REVIEW

Beyond immunosuppression – challengesin the clinical management of lupus nephritis

S Masood1, D Jayne2 and Y Karim3

1Department of Internal Medicine, Franklin Square Hospital Center, Baltimore, Maryland, USA; 2Director of Vasculitis & Lupus Clinic, RenalServices, Addenbrooke’s Hospital, Cambridge, UK; and 3Lupus Research Unit, St Thomas’ Hospital, London, UK

LupusnephritisremainsthemostcommonseveremanifestationofSLEwithincreasedriskofdeathandend-stage renal disease. Although, recent research has focused on the choice of immunosuppressive inits treatment, other factors, including the quality anddelivery of healthcare, themanagement of gluco-corticoids and co-morbidity are probably of more importance. There has been significant progress ininduction regimes with the successful use of mycophenolate mofetil, low dose intravenous cyclophos-phamide and development of sequential regimenswhereby cyclophosphamide is followed by an alter-native immunosuppressive. However, the attention on the day-to-daymanagement of lupus nephritisin the clinic has merited less attention. In this article, we aim to address more widely the major issueswhich are encountered regularly in the long-termmanagement of these patients. The overall goals arethe reduction ofmortality and preservation of renal function. Lupus (2009) 18, 106–115.

Key words: antiphospholipid syndrome; cardiovascular disease; nephritis; renal lupus

Introduction

Lupus nephritis remains the most common severemanifestation of systemic lupus erythematosus (SLE)with increased risk of death and end-stage renal dis-ease (ESRD). Although, recent research has focusedon the choice of immunosuppressive in its treatment,other factors, including the quality and delivery ofhealthcare, the management of glucocortioids andco-morbidity are probably of more importance.

Combination therapy with high dose glucocorti-coids and an immunosuppressive is widely acceptedtherapy with an initial phase ‘induction’ aimed at con-trolling disease activity, and a longer follow-up phase,‘maintenance’, aimed at preventing disease recur-rence. There has been significant progress in inductionregimes with the successful use of mycophenolatemofetil (MMF), low dose intravenous cyclophospha-mide (IVC) and development of sequential regimenswhereby cyclophosphamide is followed by an alterna-tive immunosuppressive. These initiatives have chal-lenged the previously recognised ‘standard of care’ of

long-term IVC developed by the National Institutes ofHealth.1,2

Replacement of cyclophosphamide by either aza-thioprine or MMF at 6 months was successful in asmall study by Contreras, et al. – the Eurolupus trialused azathioprine as the maintenance agent in its ini-tial study. Direct comparison of azathioprine andMMF is being evaluated in the ongoingMAINTAINstudy and themaintenance phase of theALMS trial.3,4

However, the attention on the day-to-day manage-ment of lupus nephritis in the clinic has merited lessattention. Few reviews on this subject have been pub-lished, and these have mainly focused on control ofproteinuria, hypertension and hyperlipidaemia.5,6 Inthis article, we aim to address more widely the majorissues which are encountered regularly in the long-term management of these patients. Table 1 sum-marises the major aims of care of lupus nephritis inthe clinic. The overall goal in considering each ofthese targets is the reduction of mortality and preser-vation of renal function.

General principles

Systemic lupus erythematosus requires a multi-disciplinary approach to care and recognition of the

Lupus (2009) 18, 106–115

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Correspondence to: Dr M. Yousuf Karim, Consultant Immunologist,Lupus Research Unit, St Thomas’ Hospital, London, UK.Email: yousuf.karim@royalsurrey.nhs.ukReceived 06 June 2008; accepted 10 June 2008

importance of co-ordinated management throughdiagnosis, remission induction, remission mainte-nance and long-term follow-up. This is particularlytrue of lupus nephritis, where the involvement of anephrologist and the need for early detection ofnephritis is important often before clinical signs ofrenal disease are apparent. Close monitoring of thepatient, with regular out-patient visits, and urine dip-stick testing is vital. This approach is designed to pickup renal flares early, and institute prompt and appro-priate treatment.

The development of ESRD has reduced with theintroduction of immunosuppressive treatment.However, varying degrees of chronic renal impair-ment often develop, and ESRD in approximately10–15% of lupus nephritis patients.7 Assessment bythe nephrologist is important not only in the initialdiagnosis and evaluation of nephritis but also in themanagement of therapy in the context of renal diseaseand, in a minority, the management of chronic renalimpairment, including preparation for transplantationand dialysis.

Risk profiling

A number of studies have identified certain risk fac-tors for the progression of lupus nephritis. These riskfactors include demographic, clinical, laboratory andhistopathological features,8–11 summarised in Table 2.

Dooley, et al.12 reported that the ESRD rate over a5-year period in African-Americans in a study from

the Glomerular Disease Collaborative Network was42%, compared with 5% in white patients. It is, there-fore, important in patients who have high-risk featuresto have a close eye on monitoring and compliance.

In the future, we may need to consider choice ofmedication as part of the risk profiling assessment.There is emerging data on reduced response rate toIVC according to race seen in the recent ALMS induc-tion trial compared withMMF.13 Of 370 patients, 100(27.0%) were reported as ‘other’, mostly comprisingblack (46 patients) and mixed-race (36 patients).Response rates with MMF and IVC were similar forCaucasian and Asian patients, but in the ‘other’ cate-gory, 60.4% responded to MMF and 38.5% to IVC(P = 0.033). The response rates among Hispanicpatients were 60.9% for MMF and 38.8% for IVC(P = 0.011).

Features suggesting good response have beenreported in the Euro-Lupus Nephritis Trial, whichincluded patients with proliferative lupus nephritis,randomised to high- and low-dose cyclophosphamideregimes.14 Multivariate analysis showed that earlyresponse to therapy at 6 months [decrease in serumcreatinine (SCr) level and proteinuria <1 g/24 h] wasthe best predictor of good long-term renal outcome. Inthis study, patients were predominantly Caucasian(14/90 black or Asian), and hence this might not bevalid to extrapolate directly to other races.

Monitoring

Why monitor?

The early recognition of renal flare is important todetect untreated renal inflammation and avoid conse-quent loss of renal function. Relapses are relativelyfrequent and early detection is associated with betteroutcomes. The risk of ESRD is reported to be multi-plied almost sevenfold in patients who experiencerenal flares, and nephritic flares may carry poorprognosis.11,15 Early detection may also impact ontreatment selection. Sensitive disease markers wouldhelp optimise initiation and escalation of therapy atthe time of active or relapsing disease. In the longterm, suchmarkersmay limit the duration of immuno-suppression by improving assessment of renal remis-sion. Reasons for monitoring are summarised inTable 3.

How to monitor?

A variety of techniques exist for the monitoring ofpatients with lupus nephritis. These are summarisedin Table 4.

Table 1 Aims of care in lupus nephritis

• Obtain a complete remission• Maintenance of renal function• Reduction of renal (especially nephritic) flares• Control of proteinuria• Control of blood pressure• Control of vascular risk factors• Identification and treatment of antiphospholipid syndrome nephropathy• Minimisation of treatment-related toxicity• Assessment of infection risk• Bone protection• Role of adjunctive therapies• Assessment and maximisation of compliance• Overall reduction of mortality

Table 2 Risk factors for the progression of lupus nephritis

• Racial origin – Afro-Caribbean• Socio-economic status• Delay between onset of nephritis and renal biopsy• Elevated serum creatinine• Renal (especially nephritic) flares• Failure to achieve remission• Histological features – extensive cellular crescents, moderate-to-severeinterstitial fibrosis, high chronicity index

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Urine dipstick testing and urine cytologySimple urine dipstick testing in the clinic is useful toperform at each clinic visit. This can semi-quantitatively detect haematuria, proteinuria, pyuria,nitrite and glucose. Positive findings can prompt therequesting of further specific testing, such as urinecytology, urine protein quantification, urine cultureand testing for diabetes (often steroid related).

Urine cytology (urinary sediment testing) canreveal the presence of dysmorphic red blood cells,and red cell casts associated with glomerulonephritis.Detection of isolated leucocytes may suggest inter-stitial nephritis or urinary tract infection. Urinecytology may also rarely identify clues to bladdermalignancy in patients, who have been treated withcyclophosphamide.

Hebert, et al.16 reported on the use of urinary sedi-ment testing in prediction of renal flare. 17 patientswith class IV lupus nephritis were followed pros-pectively for 1129 patient-months. Semiquantitativeurinalyses were performed at 2-month intervals duringperiods of low grade or absent SLE activity and morefrequently during periods of increased SLE activity.They performed 877 semiquantitative urinalyses, and43 renal relapses were observed in 14 patients (noflares in three patients). Red blood cell and/or whitecell casts (cellular casts) were observed before or at theonset of 35 of the 43 renal relapses (sensitivity, 81%).The mean and median intervals between appearanceof cellular casts and onset of renal relapse were 10 ±2 weeks and 8 weeks respectively.

Assessment of renal functionMeasurement of SCr, while a useful test, has manylimitations which must be considered. Progressive glo-merular injury may not initially lead to a rise in theSCr due to compensatory hypertrophy and hyperfil-tration in normal or less-affected nephrons. It is esti-

mated for the SCr to rise above the normal range thatrenal function may diminish by 50%. Normal rangesfor SCr vary according to age, sex and race. This isimportant to note as lupus is nine timesmore commonin women, and lupus nephritis is more common inpatients of Afro-Carribean origin and Chinese origin,who have very different normal ranges for SCr.

A 24-h urine collection to determine the creatinineclearance (CrCl) is a widely used method for assess-ment of glomerular filtration rate (GFR) as it is moreaccurate than SCr alone. However 24-h urine collec-tion is time consuming, inconvenient and difficult toperform. Patients often over- or under-collect urineleading to inaccurate results. It may be that tubularcreatinine secretion is significantly elevated in patientswith nephrotic syndrome, leading to a less accuratemeasurement.17

Glomerular filtration rate estimating equations(eGFR) improve upon SCr alone by incorporatingknown demographic and clinical variables asobserved surrogates for the unmeasured physiologicalfactors other than GFR that affect SCr concentration.Examples include the Cockcroft-Gault (CG) equa-tion, the Modification of Diet in Renal Disease(MDRD) study equation or the abbreviated MDRD(aMDRD) study equation. Kasitanon, et al.18 com-pared performance of CG and MDRD equations in97 lupus nephritis patients in the Hopkins LupusCohort. They found that CG was more precise andmore accurate than the MDRD, whereas Leung,et al.,19 based in Hong Kong, found MDRD andaMDRD to be superior than CG. In our unit, wemeasure the nuclear medicine GFR in patients withSCr in the middle or upper normal range every1–2 years, using chromium-51 ethylenediamine tetra-acetic acid (EDTA-GFR). Godfrey, et al.20 foundthat EDTA-GFR was a more sensitive tool in detect-ing mild renal impairment in lupus nephritis, com-pared with calculated CrCl (CG formula).

Estimation of proteinuriaProteinuria is an important marker of renal involve-ment in SLE, useful in diagnosis and in monitoring.Various techniques exist, including qualitative urinedipstick, 24-h urine collection, and more recently,spot urinary protein-creatinine ratio. The validity ofqualitative urine dipstick vs. quantitative 24-h mea-surement of urinary protein/creatinine (P/C) ratio wasassessed by Siedner, et al.21 They assessed three urinedipstick assays with varying results. None of theassays showed both high sensitivity and specificity.While the Atlas assay showed high sensitivity(97.7%) in detecting proteinuria (≥0.5 g), it had alow specificity in excluding proteinuria (62.2%). The

Table 3 Why monitor in patients with lupus nephritis?

• Detection of renal remission in lupus nephritis• Early detection of renal flare in known lupus nephritis• Distinction between flare and chronic damage• Assistance in assessing likely duration of immunosuppression• Assessment of extra-renal SLE• Detection of treatment-related toxicity

Table 4 Methods of monitoring in lupus nephritis

Urinalysis and microscopy: dipstick, urine cytology (sediment)Renal function: serum creatinine, eGFR, isotopic GFRProteinuria: spot urine protein-creatinine ratio, 24-h urine proteinAutoimmune serology: anti-dsDNA antibodies, anti-C1q antibodies, C3, C4Repeat renal biopsy: Histological class, AI, CI, changes of APSNNovel urine markers: MCP-1, TWEAK, lipocalin-2, proteomics, urine C3d

Abbreviations: AI: activity index; CI: chronicity index.

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Clinitek assay showed the highest specificity (86.1%)in correctly excluding proteinuria <0.5 g.

The convenience of spot urinary protein-creatinineratio has lead many units to adopt this technique inpreference to 24-h collections. The evidence for thiscomes from general nephrology clinics, and there issome data in SLE. Lane et al. studied patients in ageneral nephrology clinic and reported a logarithmicrelationship between spot urinary P/C ratio and 24-hurine protein excretion with a correlation of 0.92(P < 0.0001). However, agreement between the actualand predicted 24 h urine protein and between spot and24 h urine P/C ratios was suboptimal at higher levelsof protein excretion.22 Leung, et al.,23 studying 165urinary samples in lupus nephritis, considered thespot urine P/C ratio to be useful in screening andmonitoring proteinuria. They also added the caveatthat this measuremight not be so reliable at high levelsof protein excretion. Birmingham, et al.24 reportedthat spot and 24-h urine P/C ratios in lupus nephritisshowed good correlation over a range of values as wellas reasonably strong concordance. However, over therange of most SLE glomerulonephritis flares, correla-tion was present but concordance was poor.

While one could advocate 24-h collection to con-firm the results of patients who have elevated spoturine P/C ratio, the performance of the latter aloneseems adequate. Ideally, further validation of the rou-tine use of the spot urine P/C ratio should be under-taken in lupus nephritis, particularly in prospectivelongitudinal studies. To deal with the issue of poorerconcordance at high levels of proteinuria, one couldrequest 24-h collection in this subgroup. The counterargument is that at high levels of protein excretion, itmay not be clinically essential to know the exactamount of proteinuria.

Autoimmune serologyAnti-dsDNA antibodies are more common in patientswith lupus nephritis compared with non-renal lupus,but they are not specific for active renal disease. Sev-eral studies show the relationship of anti-dsDNA anti-bodies with SLE disease activity (reviewed in ter Borg,et al.25). In a meta-analysis, the mean positive likeli-hood ratio of anti-dsDNA antibodies as a marker oflupus activity was 4.14, indicative of low overall pre-dictive value.26 We agree with Fernando and Isen-berg,27 who recommend increased vigilance of flaredevelopment in patients with rising anti-bodies todsDNA, especially together with reducing C3 levels.

Anti-C1q antibodies seem to be more frequent inactive lupus nephritis. Marto, et al.28 showed higherprevalence of anti-C1q antibodies in active lupusnephritis compared with non-renal SLE (74% vs. 32%,P < 0.0001), but no significant difference in anti-C1q

prevalence between active and non-active nephritis(74% vs. 53%, P = 0.06). Patients with nephritis hadhigher anti-C1q levels than those without nephritis(P < 0.001). Sinico, et al.29 also showed that anti-C1q antibodies were more common in SLE withnephritis compared with non-renal SLE (60% vs. 14%,P < 0.05). However, they found that higher titres werepresent in active compared with inactive nephritis(89% vs. 0%).

Trendelenburg, et al.30 reported anti-C1q antibo-dies in 97.2% of patients with proliferative nephritis,35% with inactive nephritis and 25% of non-renallupus patients. Moroni, et al.31 showed nti-C1q anti-bodies correlated with renal disease activity (sensitiv-ity 87%, specificity 92%), better than anti-dsDNA,anti-endothelial cell and antiphospholipid antibody–binding levels.

Estimation of complement components C3 and C4does not directly reflect disease activity as their serumlevels merely express the balance between synthesisand catabolism. Nevertheless measurement of C3and C4 is a useful parameter to monitor,27 oftenreducing with the onset of increased disease activity,including nephritis.Measurement of complement deg-radation products is not routinely available, but couldoffer a more accurate measure of complement activa-tion. Negi, et al.32 reported serum C3d to be compa-rable in patients with active renal and extra-renalSLE. However, urine C3d was highest in activelupus nephritis compared with patients with activeextra-renal disease and inactive renal disease.

Repeat renal biopsyRenal biopsy is the gold standard in baseline assess-ment of renal disease, byproviding important informa-tion regarding the examination of morphology andinflammatory cell infiltration. However, as biopsy isinvasive and associated with a significant risk, particu-larly in patients with associated antiphospholipid anti-bodies (aPL)/antiphospholipid syndrome (APS) whomay be anticoagulated,33 the use of noninvasive mea-sures to assess activity of nephritis is desirable. Never-theless, there are situations in which re-evaluation ofrenal histology is desirable, for example in the presenceof fallingGFR.Moroni, et al.34 considered indicationsfor repeat biopsy in three categories: improvement ofrenal disease, but persistence of non-nephrotic protein-uria; persistent or relapsing nephrotic syndrome andincrease in plasma creatinine level of at least 50% com-pared with basal value. Bajaj, et al.35 reported thatresults of repeat biopsy frequently showed changes inhistological class, although changes were often withina class. Changes between proliferative and non-proliferative classes were less common. In our experi-ence, most patients who had a repeat renal biopsy

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underwent a treatment change (submitted for publica-tion).Repeat renal biopsy has also been used followinginduction therapy to evaluate the response of histolog-ical activity and the progression of renal fibrosis. Thesestudies have demonstrated ongoing histological activ-ity despite normal urine analysis.

Novel urinary markersThe urine is an obvious potential source to study mar-kers of active renal inflammation. Various biomarkershave been studied to date. Urinary monocyte che-moattractant protein-1 (MCP-1) has been shown tobe a useful correlate of lupus renal flare,37,38 withlevels increasing 2–4 months before a flare. UrinaryMCP-1 levels reduced in responders to treatment,but persisted in non-responders. The TNF superfam-ily cytokine TNF-related weak inducer of apoptosis(TWEAK) regulates secretion of MCP-1, Interferon-gamma-inducible 10 kD protein (IP-10) and regulatedon activation, normal T expressed and secreted(RANTES), also known as CCL5. Schwartz, et al.39showed that urinary TWEAK levels were higher inactive nephritis and correlated with the renal SLEdisease activity index.

Urinary lipocalin-2 levels have been found to besignificantly higher in those with lupus nephritisthose without nephritis. The presence of lipocalin-2in the urine of patients with lupus nephritis correlatedsignificantly with the renal SLEDAI score (r = 0.452,P = 0.009), but not with extrarenal disease activity.40Mosley, et al.41 used surface enhanced laser desorp-tion/ionisation time-of-flight spectrometry to studyurine proteomics in patients with lupus nephritis.Discriminant function analysis was used to defineminimum number of proteins whose levels best distin-guished between the two groups. Proteins with massesof 3340 and 3980 distinguished active from inactivelupus nephritis with 92% sensitivity and 92%specificity.

Control of proteinuria

Proteinuria has been identified as both an importantrisk factor and a mechanism for the progression ofrenal disease.5,42 Studies in this area with respect tolupus nephritis are limited, and the approach hasbeen largely to extrapolate from the data on chronicrenal impairment and from diabetic nephropathy.5,6,43

The renoprotective effects of ACE-inhibitors(ACE-I) and angiotensin receptor blockers (ARB)have been reviewed elsewhere.44 Briefly, ACE-I andARB can be used as antiproteinuric agents withoutnecessarily inducing a change in blood pressure.

Both agents have been shown to decrease progressionto ESRD in patients with non-diabetic and diabeticchronic renal impairment.43,45 It may be that combi-nation therapy with ACE-I and ARB is more effectivein reduction of proteinuria than the use of either agentalone.46,47

Tse, et al.48 reported a retrospective study of effectsof ACE-I/ARB in lupus nephritis with persistentproteinuria >1 g despite resolution of active nephritiswith immunosuppressive treatment. Fourteen outof 92 patients were included. Patients with systolicblood pressure >150 or diastolic >100 mmHg wereexcluded. Patients were started on ACE or ARB andfollow-up was 52 ± 35.7 months. Proteinuria andserum albuimn were significantly improved at 6 and24 months of treatment. Systolic blood pressure wassignificantly reduced from 6 months onwards, but thisdid not correlate with proteinuria reduction.

Kanda, et al.49 retrospectively studied the use ofARB for 6 months in lupus nephritis patients, whoremained proteinuric despite treatment with steroidsand/or immunosuppression. Median proteinuriareduced from 2530 mg/g creatinine to 459 mg/g creat-inine (P = 0.030), reducing in 83% of patients. As withTse, et al.,48 the antiproteinuric efficacy did not corre-late with reduction of blood pressure.

These small studies together with the large studiesin chronic renal impairment and diabetic nephropathysuggest that treatment with ACE-I/ARB could reduceproteinuria in patients with lupus nephritis. However,long-term prospective studies are needed to investigatethe effect of these drugs on renal preservation in lupusnephritis.

In an interesting recent publication from the multi-ethnic LUMINA lupus cohort in North America, itwas reported that ACE-I use delayed the occurrenceof nephritis.50 Eighty of 378 patients (21%) wereACE-I users. The probability of renal involvementfree-survival at 10 years was 88.1% for ACE-I usersand 75.4% for non-users (P = 0.0099, log-rank test).Users of ACE-I developed persistent proteinuriaand/or biopsy-proven lupus nephritis (7.1%) less fre-quently than non-users (22.9%, P = 0.016). ACE-I usewas associated with a longer time-to-renal involve-ment occurrence, whereas African-American ethnicitywas with a shorter time. ACE inhibitor use (54/288case and 254/1148 control intervals) was also associ-ated with a decreased risk of SLE disease activity(HR 0.56; 95% CI 0.34, 0.94).

Blood pressure control

It is important to control blood pressure both forreducing the progression of renal disease, but also

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for the reduction in vascular risk in these patients. Theagent of choice ideally would be an ACE-inhibitor oran ARB drug as this would have the combined effectof reduction in proteinuria, renal protection, andblood pressure reduction.

Combinations of more than one drug may berequired to achieve satisfactory blood pressure reduc-tion. Diuretics and calcium-channel antagonists areamong the other possible agents.5

In terms of target blood pressure in lupus nephritis,a stricter figure of <130/80 mmHg is desirable. Wehave extrapolated this figure from guidelines formanagement of hypertension in diabetes given itsincreased vascular risk, and from guidelines forchronic renal impairment.44,51 A target figure of125/75 mmHg has been proposed in general forpatients with renal impairment with proteinuria>1 g/day.

A recent meta-analysis has shown that blockade ofthe renin-angiotensin system in patients with chronicrenal impairment of all causes decreased the risk forcardiovascular outcomes and heart failure comparedwith control therapy in patients with proteinuria.52

One caveat, regarding use of ACE-I which may beimportant in lupus with associated APS, is that therisk of renal artery stenosis is increased in thisgroup.53 It may be useful to consider magnetic reso-nance angiography of the renal arteries in SLEpatients with resistant hypertension and APS.

Vascular risk and hyperlipidaemia

It is well known that patients with SLE have anincreased vascular risk.54 This would most likely befurther increased in lupus nephritis, as these patientsmay be hypertensive, and have hyperlipidaemiarelated to steroids, nephrotic syndrome and chronicrenal impairment. Abnormal lipid profile has beenreported in SLE, and lipoprotein (a) has been reportedto elevated in lupus nephritis.55,56 It is, therefore, criti-cal to address classical risk factors to include smoking,blood pressure, glycaemic control and lipid levels.

To draw a parallel with diabetes, the impact oftight control of risk factors was shown by Gaede,et al.,57 who showed tight glucose regulation and useof renin–angiotensin system blockers, aspirin, andlipid-lowering agents reduced the risk of nonfatalcardiovascular disease in patients with type 2 diabetesmellitus and microalbuminuria. Although, not all riskfactors have been identified as yet for the increasedvascular disease in lupus, it is clear that some of thetraditional Framingham risk factors are important,and hence merit close control. Bruce55 suggested

that the increased vascular risk in SLE was notaccounted for by classical risk factors alone. It mayalso be that close control of lupus itself could contrib-ute by decreasing systemic inflammation which mayincrease vascular risk.

For SLE, as with most other causes of hyperlipi-daemia, the drug of choice would be a statin.58 Thepatient should be advised of the risk of statin-associated myositis. Care with fibrates is necessaryin chronic kidney disease, because of increased riskof a myositis-like syndrome, and risk of increase inSCr. The combination of a fibrate with a statinincreases the risk of muscle effects (especiallyrhabdomyolysis).

It has been clearly shown that statins have signifi-cant effects on reduction in morbidity in cardiovascu-lar disease, and theremay be some additional effect onrenal disease. A meta-analysis from 2006 suggestedthat statin therapy reduced proteinuria modestly,with a small reduction in the rate of kidney functionloss, especially in populations with cardiovasculardisease.59 However, a more recent meta-analysisfrom 2008 suggested reno-protective effects of statinswere uncertain due to lack of data and possible out-comes reporting bias.60 Currently, the LORD trial61 isa randomised double-blind placebo controlled trialassessing the effect of atorvastatin on the progressionof kidney disease.50

Infection risk and vaccination

Understandably, much of the attention in SLErecently has focused on the increased vascular risk inthese patients. However, though this is responsible fora high proportion of late mortality, early mortalityoften relates to either overwhelming lupus activity orsevere infections.62 It is, therefore, important to takean infection history to assess the nature of previousinfections, the patient has experienced. Infectionsmay relate to immunosuppressive therapy or to anumber of immune defects associated with SLE.Such defects include congenital or acquired immuno-globulin deficiency, complement deficiency, mannose-binding lectin deficiency, impaired splenic functionand an increased risk of salmonella infections.63,64 Itis likely that further predisposing factors for infectionin lupus will be identified in the future.

The issue of vaccination is important as this mayhelp to reduce the risk of infection. However, it is alsorecognised that vaccinations in some instances cantrigger lupus flares. It may be that the risk mightvary with the nature of the vaccine, being highestwith live vaccines. We adopt an approach based on

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the individual patient, assessing both the infection riskand whether the disease has previously flared withvaccinations. Our general advice is that pneumovaxand influenza vaccination would be reasonable, asthese are subunit and inactivated vaccines respec-tively. Live vaccines would be contraindicated in anypatients on immunosuppressive medication, or highdoses of corticosteroids. We would refer readers to areview on the subject by O’Neill and Isenberg.65

Antiphospholipid antibodies

It is increasingly recognised that aPL can affect thekidney. There is evidence that aPL can affect both themicro- and macro-vascular circulations of the kidney.Associations have been reported with renal artery ste-nosis and renal artery thrombosis.53,66 Microvasculardisease, particularly renal thrombotic microangiopa-thy (TMA), and glomerulopathy may be seen. Theterm APS nephropathy has been coined to describerenal TMA, and other suggestive renal histologicalappearances, listed in Table 5.67 APS nephropathycan occur in primary and in secondary APS, such asin patients with lupus nephritis. However, APSnephropathy is not yet considered a clinical criterionfor APS.67

The presence of aPLmay adversely affect outcome,although this has not been found in all studies. Mor-oni et al.68 reported an association between aPL anddevelopment of chronic renal impairment. Tektoni-dou, et al.69 reported that patients with APS nephrop-athy had a higher frequency of hypertension andraised SCr levels at renal biopsy, but no higher ratesof renal impairment, ESRD or death during follow-up. These effects on renal function may relate to aneffect on the renal microcirculation. It is, therefore,important to test patients with lupus nephritis for thepresence of aPL, and to examine the renal biopsyclosely for any evidence of APS nephropathy. There

is a lack of any controlled data for treatment of APSnephropathy, and evidence is mainly based from casereports where patients have been treated with antic-oagulation, or with aspirin and ACE-inhibition(reviewed in Karim, et al.70). Post-transplant renalthrombosis has been reported with aPL,71 which is,therefore, important to check prior to transplantationin lupus nephritis.

Bone protection

Patients with lupus nephritis will undoubtedly bereceiving or have received corticosteroids with conse-quent impact on calcium absorption in the bowel, andon bone metabolism. It is essential, therefore, that allsuch patients, who have no contraindication, receivecalcium supplementation usually in the form of cal-cium together with vitamin D. This is also importantas deficiency of vitamin D is common in SLE.72

It is important to recognise that compliance of cal-cium/vitamin D supplementation is poor as patientsdo not like the chalky taste. In this event, effervescentcalcium/vitamin D can be tried and if this also is nottolerated, then the next step could be vitamin D injec-tions. It is advisable to ensure calcium and vitamin Dintake and compliance is adequate when consideringany further levels of osteoporosis prophylaxis. The useof a bisphosphonate for corticosteroid osteoporosisprophylaxis would be encouraged in high risk patients,or in patientswhohave completed their family. Studiesof bisphosphonates in osteoporosis have used concom-itant calcium/vitamin D supplementation, and theimpact of suboptimal vitamin D levels on efficacy ofbisphosphonates is not clear.73 Regular assessment ofthe bone mineral density on a 2–3 yearly basis isrecommended.

In patients with significant reduction in GFR, theremay be also contribution from secondary hyper-parathyroidism and consequent renal osteodystrophy.Management would include the use of phosphate bin-ders, and calcitriol to suppress PTH secretion, in achronic kidney disease clinic.

Compliance and polypharmacy

Polypharmacy

With the increasing sophistication of management,this invariably results in a longer list of medicationsfor patients. This increases the risk of drug interaction,especially in patients with APS who are receiving oralanticoagulation. We do know that patient adherenceto prescribed medication is not perfect.74 It is likely

Table 5 Proposed features of APS nephropathy67

• Thrombotic microangiopathy involving both arterioles and glomerularcapillaries

and/or one or more of:• Fibrous intimal hyperplasia involving organised thrombi with or withoutrecanalisation

• Fibrous and/or fibrocellular occlusions of arteries and arterioles• Focal cortical atrophy• Tubular thyroidisation (large zones of atrophic tubules containingeosinophilic casts)

Vasculitis, thrombotic thrombocytopenic purpura, haemolytic uraemicsyndrome, malignant hypertension, and other reasons for chronic renalischaemia were excluded. The authors also note that if SLE is also present,the above lesions should be distinguished from those associated with lupusnephropathy.67

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that as the list of medications increases that the degreeof compliance may reduce. It may be that patient willnot end up taking the most important medicationsfrom their list. There are particular drugs wherethere is known to be poor compliance, e.g. calciumsupplementation.

Therefore, it is important to assess compliance andto reiterate the importance of the medication and tostress the reasons for the different medications. Inimportant situations, the use of intravenous medica-tion may ensure delivery of the drug to the patientwhere compliance otherwise might be poor, e.g. useof IVC for remission induction.

Patient choice

Patient choice is likely to impact on the choice of drugprescribed with the introduction of MMF and lowdose cyclophosphamide. A major demographic pop-ulation in SLE consists of women of child bearingage. Low dose cyclophosphamide has low incidenceof ovarian toxicity.1 MMF has no ovarian toxicity,although must be discontinued before pregnancy.75,76

Adjunctive therapies – antimalarials

Further medications may be identified which contrib-ute to the patient’s prognosis, although this may addfurther to the patient’s prescription.Most recently, theuse of antimalarials has been reviewed. It has beenshown that such therapy may influence mortalityrate in SLE. Sisó, et al.77 studied the effect of exposureto antimalarial drugs at diagnosis of lupus nephritis onthe outcome of disease in a cohort of 206 consecutivepatients with lupus nephritis. They showed that expo-sure to antimalarials before the diagnosis of lupusnephritis was negatively associated with the develop-ment of renal failure, hypertension, thrombosis andinfection, and with a better survival rate at the endof the follow-up. Withdrawal of antimalarialsincreases the risk of flare in lupus nephritis.

There has been a revival in the use of antimalarialsin SLE, and we would recommend continuing ratherthan stopping these drugs in patients who developnephritis. It is important to focus on overall mortality,as well as renal survival. The data with antimalarials isinteresting when one considers that cyclophospha-mide has been reported not to influence overall mor-tality. Flanc, et al.78 reported in a meta-analysis thatcyclophosphamide plus steroids reduced the risk fordoubling of SCr level (four RCTs, 228 patients; RR0.59; 95% CI 0.40–0.88) compared with steroidsalone, but had no impact on overall mortality (fiveRCTs, 226 patients; RR 0.98; 95% CI 0.53–1.82).

Kasitanon, et al.79 reported that patients withmembranous lupus nephritis treated with hydroxy-chloroquine did better: 7/11 (64%) were in remissionwithin 12 months compared with 4/18 (22%) of thosenot on hydroxychloroquine (P = 0.036 based on a log-rank test).

Summary

Management of lupus nephritis in the clinic in themodern era goes beyond selection of immunosuppres-sive therapies for induction andmaintenance of remis-sion. It is important to consider the patient as a whole,focusing on strategies to reduce progression of renaldisease, development of vascular disease, miminisa-tion of side effects of therapy. We must rememberthat patients may not share our enthusiasm for start-ing medication for the various aspects of their disease.Taking time to explain the rationale for the pills weprescribe may be an essential part of management.

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