old woman developed cough, headache, and malaise with a 2-kg weight loss over a period of 2 months. For 2 weeks, she noted thirst and nocturia. There were no abnormal findings on physical examination and blood pressure was 110/80 mm Hg. Investigations showed a hemoglobin of 11.5 g!dL, white blood cell (WBC) count 11.2 X 109/L (II ,200/ ILL), platelets 784,000/L, plasma creatinine 160 ILmol/L (1.8 mg!dL) (normal, <125 ILmol/L [<1.4 mg/dL]), creatinine clearance 0.82 mL/s (49 mL/min), and a 24-hour urine protein 0.36 g. Alkaline phosphatase was 252 U/L (normal, <130 U/ L) and ANCA 49% (normal, < 16%) (Fig IA). Indium-labeled polymorph scan showed renal localization, as pictured in Fig 2B. Renal biopsy showed a marked chronic inflammatory cell interstitial infiltrate with no glomerular involvement, as shown in Fig 3A. Without treatment, this patient improved spontaneously, as shown in Fig 4.
Case 2 This 57-year-old man was well until 5 days before admission when he developed a pyrexia, rigors, and malaise. On examination he had bilateral loin tenderness. On admission hemoglobin was 11.3 g/dL, WBC 21.7 X 109/L (21,700/ILL), platelets 269,000/L, C-reactive protein (CRP) 400' mg/L (normal, <6 mg/L), and ANCA 39% (Fig IB). Creatinine at referral was normal, later increasing to 341 ILmol/L (3.9 mgt dL). Indium-labeled scan showed intense renal localization
From the University o/Cambridge School o/Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK. Address reprint requests to C. Martin Lockwood, FRCP, University 0/ Cambridge, School 0/ Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK CD2 2SP. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/91/1802-0006$3.00/0
American Journal of Kidney Diseases, Vol XVIII, No 2 (August), 1991: pp 171-174
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c.
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MARTIN LOCKWOOD
Case 4 A 24-year-old man was admitted to the hospital with a blood pressure of 160/100 mm Hg, and mild renal impairment. He had a hemoglobin of8.9 gJdL, WBC 10.4 X 109/L (400/ILL), platelets 297,OOO/L, CRP 192 mgJL, creatinine 325 ILmol/L (3.7 mgJdL), and ANCA 24% (Fig 10). WBC scan showed mild bilateral renal uptake (Fig 20). Renal biopsy showed five glomeruli, three of which were sclerosed, and the remaining two showed mesangial cell increase. The tubules showed extensive tubular atrophy and there was a diffuse mononuclear cell infiltrate with mononuclear cells and some polymorphs. In addition, there were loose granulomatous aggregates ofiymphocytes and histiocytes within the interstitium. Definite giant cells were not identified. Vessels showed medial hypertrophy in keeping with the hypertension (Fig 3~). Creatinine clearance increased to 803 ILmol/L (9.1 mgJdL) before treatment with corticosteroids (prednisone, 40 mgJd) reversed the decline in renal function.
DISCUSSION
Fig 1. (A-D) Indirect immunofluorescence microscopic appearance of ANCA from patients 1 through 4, respectively. (Fig 2B). Renal biopsy showed intense acute inflammatory cell infiltrate, mostly polymorphonuclear leukocytes, with sparing of the glomeruli. Vessels and tubular structures were normal (Fig 3B). No infectious agents were localized. After 5 days, fever resolved and creatinine levels decreased spontaneously (Fig 4).
Case 3 A 71-year-old man developed a f ever, urinary frequency, nocturia, and dysuria for 5 days. On admission he was noted to have microscopic hematuria. His hemoglobin was 11 .2 gJ dL, WBC 9.7 X \09/L (9,700/ILL), platelets 319,OOO/L, CRP \03 mg/L, creatinine 171 ILmol/L (1.9 mgJdL), and ANCA 20% (Fig 1C). Indium-labeled WBC scan showed moderate bilateral renal uptake (Fig 2C). Renal biopsy showed abnormal medullary tubules lined by degenerating and necrotic epithelium. The surround interstitium was severely abnormal, with numerous infiltrating neutrophils, eosinophils, and lymphocytes. Aggregates of inflammatory cells were forming microabscesses. There was no significant abnormality in the vessels and mild focal mesangial matrical increase in the glomeruli (Fig 3C). Renal function deteriorated to a creatinine of 865 ILmol/L (9.8 mgJdL) before recovering spontaneously. No infectious agent was ever isolated.
The case histories of these four patients illustrate the need for caution in the interpretation of serological markers for vasculitis. Without WBC scanning and renal biopsy, the interstitial nature of the renal lesion would have been overlooked. The ANCA positivity was shown both by indirect immunofluorescence, as well as solidphase assay, and verified by specific inhibition tests.4 These ANCA results in the presence ofimpaired renal function might have tempted a trial of cytotoxic drug and corticosteroid therapy. In fact, three of the four patients improved without treatment. The nature of the disease affecting these patients remains an enigma. In full blown vasculitis, when glomerular necrosis is readily apparent, then interstitial damage may be an accompanying feature. In patient 1, it could be argued that the presentation was clinically that of an atypical microscopic polyarteritis, with relatively little extrarenal involvement, or an idiopathic rapidly progressive nephritis. However, in patients 2 and 3, this is less easy to justify and it would appear that all the patients could equally be classified as having a primary interstitial vasculitis. Certainly the indium-labeled polymorph scans would support this, and interestingly there was no abnormal renal uptake when this was repeated in patient 1, after remission had occurred.
ANCA-POSITIVE INTERSTITIAL NEPHRITIS
Fig 2. (A-D) Indium-labeled polymorphonuclear leukocyte scans of patients 1 through 4, respectively.
173
C. MARTIN LOCKWOOD
174 900
....
:3800 0700
E
...
0600 (.l
~500
W400 Z
~300
I-
~200
a:
0100 0 0
4
8
12
16
20
24
28
32
36
40
DAYS Fig 4. Serial serum creatinines in patients 1 through 4. Note that in patient 3 1 month elapsed before he presented again with a creatinine of 800 /Lmol/L (9.1 mg/ dL); in patient 4, treatment with corticosteroids was started when the creatinine reached 803 /Lmol/L (9.1 mg/ dL).
Fig 3. (A-D) Renal biopsy light microscopic appearances of patients 1 through 4, respectively.
In conclusion, ANCA positivity should alert the nephrologist to the possibility of interstitial, as well as glomerular, nephritis. Renal biopsy should continue to be used as an adjunct to the management of patients presenting with undiagnosed renal impairment.
REFERENCES I. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic au-
toantibodies and associated diseases: Areview. Am J Kidney Dis 15:517-529,1990 2. Cohen-Tervaert JW, Goldschmeding R, Elema JD, et al: Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int 37:799-806, 1990
3. Savage COS, Lockwood CM: Anti-neutrophil antibodies in vasculitis. AdyNmhrQI 19:225-236, 1990 4. Savage COS, Winearlsk CG, Jones S, et al: Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet 1:13891393, 1987
• Serologic tests for antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in patients with nephritis and systemic vasculitis. Four case histories are discussed that illustrate ANCA positivity in patients with renal impairment caused by interstitial, rather than glomerular, nephritis. Renal biopsy should continue to be used to diagnose the cause of renal impairment in ANCA-positive patients. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: anti neutrophil cytoplasmic autoantibodies; systemic vasculitis; interstitial nephritis.
T
HERE IS NOW considerable evidence that antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in a variety of systemic vasculitides associated with nephritis. I -3 For nephrologists, this information illuminates an area of clinical practice that has hitherto relied on histological interpretation of renal biopsies, since such noninvasive tests were not previously available. One consequence of this is to raise in the nephrologist's mind the question of whether renal biopsies are really necessary, particularly because renal involvement in systemic vasculitis usually takes the form of a rapidly progressive glomerulonephritis (RPGN). Set in the context of an unexplained decline in renal function, a positive ANCA test might, therefore, indicate a renal limited vasculitis. Since conventional treatment for RPGN is cyclophosphamide and corticosteroid therapy, a decision to treat on the basis of a positive ANCA test carries considerable implications in terms of risk from the side effects of these drugs. Should ANCA positivity be a feature of mechanisms producing renal impairment other than by vasculitic injury to the glomerulus, then the need for renal biopsy would still have high priority. This report documents four patients seen in one renal unit over a 2-year period, where ANCA positivity was a feature of renal impairment produced by an interstitial, rather than a glomerular, nephritis. That these patients merit segregation was justified not only on morphological grounds, but also by evidence deduced from diagnostic imaging and clinical course, since three of the four showed spontaneous remissions. In none of
the four was it possible to identify pharmacological agents as initiators of renal injury. PATIENTS (CASE HISTORIES)
Case 1 This 57-year-old woman developed cough, headache, and malaise with a 2-kg weight loss over a period of 2 months. For 2 weeks, she noted thirst and nocturia. There were no abnormal findings on physical examination and blood pressure was 110/80 mm Hg. Investigations showed a hemoglobin of 11.5 g!dL, white blood cell (WBC) count 11.2 X 109/L (II ,200/ ILL), platelets 784,000/L, plasma creatinine 160 ILmol/L (1.8 mg!dL) (normal, <125 ILmol/L [<1.4 mg/dL]), creatinine clearance 0.82 mL/s (49 mL/min), and a 24-hour urine protein 0.36 g. Alkaline phosphatase was 252 U/L (normal, <130 U/ L) and ANCA 49% (normal, < 16%) (Fig IA). Indium-labeled polymorph scan showed renal localization, as pictured in Fig 2B. Renal biopsy showed a marked chronic inflammatory cell interstitial infiltrate with no glomerular involvement, as shown in Fig 3A. Without treatment, this patient improved spontaneously, as shown in Fig 4.
Case 2 This 57-year-old man was well until 5 days before admission when he developed a pyrexia, rigors, and malaise. On examination he had bilateral loin tenderness. On admission hemoglobin was 11.3 g/dL, WBC 21.7 X 109/L (21,700/ILL), platelets 269,000/L, C-reactive protein (CRP) 400' mg/L (normal, <6 mg/L), and ANCA 39% (Fig IB). Creatinine at referral was normal, later increasing to 341 ILmol/L (3.9 mgt dL). Indium-labeled scan showed intense renal localization
From the University o/Cambridge School o/Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK. Address reprint requests to C. Martin Lockwood, FRCP, University 0/ Cambridge, School 0/ Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK CD2 2SP. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/91/1802-0006$3.00/0
American Journal of Kidney Diseases, Vol XVIII, No 2 (August), 1991: pp 171-174
171
c.
172
MARTIN LOCKWOOD
Case 4 A 24-year-old man was admitted to the hospital with a blood pressure of 160/100 mm Hg, and mild renal impairment. He had a hemoglobin of8.9 gJdL, WBC 10.4 X 109/L (400/ILL), platelets 297,OOO/L, CRP 192 mgJL, creatinine 325 ILmol/L (3.7 mgJdL), and ANCA 24% (Fig 10). WBC scan showed mild bilateral renal uptake (Fig 20). Renal biopsy showed five glomeruli, three of which were sclerosed, and the remaining two showed mesangial cell increase. The tubules showed extensive tubular atrophy and there was a diffuse mononuclear cell infiltrate with mononuclear cells and some polymorphs. In addition, there were loose granulomatous aggregates ofiymphocytes and histiocytes within the interstitium. Definite giant cells were not identified. Vessels showed medial hypertrophy in keeping with the hypertension (Fig 3~). Creatinine clearance increased to 803 ILmol/L (9.1 mgJdL) before treatment with corticosteroids (prednisone, 40 mgJd) reversed the decline in renal function.
DISCUSSION
Fig 1. (A-D) Indirect immunofluorescence microscopic appearance of ANCA from patients 1 through 4, respectively. (Fig 2B). Renal biopsy showed intense acute inflammatory cell infiltrate, mostly polymorphonuclear leukocytes, with sparing of the glomeruli. Vessels and tubular structures were normal (Fig 3B). No infectious agents were localized. After 5 days, fever resolved and creatinine levels decreased spontaneously (Fig 4).
Case 3 A 71-year-old man developed a f ever, urinary frequency, nocturia, and dysuria for 5 days. On admission he was noted to have microscopic hematuria. His hemoglobin was 11 .2 gJ dL, WBC 9.7 X \09/L (9,700/ILL), platelets 319,OOO/L, CRP \03 mg/L, creatinine 171 ILmol/L (1.9 mgJdL), and ANCA 20% (Fig 1C). Indium-labeled WBC scan showed moderate bilateral renal uptake (Fig 2C). Renal biopsy showed abnormal medullary tubules lined by degenerating and necrotic epithelium. The surround interstitium was severely abnormal, with numerous infiltrating neutrophils, eosinophils, and lymphocytes. Aggregates of inflammatory cells were forming microabscesses. There was no significant abnormality in the vessels and mild focal mesangial matrical increase in the glomeruli (Fig 3C). Renal function deteriorated to a creatinine of 865 ILmol/L (9.8 mgJdL) before recovering spontaneously. No infectious agent was ever isolated.
The case histories of these four patients illustrate the need for caution in the interpretation of serological markers for vasculitis. Without WBC scanning and renal biopsy, the interstitial nature of the renal lesion would have been overlooked. The ANCA positivity was shown both by indirect immunofluorescence, as well as solidphase assay, and verified by specific inhibition tests.4 These ANCA results in the presence ofimpaired renal function might have tempted a trial of cytotoxic drug and corticosteroid therapy. In fact, three of the four patients improved without treatment. The nature of the disease affecting these patients remains an enigma. In full blown vasculitis, when glomerular necrosis is readily apparent, then interstitial damage may be an accompanying feature. In patient 1, it could be argued that the presentation was clinically that of an atypical microscopic polyarteritis, with relatively little extrarenal involvement, or an idiopathic rapidly progressive nephritis. However, in patients 2 and 3, this is less easy to justify and it would appear that all the patients could equally be classified as having a primary interstitial vasculitis. Certainly the indium-labeled polymorph scans would support this, and interestingly there was no abnormal renal uptake when this was repeated in patient 1, after remission had occurred.
ANCA-POSITIVE INTERSTITIAL NEPHRITIS
Fig 2. (A-D) Indium-labeled polymorphonuclear leukocyte scans of patients 1 through 4, respectively.
173
C. MARTIN LOCKWOOD
174 900
....
:3800 0700
E
...
0600 (.l
~500
W400 Z
~300
I-
~200
a:
0100 0 0
4
8
12
16
20
24
28
32
36
40
DAYS Fig 4. Serial serum creatinines in patients 1 through 4. Note that in patient 3 1 month elapsed before he presented again with a creatinine of 800 /Lmol/L (9.1 mg/ dL); in patient 4, treatment with corticosteroids was started when the creatinine reached 803 /Lmol/L (9.1 mg/ dL).
Fig 3. (A-D) Renal biopsy light microscopic appearances of patients 1 through 4, respectively.
In conclusion, ANCA positivity should alert the nephrologist to the possibility of interstitial, as well as glomerular, nephritis. Renal biopsy should continue to be used as an adjunct to the management of patients presenting with undiagnosed renal impairment.
REFERENCES I. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic au-
toantibodies and associated diseases: Areview. Am J Kidney Dis 15:517-529,1990 2. Cohen-Tervaert JW, Goldschmeding R, Elema JD, et al: Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int 37:799-806, 1990
3. Savage COS, Lockwood CM: Anti-neutrophil antibodies in vasculitis. AdyNmhrQI 19:225-236, 1990 4. Savage COS, Winearlsk CG, Jones S, et al: Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet 1:13891393, 1987