Journal of the Royal Society of Medicine Volume 72 October 1979


Renal vasculitis in microscopic polyarteritis nodosal D Gwyn Williams MD FRCP Renal Unit, Guy's Hospital, London SE] 9RT

Introduction Renal vasculitis may occur in most conditions which are characterized by a vasculitis affecting organs other than the kidney and consequently is found in several systemic diseases. Inflammation of the renal veins and venules is uncommon, so in practice it is the renal arteries and their branches down to and including those of the glomerular tuft which are abnormal in renal vasculitis. In this paper the term 'vasculitis' is therefore used interchangeably with arteritis. Arteries of any size in the kidneys may be involved in polyarteritis nodosa (PAN). The renal arteries themselves and their arcuate and interlobular branches seem to be infrequently affected in PAN, but this may be a reflection of the assiduousness with which a search for the lesions, well known to be intermittent along the course of an artery, is performed. When they are involved, total or partial infarction of the kidney may ensue. To the nephrologist, a much commoner presentation of PAN is the so-called microscopic polyarteritis. This is characterized histologically by a crescentic glomerulonephritis with infarction and fibrinoid necrosis affecting the glomeruli. Surprisingly, arteritis itself affecting the renal vessels is found in only a small proportion of renal biopsies. This is probably a reflection of the intermittent changes along the course of the vessels, as is well recognized in polyarteritis affecting arteries elsewhere in the body. As in the more usual form of polyarteritis, microscopic renal polyarteritis may be associated with clinical and histological evidence of arteritis in more than one organ. Although familiar to nephrologists, this rather uncommon form of polyarteritis has received scant attention in the literature.

Clinical features Eighteen patients with histological evidence of microscopic polyarteritis have been seen in the Renal Unit at Guy's Hospital in recent years. The sex distribution was equal, and the age range 4-76 years, with a mean of 50 years, indicating the preponderance of this disease, as with classical PAN, in the middle-aged and elderly. Most patients recalled their illness beginning with fatigue and malaise, frequently accompanied by fevers and pains in joints and muscles, and the disease was often labelled as 'influenza' in its early stages. Clinical signs due to arteritis or vasculitis were not often found, the commonest being a purpuric rash reminiscent of Henoch-Schonlein purpura affecting the limbs, and sometimes the trunk. The systemic nature of microscopic renal polyarteritis is further emphasized by the post-mortem demonstration in 3 patients of arteritis affecting other tissues, namely spleen, lung, adrenal gland, and pericardium. Small infarcts of the skin may be seen in the nail folds or occasionally in other parts of the hands and feet. Signs and symptoms due to oliguria and uraemia naturally developed if renal function was reduced sufficiently. Renal failure was, in fact, present in 16 of the 18 patients, and 7 of these were anuric or oliguric. Surprisingly, hypertension was recorded in only 4 patients.

Investigations Eosinophilia was detected in a minority of patients. The chest X-ray in a few instances demonstrated shadows which, in the absence of any proof of infection, were taken to indicate 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 28 March 1978. Accepted 2 July 1979

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Journal of the Royal Society of Medicine Volume 72 October 1979

vasculitis affecting the lung. Clearly, the diagnosis of Wegener's granuloma would have to be considered in such patients, and it is important to enquire after epistaxis, nasal discharge and stuffiness in patients with microscopic polyarteritis. One patient in our group had Wegener's granuloma, and another had relapsing polychondritis. The diagnosis is made by renal biopsy. Typically this shows fibrinoid necrosis of the glomeruli, which may extend from segmental to total involvement, and may affect only some glomeruli (focal) or all (diffuse). Frequently there is proliferation of cells of the glomerular tuft, crescent formation due to epithelial cell proliferation, and red cells and fibrin in the capsular space (Figure 1). Arteritis itself is seen in a minority of cases, and consists of fibrinoid necrosis of the wall with destruction of the internal elastic lamina and periarterial inflammation with polymorphs and mononuclear cells (Figure 2).

Figure 1. A glomerulus showing a normal area (a) segmental fibrinoid necrosis (b) and a cellular crescent (c). M.S.B. x 160

Figure 2. A large interlobular artery showing fibrinoid necrosis of its wall (f) and surrounded by a cuff of inflammatory cells. M.S.B. x 60

In the treatment of cases with microscopic polyarteritis, our practice has been to use steroids with azathioprine and, during the last four years, dipyridamole and anticoagulants. Subcutaneous heparin is used initially, succeeded by warfarin after a period of approximately six months. This regime of quadruple therapy has been used in several patients with a rapidly progressive glomerulonephritis accompanied by oliguria or anuria (Brown et al. 1974). In addition, raised blood pressure is strictly controlled and, of course, renal failure is treated


Journal of the Royal Society of Medicine Volume 72 October 1979


Results Thirteen of the 18 patients were treated. Of the 5 untreated patients, 4 were not treated because they had histological evidence of end-stage renal failure by the time they were referred and their age made chronic dialysis or transplantation impracticable. One patient, aged 69, had only slight impairment of his renal function and was considered too frail for the rigours of the quadruple therapy outlined above. Of the 13 treated patients, 6 died and 7 survived. In the former group, renal function was impaired in all but one at the time of presentation (mean plasma creatinine 536 imol/l; range 103-1010 imol/l) and survival was short, being a few weeks in most. One patient, however, survived two years with a fall in creatinine from 347 ,ug/l to 158 gg/l. The therapy may have contributed to the deaths of 4 patients, since 3 died with lung bacterial infections and one with acute pancreatitis, which has been reported to be a complication of steroid therapy (Riemenschneider et al. 1968). The 7 patients who survived have done so for a period ranging from 15 to 72 months (mean 31 months). In all but one renal function has improved compared with that at the time of presentation, when it was impaired in all (mean plasma creatinine 284 Rmol/l; range 1401000 gmol/l); the remaining patient went gradually into terminal renal failure and is now on chronic haemodialysis. Apart fron chest infections there were no major complications from the quadruple therapy in these patients.

Discussion In addition to polyarteritis nodosa, renal vasculitis is found in the following conditions.

Systemic lupus erythematosus (SLE): Vasculitis may be present in tissues damaged in SLE, and interlobular renal arteries are occasionally affected in kidneys with SLE nephritis. Scleroderma: Although the vascular lesions have a less pronounced inflammatory component in scleroderma than in SLE or polyarteritis, fibrinoid necrosis can occur in smaller arteries, occasionally with periarterial leukocytes. The typical gross intimal proliferation, although not strictly an arteritis itself, may be another manifestation of the vascular insult in these patients. Rheumatoid arthritis: The kidney is somewhat surprisingly spared in this condition. Minor proliferative glomerular changes and vasculitis have been seen in a small proportion of patients, but rarely constitute a practical -problem, in contrast to the complication of amyloidosis. Wegener's granulomatosis: This disease is often complicated by a renal necrotizing vasculitis affecting small arteries and a crescentic glomerulonephritis. This serious complication is histologically indistinguishable from the microscopic form of polyarteritis affecting the renal vessels and glomeruli (v. infra). Henoch-Schonlein purpura: The kidney has long been recognized to be affected in HenochSchonlein purpura, along with the skin, joints, and small intestine. In a few cases arteritis may be seen histologically in the kidney in addition to the typical glomerulonephritis, which exhibits the hallmark of mesangial IgA on immunofluorescence. BehVet's disease: Vasculitis is a component of the pathology of Behqet's disease, but the kidney seems markedly spared in that serious renal disease is not part of the clinical picture. Proteinuria and/or microscopic haematuria occasionally accompany Beh9et's disease, and we have recently studied a patient who had proteinuria of 0.5-1.0 g/day, whose renal biopsy showed proliferative glomerular changes with IgA and IgG on immunofluorescence. It is interesting to note in this condition, as well as in rheumatoid arthritis, the lack of renal involvement in diseases considered to be caused by the deposition of chronic circulating immune complexes.


Journal of the Royal Society ofMedicine Volume 72 October 1979

Relapsing polychondritis: This rare disease is accompanied by renal vasculitis and crescentic glomerulonephritis which is similar histologically to the microscopic form of polyarteritis.

Microscopic renal polyarteritis should be distinguished from: (1) Wegener's granuloma with renal involvement, although this cannot be done histologically, as the changes in the kidney are so similar. (2) Idiopathic diffuse crescentic glomerulonephritis (rapidly progressive glomerulonephritis). In this condition there are no associated features of systemic disease and histologically, although there is a crescentic glomerulonephritis, which may be accompanied by glomerular tuft necrosis, arteritis is not found, either in the kidney or in other organs. Many drugs, mostly antibiotics among which penicillin and the sulphonamides are foremost, have been considered responsible for causing polyarteritis by acting as the antigens in a hypersensitivity angiitis. Although there is reasonable proof that drugs behave in this way in a small number of instances (Bjornberg & Gisslen 1965), in most cases the evidence is that of mere association. With the influenza-like presenting symptoms of polyarteritis occurring in older patients it is inevitable that many of them will receive antibiotics, and will do so probably after the arteritis has begun, and in the absence of individual convincing evidence to the contrary it must be concluded that the association with antibiotics is mostly fortuitous and not causative. It has been suggested that in polyarteritis the Australia antigen is a causative agent, acting as an antigen in an immune complex disease. This conclusion was first based on Australia antigen having been detected in the sera of 4 of 11 (Gocke et al. 1970) and 30 of 55 patients (Trepo et al. 1974) with polyarteritis. Further support for this role for Australia antigen comes from a study in which Australia antigen was demonstrated in vascular lesions in patients with polyarteritis (Michalak 1978). None of the patients included in this study, however, were found to have Australia antigenaemia. No other infectious agents have been particularly linked with polyarteritis. The microscopic changes of polyarteritis are similar to those found in experimental animals in which immune complex disease has been induced with the production of vasculitis, nephritis and arthritis. Cryoglobulins, which are cold-precipitable proteins containing immunoglobulins and which have the properties of immune complexes, have been found in the serum of some patients with PAN (Barnett et al. 1970). Immune complexes and cryoglobulins have also been detected in other diseases in which renal vasculitis occurs, such as SLE (Davis et al. 1978) and Henoch-Schonlein purpura (Garcia-Fuentes et al. 1977). There is, therefore, strong circumstantial and analogous evidence that the vasculitis in polyarteritis is a result of circulating immune complexes. The injury is presumably mediated by the leukocytes characteristically seen in and surrounding the arterial wall, and by the complement system and fibrin. Evidence that the latter two are involved comes from immunofluorescent studies which show C3 and fibrin in the glomeruli and affected arteries (Paronetto & Strauss 1962, Lachmann et al. 1962); earlier components of the complement system are not detected in polyarteritis and it is therefore possible that the C3 and fibrin, and indeed the leukocytes, are present merely as secondary events following tissue damage, and do not represent the means by which the damage was initiated. Serum complement components are not lowered in polyarteritis, which again hints that the complement system may not be involved, although turnover studies to measure the rate of catabolism would be required to answer this question correctly. On the basis that polyarteritis is an inflammatory disease related in certain respects to the other 'collagen' diseases, steroid therapy has been used for several years in the treatment of polyarteritis, including its renal forms. With the evidence described above that polyarteritis may be an immune complex disease, there is possibly further justification for steroid therapy as immunosuppression, with the addition of other immunosuppressive agents such as azathioprine and cyclophosphamide. Other drugs we have recently employed in the treatment of microscopic renal polyarteritis are dipyridamole and anticoagulants. The former is used on the grounds that platelets may be involved in the mediation of tissue injury, and may also cause damage by thrombus formation within the affected vessel. Heparin and warfarin are

Journal of the Royal Society ofMedicine Volume 72 October 1979


used ostensibly to prevent fibrin deposition (although there is no evidence that fibrin is deposited via the normal coagulation pathway) and secondary thrombus formation. The mandatory controlled trial to prove the efficiency of any of these drugs either alone or in any combination of them has yet to be performed (and with the rarity of the condition and its complex treatment is unlikely to be generated). The only information on the effectiveness of any of these drugs concerns the use of steroids: a retrospective study of 130 patients with polyarteritis showed that of 20 untreated patients 13% survived 5 years, whereas of the 110 treated patients 48% survived for 5 years (Frohnert & Sheps 1967). In the treated group of 13 patients described in this paper, just over half have survived a mean period of 31 months, with improved renal function and therefore presumed regression of disease in all but one of the survivors. Treatment of hypertension does not explain this improvement as only 2 patients had high blood pressure, with initial diastolic readings of 110 and 100 mmHg respectively. The surviving treated patients had a lower mean plasma creatinine which suggests that lesser renal involvement, or earlier presentation, influences the outcome. Our experience in the treatment of microscopic renal polyarteritis is similar to that of an Australian group, who found renal function to improve in 66% of 21 patients who were treated with a combination of steroids, azathioprine and anticoagulants (Friedman & KincaidSmith 1972). Thus, although obviously a serious disease, it is reasonable to expect an acceptable quality of survival in approximately 50% of patients, provided that the diagnosis is made while there is reversible renal damage. As already stated, there is no indisputable evidence that the drugs used for treatment are effective, but it is our strong impression that prompt treatment as described above is responsible for reversing the tissue damage and renal dysfunction. It is notable that 2 patients in the treated group who survived have been able to cease therapy, and that the patient who was untreated but survived gained an improvement in renal function, the glomerular filtration rate rising from 69 ml/min to 90 ml/min over a period of six months. These observations suggest that the arteritis in these patients may well have been a self-limiting disease analogous to experimental 'one-shot' serum sickness, and further emphasize the benefits which may result from early diagnosis and treatment.

Acknowledgments: I am grateful to Dr D R Turner for his constructive criticisms and to him and Dr J Heaton for the photomicrographs. References Barnett E V, Bluestone R, Cracchiolo A, Goldberg L S, Kantor G L & McIntosh R M (1970) Annals of Internal Medicine 73, 95-107 Bjornberg A & Gisslen H (1965) Lancet ii, 982-983 Brown C B, Wilson D, Turner D, Cameron J S, Ogg C S, Chantler C & Gill D (1974) Lancet ii, 1166-1172 Davis J S, Godfrey S M & Winfield J B (1978) Arthritis and Rheumatism 21, 17-22 Friedman A & Kincaid-Smith P (1972) In: Glomerulonephritis, Part II. Eds. P Kincaid-Smith, T H Mathew & E L Becker. John Wiley & Sons, New York; pp 1047-1056 Frohnert P P & Sheps G S (1967) American Journal of Medicine 43, 8-14 Garcia-Fuentes M, Chantler C & Williams D G (1977) British Medical Journal ii, 163-165 Gocke D I, Hsu K, Morgan C, Bombardierei S, Lockshin M & Christian C L (1970) Lancet ii, 1149-1153 Lachmann P J, Muller-Eberhard H J, Kunkel G F & Paronetto F (1962) Journal of Experimental Medicine 115, 63 Michalak T (1978) American Journal of Pathology 90, 619-628 Paronetto F & Strauss L (1962) Annals of Internal Medicine 56, 289 Riemenschneider T A, Wilson J F & Vernier R L (1968) Pediatrics 41, 428 Trepo C G, Zuckerman A J, Bird R C & Prince R M (1974) Journal of Clinical Pathology 27, 863

Renal vasculitis in microscopic polyarteritis nodosa.

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