GLOMERULONEPHRITIS AS A PART OF SYSTEMIC VASCULITIS
Systemic lupus erythematosus
Renal disease in SLE is 10 times as common in women as in men. All varieties of histological abnormality are seen, ranging from a minimal-change lesion to crescentic glomerulonephritis. Serial renal biopsies show that in approximately 25% of patients, histological appearances alter from one histological classification to another during the interbiopsy interval. The prognosis is better in patients with the minimal-change and membranous lesions than in those with proliferative glomerulonephritis. Pregnancy is associated with significant risk to the lupus patient, not only owing to hypertension and premature delivery, but also to more rapid progression of the glomerular lesion following delivery.
Whilst corticosteroid therapy improves the extrarenal manifestations of SLE, evidence is lacking that this treatment alters the renal prognosis. Both azathioprine and cyclophosphamide improve renal function, but long-term studies suggest that cyclophosphamide is better. Intermittent intravenous ‘pulse’ cyclophosphamide treatment may be safer and is likely to be as effective as continuous oral therapy.
The indications for treatment vary. Those whose urine sediment contains many red cells and red-cell casts and those in whom renal function is impaired or is observed to deteriorate are strong candidates for treatment. A histological diagnosis should be obtained before commencing such potentially hazardous treatment.
In this group of disorders there is considerable overlap between individual varieties. The common feature is an immunologically mediated inflammation of vessels of varying size. A major advance in understanding has followed the discovery of autoantibodies directed against constituents of the cytoplasm of normal human granulocytes and monocytes in patients with systemic vasculitis. Antineutrophil cytoplasmic antibodies (ANCA) are now established as a marker for vasculitides involving the kidney with or without signs of systemic disease. Two forms of ANCA can be demonstrated by immunofluorescence, one with cytoplasmic staining, named c-ANCA, and one with perinuclear staining, named p-ANCA. In most instances, c-ANCA is directed to a serine protease called proteinase C, whereas p-ANCA is, at least in renal disease, mainly directed at myeloperoxidase. Whether ANCA is only a marker of disease or whether it takes part in the pathogenic process is currently undetermined. ANCA levels can be measured by enzyme-linked immunosorbent assay (ELISA) and variations in the ANCA titre have been used in the assessment of disease activity.
Polyarteritis nodosa (PAN)
Classical PAN is a multisystem disorder. Aneurysmal dilatation of medium-sized arteries may be seen on renal arteriography. The condition is commoner in men and in the elderly and, typically, the patient is ANCA negative. Hypertension and haematuria occur and eventually renal failure which is the usual cause of death.
In this condition necrotizing crescentic glomerulonephritis without immune complex deposition occurs with p-ANCA positivity. The lungs may be involved but granuloma are not seen.
In this condition, glomerulonephritis occurs together with necrotizing granulomatous lesions affecting the nasopharynx, lungs and kidneys. The necrotizing glomerular lesions do not appear to be due to immune complex deposition. c-ANCA positivity is the rule.
Treatment of systemic vasculitis The sooner treatment is instituted the more chance there is of recovery of renal function. Corticosteroids and cyclophosphamide are of benefit: pulsed high dose methylprednisolone and plasmapheresis may reverse advanced disease. Once remission has been achieved, azathioprine may be substituted for cyclophosphamide.
RENAL INVOLVEMENT IN OTHER
Renal disease is a major complication of diabetes; it is discussed.
Interlobular renal arteries are affected with intimal thickening and fibrinoid changes occur in afferent glomerular arterioles. Glomerular changes are non-specific. The pathogenesis is unknown and neither steroid nor immunosuppressive therapy is of value. ANCA are not present.
The kidney is often affected in amyloidosis. Presentation is with asymptomatic proteinuria, nephrotic syndrome or renal failure.
On light microscopy eosinophilic deposits are seen in the mesangium, capillary loops and arteriolar walls. Staining with Congo red renders these deposits pink and they show green birefringence under polarized light. Immunofluorescence is unhelpful but on electron microscopy the characteristic fibrils of amyloid can be seen. Amyloid consisting of immunoglobulin light chains (AL amyloid) can be distinguished by immunological techniques from the protein found in secondary amyloid (amyloid protein A, AA amyloid). AL amyloid is found in disorders associated with lymphoproliferative diseases such as myeloma, Walden strom’s macroglobulinaemia or non-Hodgkin’s lymphoma. It is also present in cases of so-called primary amyloidosis where an abnormal clone of cells is presumed to be responsible, although at present not identifiable. AA amyloid is found following long-standing inflammatory conditions such as suppurative infections or rheumatoid arthritis and familial Mediterranean fever.
The diagnosis can often be made clinically when features of amyloidosis are present elsewhere. On imaging, the kidneys are often large. Renal biopsy is necessary in doubtful cases.
Treatment of the underlying cause should be undertaken. In primary amyloid, treatment also used in myeloma such as corticosteroids and melphalan are of benefit. The success of dialysis and kidney transplantation is dependent upon the extent of amyloid deposition in extrarenal sites, especially the heart.
Haemolytic uraemic syndrome (H U5) HUS is a disorder of infancy and childhood that is characterized by intravascular haemolysis with red-cell fragmentation (microangiopathic haernolysis), thrombocytopenia and acute renal failure. The syndrome often follows a febrile illness, particularly gastroenteritis or upper respiratory tract infection. A few particular strains of pathogenic Escherichia coli have been isolated in many cases. Clustering of cases and the occurrence of ‘epidemics’ of HUS provide further support for an infective aetiology. It has been suggested that infection triggers endothelial damage and that derangements of the haemostatic coagulation system then occur in susceptible individuals. Recurrent episodes of HUS have been described in the same individual. Fibrin deposition is seen in the vascular endothelium, particularly in the renal arterioles and glomerular capillaries. Most children recover spontaneously. Treatment with heparin, inhibitors of platelet aggregation, synthetic prostacyclins, infusion of fresh frozen plasma and plasma exchange have been employed, but controlled trials of treatment are lacking.
Thrombotic thrombocytopenic purpura (TTP)
TTP is characterized by the presence of widespread hyaline thrombi in small vessels. Young adults are most commonly affected. Microangiopathic haemolysis, renal failure and evidence of neurological disturbance are characteristically found. The pathogenesis is unknown. Some patients with TTP have underlying SLE or polyarteritis nodosa and there is clearly considerable overlap between HUS, TTP and the connective tissue disorders. Corticosteroid therapy and measures employed in HUS may be of benefit.
Acute renal failure is relatively common in myeloma, occurring in 2-8% of affected individuals. Histological appearances may be simply those of acute tubular necrosis; tubular blockage by Tamm-Horsfall glycoprotein, light chains and immunoglobulin may be apparent. Dehydration and the administration of intravenous or intra-arterial contrast medium to the volume-depleted patient with myeloma predispose to the development of actue renal failure.
In myeloma, free K and A light chains are excreted. Blockage of tubules by casts composed in part at least of light chains, and perhaps their toxic effects upon tubular cells, account for the proteinuria and chronic renal impairment associated with ‘myeloma kidney’. Renal amyloid deposition often complicates myeloma, accounting both for proteinuria-sometimes of nephrotic proportions- and chronic renal failure.
Hypercalcaemia, renal sepsis and-rarely-urinary tract obstruction due to bulky myeloma deposits are further causes of renal impairment in myelomatosis.
Iodinated radiological contrast media are nephrotoxic, possibly by causing renal vasoconstriction. The effect is dose dependent and therefore more commonly seen in procedures which require large amounts of contrast media such as angiography with or without angioplasty. In many patients the effect is mild, transient, fully reversible and of no clinical significance. The risk and severity of contrast nephropathy is amplified by the presence of coexisting conditions which also cause renal hypoperfusion:
• Pre-existing renal impairment
• Low cardiac output
• Diabetes mellitus
• Hyperviscosity (myeloma)
As many as possible of these risk factors should be corrected prior to the use of contrast media. The dose should be minimized. The newer non-ionic and low osmolality media carry less risk of allergic contrast reactions but do not decrease the risk of contrast nephropathy. The use of calcium antagonists to prevent contrast nephropathy is under investigation. Mannitol and dopamine may also protect against nephrotoxicity in non-diabetics but not in diabetics.