Postgrad Med J (1993) 69, 516-546 © The Fellowship of Postgraduate Medicine, 1993 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from Reviews in Medicine Nephrology, dialysis and transplantation K. Farrington1 and P. Sweny2 'Lister Hospital, Stevenage and 2Royal Free Hospital, London, UK Nephrology 1. Urine microscopy Pathogenesis of ARF Careful phase contrast microscopy of freshly Changes in renal haemodynamics are a feature of prepared urine sediment is one of the simplest, all types ofARF irrespective ofprecipitating insult. cheapest and most helpful investigations in neph- Recent studies have examined the role of rology and urology, but it is often omitted or endothelium-derived vasoactive factors in these delegated to the routine microbiology laboratories.1 changes. It should be the first investigation in all cases of haematuria or suspected glomerular disease. The Endothelin Endothelin is a 21-amino acid pep- rapid identification of red cell casts or dysmorphic tide. It is the most potent vasoconstrictor yet red cells can point the clinicians in the direction of discovered, being ten times more potent than renal and away from cystoscopy and angiotensin II. It has many other properties includ- arteriography.2 Doctors investigating renal pa- ing effects on ion transport, eicosanoid synthesis, tients should have access to a centrifuge and a good and renin and atrial natriuretic peptide (ANP) quality phase contrast microscope. With phase release. The renal vasculature appears particularly copyright. contrast, damaged or distorted red cells can easily susceptible to its vasoconstrictive effect. Renal be recognized (dysmorphic red cells).3 The ex- vascular resistance is increased by an effect on both tremes of osmolarity experienced with passage afferent and efferent . It also reduces the along the nephron may be important in producing glomerular ultrafiltration coefficient by inducing dysmorphic cells. Dysmorphic cells may have mesangial cell contraction.5 Thus both renal blood gained entry to the urinary tract via a ruptured flow and glomerular filtration rate (GFR) are glomerular basement membrane in an inflamed compromised (Table I). Factors known to increase glomerulus or through a ruptured tubular base- its production rate include hypoxia, shear stress, http://pmj.bmj.com/ ment membrane damaged by interstitial inflam- endotoxin, thrombin, adrenalin, neuropeptide Y, mation. The injury sustained during this passage is and interleukin 1. Many of these factors are thought more likely to account for their variable thought to be important in the pathogenesis of and abnormal morphology.4 If all the red cells are ischaemic ARF. Endothelin may well have a of a similar size and shape and well preserved, the pathogenic role in this setting. In support of this, haematuria is more likely to have been caused by a circulating levels of endothelin have been found to lesion below the nephron. Urological workup is be elevated in patients with ARF.6 Experimentally, on September 30, 2021 by guest. Protected then appropriate. monoclonal antibodies to endothelin and specific non-peptide endothelin antagonists have been 2. Acute renalfailure (ARF) found to protect against the development of post- ischaemic renal damage.7'8 Anti-endothelin anti- Progress in this area has centred on efforts to clarify bodies also protected against endotoxin-induced the pathogenesis of ARF and on the development falls in GFR3. of a variety of potential treatments most of which remain experimental. In the clinical setting, con- Endothelium-derived relaxing factor (EDRF) tinous modes of renal replacement therapy have Vasodilatation in response to acetylcholine and become routinely available for the treatment of bradykinin is mediated by a diffusible EDRF, ARF in the intensive care unit. In spite of this, the which has subsequently been identified as nitric mortality remains high. oxide. Its synthesis is catalysed by nitric oxide synthase from L-arginine, and blocked by the Correspondence: P. Sweny, M.A., M.D., F.R.C.P., arginine analogue L-NMMA. There are two Department of Nephrology and Transplantation, Royal enzyme systems, one constitutive, and responsible Free Hospital, Pond Street, London NW3 2QG, UK. for the physiological production ofEDRF, and the NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 517 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Table I Effects of endothelin and EDRF on renal onstrated in the amelioration of radiocontrast haemodynamics induced renal impairment19 and post-transplant ARF.20,21 Endothelin EDRF ANP alone, or in combination with dopamine, Renal blood flow Decreased Increased protects against post-ischaemic ARF.22,23 The Glomerular filtration rate Decreased No change effect of the drugs in combination appears no Afferent resistance Increased Decreased greater than the effect of ANP alone,24 in spite of Efferent resistance Increased Decreased the prevention, by dopamine, of the hypotensive Glomerular ultrafiltration Decreased ?Increased response to ANP. Loop diuretics produced long- coefficient term improvement in renal function after an ischaemic insult, perhaps by reducing the propor- tion of nephrons obstructed by Tamm-Horsfall protein cylinders.25 other inducible, and responsible for prolonged Most studies of therapy in experimental ARF EDRF production in some pathological circums- have concentrated on attempts to modify the tances. In addition to its vasodilator effect, nitric haemodynamic processes involved in the initiation oxide inhibits platelet adhesion and aggregation. In of the condition. Agents which stimulate regenera- these two actions, nitric oxide and prostacyclin tion ofdamaged tubules may also have therapeutic potentiate each other. EDRF also reduces the potential. Epidermal growth factor is one such release of renin and ANP9. Infusion of L-NMMA agent. It is a potent growth promoter to renal produces implying a physiological tubular cells, and has been found to accelerate role for EDRF in the maintenance ofnormal blood recovery in mercuric chloride-induced ARF in pressure.'1 Endothelium-derived nitric oxide also rats.26 exhibits profound effects on glomerular haemodynamics,7 L-NMMA inducing increased renal vascular resistance, decreased renal blood flow, with little effect on GFR (Table I). In Clinical Therapy in ARF is firmly based on post-ischaemic ARF, the vascular responses to aggressive resuscitation and optimization ofhaem- copyright. acetylcholine and bradykinin are blunted, suggest- odynamic parameters, attempts to nullify or re- ing impaired release of EDRF. " Haemoglobin and verse the precipitating insults, the appropriate use myoglobin are both potent inhibitors ofEDRF,'2'l3 of loop diuretics and low-dose dopamine, and the and this action may be important in the early institution of renal replacement therapy pathogenesis of ARF associated with haemolysis should sufficient renal function not be restored by and rhabdomyolysis. On the other hand, endotoxin these former measures. Continuous modes of renal and cytokines can stimulate the inducible nitric replacement have become standard in this situa- oxide synthase to produce a sustained burst of tion, especially for patients managed in intensive http://pmj.bmj.com/ EDRF, with resulting vasodilatation and resis- care units. There is very little controlled informa- tance to vasoconstrictor agents characteristic of tion comparing different modes oftherapy, but the septic shock. Administration of L-NMMA to rats firm clinical impression is that continuous treat- with septic shock produced improvements in blood ments have considerable advantages over intermit- pressure, renal function, and survival.'4 There is tent treatments particularly with respect to the also some limited clinical experience with the use of maintenance of haemodynamic stability, the de- L-NMMA in and of metabolic control and the septic shock.'5 gree stability on September 30, 2021 by guest. Protected capacity to provide optimal nutrition. A recent controlled trial has reported a significant benefit of Treatment of ARF pump-driven haemofiltration (continuous veno- venous haemofiltration-CVVH) over spontaneous Experimental Calcium antagonists have a num- arteriovenous haemofiltration (CAVH). Mortality ber of potentially beneficial effects on the com- in the CVVH group was less than in the CAVH promised . These include antagonism of group in spite of a comparable degree ofcontrol of preglomerular vasoconstriction, reduction in cel- uraemia apparently based on serum lular calcium uptake in response to cell injury, and levels. Mortality was inversely related to the a possible action as a free radical scavenger.'6 volume of ultrafiltrate.27 It was suggested that Protective effects against the development of ARF differences in 'middle molecule' clearance resulting have been demonstrated in experimental models of from the differences in ultrafiltration volume might a number of different types of ARF including explain the effect. However, static biochemical post-ischaemic'7 and toxic.'8 Studies have been parameters often provide a poor assessment of the extended into the clinical setting, in which protec- adequacy of renal replacement treatments (vide tive effects of calcium antagonists have been dem- infra). 518 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

3. Glomerulonephritis curately gauged from initial biopsy then a policy of biopsying all patients with clinical features com- i. Mesangial IgA disease patible with mesangial IgA disease may then be justified. Table II summarizes factors associated Mesangial IgA disease (Berger's disease) is the with a poor prognosis. Elevated urinary interleukin commonest cause of recurrent episodes of macro- 6 (I16) (originating from mesangial cells or invading scopic haematuria in young adults, a point worth ) appears to correlate with an adverse emphasizing to urologists. It is also the commonest prognosis.39 C4A deficiency is associated with type of glomerulonephritis. Recent research has severe disease, perhaps by reducing solubilization concentrated on three areas: aetiology, prognosis of deposited complexes.4 Low molecular weight and therapy. proteinuria, probably reflecting more extensive tubulo-interstitial damage, also correlates with a Aetiology Serum IgAl levels are higher than poor prognosis.1'42 IgA2 in patients with mesangial IgA disease. This implies a systemic origin of the IgA rather than Treatment There are no large-scale randomized, mucosal.28 A variety ofautoantibodies ofIgA class prospective trials of treatment in mesangial IgA have been described. Circulating complexes of IgA disease showing that any form of therapy is of and fibronectin have been demonstrated.29 The benefit. Table III summarizes some of the more fibronectin component may be responsible for recent trials. The correlation between proteinuria mesangial deposition of IgA rather than true IgA and hypertension and poor prognosis argues for autoimmunity to glomerular antigens. There are the early introduction ofan angiotensin converting other possibilities. IgA autoantibody to fibronectin enzyme (ACE) inhibitor. Combinations of anti- may be present. Fibronectin may also bind to platelet agents, , steroids and cytotoxic whatever antigen binds the IgA. An attractive drugs have all been tried with some claims of hypothesis is that micro-organisms or their anti- benefit.50 gens that present to mucosal surfaces are bound to fibronectin. The resulting immune response pro- ii. Focal necrotizing and crescentic duces circulating immune complexes of microbial glomerulonephritis copyright. antigens, fibronectin and IgA. Indeed, complexes such as these made in vitro preferentially deposited Excluding cases occurring as part ofa multi-system in the mesangium of experimental animals.30 IgA disease, primary focal necrotizing and crescentic reacting with human endothelial cell surface anti- glomerulonephritis can be caused by antibodies to gen has been demonstrated by ELISA and Western glomerular basement membrane (10-25%), the blotting in patients with mesangial IgA disease.3' deposition of immune-complexes (10-30%) or be Whether these are true autoantibodies to endothe- the so-called 'pauci-immune' type (50-70%) in lial cells or represent IgA binding to fibronectin, is http://pmj.bmj.com/ not clear. to yet IgA-fibronectin complexes appear Table II Adverse factors in mesangial IgA disease (see be useful serological markers for mesangial IgA Alambartine et al., 1991)36 disease and probably also for Henoch-Schonlein purpura (HSP).32 The nature of the immune res- Clinical ponse may be abnormal with low affinity IgA Older age at onset antibodies being produced with no evidence of Absence of macroscopic haematuria with time. Arterial hypertension increasing affinity on September 30, 2021 by guest. Protected Platelets are thought to be involved in the pathogenesis ofmesangial IgA disease, as they can Histological be seen in affected glomeruli on electron micros- Glomerular sclerosis (Okada et al., 1992)37 copy.33 They may also be found in the urine Tubulointerstitial scarring (Nagy et al., 1987)38 deposit.34 Evidence of platelet involvement can be Vascular sclerosis deduced from the finding ofelevated platelet factor Diffuse crescents 4 levels in urine.35 Urinary platelet factor 4 levels Glomerular may help to differentiate mesangial IgA disease Laboratory from thin membrane disease, both of which cause Urinary 116 (Dohi et al., 1991)39 persistent isolated microscopic haematuria. The C4A deficiency (Wyatt et al., 1991)4° origin of urinary platelet factor 4 is from glom- HLA B35 erular rather than filtration. High serum IgA plasma Elevated creatinine (Okada, 1992)37 Heavy proteinuria (Okada, 1992)37 Prognosis Twenty-five to 30% of patients with Low molecular weight proteinuria (Nagy, 1987; Woo, mesangial IgA disease deteriorate to end-stage 1991)38'41 chronic renal failure. If prognosis could be ac- NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 519 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Table III Trials of therapy in mesangial IgA disease (see Schena (1989) for review43) Agent Author (year) Outcome Steroids Kobayashi (1987)44 ? Helpful if nephrotic Lai (1987b)45 Cyclosporin A Lai (1987a)46 Transient decreased proteinuria Eicosapentaenoic acid Bennet (1989)47 Cyclophosphamide + Woo (1991)41 No benefit dipyridamole + warfarin Stable renal function Dipyridamole + warfarin Lee (1989)48 Less proteinuria Chan (1987)49 Stable renal function Phenytoin Egido (1984)50 Less proteinuria No benefit which antibodies to neutrophil cytoplasmic syndrome. Histologically the lesion is similar to antigens antinuclear cytoplasmic antibody focal segmental glomerulosclerosis with deposits of (ANCA) are frequently detected. With the excep- IgM, C3 and Clq. Endothelial cells contain tion of anti-glomerular basement membrane anti- numerous tubulo-reticular inclusion bodies. There body-mediated disease, treatment with high dose are numerous nuclear bodies in the interstitial cells. steroids and cyclophosphamide, at least in the Microcystic dilatation of the tubules is prominent. short term, appears effective. In anti-glomerular Despite these appearances which suggest the basement membrane antibody-mediated disease, presence of viral particles, HIV antigens and DNA immediate plasma exchange in addition to drug have not always been demonstrated in renal tissue. therapy is considered mandatory to preserve renal Prognosis is poor with death in 12 months despite function. Plasma exchange as an adjunct to dialysis. There is no effective treatment. immunosuppressive drugs remains an option in other forms of crescentic nephritis, particularly if IgA nephropathy The light microscopy lesion copyright. severe renal impairment is present.5' In one recent seen is a mesangial proliferative glomeruloneph- study plasma exchange was shown to be of benefit ritis.56 Compared with HIVAN this is a relatively only in dialysis-dependent patients, other patients benign condition characterized clinically by mic- doingjust as well with combination drug therapy.52 roscopic haematuria and moderate proteinuria. Idiotypic IgA antibody reacting with anti-HIV IgG iii. Glomerulonephritis in human immunodefici- or IgM is present in the blood.57 Elution studies virus have shown the of HIV DNA in the

ency (HIV)-positive patients presence http://pmj.bmj.com/ kidney. Two well-characterized nephropathies have recently been described in HIV-positive patients.53 iv. Serological tests for glomerulonephritis and Microalbuminuria may precede overt neph- ropathy54 and appears to be a marker for acquired immunodeficiency syndrome (AIDS) progression Diagnosis and monitoring The laboratory inves- being positively correlated with low CD4 counts, tigation ofpatients with glomerulonephritis/vascu- lymphopaenia, tumour necrosis factor alpha, and litis hopes to provide a specific diagnosis and to on September 30, 2021 by guest. Protected elevated beta-2-microglobulin levels. measure disease activity so that response to therapy can be monitored. Tables IV and V summarize HIV-associated nephropathy (HIVAN) The light diagnostic tests that can support a clinical or microscopy appearances of this lesion are of focal histological diagnosis in glomerulonephritis. Some and segmental glomerulosclerosis.55 This is a of these tests also provide clinically useful markers rapidly deteriorating severe nephrotic syndrome of disease activity. It is helpful to attempt to define with progression to chronic renal failure in about 4 which laboratory parameters best reflect disease months. is usually normal and activity in an individual patient. Anti-entactin oedema often minimal. It is seen typically, but not antibodies are found in many types of primary exclusively, in young, black intravenous drug glomerulonephritis (proliferative, crescentic, mem- abusers. It is distinct from heroin nephropathy. branous, membranoproliferative, IgA nephropa- Nephrotic syndrome can precede AIDS by many thy) and therefore have little diagnostic value.59 Of months. On ultrasound the kidneys are echogenic most value are C-reactive protein, ANCA,62 anti- and enlarged remaining so despite progression to bodies to native double-strand DNA, C3 and C4 chronic renal failure. Hyperlipidaemia is said to be and of course creatinine clearance and 24 hour less marked than in other types of nephrotic protein. The limited causes of low complement 520 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Table IV Laboratory markers in primary glomerulonephritis Primary glomerulonephritis (GN) Lesion (Caucasians) Laboratory marker HLA associations Minimal change Highly selective proteinuria DR7, B8, B12 DQW2 Diffuse proliferative Post-infections DR4 Idiopathic Low C3 (Hebert, 1991)58 Focal/mesangial proliferative None Idiopathic Mesangial IgA None BW35, DQW7 IgA-fibronectin complexes (Cederholm et al., 1988)29 Membranous IgA anti-entactin Ab (Saxena, 1991)59 B8 + DR3 Focal segmental Urinary C5b-9 (Schulze et al., 1991)60 ?DR4, DR3 + 7 glomerulosclerosis None Focal nectrotizing and DQW7 crescentic ANCA (Kallenberg & Tervaert 1992)6' B7 + DRW15(DR2) Anti-GBM Ab + DQW6 Membranoproliferative Low C3 (Hebert, 1991)58 DR7? C3 Nephritic factor B8 + DR3

Table V Diagnosis and monitoring of disease activity in the multi-system vasculitides with GN Disease Micro PA SLE HSP SBE WG C-SS Cryog Diagnosis pANCA a ds DNA Ab IgA + ve blood cANCA pANCA Cryoglobulins culture CXR C4

complexes copyright. ECHO Activity pANCA a ds DNA Ab SCAT cANCA Cryocrit CRP C3 CRP CRP C4 PMN count C4 C3 SCAT CRP C4 a ds DNA AB = antibody to native double-strand DNA; CRP = C-reactive protein; PMN = polymorphonuclear leucocyte; SCAT = sheep red cell agglutination titre; CXR = chest X-ray; ECHO = echocardiogram; Micro PA = microscopic polyarteritis; SLE = systemic lupus erythematosus; HSP = Henoch Schonlein purpura; SBE = subacute http://pmj.bmj.com/ bacterial ; WG= Wegener's granulomatosis; C-SS = Churg-Strauss syndrome; Cryog = cryog- lobulinaemia; pANCA = perinuclear and nuclear anti-neutrophil cytoplasmic antibody (ANCA); cANCA = diffuse cytoplasmic staining ANCA. levels are of diagnostic value (Table VI). Repeated tase or lactoferrin. Confirmation of a pANCA by urine microscopy (see above) should not be over- ELISA with a purified antigen is necessary.61a looked as a marker of disease activity. Anti-proteinase 3 and anti-myeloperoxidase anti- on September 30, 2021 by guest. Protected bodies can activate primed neutrophils in vitro. Anti-neutrophil cytoplasmic antibody (ANCA) These antibodies bind to the site on the enzyme ANCA is best detected bytesting serum on alcohol- normally occupied by the natural inhibitor of the fixed buffy coat polymorphs. Two patterns of proteinase. If polymorphonuclear leucocytes are staining are recognized: cANCA (diffuse cytoplas- activated by intercurrent infections then anti- mic staining) and pANCA (perinuclear and nu- proteinase antibodies could provoke a flare of the clear).61 The antigens involved have been identified underlying disease. Proteinase 3 is highly cationic (Table VII). It is now known that the perinuclear and would be expected to bind to anionic sites in and nuclear staining is an artefact caused by the glomerulus. In pauci-immune necrotizing/ alcohol fixation which allows the cationic myelo- crescentic glomerulonephritis a cell-mediated im- peroxidase antigen to bind the anionic nuclear mune response could be responsible for the membrane (fixation with formalin or glutaral- glomerulitis. dehyde shows the true pattern of antigen distribu- tion and gives a cytoplasmic pattern). False Lupus The kidney in systemic lupus positive results may therefore be seen in patients erythematosus (SLE) may be damaged by the with antinuclear antibodies and antibodies to elas- deposition of immune complexes (glomeruloneph- NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 521 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Table VI Causes of low complement levels (Hebert et al., 1991)58 I. Immune mediated (A) Associated with GN Post-infections GN C3 Membranoproliferative GN C3 Subacute bacterial endocarditis C3, C4 Lupus-like syndromes C2 deficiency, C4 null allele Cryoglobulinaemia C3, C4 Systemic lupus erythematosus C3, C4 GN associated with persistent active infections C3, C4 (B) Not usually associated with GN Vasculitis Rheumatoid C3, C4 Idiopathic C3, C4 Drug-induced lupus C3, C4 Serum sickness C3, C4 Drug hypersensitivity C3, C4 Chemotherapy for lymphoma/leukaemia C3, C4 Thyroiditis C3, C4 B-cell lymphoproliferative disorders C4, C2 II. Non-immune mediated Atheroembolism C3 Severe sepsis C3, C4 HUS, TTP C3 C3, C4 Malnutrition C3 Jejunal ileal bypass C3, C4 Severe liver disease C4

C3, copyright. Burns C3, C4 Acute myocardial C3, C4 Haemolytic crisis in malaria C3, C4 GN = glomerulonephritis; HUS = haemolytic-uraemic syndrome; TTP = thrombotic thrombo- cytopenic purpura. http://pmj.bmj.com/

Table VII Anti-neutrophil cytoplasmic antibodies (ANCA) ANCA cANCA pANCA

Pattern Diffuse cytoplasmic Perinuclear/nuclear on September 30, 2021 by guest. Protected (ethanol-fixed buffy coat) Antigen Proteinase 3 Myeloperoxidase Clinical association Wegener's > microscopic PA Microscopic PA > Wegener's Necrotizing GN Necrotizing GN Crescentic GN Crescentic GN Rheumatoid arthritis aGBM Ab disease Drug-induced lupus Ulcerative colitis Chronic active hepatitis Myasthenia gravis Juvenile chronic polyarthritis False positive Rare in normals 1-8% normals ANF positive patients: aHistone Ab aElastase Ab aLactoferrin Ab a = denotes anti; Ab = antibody; ANF = antinuclear factor; PA = polyarteritis; GN = glomerulonephritis. 522 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

ritis and vasculitis), hypertension (both accelerated Table IX Anti-phospholipid syndrome phase and chronic) and by a thrombotic microan- giopathy. Cell-mediated immunity also plays a Obstetric role. These are not exclusive Recurrent spontaneous abortions (placental processes mutually ) and probably frequently coexist (Table VIII). Lupus anticoagulant is an IgG (occasionally Recurrent deep venous thrombosis IgM) autoantibody to widely distributed complex Pulmonary emboli anionic phospholipid antigens. In vitro these antibodies prolong the partial thromboplastin time Budd-Chiari syndrome but clinically are associated with widespread Arterial lesions arterial and venous thrombosis.63 Peripheral A clinical syndrome (Table IX) has evolved Mesenteric occlusion which is associated with the lupus anticoagulant Cardiac manifestations both in patients with SLE and others.64 Two types Endocarditis and valvular lesions of Atrial myxoma like lesions anti-phospholipid antibody have been des- Multiple small coronary occlusions cribed. One binds the phospholipid antigens di- (pseudocardiomyopathy) rectly and the other requires beta-2-glycoprotein- Renal lesions and is particularly associated with thrombosis.65 Glomerular thrombosis The recognition of this syndrome has important Arteriolar and arterial thrombosis implications for the treatment of lupus nephritis. Renal thrombosis Therapeutic options now include treatment of Proteinuria acute immune-mediated inflammation, hyperten- Hypertension sive and thrombotic Renal insufficiency microan- CNS manifestations giopathy. Agents useful against the latter include Migraine low-dose aspirin, possibly eicosapentaenoic acid Epilepsy (EPA) and suitable antihypertensives such as cal- Chorea cium channel blockers. Multi-infarct dementia Retinal artery occlusion copyright. v. Treatment of nephrotic syndrome Pseudo-multiple sclerosis Despite expanding knowledge about pathogenesis, (With cerebral thrombosis = Sneddon's syndrome) therapy remains largely empirical. The three his- Thrombocytopenia tological lesions most often associated with the nephrotic syndrome will be briefly discussed. drome in children. Minimal change nephrotic syndrome Minimal Cyclosporin A is now an http://pmj.bmj.com/ is the commonest cause of acceptable alternative to steroids for inducing a change nephrotic syn- remission. It does not reduce the incidence of Table VIII Mechanisms in lupus nephropathy relapses unlike cyclophosphamide. Cyclosporin A is also of value in maintaining a remission either Renal lesions of SLE alone or with low-dose steroids.66 Glomerular Membranous glomerulonephritis Membranous Proliferation (IC ± CMI?) glomerulonephritis is the commonest cause of on September 30, 2021 by guest. Protected Focal necrosis (IC, HT) nephrotic syndrome in adults. Treatment is prob- Thrombosis (TM) best reserved for Sclerosis (end stage) ably patients with heavy pro- Arteriolar teinuria, severe hypoalbuminaemia and impaired Vasculitis + necrosis (IC) renal function. Children and adults with asympto- Vasculitis + fibrinoid necrosis (HT, TM) matic membranous glomerulonephritis do not war- Arterial rant immunosuppressive treatment. There is no consensus about to the best and safest regime. (HT, TM, end stage) Intravenous methylprednisolone followed by oral Venous steroids can induce a remission and may preserve (NS + TM) renal function.67 Duration of therapy may be an Interstitial tissues factor in A Acute interstitial nephritis (CMI, IC) important efficacy. cyclical regime has Ischaemia (HT, been developed based on monthly cycles of TM) chlorambucil followed by a month of steroids IC = Immune complex; HT = hypertension; TM = initiated with intravenous pulse methylprednis- thrombotic ; NS = nephrotic syndrome; olone. This has been shown in a controlled trial to CMI = cell-mediated immunity. be of benefit.68 A regime involving 6 months NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 523 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from therapy with cyclophosphamide followed by 2 vi. The use of intravenous immunoglobulin (i.v. years of warfarin and dipyridamole showed a Ig) reduction in proteinuria in the treatment group.69 The use of intravenous immunoglobulin appears Intravenous immunoglobulin (i.v. Ig) was first promising.7 reported to increase platelet counts in idiopathic thrombocytopenic purpura. In 1984 it was shown to be effective in Kawasaki disease76 and is now the treatment of choice. Its use has recently been Focalsegmentalglomerulosclerosis (FSGS) FSGS expanded to include the multi-system vasculitides77 accounts for 10% of cases of nephrotic syndrome membranous glomerulonephritis70 and the anti- in children and 20% in adults. Only a minority of phospholipid syndrome.7 A multi-centre trial is patients enter remission with steroids.7 Cyclo- currently in progress to assess the efficacy of i.v. Ig sporin A can induce a partial remission,72 but in the multi-system vasculitides. relapse on cessation of therapy is common. Vas- Several theories have been advanced to explain cular lesions associated with focal segmental the mechanism of action. Intravenous Ig may glomerulosclerosis may be accelerated by cyclo- produce reversible blockade or down regulation of sporin A which is not suitable for long-term use in Fc receptors on the cells of the reticuloendothelial glomerulonephritis because of its nephrotoxic system. Alternatively it may contain anti-idiotypic potential. Analogies between focal segmental antibodies that suppress autoantibody produc- glomerulosclerosis and atherosclerosis have tion.79'80 emphasized the use of other therapies such as angiotensin converting enzyme (ACE) inhibitors 4. Diabetic nephropathy and lipid lowering drugs. Diabetic nephropathy accounts for increasing numbers of patients on renal replacement pro- grammes. The resulting vast economic and social treatments in the burden has stimulated into means of retar-

Adjunctive management ofnephrotic inquiry copyright. syndrome Control of hypertension is essential ding disease progression. and there is increasing evidence that the use ofACE inhibitors may confer additional benefits over and i. Predictors of progressive nephropathy above other anti-hypertensive agents. ACE inhibitors by themselves can significantly reduce The concept that microalbuminuria (the excretion proteinuria in nephrotic syndrome. Care should be of small amounts of albumin in the albustix taken not treat patients who are hypovolaemic. negative range) is an important predictor of pro- is now well established. Control of hyperlipidaemia in patients with persis- gressive nephropathy, http://pmj.bmj.com/ tent proteinuria may reduce the long-term risks of Some problems ofdefinition have been resolved. A atherosclerosis and preserve renal function. The urinary albumin excretion rate of between observation that plasma lipoprotein-a, an indepen- 20-200 Lg/minute in a timed overnight sample or dent risk factor for coronary heart disease, may be an albumin to creatinine ratio of2-20 mg/mmol in raised in patients with proteinuria, adds further an early morning specimen are commonly accepted impetus to the need to control the dyslipidaemia criteria.81 Lower levels of albumin excretion may associated with this condition.73 Dietary advice also be predictive of renal damage.82 together with the HMG CoA reductase inhibitors The importance of microalbuminuria as a pre- on September 30, 2021 by guest. Protected represent the current best treatment approach. dictor of progressive renal disease has been under- Chan et al. treated 14 patients with nephrotic lined by the clear associations which have been syndrome with lovostatin for 6 months.74 One demonstrated with structural renal damage. Pa- patient developed rhabdomyolysis and one patient tients with microalbuminuria have increased base- severe hypertriglyceridaemia. Total fell ment membrane thickening and more mesangial by 31% and LDL cholesterol by 43%. In the group expansion compared with normoalbuminuric pa- as a whole there was no change in proteinuria or tients.83 The concept has also emerged that excre- glomerular filtration rate although those patients tion of abnormal amounts of protein might itself with well preserved pretreatment glomerular filtra- cause glomerular damage and contribute to the tion rate showed an increase suggesting that early downward spiral of renal function in diabetic and intervention might help preserve renal function. other proteinuric nephropathies.84 Lovostatin treatment for 12 weeks in diabetics also Diabetics with microalbuminuria also have ele- showed a marked reduction in total cholesterol and vated blood pressures compared with their nor- LDL cholesterol, but no effect on proteinuria or moalbuminuric counterparts.85 There is a complex creatinine clearance.75 Clearly much longer term relationship between these two factors and the larger studies are required. progression of renal damage. Clearly both micro- 524 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from proteinuria and hypertension can result from renal diabetes than treatment with metoprolol plus damage inflicted by the metabolic derangements of frusemide, in the face ofa comparable reduction in diabetes. Both may accelerate progression of renal blood pressure.93 A similar result was obtained disease. They are not independent since hyperten- when enalapril plus conventional therapy was sion aggravates microalbuminuria. Recently it has compared with placebo plus conventional therapy been suggested that hypertension may play a more in non-insulin-dependent diabetics with neph- fundamental role. Some studies have shown a ropathy.94 In both studies the protective effect was higher incidence of parental hypertension in dia- biphasic. The initial 6 months of therapy was betics with nephropathy compared to those with- characterized by a more rapid fall in glomerular out, suggesting that a genetic predisposition to filtration rate in the enalapril group, with the hypertension may be an important determinant of protective effect emerging in the later periods of progression. study. Although these data are suggestive of a This notion gained support from studies demon- specific benefit ofACE inhibitors in diabetic neph- strating significantly increased red cell sodium- ropathy, other studies have shown no such effect95 lithium countertransport (Na-Li CT), a marker and the results of ongoing trials are awaited. for , in diabetics with neph- Other avenues of treatment have been explored. ropathy compared to those without.72 86 It was also There is some evidence that protein and phosphate demonstrated that this abnormality preceded the restriction may be useful,92 but the benefits are onset of clinical nephropathy and correlated with probably small in relation to those obtained with hyperfiltration,87 itself a possible marker of impen- anti-hypertensive therapy and may not be additive. ding clinical nephropathy. Recently, however, a There is little evidence that improved diabetic number of studies have cast doubt on these find- control reduces the rate of progression of estab- ings, suggesting variously that the abnormality is lished nephropathy. However, dramatic histolo- confined to a subgroup of patients with diabetic gical improvements were seen after transplantation nephropathy,88 that it is a characteristic of the of kidneys affected by diabetic nephropathy into diabetic process itself,89 and that it does not exist at non-diabetic recipients.96 Successful all in this setting.90 It is difficult to reconcile these transplantation has also been shown to be diverse findings. A recent study has shown that associated with less severe nephropathy in kidneyscopyright. Na-Li CT activity in red cells is dramatically previously transplanted into diabetic patients.97 higher post-prandially compared with the fasting This testifies to the vast gap in quality separating state.91 This study confirmed that Na-Li CT the degree of control achieved by our treatment activity is elevated in diabetic nephropathy, regimes and that associated with normal glucose though, in the post-prandial state, a modified homeostasis. method using a higher external sodium concentra- tion was to demonstrate it. metabolic con-

required Incipient nephropathy Improved http://pmj.bmj.com/ A number of other factors have been implicated trol can retard the progression from micro- in the progression of diabetic renal disease includ- albuminuria to clinical proteinuria. Conventional ing protein intake, hyperfiltration and lipid abnor- anti-hypertensive therapy has a similar protective malities. There is some evidence for the former, in effect, as do ACE inhibitors. Whether ACE that dietary protein restriction has been shown to inhibitors confer specific protection, in addition to reduce the rate ofprogression ofestablished neph- that afforded by their anti-hypertensive effect, has ropathy.92 There is little evidence though, that the been the subject of intense enquiry. Evidence in other influences mentioned above, operate as favour ofsuch a specific effect is accumulating. The on September 30, 2021 by guest. Protected independent risk factors. There is, however, little addition of an ACE inhibitor to conventional doubt that the major forces influencing progression anti-hypertensive therapy in microalbuminuric dia- are microalbuminuria and hypertension. betics produced a significant reduction in the urinary albumin excretion rate, with no change in ii. Treatment glomerular filtration rate or blood pressure asses- sed by 24 hour ambulatory monitoring.98 In nor- Established nephropathy Anti-hypertensive tre- motensive patients, treatment with captopril also atment is of proven benefit in preventing the demonstrated a significant anti-proteinuric effect progression of established nephropathy. There is when compared to placebo, though blood pressure now some evidence for the concept that ACE fell slightly in the captopril-treated group.99 A inhibitors may confer some specific benefit, addi- meta-analysis of published studies of different tional to those obtained by use of conventional anti-hypertensive agents in microalbuminuric and anti-hypertensive agents. In a long-term prospec- overtly proteinuric diabetics demonstrated that tive study, treatment with enalapril plus frusemide treatment with an ACE inhibitor resulted in a resulted in a significantly slower rate of decline of greater anti-proteinuric effect for a similar blood renal function in patients with insulin-dependent pressure fall."'° Interestingly treatment with nifedi- NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 525 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

pine produced an increase in proteinuria, a finding about 25% of patients with will have which is consistent with its known effects on renal multiple aneurysms. The probability of rupture of haemodynamics. an asymptomatic in adult polycystic kidney disease is unknown. The size of the 5. Polycystic kidneys aneurysm (>10 mm) is related to rupture risk. Some authors have recommended elective surgery Clinical features The clinical spectrum of adult in men under the age of 69 and women under the autosomal dominant polycystic kidney disease age of75 with aneurysms over 10 mm in diameter.'09 (APKD) has been widened in recent years to The decision to operate will have to incorporate involve other organs, perhaps indicating a common such factors as local expertise and the surgical defect in connective tissue or ground substance accessibility ofthe aneurysm. In patients who have (Table X). The most serious of these associated already survived aneurysm rupture, the indication is the presence of intracranial aneu- for surgery is much stronger. rysms. Chapman et al.'03 studied 92 young subjects with APKD and found an incidence of 4%, a Screening for APKD There are at least two dis- four-fold increase over the general population. tinct genetic inheritances for APKD. One is on the They recommended high-resolution computed to- short arm of chromosome 16 and linked to the mographic (CT) scanning as a relatively non- alpha-globin gene (APKD1) and another appears invasive safe screening test. Nuclear magnetic to be on chromosome 2 (APKD2). The clinical resonance will probably prove presentation ofAPKD in those cases not linked to superior. chromosome 16 is different with patients presen- Is screening for unruptured intracranial aneu- ting much later in life with cysts and chronic renal rysms in APKD justified? The early mortality rate failure. The limitations of pre-natal and family of a ruptured is in excess screening techniques for APKD have recently been of 50%. Conventional angiography carries an reviewed."1 To be reliable a large kindred spanning appreciable morbidity and mortality as does sur- several generations should be available for study. gical intervention. At present it does not seem possible to identify high-risk patients as familial Cystgrowth Only one to two nephrons contribute copyright. clustering of aneurysms has not been confirmed. to cyst formation. Tissue culture work suggests There does seem to be a marked intrafamilial that cyst growth is due to an enhanced capacity of variation in phenotypic expression.'08 Furthermore tubular epithelial cells to proliferate. Epidermal growth factor provokes an exaggerated pro- liferative response in culture experiments and has been found in cyst fluid. In a mouse model of Table X Clinical spectrum of APKD (Gabow, recessive increased ex- 1990)'10 polycystic kidney disease, http://pmj.bmj.com/ pression of several oncogenes has been detected."' Adult polycystic kidney disease on the of secretion Kidney Cyst growth depends presence Cysts by the epithelial cells which is enhanced by factors Hypertension that increase cyclic AMP and is suppressed by CRF (50% by age 73) factors that inhibit it. In human cyst tissue there Renal adenomata (Gregoire, 1987)102 appears to be altered epithelial cell polarity with the Brain sodium/potassium ATPase pump located on the Intracranial aneurysms (0-41%) apical border of the cells and thus lining the inner on September 30, 2021 by guest. Protected Anomalous vessels (Chapman, 1992)103 wall of the cyst. It has also been shown that Heart activation ofthe renin angiotensin system enhances Mitral valve prolapse (Timio, 1992)'°4 in an animal model."2 Aortic regurgitation cyst growth Gut Diverticulosis (Scheff, 1980)'05 Extracellular matrix The simplest hypothesis Liver that explains at least in part the renal and extra- Cysts (bile ducts) > 30% (Milutinovic, 1980)'°6 renal manifestations of APKD is that the fun- Hepatic fibrosis in APKD (Cobben, 1990)'07 damental defect is of basement membrane or Pancreas extracellular matrix structure. Early changes in the Cysts kidney include splitting and reduplication of base- Ovary ment membrane with more advanced abnor- Cysts malities seen in Uterus being the basement membrane Cysts around cysts. A wide range of abnormalities in Abdominal wall composition of extracellular matrix has been dem- Hernia onstrated but no single defect has been clearly (Gabow, 1990)101 identified.'3 526 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Treatment ofAPKD Hypertension develops early there is a halving ofGFR. Thus a plasma creatinine in some patients with APKD even before there is that appears only slightly elevated, for example significant renal impairment. There appears to be 150 gtmol/l, represents a loss of over half the total activation of the renin angiotensin system early in renal function. Similarly the criteria for what is the course of the disease."4 Renovascular resis- considered to be an elevated blood pressure need to tance is increased and effective renal plasma flow be revised downwards in the light of recent studies (ERPF) reduced. Treatment with ACE inhibitors in older patients. Blood pressures in excess of has been shown to reduce the elevated renal 160/90 mmHg in the over 60s probably warrant vascular resistance without changing the investigation and treatment.121'122 It is just this glomerular filtration rate. Filtration fraction group of patients with minimally elevated plasma (GFR/ERPF) fell, indicating a rise in ERPF. Mean creatinine and hypertension over the age of 60, in arterial blood pressure also fell. In normal family which atherosclerotic disease in general is most controls ACE inhibition produced no significant likely to be found. changes."" It was then suggested that there is The clinical presentations of ARAS include inappropriate activation of the renin angiotensin hypertension (often of less than 5 years duration). system for the state of the extracellular fluid The hypertension may be 'newly worse' and more volume,"5 and thence that ACE inhibition may difficult to control. Pickering recently pointed out have a beneficial effect on progression. Long-term that hypertension with recurrent episodes of left trials are clearly needed. Recently there has been ventricular failure is commonly associated with some renewed interest in cyst drainage. Pain can be ARAS.123 The expanding use ofACE inhibitors has relieved without deleterious effect on the rate of revealed unsuspected cases of ARAS and in one progression. 16 series this condition accounted for 4% of all patients presenting with acute renal failure.'24 Fre- quently ARAS is part ofa more generalized disease Chronic renal failure process with of the coronary and cere- bral circulations as well as lower limb and some- 1. Atherosclerotic renal artery times mesenteric ischaemia. In order to diagnose patients with ARAS a highcopyright. Introduction degree of clinical suspicion is essential. Hyperten- sion in an arteriopath with a missing pulse or a Atherosclerotic (ARAS) is bruit (not necessarily a renal bruit) should alert the underdiagnosed in life, often inadequately inves- clinician to the possibility of underlying ARAS. tigated and frequently managed inappropriately. Diagnosis Incidence The pre- and post-captopril renogram is a helpful http://pmj.bmj.com/ The precise incidence of ARAS is unknown. It has preliminary screen.125 A baseline renogram (DTPA been estimated that about 105 patients per million or Mag III) is repeated on a subsequent day, one per year develop ARAS. Clearly the prevalence hour after 25 mg of oral captopril. The ischaemic depends on the population being studied. Fourteen kidney or kidneys elaborate angiotensin II (A II). A per cent of our patients with end-stage chronic II constricts the efferent glomerular renal failure over the age of 55, have ARAS."7 preserving glomerular filtration pressure despite

Where the renal have been seen during reduced perfusion. Abolition of intrarenal A II on September 30, 2021 by guest. Protected coronary angiography or lower limb angiography, production reduces glomerular filtration but less so the incidence of ARAS has been reported at 19% renal blood flow. This is reflected in a change in the and 42%, respectively."118'9 In non-insulin- renogram which shows an increased disparity of dependent diabetics with an elevated plasma divided renal function and a prolonged time to creatinine the incidence of ARAS is about 40%.120 peak activity in the ischaemic kidney. In patients in whom the clinical probability ofARAS is very high Clinical features and the baseline renogram typical, the post- captopril scan may be omitted and intra-arterial It is clear that ARAS can often be asymptomatic or digital subtraction angiography (IA-DSA) under- overshadowed by the clinical manifestations of taken. Intravenous DSA does not give the surgeon atheroma in other major arteries. Before diagnos- or radiologist enough anatomical detail on which ing asymptomatic ARAS it is worth considering to plan intervention. Magnetic resonance imaging what constitutes a normal plasma creatinine. In (MRI) angiography may replace conventional young adults a plasma creatinine of 60 tmol/l arteriography. Even with smaller catheters and represents a GFR of approximately 120ml/ lower doses of contrast IA-DSA may produce minute. For each doubling of plasma creatinine significant morbidity both with respect to local NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 527 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from trauma to the punctured artery and more remote unusually present clinically after one kidney has complications (emboli and contrast nephrotoxi- virtually ceased to function and the second kidney city). Selected patients need special precautions, for is now failing. Appropriate intervention can avoid example, good hydration (left ventricular function such patients requiring dialysis. permitting) and low dose dopamine. It is some- times necessary to dialyse patients after angio- Significance of renal artery lesions graphy if renal failure or cardiac decompensation occur. Clinicians should be aware ofthe cholesterol The finding of a renal artery narrowing does not emboli syndrome which presents like a vasculitis necessarily mean that the lesion is haemo- (livedo reticularis, and acute renal failure). dynamically significant. A stenosis of 70-75% or Hypocomplementaemia and eosinophilia are greater is usually significant. A unilaterally small typical.'26 The syndrome may occur spontaneously kidney, particularly if perfusion and uptake are or after angiography in patients with athero- delayed, also suggests a significant stenosis. A sclerosis. positive captopril renogram or a rise in plasma Investigation must include an assessment ofboth creatinine with an ACE inhibitor suggests that the coronary and cerebral circulations as well as a stenosis is impairing perfusion and function. Renal detailed assessment ofthe risk factors and causes of vein renins are sometimes of value. atherosclerosis. Critical coronary or cerebral le- sions may need attention before the renal artery.127 Surgical intervention Intervention in ARAS With the proviso that cerebral or coronary may be needed first, renal revascularization Can aggressive investigation and intervention in is of proven value both for the control of blood ARAS be justified? There are three main points pressure and the preservation/salvage of renal that justify an active approach. function. Operating on kidneys less than 8 cm in 1. Natural history of ARAS. Serial angiogram length in which there is no perfusion or nephro- studies have shown that ARAS is a is to be successful. progressive gram, unlikely Regrograde copyright. disease. Forty per cent of patients with unilateral filling of the renal artery on angiography is an ARAS develop contralateral disease over 4 to 5 encouraging signindicating good collateral circula- years. Forty per cent of severe stenoses (> 75%) tion despite an apparently totally occluded renal occlude over a 2 year period.'28 artery. A perioperative can be helpful 2. Developments in interventional techniques. in identifying kidneys in which the glomeruli are (a) Percutaneous translumenal angioplasty (PTA). non-sclerosed and therefore capable of function- For lesions that are more main trunk than ostial, ing. PTA and surgical revascularization should not PTA has a In selected place. patients with high be seen as mutually exclusive. Failure of one http://pmj.bmj.com/ surgical risk, PTA may be the only intervention technique in a given patient may be followed by available. In experienced hands and with careful success of the other, There are promising early patient selection this technique can be safe and reports of the use of stents placed after PTA for effective. Recurrence of the stenosis may occur so ostial lesions.130,131 that follow-up and repeat PTA may be required. (b) Renal revascularization by bypass procedures. Medical intervention There have been great strides made in vascular surgery over the last two decades. It is safer to Atherosclerosis is a generalized and progressive on September 30, 2021 by guest. Protected bypass severe aortic/ostial lesions than to attempt a disease. A case can be made for the intensive formal repair. It is worth emphasizing that ostial medical management of all patients with ARAS, ARAS is really an aortic disease. A right renal whether or not intervention is undertaken. The artery stenosis can be bypassed using the hepatic or aetiological factors for atherosclerosis are well gastroduodenal artery (with or without a segment known and the cellular and molecular basis of of graft). The splenic artery may be used for a left atherosclerosis is being delineated in ever greater renal artery. Synthetic grafts can be inserted higher detail. Evidence is accumulating that atheroma can up the and implanted beyond the renal artery be reversed in other vascular beds so why not in narrowing. These procedures have significantly ARAS?132-134 The most important prerequisite for reduced the morbidity and mortality ofrenal artery all medical therapy is that the patient should stop surgery.'29 smoking. Perhaps the second most important fac- 3. Preservation of renal function. The classical tor is obsessional control of the blood pressure. view of renal artery surgery was that it was carried Here the choice ofagents may be critical with ACE out to cure hypertension or to render it easier to inhibitors and beta blockers being contraindicated. control. A more important consideration is preser- In the over 65s is diet and control of hyper- vation of renal function. Patients with ARAS not lipidaemia likely to help? Certainly patients should 528 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from be advised to diet to ideal weight and avoid sodium adequate plasma levels rather than the absolute rich foods if hypertensive. With the arrival of safe height of the peak plasma level,'45 and numerous and effective lipid-lowering agents, patients with studies have demonstrated the superiority of the proven ARAS should be studied in a properly subcutaneous route in clinical practice.'45'147-149 designed randomized controlled trial of intensive Thrice weekly subcutaneous injection is as effective medical therapy. as thrice weekly intravenous injection but permits a dose reduction in the range of 30-50%. Once 2. Erythropoietin weekly subcutaneous injection is equally effective but permits no dose reduction.'50 The erythropoeitin (Epo) revoluton was triggered The response to therapy is dose dependent but by the isolation and cloning of the Epo gene135'136 there are great variations in response between and subsequent clinical use of recombinant human patients.'38 Most patients require 50-200 IU/kg/ Epo to treat the anaemia of patients with chronic week given in two or three subcutaneous doses to renal failure requiring haemodialysis.'37'38 The last achieve and maintain target haemoglobin levels. few years have seen an explosion in our understan- Therapy requires to be individualized and based on ding ofthe biology and clinical applications ofEpo. rigorous monitoring, and a mathematical model The human Epo gene is located on chromosome for Epo dosing has been proposed.'5' In spite ofthe 7 where it is encoded as a single copy gene growingexperience in the clinical use ofEpo, recent consisting of five exons separated by four in- studies suggest that underdosing is endemic.147"'52 trons.'39 Besides the kidney, the liver is a well- Many studies have demonstrated the effective- established site of Epo production. The probable ness of Epo in continuous ambulatory peritoneal site of production in the kidney is the endothelial dialysis (CAPD) patients.153-155 The subcutaneous cells ofperitubularcapillaries, though there is some route has been most commonly used and has been evidence that interstitial cells and tubular cells may shown to be more effective than the intraperitoneal also be involved."40 Epo secretion is stimulated by route.156'157 The optimum frequency of administra- hypoxia by a mechanism which involves an oxygen tion is not yet known and may be subject to sensor located near the proximal tubules. It is not variation between individuals though once weekly known whether the oxygen-sensing cells are the treatment has been shown to be effective.'58'159copyright. cells which secrete Epo. The oxygen sensor has There are suggestions that CAPD patients may be recently been shown to be a heme protein which more responsive to Epo than haemodialysis pa- triggers Epo production when in the deoxy confor- tients perhaps because of chronic blood losses in mation. DNA sequences both upstream and down- the latter group.'60 stream ofthe Epo gene are required for the hypoxic There is an increasing experience with the use of response in liver and kidney.'4 The target cells for Epo in predialysis patients,1'61166 in whom the dose the action of are committed and for subcutaneous administra- Epo erythroid pro- range frequency http://pmj.bmj.com/ genitor cells in the bone marrow, which have tion have been found to be similar to those required specific Epo receptors.'41 in dialysed patients. There were initial fears that therapy with Epo may be associated with an Dosage and route of administration increase in the rate of progression of renal failure. This was based on the propensity of Epo to The initial clinical trials of Epo demonstrated produce an exacerbation of hypertension and a dramatic improvements in the anaemia of haemo- reduction in effective renal plasma flow. These fears dialysed patients.'37'38 The doses and route of appear to be largely unfounded'62-'66 though on September 30, 2021 by guest. Protected administration used in these initial studies were careful monitoring of blood pressure is essential necessarily empirical and much subsequent work in and the initiation of therapy with small doses has this area has focused on optimizing these. Studies been advocated.'66 of the pharmacokinetics of Epo after an intra- Patients with haemoglobinopathies and end- venous dose have shown that the mean half-time stage renal failure often respond to Epo but may for clearance from the plasma is about 5-7 require substantially larger doses.167 Those with hours.'42-145 The apparent volume ofdistribution is end-stage renal failure complicating myeloma may close to the plasma volume.142'46 Renal clearance also respond.168'169 accounts for less than 3% of total body clear- ance.46 The peak concentration achieved after a Beneficial effects of Epo subcutaneous dose is 12.5-20 times lower than that after the same intravenous dose. Absorption from The beneficial effects of Epo can usually be related the subcutaneous site is complete after about 120 to the improvement of anaemia. There may be hours with a bioavailability of about 30%.44 other direct effects including alterations of haemo- It appears though that the quality ofthe erythro- static parameters and improvement of platelet poietic response depends on the maintenance of function though even these may be related to the NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 529 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

rise in haematocrit.170-172 Many studies have shown Table XII Possible adverse effects of treatment with improvements in quality of life scores.'73-'77 Epo Regression of left ventricular hypertrophy in spite of the tendency to exacerbate hypertension has Hypertension been another These and Fits important finding.178-'81 Increased clotting other effects of Epo are alluded to in Table XI. Flu-like syndrome Reduced Adverse effects of Epo dialyser efficiency Treatment with Epo is usually very well tolerated and there are few serious adverse effects. Never- Table XIII Factors associated with the rise in systemic theless a number of possible problems may arise vascular resistance during Epo therapy (Table XII). Increased blood pressure is the most commonly reported of these and occurs in about Increased blood viscosity one third of with renal failure. The risk Increased haematocrit patients Decreased red cell fluidity appears maximal in the early stages of treatment Loss of hypoxic vasodilatation when the haematocrit is increasing. Nevertheless Direct vasoconstrictor effect of Epo there appears to be no clear association with the Activation of neurohumoral systems dose of Epo nor with the rate of rise of haemato- Renin-angiotensin system crit.182 Blood volume does not change on Epo Sympathetic system treatment"83 so is unlikely to be a hypertensive Imbalance of local endothelial factors mechanism. Haemodynamic studies though, have EDRF repeatedly shown an increase in systemic vascular Endothelin resistance coupled with a reduction in cardiac output during therapy with Epo.183-185 Factors which may be important in the rise in the clinical studies of Epo,'38 though subsequent con- systemic vascular resistance are shown in Table trolled studies showed no difference in

prevalence copyright. XIII. The major factor appears to be a rise in the between the treated and placebo groups.'9' Never- blood viscosity during Epo treatment which is theless, seizures do occur in some patients early in largely related to the rise in haematocrit, though the course of Epo therapy at a time when the fluidity of the red cells may also be dis- haematocrit and blood pressure are increasing turbed.186'187 Another contributory factor may be rapidly, and most of these patients appear to have loss of the vasodilatory response to hypoxia.'88 hypertensive encephalopathy.'92 Hypertensive en- Other factors appear less important though altera- cephalopathy is usually the result of a breakdown tions in function have been descri- in cerebral sympathetic autoregulation,'93 resulting in hyperper- http://pmj.bmj.com/ bed.'89'190 If the rise in systemic vascular resistance fusion, damage to the blood-brain barrier, exuda- observed during Epo therapy was accompanied by tion of protein, and focal cerebral oedema. Cere- an appropriate reduction in cardiac output, no bral blood flow is usually reduced in response to the change in blood pressure would be observed. There rising haematocrit during Epo therapy,'94'95 but is some evidence that cardiac output remains whether this adaptation is always complete remains inappropriately high in those patients who develop to be established. hypertension,'83 perhaps due to baroreceptor dys- An increase in the number of thrombotic events function and impaired myocardial compliance. has been reported during Epo therapy, though the on September 30, 2021 by guest. Protected Grand mal seizures were reported in the early finding is not substantiated by placebo-controlled studies.'96 As haematocrit increases, vascular access PTFE and bovine Table XI Reported beneficial effects of treatment with particularly grafts, may be in chronic renal failure at increased risk and low-dose aspirin prophylaxis Epo has been recommended. Other haemostatic Effect changes occur170-172 but there is no evidence that Epo produces a hypercoagulable state.l'9 Quality of life Exercise capacity Epo and the efficiency of dialysis Cognitive function Neuromuscular function An increase in haematocrit reduces plasma water Sexual potency flow the to a Regression of LVH through dialyser leading decrease in Improved haemostasis solute clearance and ultrafiltration rate. This effect Improved pituitary function on solute clearance is dependent on the diffusabilty Reduced cytotoxic antibody titres of the solute across the semipermeable membrane. The clearances of easily diffusible solutes, such as 530 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from , are less affected than those of less readily Table XIV Factors associated with resistance to Epo diffusible solutes. This is because the fall in plasma treatment water flow is offset by an increased delivery of intracellular water (red cells contain 80% water), Iron deficiency from which solutes such as urea can diffuse. Occult blood loss readily Vitamin deficiency Clearances of less readily diffusible substances, Folate such as creatinine, and those whose intracellular B12 concentrations are maintained by active transport B6 processes, such as potassium and phosphate, are Inflammatory states much more susceptible to a rising haematocrit.'97 Infection The magnitude of the expected reduction in Surgery dialyser efficiency consequent on an increase in Secondary hyperparathyroidism haematocrit from 20% to 33% would be expected Aluminium intoxication to be of the order of 16% for diffusible Haemoglobinopathies poorly Chronic haemolysis substances and less for those readily diffusible, Malignancy since this is the proportional reduction of plasma- Protein-calorie malnutrition crit (from 80% to 67%). A number of studies have addressed the clinical relevance of these theoretical considerations. In chronic haemodialysis employing conventional does serum ferritin, suggesting that the functional membranes, there was no change in Kt/V (urea) availability of iron in the plasma may be more and protein catabolic rate (see p. 532) consequent important than the actual size of the body iron on a mean increment in (a measure of dialysis stores in determining response.203 Determination of efficiency) haematocrit from 21 to 34%. However, the percentage of hypochromic red-cells may be a predialysis potassium concentrations were more sensitive index of iron deficiency.'81 Almost significantly higher, the use of phosphate binders all patients require supplementation with iron in increased (as did the heparin dose), and the dialyser order to maintain a response and many require iron efficiency for creatinine, potassium and phosphate by the intravenous route. The suggestion has beencopyright. decreased by 15%, 9% and 17%, respectively. made that suboptimal doses of Epo markedly Similar changes were seen in patients undergoing reduce serum ferritin levels.204 high-efficiency dialysis.'98 Hence it appears that The other major cause ofpoor response to Epo is only small changes to dialysis schedules, heparin the presence of inflammation due to infection, dose and phosphate binder dose are required to surgical interventions, autoimmune disorders or counteract the effects of clinically relevant inc- malignancy.205 A reduction in iron availability for rements in haematocrit. haem production from iron stores in the

endoplas- http://pmj.bmj.com/ The effect of rising haematocrit on solute mic reticulum,205'206 and increased cytokineproduc- clearance and ultrafiltration rate in CAPD patients tion leading to decreased Epo production or end- is less well studied. The available studies have organ resistance to the action of Epo207'208 are shown no effect on either solute clearance or possible explanations for this phenomenon. An ultrafiltration,99'200 decreased solute clearances,201 interesting exception is the increased response to and surprisingly increased ultrafiltration.202 Epo which occurs in the context of viral hepatitis. This may be attributable to increased production

Resistance to Epo of Epo by newly formed hepatocytes.209 on September 30, 2021 by guest. Protected Most patients with chronic renal failure respond 3. Mineral metabolism and renal bone disease well to Epo therapy. However, a small proportion of patients require much larger than average doses Pathophysiology of secondary hyperparathyroid- and a tiny minority do not respond at all. The ism common causes of poor response (termed Epo resistance) are shown in Table XIV. By far the 1,25(OH)2D3 directly suppresses parathyroid hor- commonest cause of poor response is iron de- mone synthesis210 and deficiency of 1,25(OH) 2D3 is ficiency which may predate Epo therapy (in which considered to be a major stimulus to hyper- case the indication for Epo is suspect), or occur as a parathyroidism in chronic renal failure (CRF). consequence of a previous good response. The However, in early CRF levels of 1,25(OH)2D3 are diagnosis of iron deficiency is difficult in patients normal. Recently it has emerged that 1,25(OH)2D3 with chronic renal failure. Both the serum ferritin receptor density on parathyroid cells is reduced in level and transferrin saturation may be misleading. CRF,211,212 though the binding affinity of the recep- The transferrin saturation and iron-binding tor for 1,25(OH)2D3 is unchanged.212 Uraemic capacity correlate better with Epo response than toxins may reduce genomic synthesis of NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 531 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

1,25(OH)2D3 receptors by inhibiting the interaction in patients with severe secondary hyperparathy- of the hormone-receptor complex with nuclear roidism.230 Pulsed therapy proved more effective chromatin.213 This reduced receptor density pro- than continuous treatment in suppressing parathy- bably accounts for the resistance ofthe parathyroid roid hormone levels in experimental animals,231 glands to suppression by 1,25(OH)2D3 which is suggesting that the parathyroid gland is more encountered in renal failure.24 Administration of responsive to peaks than to steady-state levels. It 1,25(OH)2D3 increases the number of vitamin D appears though that intermittent oral treatment is receptors in a dose-dependent fashion,215 thus as effective as intermittent intravenous treat- restoring the regulation of parathyroid hormone ment.232 One of the major problems in treating secretion toward normal, and increasing the sensi- secondary hyperparathyroidism is the remarkable tivity ofthe glands to calcium. In line with this, the capacity of the parathyroids to escape from con- elevated set point for parathyroid hormone sup- trol. It seems that tolerance to pulsed calcitriol may pression by calcium in CRF is reduced by the also emerge after relatively short treatment administration of 1,25(OH)2D3.216'217 times.233 Other approaches have been used. Oral Skeletal resistance to the calcaemic action of 24,25(OH)2D3 has been shown to suppress para- parathyroid hormone may also contribute to the thyroid hormone levels in dialysed patients many genesis ofsecondary hyperparathyroidism in CRF. of whom had hypercalcaemic hyperparathyroid- Deficiency of 1,25(OH)2D3 and hyperphospha- ism.234 The synthesis of a non-calcaemic analogue taemia are factors which augment this resistance.218 of vitamin D3 is an exciting development. This Parathyroidectomy reverses the problem. In spite compound, 22-oxacalcitriol (OCT), has been of this it does not seem that the resistance is due to shown to be as effective as 1,25(OH)2D3 in suppres- down regulation ofparathyroid hormone receptors sing parathyroid hormone levels, but 100 times less in response to high circulating levels ofparathyroid effective in mobilizing bone calcium, and 1000 hormone.219 Calcitonin may be involved since its times less effective in stimulating intestinal calcium absence normalizes the calcaemic response to transport.235 Clearly such compounds have major parathyroid hormone in uraemic rats.220 clinical potential in the treatment of secondary Phosphate retention is also thought to play a role hyperparathyroidism in chronic renal failure. in the development of secondary hyperparathy- copyright. roidism in CRF. The mechanisms have been thought to be either direct physicochemical interac- tion of phosphate with calcium leading to relative Adynamic bone disease hypocalcaemia, and phosphate-induced suppres- sion of 1,25(OH)2D3 synthesis. The finding that The spectrum ofbony abnormalities associated with phosphorus restriction can reverse hyperparathy- chronic renal failure has been increased by the roidism in uraemia of in of a novel form of bone independently changes description adynamic http://pmj.bmj.com/ serum calcium and calcitriol levels is therefore disease.236 Adynamic changes in bone were intriguing.22 formerly thought to occur in this group of patients entirely as a result of aluminium toxicity. Now similar histological changes have been described in patients in whom there is no evidence ofaluminium Therapy of renal bone disease accumulation. This idiopathic form of the disease may account for up to 24% of cases.237 The

Treatment and prevention ofphosphate accumula- problem may be more common in elderly patients, on September 30, 2021 by guest. Protected tion in CRF remains unsatisfactory.222 Problems in diabetics, and in CAPD patients.237 The entity with aluminium accumulation place great restric- has also been seen in predialysis patients and the tions on the use of aluminium-containing phos- suggestion made that overtreatment with calcium phate binders. Calcium carbonate is a useful alter- supplements and active vitamin D compounds may native223 but hypercalcaemia occurs frequently.224 predispose to the problem by oversuppressing Calcium acetate has theoretical advantages,225226 parathyroid hormone levels to a degree inappro- but these have proved difficult to demonstrate priate for the prevailing level of renal function.238 clinically,227 and hypercalcaemia remains a prob- Histologically the disease is characterized by lem. Lowering of the dialysate calcium concentra- markedly reduced bone turnover, with a paucity of tion has enabled larger doses ofcalcium-containing osteoid, bone cells and a significant reduction in phosphate binders to be used, in both haemo- active remodelling sites and tetracycline uptake.237 dialysed and CAPD patients, with less risk of The clinical relevance of these histological abnor- hypercalcaemia and without compromising net malities await firm definition. Patients with the calcium balance.228'229 problem do seem to have a propensity to develop Intravenous pulse therapy with 1,25(OH)2D3 is hypercalcaemia, and may be at increased risk of effective in suppressing parathyroid hormone levels microfracture.237 532 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Dialysis evaluation in the National Cooperative Dialysis Study (NCDS).250'251 A re-examination of this Adequacy study252 showed a lower morbidity in patients: (1) with a Kt/V>0.8 (in thrice weekly dialysed pa- All currently available modes of renal replacement tients), where K= total urea clearance (residual therapy, with the exception of successful renal renal clearance plus clearance by dialyser (ml/ transplantation, fall a long way short of the gold minute), t = dialysis time (minutes), and V = the standard 'to clean blood and biological fluids to a urea distribution volume (= total body water degree comparable to normal renal function'.239 (ml)); and (2) with a protein catabolic rate (PCR) These inherent limitations of dialysis therapies from 0.8 to 1.4 g/kg/body wt/day. PCR is derived dictate the need for some criteria of adequacy of from the urea generation rate and in stable patients therapy, difficult though they are to define. is considered to be an index of the adequacy of protein intake. There is a strong correlation Adequacy ofhaemodialysis and related techniques between Kt/Vand PCR which may suggest that the poor control of the uraemic state resulting from 'Traditional' haemodialysis treatment employed inadequate dialysis causes the retention ofappetite- long hours ordained by the 'square metre-hour' suppressing uraemic toxins, resulting in malnutri- hypothesis,24 the rationale ofwhich was to provide tion and increased morbidity and mortality.252'253 adequate clearance of 'middle molecules'. Treat- UKM is becoming increasingly used to prescribe ment was monitored by clinical assessment and by and monitor the delivery of haemodialysis. The the measurement of predialysis blood urea and targets are derived from the NCDS, that is, K,/V serum creatinine levels. Adequacy, at least as far as > 1.0 and PCR = 0.8-1.2. Whilst it is widely small molecular weight solute clearance was con- recognized as a potentially useful tool there remain cerned, was not a critical issue. areas of concern. The choice of urea as a marker Now, however, the question of adequacy has solute is subject to criticism, but there is no ideal been brought into sharp focus by pressures, largely marker solute,239 and urea at least has the advan- economic, to shorten haemodialysis times. This tage of reflecting protein catabolism, the products trend has taken place without any adjustment to of which are central to the concept of uraemiccopyright. the monitoring process and has resulted in toxicity. Its use also has the substantial backing of significantly increased mortality in haemodialysis the NCDS.250-252 Whilst the parameter K,/V is patients, especially in the USA.241'242 This implies becoming well accepted, the exact means of cal- that some of the basic requirements for adequacy culating it for routine clinical purposes still inspire have remained unfulfilled and yet have been over- debate.254-257 There is also some discussion about looked by traditional monitoring methods. what constitutes an optimal target K,1 Vfor chronic Clinical assessment remains an tool and the view has been

important haemodialysis patients http://pmj.bmj.com/ for monitoring adequacy, but inadequate therapy expressed that morbidity continues to decline with can remain undetected when guided solely by increasing K, V with no obvious optimum.258 The clinical parameters.243'244 'Static' biochemical remarkable survival figures from Tassin,259 achie- parameters such as predialysis urea and creatinine ved with a mean K, V = 1.67, may constitute some concentrations have also been found wanting. support for this view, though there are other When protein intake is deficient, the predialysis possible explanations including case-mix and con- urea may remain low in spite ofinadequatedialysis, trol ofhypertension. Whether the same target K,1 V and a low predialysis urea has been found to be is appropriate for stable chronic patients (such as on September 30, 2021 by guest. Protected predictive ofhigh mortality.45 Similarly it has been those studied in the NCDS) and sicker, more demonstrated that predialysis creatinine levels are catabolic patients is also unclear.239 inversely related to mortality.246'247 In the dialysis The use of UKM to maintain adequacy when population, with relatively constant rates of crea- dialysis times are shortened can be highly tinine removal, the major determinant ofthe serum beneficial.26 The safety margin though is small and creatinine level is the creatinine generation rate,247 a rigorous monitoring is required to ensure adequate reflection of somatic protein content.248 This im- delivery. Rapid treatments may expose a further plies that, in this population, creatinine levels are problem. The degree of post-dialysis urea rebound an indicator of nutritional status. This notion is is greater after such treatments because of the supported by the strong correlation between pre- limiting effect ofintercompartmental shifts on urea dialysis creatinine and serum albumin, which is a clearance.26' This effect will lead to underdialysis strong predictor of mortality in all populations.249 unless allowance is made by the appropriate timing There are a number of alternative methods of of post-dialysis blood sampling or by modification defining and monitoring adequacy. The most pro- of the single-pool based UKM parameters to minent of these is urea kinetic modelling (UKM) account for these two-pool effects.261 The dialysis which received considerable impetus from its membrane used may also have important effects. NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 533 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Standard cellulosic membranes were employed in correlations between K/ Vand PCR normalized for the NCDS. It has been suggested that high-flux total body water.263265 dialysers with better biocompatibility characteris- There are two related but major difficulties in tics require less rigorous urea clearance.253 interpreting UKM data in CAPD patients. First is Concern has also been expressed that the two its lack ofvalidation by clinical outcome measures. major parameters derived from UKM are not Recently, however, three studies have demon- independent since they are mathematically derived strated an inverse correlation of Kt/V and hos- from similar parameters. This counsels caution in pitalization rate.264-266 There are no studies relating interpreting the correlation between them.239 Fin- CAPD adequacy and mortality. Secondly there is ally, and perhaps most importantly, the use ofthese considerable debate on the values of Kt/V consis- criteria of adequacy are not yet supported by tent with adequacy. Theoretical considerations long-term studies with mortality as the end point. based on the 'peak hypothesis'267 suggest that for This will be the definitive test. CAPD to produce the same steady-state concentra- tion of urea as the midweek prehaemodialysis Adequacy of CAPD concentration, a daily Kt/V of 0.3 is required (Figure 1). There is a paucity of data but patients In contrast to haemodialysis, the adequacy of with a daily Kt/V <0.25 had significantly more CAPD has received little attention. Most patients hospitalizations than those with a higher Kt/V.265 on this treatment are prescribed a standard regime A worrying feature is the finding of a decline of of 8 litres of fluid daily. Taking into account the K,/ V with loss ofresidual renal function. There is a wide range of patient size, and their considerable limited capacity in CAPD to compensate for loss of diversity in residual renal function, it would be residual renal function by increasing dialysate suprising if there were not wide variations in volumes. This implies that there must be con- dialysis adequacy. The available studies confirm siderable doubt about the long-term viability ofthe that CAPD patients received a wide range of technique especially in patients with larger than dialysis dose expressed as Kt/V.263-265 average body mass. It is also that declines

apparent dialysis adequacy copyright. with increasing time on dialysis, and that this is Other aspects of adequacy related to a decline in residual renal function263-265 rather than in the parameters of peritoneal mass The discussion above has been dominated by the transfer.264'265 There are also highly significant concept ofbiochemical adequacy. There are clearly

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5 0 1 2 3 4 5 6 7 8 9 10 Time (days) Figure 1 Interrelationships of adequacy parameters in haemodialysis and CAPD. The saw-tooth line represents the blood urea concentration in a typical patient haemodialysed three times weekly with NPCR = 1 and K, V = 1. The horizontal lines represent the situation in CAPD patients with varying adequacy parameters. The horizontal solid line represents a daily K,/V = 0.2, the dotted line a daily K,/V= 0.3, and the dashed line a daily Kt/V= 0.4. 534 K. FARRINGTON & P. SWENY Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from other aspects. Perhaps the most important ofthese ment activation.279 281 In addition, there is in vitro is adequacy of control of salt and water balance evidence of increased P2m production by lym- and hypertension. There is evidence that in both phocytes and monocytes harvested at the end of short hours haemodialysis and CAPD that blood haemodialysis.282 Many of these processes were pressure control may be suboptimal and associated more pronounced in or confined to dialysis involv- with progressive cardiovascular damage.268269 The ing cuprophane membranes when compared with requirement for adequate control of hypertension dialysis involving newer, more biocompatible may play a significant role in the design ofoptimal membranes, composed of polymethylmethacry- dialysis schedules. After all most dialysis patients late, polyacrylonitrile or polysulphone. There is, die a cardiovascular death. however, very little evidence of P2m production during clinical haemodialysis when correction is made for dialysis-induced changes in extracellular Dialysis-related amyloidosis fluid volume.283-286 As well as possible membrane effects on P2m production, the composition and Dialysis-related amyloidosis is now recognized as a purity of the dialysis fluid may also have a role, major, and potentially limiting complication of since acetate and endotoxin both promote inter- chronic dialysis treatment. The syndrome was leukin-1 production.287'288 recognized in the early 1980s270 and soon after Whilst doubts remain about differences between P2-microglobulin (B2m) was identified as the amy- membranes with respect to their capacity to loid precursor protein.27' The main clinical features generate B2m, there is little doubt that a significant are carpal tunnel syndrome and destructive arthro- clearance of P2m can be achieved using high flux pathy, predominantly affecting large and medium- membranes compared to that achieved by cup- sized joints, and associated with bone cysts.272 The raphane.289'290 As well as increased removal of B2m spine is also involved though mechanisms other by filtration through these high flux membranes, than amyloid deposition may be of importance in there is also evidence of enhanced adsorption of the pathogenesis of the spondyloarthropathy.273'274 P2m on to the membrane surface,289-291 an effect The incidence of both tunnel and which be modified

carpal syndrome may by dialyser reprocessingcopyright. the osteoarticular lesions increase with the dura- techniques. 291 Increased P2m clearance by highly tion of treatment. There is virtually permeable membranes may well be clinically 100% involvement by 15-20 years.275,276 Age at important, since a large multi-centre retrospective onset of dialysis is an important predictor, older study has shown a decreased incidence of dialysis- patients being more likely to develop the prob- related amyloidosis in patients dialysed using lem.277 Visceral involvement occurs infrequently, polyacrylonitrile compared to patients dialysed but can have clinical consequences.278 using cuprophane.267 Haemofiltration has a greater The of retention as the essential to recognition B2m capacity remove P2m than even high flux http://pmj.bmj.com/ requirement for the development ofdialysis-related dialysis.292 amyloidosis, has stimulated enquiry into factors Although experience with long-term CAPD is affecting its rate ofsynthesis, release and clearance. still limited, there are now a number of reports of P2m is an 11,800 dalton protein which, as part ofthe dialysis-associated arthropathy occurring in pat- human class 1 major histocompatibility complex, is ients treated solely by this modality,293-295 and found on the surface ofall nucleated cells. It is also reports of the disease progressing after transfer to found in neutrophil granules, and is a secretory CAPD from haemodialysis.l87 There is significant protein of hepatocytes. Increased synthesis and clearance ofP2m by the peritoneal membrane,296,297 on September 30, 2021 by guest. Protected release into extracellular fluid are mediated by which is of the same order as that achieved by various cytokines including tumour necrosis fac- high-flux dialysis. Hypertonic exchanges,296 and the tor, interleukin-2, and alpha and gamma inter- use of glucose polymer,298 both increase peritoneal ferons. High serum levels occur in inflammatory clearance. There is no evidence of P2m generation and malignant lymphoproliferative disorders. It is during the dialysis process, though, like eliminated from the body largely (95%) by glom- haemodialysis, CAPD can induce cellular activa- erular filtration and subsequent tubular absorption tion and the release of inflammatory mediators.299 and degradation, hence its accumulation in renal The propensity for CAPD patients to develop the failure. dialysis-related amyloidosis may well be less than The possibility that dialysis specific factors may that for haemodialysed patients, at least those be important in the accumulation of P2m has treated using standard cuprophane membranes, received much attention. There is growing evidence but only further studies will tell. that haemodialysis incites an inflammatory res- Recent work has provided further insights into ponse, stimulating the cellular release of inter- the pathogenesis of the disease, and argues against leukin-1 and TNF, granulocyte activation with the the role of simple precipitation of P2m into generation of reactive oxygen species, and comple- amyloid-like fibril structures as the sole cause. NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 535 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Amyloid fibrils seem to consist not only of intact FK506 P2m, but also ofproteolysed fragments, at least one ofwhich has also been demonstrated in the plasma FK506 is a macrolide313 which acts in a similar of long-term haemodialysed patients.300'30 Pro- manner to cyclosporin A by blocking the phos- teolysis of P2m, perhaps by proteases released as phatase activity of calcineurin which leads to a part of the inflammatory response to haemodi- failure of transcription of 112 and other T-cell alysis, may be important in the development of the activation genes. Both cyclosporin A and FK506 disease. On the other hand it has been argued that it enhance the transcription of TGF-b which is a is incomplete proteolysis of P2m which is the potent inhibitor of 112 stimulated T-cell prolifera- necessary condition for amyloid fibril formation, tion. FK506 is more potent in these regards than and that inhibition of proteolysis by 'amyloid cyclosporin A and is also a more potent inhibitor of enhancing factors' such as the anti-protease a2- B cells. Nephrotoxicity is a major problem but macroglobulin predisposes to the condition.302 early reports suggest that hypertension is less of a Treatment options are limited for established problem with FK506. The impression is that disease. Renal transplantation has been shown to FK506 may well replace cyclosporin A in liver limit disease progression294 but there is no other transplantation but that it is unlikely to do so in effective therapy. Prevention is therefore of the renal transplantation. The results of several trials utmost importance. High-flux dialysis using bio- comparing FK506 and cyclosporin A should be compatible membranes, bicarbonate as the buffer available soon. and ultrapure water seem rational measures to adopt.303'304 Haemodiafiltration offers the best hope ofpreventing the disease but is an expensive option Rapamycin with currently available technology. The place of CAPD in prevention strategies is presently un- Rapamycin314 is also a macrolide and like FK506 known. Prospective studies are required to evaluate binds to FK-binding protein, but this is not its these options perhaps employing recently des- mode of action. It blocks 112-mediated signal cribed radionuclide tracing and imaging of P2m transduction and can block 112 driven T-cell pro- copyright. amyloid deposits to monitor disease progres- liferation. It does not block the induction of 112 sion.305-307 gene expression. It is synergistic with cyclosporin A but antagonistic to FK506. In rats it produces myocardial toxicity. Transplantation RS-61443

Matching http://pmj.bmj.com/ This is a derivative of a Despite the absence of large randomized prospec- agent315 semi-synthetic tive controlled HLA is now fungal antibiotic, mycophenolic acid. It is an trials, matching inhibitor of like accepted as one of the prime determinants of both purine synthesis, azathioprine, early and, increasingly importantly, long-term which it may replace. It is synergistic with cyclo- survival.308 It has also become clear that sporin A and 15-deoxyspergualine. It does not graft to be marrow that neither a appear toxic. Its major side effects are kidneys undergo rejection episode on the tract. nor primary non-function do very much better gastro-intestinal on September 30, 2021 by guest. Protected than those that do.309 This observation has been advanced as a justification for intensive induction regimes usually including biological anti-lympho- 15-Deoxyspergualin (15-DS) cyte preparations. The impact of DNA typing on transplantation is yet to be felt but graft survival of This agent316 is a derivative of spergualin from 90% may be attainable.310 Although with DNA Bacillus laterosporus. Its mode of action is un- typing matching will become more difficult, it will known. It suppresses function (inter- be more exact. leukin 1 production, production of oxygen derived radicals, reduction of class II expression), and New drugs decreases cytotoxic T-cell proliferation. It appears more potent than cyclosporin A and may be A variety of new immunosuppressive drugs is being synergistic with both cyclosporin A and FK506. studied both in animal models of transplantation 15-DS has been shown to reverse established and in pilot studies in man.31 It seems likely that rejections and to prevent their occurrence. It is some will soon find acceptance in routine clinical toxic to bone marrow and may cause gastro- practice.311,312 intestinal disturbances. Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from 536 K. FARRINGTON & P. SWENY

Table XV Antibodies being used in transplant rejection Cytokine Cytokine release Antibody Mitosis ADCC Modulation Lysis N-K cells release syndrome ATG - ++? 4+94,4 TNFa ++ OKT3 ++ ++ ++ - 4 TNFa, INFy + + + + GMCSF 112, 3, 6, 10 T10 B9 + + + + + TNFa, INFy 112 CAMPATH-1 - ++ + 4 ++ 33B3.1 - + ?- - SDZ CHI 621 - + + --- SDZ CHH 380 - + + + - - TNFa + 116 TNFa =Tumour necrosis factor alpha; INFy = gamma interferon; GMCSF = granulocyte monocyte colony stimulating factor; ADCC = antibody-dependent cell-mediated cytotoxicity; NK = natural killer; ATG = anti- thymocyte globulin. - negative or absent; ± weak or equivocal; + positive or present; 4, reduced; -> no change; + increased; ? unknown.

Table XVI Immunogenicity of antibodies being used in transplantation Immunogenicity Half life Antibody aID (%) aALLO/aXENO (%) (hours) Specificities (CD) ATG -70-80 ? HLA DR, LEU-C

45, 18, 2, 4, 8 copyright. OKT3 30-70 30-100 24 3 T10 B9 10 30-50 4 3 CAMPATH-1 ? 80 8 W52 33 B3 1 30 80-90 24 25 SDZ CHI 621 0 0 312 25 SDZ CHH 380 1.3 4.5 77-151 7 HLA = Histocompatibility locus antigen; LEU-C = leucocyte common antigen; aID = anti-idiotypic antibody; aALLO = anti-allotypic antibody; aXENO = anti-xenotypic antibody; CD = cluster determinant. http://pmj.bmj.com/

New biologicals Other MOAB Molecular biology is producing an increasing range Other reagents with effects on lymphocyte of pure and specific animal antibodies to defined adhesion are being developed and evaluated, such specificities on human lymphocytes.317 These anti- as antibodies to CD2, CD8, LFA1, ICAM-1, bodies can be chimaerized or humanized.38 This LFA3. Development is still largely at the stage of on September 30, 2021 by guest. Protected additional step, although increasing cost con- animal studies although preliminary results with siderably, renders the end product either less or anti ICAM-1 (CD54) antibodies in humans appear non-immunogenic. Some ofthe currently available promising.321 The mode of action of these anti- antibodies are summarized in Tables XV and XVI. bodies varies depending not only on the surface determinant against which the antibody is directed Chimaeric antibodies but also on whether or not the antibody is lytic, depleting or modulating (Table XV). Of con- Anti-CD7 antibodies, although non-immunogenic, siderable clinical importance is the cytokine release had no significant impact on either the number or syndrome seen most markedly with OKT3. It now onset of rejection episodes in first cadaveric renal seems likely that antibodies causing the release of allograft recipients.39 Chimaeric anti-CD25 TNFa may also predispose to graft thrombosis.322 antibodies are currently being evaluated. Limited experience with anti-CD4 antibodies indicates that, Optimal immunosuppression although these reagents are very potent in animal models,320 they may elicit an anti-idiotypic re- There is still no agreement as to what is the optimal sponse. immunosuppressive regime for renal allografts. NEPHROLOGY, DIALYSIS AND TRANSPLANTATION 537 Postgrad Med J: first published as 10.1136/pgmj.69.813.516 on 1 July 1993. Downloaded from

Strategies need to be developed that take into Treatment of rejection crises account an early induction phase, an intermediate semi-stable phase of graft acceptance and then a Steroids still remain the mainstay of treatment of prolonged maintenance phase during which drug early rejection crises, because of the ease of toxicity may well be more important than the risk administration and cost. OKT3 can be used suc- of rejection. cessfully for the treatment of rejection and for the rescue of patients from steroid-resistant rejection Induction crises.326 Polyclonal anti-lymphocyte or anti- thymus globulin similarly can be used for rescue. The use of a monoclonal anti-CD25 antibody for Anti-CD25 antibodies do not appear effective for induction is promising for first transplants.33 the reversal of rejection episodes.327 Second or subsequent transplants may benefit from the use of the more widely reactive polyspecific Long-term medical management ofrenal antibody such as anti-thymocyte globulin. Induc- transplants tion should be tailored in the light of the relative risk of early rejection. Fully matched first grafts The principal cause ofdeath after successful trans- have a much lower risk of rejection than poorly plantation is a cardiovascular or cerebrovascular matched grafts or second or subsequent trans- event. It is now time that transplant physicians plants. Transplants into the highly sensitized assessed cardiovascular risk factors more thor- recipient also have an increased risk of early oughly. It is interesting to note that not only are rejection. By targeting the early activation steps of many transplant patients hypercholesterolaemic the immune response, using agents effective only but that lipoprotein-a is also markedly elevated.328 against activated lymphocytes, a degree of Preliminary studies suggest that cyclosporin A may specificity can be obtained which should not result be particularly prone to raise lipoprotein-a. Inter- in an unacceptably high risk of infection. actions (for example, rhabdomyolysis) between lipid lowering agents and cyclosporin A have to be Maintenance borne in therapy mind when prescribing. copyright. Long-term medical management of renal trans- Cyclosporin A usually with prednisolone and plants must include a determined attempt to reduce azathioprine, is the most widely accepted and stop smoking, obsessional blood pressure maintenance regime for both the early and control, using agents not associated with dys- intermediate period after grafting. The best regime lipidaemias and diet. These measures may well help for long-term therapy is not clear. Steroids can be to retard or even prevent chronic vascular rejection withdrawn safely in some patients.324 Cyclosporin which has many pathogenetic similarities with

A can be stopped, particularly in those in whom atherosclerosis. An up-to-date review of the com- http://pmj.bmj.com/ marked or progressive nephrotoxicity is a problem, mon ground between atherosclerosis and chronic but there does appear to be a significant risk of vascular rejection can be found in the proceedings rejection episodes occurring in these patients.35 of the Fourth Alexis Carrel Conference.329

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