Systemic Vasculitis with Renal Involvement - A Review

Y. O'Meara, A. Green, M. Carmody, G. Doyle, J. Donohoe

Departments of Pathology and Nephrology, Beaumont Hospital, Dublin 9.

Summary Twenty five patients with renal vas-

culitis presenting over an eight year period were reviewed. Ten had micro- scopic polyarteritis, 6 classic polyarteri- tis, 5 overlap syndrome, 2 Churg-Strauss syndrome and 2 Wegener's granuloma- tosis. Clinical features included hyper- tension, pulmonary involvement, neuro- logical involvement and arthralgia. Serum creatinine was over 500 umol/1 in 13 patients, 10 of whom required di- alysis. Visceral angiography was posi- tive in 80% of those studied, Focal and segmental necrotising glomeruloneph- ritis was the commonest renal lesion. Treatment consisted of corticosteroids and cytotoxic agents in most cases. Plas- mapheresis was used for rapidly pro- gressive renal failure, severe pulmonary haemorrhage or cerebral vasculitis. Improvement or stabilisation of renal function was seen in 68% of patients treated. There were 4 early deaths and one late death.

The diagnosis, histology, treatment and outcome of renal vasculitis is dis- cussed. The importance of early diag- nosis and treatment is emphasised in this potentially reversible cause ofacuterenal failure.

Introduction The clinical spectrum of systemic

vasculitis encompasses a wide range of disease entities with many and varied clinical presentations. Renal involve- ment with rapidly progressive renal fail- ure may in some cases dominate the clinical picture. In contrast, asympto- matic haematuria and proteinuria may be the only evidence of renal vasculitis. Current classifications of systemic vas- culitis focus on the size of vessel in- volved by the process of inflammation and fibrinoid necrosis. In classic poly-

Address for correspondence: Dr. J. Donohoe, Consultant Nephrologist, Beatmaont Hospital, Dublin 9.

arterifts nodosa, originally described by Kussmaul and Meier °~, medium sized arteries are involved, whereas in micro- scopic polyarteritis, recognised histol- ogically by the presence of focal and segmental necrotising glomeruloneph- rifts, smaller blood vessels are involved. In some patients, both medium and small vessels are involved, leading to the des- ignation "overlap syndrome". Other forms of systemic vasculitis have dis- tinct clinical features which aid in their diagnosis e.g. Wegener's granulomato- sis, Henoch Schonlein syndrome and Systemic Lupus Erythematosis (SLE).

The purpose of this paper is to review the clinical spectrum, treatment and outcome of patients with renal vasculitis presenting to a single centre over a pe- riod of eight years.

Patients and Methods A retrospective study was carried out

of the records of 25 patients with vascu- lifts presenting to our unit between 1980-1987. Vasculitis was diagnosed on the basis of clinical, histological and radiological evidence. Clinical mani- festations of vasculitis comprised signs of systemic disease, with malaise, fever and weight loss, plus evidence of a multisystem disease with two or more major organs involved.

Histological confirmation was on the basis of inflammation and fibrinoid ne- crosis in blood vessels in renal biopsy specimens. Also included werepatients with focal and segmental necrotising glomerulonephritis, without histologi- cal evidence of extraglomerular vascu- litis, whose clinical picture supported a diagnosis of vasculitis. Patients with SLE and Henoch Schonlein purpura were specifically excluded.

Radiology consisted of visceral angiography to detect the presence of microaneurysms.

Laboratory investigations included the following: full blood count with white cell differential, blood urea and serum creatinine levels, ESR,liver func- tion tests, serum albumin, rheumatoid

factor, antinuclear antibody titre, anti DNA antibody titre, circulating im- mune complexes, complement levels and hepatitis B surface antigen.

Treatment included high dose ster- oids administered intravenously as pulsed methylprednisolone 1 gm daily for 3 days, or orally as prednisone 60 mg daily followed by a tapering dose sched- ule. These were combined with cyclo- phosphamide 2.5 mg/kg/day or azathi- oprine 2.5 mg/kg/day in most cases. In selected cases, plasmapheresis was used.

Results

Clinical Features

Twenty-five patients with vasculitis were reviewed. There were 15 males and 10 females. The mean age was 51 years, with a range of 15-75 years. The duration of symptoms prior to referral varied between 1 month and 1 year. Ten patients had a diagnosis of microscopic polyarteritis, 6 had classic PAN, 5 over- lap syndrome, 2 Churg-Strauss syn- drome and 2 Wegener's granulomatos~s.

The clinical features at presentation are shown in Table 1. The commonest symptoms were those of a systemic ill- ness with malaise, fever and weight loss. Hypertension was noted in only 40% of patients. Arthralgia was the most fre- quent musculoskeletal symptom, oc- curring in 40%. Dermatological mani- festations included purpura and necrotis- ing ulcers. 32% of patients had a history of abdominal pain. One patient pre- sented with cholestatic jaundice and pan- creatitis.

19% of patients had haemoptysis, with one requiring mechanical ventila- tion for hypoxic respiratory failure from massive pulmonary haemorrhage. Only 16% of patients had a history of asthma. Peripheral neuropathy occurred in 16%. Less common manifestations included one case of episcleritis and one case of cerebral vasculitis, with recurrent epi- sodes of confusion and drowsiness. One patient has a left hemiparesis at the age of 36 years, 6 years prior to presentation.

300

VoL 158 No. 12 Systematic vasculitis with renal involvement 301

Renal Abnormalities at Presentatinon (Table 2)

Microscopic haematuria and protein- uria were present in 24 of 25 patients. One patient who was anuric did not have urinalysis performed. Proteinuria var- ied from 2+ to 4+ on dipstick. 24 hour protein excretion measured in 11 pa- tients ranged between 200 mg- 6 gm. The serum creatinine was less than 500 umol/1 in 12 patients and was normal in 2 of these. Thirteeen patients had a serum creatinine greater than 500 umol/ 1. Ten of these were oligoanuric on admission and required immediate di- alysis.

Laboratory Investigations The results of laboratory investiga-

tions are summarised in Table 3. An elevatedESRandanormochromic norm- ocytic anaemia were almost invariable with the ESR ranging from 50-150 and an average haemoglobin of 10.3 g/l. Leucocytosis, when present, was pre- dominantly polymorphonuclear. Eosi- n ophilia was present in only 5 patients. The incidence of positive autoantibod- ies and elevated circulating immune complexes was low, and serum comple- ment was normal in all cases. Hepatitis B surface antigen was negative in all pa- tients.

TABLE 2

Renal Findings at Presentation Number of Patients (%)

Microscopic haematuria 24 (96) Proteinuria 24 (96) Se. Creafinine <500mmol/l 12 (48) Se. Creatinine > 500 mmoi/l 13 (52) Oligoanuria 11 (44)

Radiology Coeliac axis artedography was per-

formed in 15 patients. Microaneurysms were demonstrated in 12 of these. (Fig. 1.)

Histology Twenty one of 25 patients underwent

percutaneous renal biopsy. The diagno- sis in the remaining 4 was based on positive visceral angiography.

The commonest glomerular lesion was a focal and segmental necrotising glomerulonephritis with associated cres- cent formation, occurring in 13 out of 21 patients. Threebiopsies showeddiffuse endocapillary crescentic proliferation. Three further biopsies showed focal mesangial proliferation with minicres- cents in 2. One biopsy showed ad- vanced glomerular sclerosis, and in this patient, angiography waspositive. Defi- nite vasculitis, with fibrinoid necrosis, endovasculitis and disruption of the

lamina propria was present in only 6 biopsies. Tubulo-interstitial changes varied from mild focal degenerative changes with scattered cellular infdtmtes, to marked tubular atrophy with intersti- tial fibrosis.

Immunofluorescence studies were performed in 19 of 21 biopsies, 6 of which showed deposition of comple- ment in the blood vessel walls. In the remainder, scattered deposits of IgG, IgM or complement alone were found in the mesangium. However, these were also present in some cases on the base- ment membrane, although in small quantities.

Treatment Seventeeen patients received high

dose oral steroids (60 mg prednisone daily) in conjunction with oral cyclo- phosphamide 2.5 mg/kg/day. One pa- tient received high dose steroids with azathioprine 2.5 mg/kg/day. Five pat- ients received steroids without cytotoxic

TABLE 1. Clinical Features of 25 Patients with Renal Vaseulltis

Clinical Features Number of Patients (%)

General Malaise 20 (80) Weight loss 12 (48) Fever 10 (40) Hypertension 10 (40)

Musculoskeletal Aahralgia 11 (44) Myalgia 5 (20) Proximal muscle weakness 2 (8)

Pulmonary Haemoptysis 10 Radiological infiltrates 7 Asthma 4 Sinusitis 1 Recurrent epistaxis 1

Gastrointestinal Abdominal pain 8 Diarrhoea 4 Bleeding per rectum 3 Pancreatitis with jaundice I

(40) (28)

(32) (16) (12)

Sldn Purpura 6 (24) Other 6 (24)

agents, high dose oral steroids in 3, and pulse methylprednisolone (lgm daily for 3 days) in 2. Six patients were addi- tionally treated with plasmapheresis therapy; three because of renal failure associated with severe pulmonary haem- orrhage and one because of cerebral vas- culitis. Two patients received no spe- cific immunosuppressive treatment. In one of these the renal biopsy showed end stage disease, and in the second patient, severe sepsis prevented the ad- ministration of immunosuppressive agents.

Outcome (Table 4a and 4b) The initial response to treatment was

favourable in 17 patients with improve- ment or stabilisation of renal function and resolution of systemic symptoms. Five of this group were oliguric on ad- mission and required temporary haem- odialysis.

Five patients remained haemodialy- sis dependant. In three patients, renal

302 O ' M e a r a et al. tJ,M.s December, 1989. TABLE 3

Laboratory Investigations

Test No. Tested No. Abnormal (%)

ESR (>20) 25 25' HgB (< 12g/dl) 25 23 Leucocytosis (> 12,000) 25 15 Eosinophilia 25 6 Platelets (> 4,000) 25 13 Hypoalbuminemia 25 17 Rheumatoid Factor 18 4 Antinudear Antibody 20 4 Hypergammablobulinemia:

IgG 22 4 IgM 22 l IgA 22 0

Complement 25 1 Liver Function Tests 25 6 Immune Complexes 17 5 Hepatitis Bs Ag 25 0

riod of 22 months. Four of these are off all medication, 4 are still on steroids

(10o) with cyclophosphamide, and 5 are on (92) low dose maintenance steroids. Two of (60) this group deteriorated and became (24) (52) haemodialysis dependant at 3 and 3.5 (6s) years after initial presentation. (21) (20)

(18)

TABLE 4a Early Response to Treatment

Renal Function No of Patients Mortality

Improvement/Stabilisation 17 2 Remained Dialysis Dependant 5 2 Progressive decline 3 0

TABLE 4b Long Term Outcome

Renal Function No of Patients Mortality

Stable Renal Function 13 O Maintenance Dialysis 5 1 Renal Transplantation 3 0

function deteriorated progressively, despite treatment. All three have under- gone successful cadaveric renal trans- plantation.

There were 4 deaths in the first 2 months, one from extensive pneumo- nia in a patient who was not immuno- suppressed, one from a cerebrovascular accident, one from a myocardial infarc-

(24) (29)

tion, and one from a perforated diver- ticular abscess. There was one late death from cardiac failure in a dialysis de- pendent patient, 3.5 years after presen- tation.

Of 15 surviving patients who showed significant improvement or stabilisation of renal function, 13 have maintained this status at an average follow-up pe-

FIG. 1. Left Renal Digital Subtraction Angiogram showing multiple microaneurysms.

Discussion Systemic vasculitis with renal in-

volvement spans a broad spectrum of disease entities (1.2~. The renal compo- nent may be incidental or may, in many cases, be of life threatening import. Classification of vasculitis is a difficult issue, but is important with respect to treatment and prognosis. The original description by Kussmaul and Meier o} was of classic polyarteritis nodosa which involves medium sized blood vessels and in which renal histology usually shows lesions consistent with infarction or ischaemia. In 1948, Dawson, Bell and Plat# ~ definied microscopic polyar- teritis as a distinct entity affecting smaller blood vessels than those involved in classic PAN. Some patients show fea- tures of both classic PAN and micro- scopic polyarteritis leading to the desig- nation of "overlap syndrome". Leavitt et alcs) described 10 patients who dis- played overlapping features of several distinct vasculitides and classified these as the "polyangiitis overlap syndrome".

The diagnosis of systemic vasculitis requires a high index of suspicion. To date, there has been no specific diagnos- tic laboratory test. The most important recent development in this area has been the identification of an autoantibody to neutrophil cytoplasm (ANCA) in the serum of patients with Wegener's Gran- ulomatosis {6}. Extension of this work has shown the presence of similar au- toantibodies in the serum of patients with microscopic polyarteritis{7). Whether such antibodies are of patho- genetic significance, or simply an epi- phenomenon, remains to be seen. Their detection by indirect immunofluores- cence constitutes a simple diagnostic test which may aid in earlier institution of therapy and in monitoring disease ac- tivity. These antibodies may also help to further classify vasculitides.

Other tests may not always help in diagnosis. Renal biopsy most com- monly shows a picture of focal and seg-

Vol. 158 Systematic vasculitis with renal involvement 303 No. 12

mental necrotising glomerulonephritis, and def'mite fibrinoid necrosis of blood vessels is not always seen. Angiogra- phic demonstration of microaneurysms is not specific for polyarteritis, and may be seen in small vessel vasculitides such

m~¢S) as Churg Strauss syndro ,, and Wegener's granulomatosis ¢9). Our se- ries showed a high incidence of positive angiography compared to other re- portsCt4,1s).

Oligoanufia on admission or a serum creatinine level greater than 500 umol/1 have been associated with a poor out- come in crescentic glomerulonephritis et0). In contrast, 6 of 11 patients in our series who fulfilled these criteria recov- ered good renal function. Five of these patients continue to maintain their renal function at an average follow-up of 20 months.

Six of our patients received plasma- pheresis therapy. All had a good initial response to treatment, although one later progressed to end stage renal failure. The most recent data on the benefits of plasmapheresis suggest that it is helpful in patients who are oligoanuric and require dialysis at presentation. This extra benefit is probably not gained by patients whose renal lesion is less ad- vanced as this group responds extremely well to steroids and cytoxic agents (un- published observation).

In the past, untreated patients with polyarteritis nodosa were shown to have a five year survival rate of 10%, which improved to 48 % with the use of steroids ctt). With the combination of cytotoxic therapy and steroids, a further signifi- cant benefit has been demonstrated t1~13).

Serra et al reported patient survival

rates of 54%, 38% and 34% at one, five an d ten years respectively, in a group of patients with renal vasculitis treated with various immunosuppressive regimes ¢t4~. While microscopic polyarteritis was thought to have a worse prognosis than classic PAN, Savage et al reported 5 year patient and kidney survival rates of 65% and 55% respectively in a group of patients with microscopic polyarteritis immunosuppressed aggressively~tS).

Based on oar experience to date, the current policy is to commence treatment with high dose oral steroids for a period of eight weeks, subsequently tapering to a low maintenance dose for a period ofatleast one year, depending on patient response. In addition, cyclophospha- mide is administered in a dose of 2.5 mg/ kg daily for a period of one year. Plas- mapheresis therapy is used where clini- cally indicated for life threatening pul- monary haemorrhage, rapidly progres- sive renal failure or major neurological involvement.

Renal failure can supervene rapidly in the setting of systemic vasculitis and the importance of early intervention and biopsy in patients with clinically sus- pected vasculitis and abnormalities of the urinary sediment, is stressed. A vigorous approach to diagnosis and therapy is warranted in this potentially life threatening but reversible cause of renal failure.

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