Granulocyte or mixed leukocyte infiltrates in biopsy specimens of arterial wallThe first report of a patient who had vasculitis was made in 1866 by Kussmaul and Maier who described a patient with 'nodular inflammation of the muscular arteries'1. They originally named the disorder 'periarteritis nodosa', which later became referred to as 'polyarteritis nodosa'1, 2. It was not until 1952 that Zeek proposed a classification system based on descriptions of the other necrotising vasculitides, this system was based on vessel size and formed the basis for future classification systems1-3. In 1990 the American College of Rheumatology (ACR) established criteria for different forms of vasculitis which was then improved on in 1994 by the Chapel Hill Consensus Conference (CHCC), who proposed uniform terms and definitions for the most common forms of vasculitis based upon the size of the blood vessel affected1-4.
Vasculitis can be divided into two broad categories, Primary vasculititides which are conditions of unknown cause in which vasculitis is the basis of the pathological tissue damage and Secondary vasculitis in which blood vessel inflammation occurs alongside with an underlying pathology or exposure1, 2, 5, 6. There are several types of systemic vasculitis can affect the kidney; renal involvement is most common in certain forms of primary systemic vasculitis, such as; polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and Wegener's granulomatosis (WG)1-3, this SSM will focus on polyarteritis nodosa and microscopic polyangiitis, in which renal involvement is reported in up to 76% of patients1-3.
In the classification system by the ACR, there was no original distinction between PAN and MPA which was said to belong to the PAN group of vasculitides2. The CHCC criteria established a distinction between the two types, PAN was defined as 'a necrotising inflammation of medium sized or small arteries, without any evidence of glomerulonephritis or vasculitis in arterioles, capillaries or venules'1-3, 7, whereas MPA was described as the 'cases previously diagnosed as PAN with evidence of arteriole, venule or capillary involvement or glomerulonephritis'1, 2.
Polyarteritis nodosa is a primary vasculitis, though there have been well documented cases of co-infection with HIV, hepatitis B virus and hepatitis C virus1, 2. It is a rare condition, more common in adulthood than childhood, affects men more than women at a ratio of 1.6:1 and most commonly presents between the ages of 40 and 60, it has an incidence in the UK of 2-6 people per 100,000 of the population per year1-3.
PAN usually presents with systemic symptoms such as malaise, weight loss and fever and further symptoms are specific to the organs involved, but the most common are hypertension, musculoskeletal symptoms and vasculitis involving the nerves, gastrointestinal tract, skin, heart and non-glomerular renal vessels1-3. Skin involvement can produce a purpuric rash, livedo reticularis (a purplish lace-like discolouration of the lower extremities), ischaemia of the distal digits and ulcerations1-3. Around 50% of PAN patients present with arthritis of neuralgia, and up to 70% of patients can have a peripheral neuropathy which may produce mononeuritis multiplex1-3. There may also be gastrointestinal involvement (GI), which are severe signs of PAN and may present with abdominal pain, small bowel perforation, ischaemia or GI bleeding1-3.
Renal involvement is reported in between 63- 76% of patients diagnosed with PAN, the underlying mechanism for renal damage is arteritis of the medium sized vessels in the kidney, which may lead to renal ischaemia and in more critical cases renal infarction1-4. PAN with renal involvement may present in several ways; loin or groin pain, macroscopic or microscopic haematuria, moderate proteinuria, slow progressive renal insufficiency and hypertension1-4. Hypertension is a common finding with PAN; the incidence has been variably reported though, with figures ranging from 25% to 71% and is usually renin- mediated1, 2. Immunochemical studies have shown that there is hyperplasia of rennin producing cells in the ischaemic parts of the renal cortex and also variations in their distribution1, 2, 5, 7-9.
The strongest evidence for the diagnosis of PAN depends upon tissue biopsy and histology1, 2. There are no laboratory investigations specifically to test for PAN, the most common findings are those which are indicative of chronic inflammation, raised erythrocyte sedimentation rate, increased C-reactive protein as well as elevated fibrinogen and complement, there may also be normochromic anaemia and leukocytosis1, 2. Renal angiography has been used to diagnose PAN, angiography has demonstrated arterial stenosis and microaneurysms, which are usually located on the level of the interlobar arteries down to the arcuate arteries, the presence of microaneurysms indicate more severe disease and have been shown to regress with treatment1, 2, 4, 9, 10.
MPA was described as early as 1946 as a microscopic form of PAN with renal involvement including segmental cresenteric glomerulonephritis, but it was not until the CHCC classification that it started being referred to a 'microscopic polyangiitis' which was defined as 'a necrotising vasculitis affecting small vessels and almost invariably associated with glomerulonephritis'1, 5, 6, 10. MPA is a rare disorder, with reports for annual incidence in the UK placed between 3.6 to 8.9 per million people; it affects males more than females at a ratio of 1.8:1 and normal age of onset is between 50 to 60 years of age1-6, 9.
Systemic symptoms such as fever, weight loss and malaise are present at diagnosis in up to 76% of patients with MPA1, 2. The clinical signs of MPA are similar to those of PAN, the main difference being that renal involvement is consistently present in MPA in the form of glomerulonephritis, compared to renal vessel vasculitis in PAN1, 2. Another significant difference between the two is that peripheral neuropathy is less common in MPA, affecting up to 19% of patients in comparison to 70% in PAN1, 2. In contrast though, pulmonary involvement is relatively common in MPA, whereas it is rare in PAN1, 2.
Renal involvement is reported in the majority of MPA patients at some point during the course of the disease1, 2, 5, 6. Only up to 36% of patients with MPA present with renal involvement, but a study found that at 15 years, as many as 79% of patients had developed renal manifestations1, 2, 5, 6. The type of renal involvement in MPA is usually rapidly progressive glomerulonephritis, although cases of renal function declining slowly have been noted1, 2, 5, 6. Renal pathology may vary from asymptomatic renal impairment, haematuria, and proteinuria to renal failure1, 2, 5, 6. Microscopic haematuria is found in between 64- 100% of patients and proteinuria is found in up to 90% of patient while functional renal impairment eventually develops in 70- 100% of patients1, 2, 5, 6. Hypertension occurs in MPA, but is not as common as in PAN, and is found in up to 35% of patients, this may be due to the fact that glomerular involvement is focal and segmental, and renal ischaemia is infrequent1, 2, 5, 6. The presence of aneurysms is also infrequent as are renal and perirenal haematomas1, 2, 5, 6.
Laboratory findings are similar for MPA as for PAN; there are non-specific signs of chronic inflammation, though an important difference is that antineutrophil cytoplasmic antibodies (ANCA) are frequently detected in MPA, whereas they are rare in PAN1, 2. The differentiation of MPA from PAN is important in diagnosis, due to the fact that vasculitis of the renal vessels is uncommon and microaneurysms rarely develop, angiographic findings are uncommon in MPA1, 2. The role of renal biopsy in MPA is critical from a diagnostic and prognostic perspective1, 2. Rapidly progressive glomerulonephritis (RPGN) is an important part of the definition of MPA if it is found, then it favours a diagnosis of MPA over PAN1, 2. Some experts claim that small vessel involvement is not sufficient criteria to differentiate MPA from PAN, so ANCA and angiographic findings must be considered in diagnosis1, 2, 6, 7, 9.
Aim
The aim of this SSM is to investigate the clinical importance of renal involved vasculitis and in particular polyarterits nodosa and microscopic polyangiitis. The SSM will explore the differences between the two forms of vasculitis and the pathology, current treatment strategies and prognosis of the two forms.
The information for this SSM was obtained from a variety of sources, at first it was necessary to grasp a general overview on the subject of vasclitis, the different classifications and the way that vasculitis can affect the kidneys, several books were used for this which were obtained from the Harold Cohen library. To acquire more detailed ionformation regarding the subject of polyarteritis nodosa and microscopic polyangiitis, many database searches were used, these included Science Direct, Ovid, Pub Med, Google Scholar, Scopus. A wide range of databases were used so as to access as many articles as was possible, also to access only the relevant articles search limitations were used in each database to narrow down the results that were given. An example of the limitations used were Only articles in english language, full articles and also articles from the year 2000 onwards so as to obtain the latest research. MeSH terms were also used in the search to ensure that the articles returned were as relevant to the subject headings as possible.
As mentioned before, PAN is a necrotising vasculitis, which according to the CHCC criteria does not involve blood vessels smaller than arteries1, 2. Evidence from biopsies has shown that the arteritis of PAN is irregular in distribution and the lesions that are produced are segmental, having a tendency to affect the site of bifurcation of vessels1, 2. At the kidney the vessels that are involved may vary from the interlobar and arcuate arteries to the interlobular arteries1, 2. The acute arterial lesions that are found with PAN are focal segmental inflammatory lesions, fibrinoid necrosis which is a form of tissue death in which there is an accumulation of basic proteinaceous material in the matrix, which when stained resembles fibrin is common, along with perivascular pleomorphic infiltrate which is infiltrate around the bloodvessels which histologically show a variability in the shapes and sizes of their cells and nuclei. Histology of early lesions show that they consist mainly of neutrophils, while the study of older lesions have shown that mononuclear leukocytes are the majority.
If at biopsy, a large enough sample is taken, lesions at different stages of development and healing can be found. They affect the blood vessel by disrupting the normal architecture and destroying the elastic lamina, when the inflammation erodes into the perivascular tissue, this can lead to aneurysm formation, thrombosis or rupture of the vessel wall leading to haemorrhage. This damage to the vessel can cause chronic arterial stenosis, which can cause chronic ischaemia resulting in zones of atrophy, the kidney compensates for these zones of atrophy by creating alternating zones of hypertrophy, and this leads to a macroscopically irregular appearance of the renal cortex. The glomeruli usually remain relatively unchanged, though hyperplasia of the juxtoglomerular apparatus and hypertensive changes in the afferent arterioles may be seen. Patients with PAN also often have tubulointerstitial changes and the inflammatory infiltrate consists of mainly lymphocytes and tubulitis.
It is often difficult to differentiate PAN from MPA histologically, MPA will have glomerulonephritis, or if the lungs are involved pulmonary capillaritis, though uneven areas of distribution where there is areas of arteritis alternating with fibrotic areas and involvement of the elastic lamina is indicative of PAN.
Pathology of MPA
By definition, MPA is characterised by a focal and segmental glomerulonephritis, which has been reported in between 80 to 100% of renal biopsies. Changes to the glomeruli include fibrinoid necrosis and prominent crescents are found in greater than 60%. Common findings also include adhesions to Bowman's capsule and disruption of the glomerular basement membrane is also seen, the necrotic glomerular segments show that there are abundant neutrophils which infiltrate around the segments. In PAN, there are lesions of different and mixed stages of healing and degeneration, in MPA however the glomerular lesions tend to be of a similar age.
Tubulointerstitial changes are commonly found in MPA with the interstitial infiltrate consisting mainly of lymphocytes, monocytes and plasma cells, though eosinophils, epithelioid and giant cells are intermittently found. The effect of the small vessel vasculitis is tubular ischaemia which commonly leads to vacuolisation, degeneration and atrophy of the tubules, reported less commonly but still a significant change is the fragmentation of the tubular basement membrane. Vasculitis of the renal vessels is reported in 19 to 34% of cases and usually affects the small vessels, subarcuate lobular arteries and arterioles, the vasculitis consist of fibrinoid necrosis with perivascular infiltrates of neutrophils and monocytes.
Microaneurysms are not normally associated with MPA, and reports vary as to the findings, with some studies finding 0% of patients having microaneurysms and some reporting up to 27% of patients. A recent study which explored the 3D morphology of vessels, found that microaneurysms of less than 1mm are frequent in patients with MPA, the aneurysms found in MPA were described as being sausage shaped, which was suggestive of necrotising panangiitis involving the complete circumference of the vessel, whereas the microaneurysms in PAN are usually saccular which suggests vasculitic involvement of only a portion of the vessel circumference.
Treatment of PAN and MPA
Before current therapy had been introduced, vasculitis was a life threatening and often fatal disorder, now it is manageable, though treatment is limited by partial efficacy and increased levels of toxicity. Studies have shown that although remission is achieved in a high proportion of patients with the most advanced treatment, 20 to 30% of patients fail to achieve complete remission, and a small proportion of those progress to more severe disease.
The undesirable effects of current therapy include the toxicity effects that the drugs have upon patients. Over 90% of patients will experience drug-related toxicity during their course of treatment, of these up to 50% experience severe reactions. The most common cause of death within the first year of treatment is infection due to immunosuppression- induced leukopaenia. In older courses of therapy involving cyclophosphamide (a chemotherapy treatment, which is also a potent carcinogen) very high rates of malignancy were reported, although recent strategies such as switching to another immunosuppressant at the time of remission or using IV pulsed cyclophosphamide have reduced the risk.
PAN and MPA have always been recognised as severe systemic conditions, their prognosis has been improved drastically by the introduction of corticosteroids and immunosuppresants, especially cyclophosphamide. Since their introduction in 1950 to treat PAN, methylprednisolone alone has been able to increase the 5 year survival rate from 10% to over 55% in the late 1970's. The survival rate was further increased to over 82% by adding cyclophosphamide to the treatment regimen.
There are several methods that can be used to treat vasculitis, the strategy adopted much depends upon the type of vasculitis, the stage of disease the patient is in, if the treatment is required for induction of remission or maintenance of remission, the pattern of different organ involvement and also medication that the patient is already taking.
Anti-proliferative drugs are one of the classes used to treat vasculitis, these include mycophenoloic acid (usually administered as mycophenolate mofetil-MMF), leflunomide and deoxyspergualin. MMF is an immunosuppressive drug, used mainly to prevent rejection in organ transplants, though it is also beginning to be used in other auto-immune disorders such as systemic lupus erythematosus. Mycophenoloic acid works by non-competitively inhibiting inosine monophosphate dehydrogenase (IMPDH) which is required for guanine synthesis and inhibits proliferation of B and T lymphocytes, it is also thought to inhibit the adhesion of activated lymphocytes at the site of inflammation. It is not yet clear what the optimal dose of mycophenoloic acid for use in auto- immune disease should be, though currently the target range is between 2 and 3 grams a day.
Deoxyspergualin has also been recently used to treat vasculitis, its function is to suppress lymphocyte and macrophage function and also inhibits neutrophil production. Deoxyspergualin has been studied in refractory ANCA associated vasculitis and cresenteric glomerulonephritis associated with MPA and in some studies it has been found to be superior to MMF and as effective as cyclophosphamide in the control of vasculitis.
Plasma exchange is another therapy which has been used with success in the treatment of renal- involved vasculitis, especially MPA. It involves the removal of circulating immune reactants such as autoantibodies and has been used in vasculitic syndromes where the pathogenic factors have been identified. As mentioned above, MPA is a focal, necrotising glomerulonephritis associated with ANCA, and the plasma exchange reduces the levels of circulating ANCA and other adhesion molecules such as coagulation factors, cytokines and chemokines in vasculitis.
Autologous stem cell transplantation has been researched in the treatment of vascultitis and currently there is limited experience regarding the procedure. An autologous stem cell transplant is a procedure in which blood forming stem cells are removed and at a later point transplanted back to the same person. In the 15 cases that have been described so far, a response rate of over 90% was reported, but of these one third relapsed and required further transplantation procedures. Appropriate patient selection appears to be crucial to the success of the procedure, care is taken to avoid patients who have had high amounts of previous cyclophosphamide exposure and those who have irreversible organ dysfunction.
The clinical course of PAN cannot always be predicted, this is due to the large variations of organ involvement that can occur. Approximately 25% of patients have a rapidly progressive course and multiple organ involvement, usually resulting in a high mortality usually within 3 to 6 months of diagnosis. 50% of patients will have moderately sever disease and includes fluctuations in the activity of the disease. Finally the last 25% will have an initial episode of vasculitis which is then proceeded by long-term remission of disease, usually independent of whether they have been treated or not. The use of corticosteroids and immunosuppressive drugs has vastly improved the mean survival rate for patients with PAN. The 5- year survival rate has increased from 10% for untreated patients, to 55 to 76% for patients treated with corticosteroids, and patients treated with a combination of corticosteroids and immunosuppressants have shown 5- year survival rates of 64 to 80%. The overall 5-year survival rate for PAN which is given in most studies is approximately 60%.
The clinical course of MPA is also unpredictable; renal involvement is invariably present and approximately two thirds of the patients will develop renal insufficiency, with one half of those progressing to end stage renal failure. A severe form of MPA with a poor prognosis has been recognised; it usually presents as pulmonary renal failure and requires intensive respiratory support with haemodialysis. The overall 5-year survival of MPA has been reported as being around 67% and in a recent study by Guillevin et al, only 12% of patients required long term haemodialysis. The factors which have been identifies to unfavourably effect the prognosis are age, renal insufficiency, proteinuria and hypertension.
PAN is described as a vasculitis of the large vessels, whereas MPA is a vasculitis affecting the medium and small vessels and is associated with glomerulonephritis. PAN and MPA both present with systemic symptoms such as malaise and fever, with the gold standard investigation being renal tissue biopsy and histology in both conditions.
A great deal of research is still required to further improve the diagnosis and treatment of renal involved vasculitis, renal biopsy is an invasive procedure, and development of non-invasive diagnostic tools would be welcomed. There has been considerable research into the treatment of PAN and MPA and new therapeutic interventions have revolutionised the treatment of vasculitis, with reports of 5 year survival rates improving from 10% to 80% in some cases of PAN. MMF and leflunomide are now recommended as second line alternatives to azothioprine and methotrexate for remission maintenance and sometimes remission induction. Plasma exchange has proven to increase the recovery of renal function in severe renal presentation and the role of autologous stem cell transplantation has also been developed and is being researched.
