diagnosis and treatment of kidney disease

Best Practice & Research Clinical RheumatologyVol. 19, No. 5, pp. 785–798, 2005

6

Diagnosis and treatment of kidney disease

Jane Cross Msc, MRCP

Renal Registrar

David Jayne* MD, FRCP

Consultant, Vasculitis and Lupus Clinic

Addenbrookes Hospital, Box 118, Cambridge CA2 2QQ, UK

Lupus nephritis remains a strong predictor for death and the development of end-stage renaldisease (ESRD) in patients with SLE. Definition of renal involvement varies but overt renaldisease is found in at least one-third of SLE patients, with up to 60% of adults and 80% ofchildren developing lupus nephritis. Clinical presentation has been found to bear littlerelationship to renal biopsy findings. Renal biopsy is therefore informative for all patientswith SLE with abnormal urinalysis or reduced renal function, even with serum creatinine inthe normal range, to guide treatment decisions. Current treatment regimens combinecorticosteroids with cyclophosphamide, azathioprine or ciclosporin, although mycophenolatemofetil has received much recent attention as a potentially superior immune suppressive.The toxicity of current drug regimens contributes significantly to existing morbidity andmortality. A new era of biological therapies holds the potential for safer, more effectivetherapies in the future.

Key words: classification; lupus nephritis; mycophenolate mofetil; renal biopsy; treatment.

Most patients with SLE do not present initially with renal disease1; only 25% of patientshave this as their initial presenting feature. In 5% of these cases, usually men older than40 years, it can be several years before other lupus criteria or serological abnormalitiesdevelop.

doi:10.1016/j.berh.2005.05.005available online at http://www.sciencedirect.com

1521-6942/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: C44 1223 217259; Fax: C44 1223 586 506.

E-mail address: [email protected] (D. Jayne).

http://www.sciencedirect.com

786 J. Cross and D. Jayne

ASSESSEMENT OF RENAL DISEASE

Assessment of urine and renal function

Urinary abnormalities of microscopic haematuria, proteinuria or pyuria (persistentwhite cells not due to infection) are usually the first clinical indication of nephritis. It isessential that all patients with known SLE have regular urinalysis, even when extra-renaldisease is thought to be controlled or minimal.

Normal-range serum creatinine does not indicate normal renal function,particularly in patients with SLE, and calculation of creatinine clearance is advised.Creatinine clearance can be estimated from a measured 24-hour urine collectionand concomitant serum creatinine measurement, but the method is inaccurate,even with carefully collected samples. The Cr-EDTA remains the gold standard forassessment of renal excretory function but is impractical for regular frequentmonitoring. Newer methods such as measurement of serum cystatin C are beingintroduced and have been found to be a more sensitive marker for changes inglomerular filtration rate (GFR) than serum creatinine.2 The derived Cockcroft–Gault formula remains a rapid way to estimate a patient’s creatinine clearance. Asthis method requires just serum creatinine, height, weight and age to be available,creatinine clearance can be calculated immediately in the clinic setting.3 There arelimitations to this formula, particularly in severely nephrotic patients, in whom anestimated weight without oedema fluid should be used.

Cockcroft–Gault formula

In men:

Creatinine clearance Zð140 KageÞ!weight ðin kgÞ

ð72!serum creatinineÞ

In women:

Creatinine clearance Zð140 KageÞ!weight ðin kgÞ

ð72!serum creatinineÞ!0:85

The Cockcroft–Gault formula can overestimate GFR, particularly in patients withimpaired renal function. In these patients the MDRD equation, which was derived fromthe Modification of Diet in Renal Disease Study Group data, is recommended.4 Theadvantages of this method are that no weight and height measurements are requiredbut that ethnicity, which is an important factor in the development of end-stage renaldisease (ESRD), is taken into account. In patients with scleroderma, with impaired renalfunction, the MDRD equation has been found to correlate more closely with measuredGFR.5

MDRD KGFRðml=min=1:73 m2Þ Z 170!½PCr�K0:999 !½age�K0:176

!½0:762 if patient is female�!½1:180 if patient is black�!½SUN�K0:170 !½Alb�0:318

In this formula, PCr, serum creatinine concentration (mg/dl) (alkaline picratemethod); SUN, serum urea nitrogen concentration (mg/dl) (urease method); Alb,serum albumin concentration (g/dl) (bromocresol green method).

Diagnosis and treatment of kidney disease 787

Ideally, both the Cockcroft–Gault and the MDRD equations should be calculated. Anumber of automatic calculators are freely available online.

Measurement of urinary protein loss can be estimated by a 24-hour collection buturinary protein to creatinine ratios have been found to be as accurate as 24-hourcollection in patients with lupus nephritis.6

Lupus nephritis less commonly presents with acute renal failure. Other severemanifestations of lupus, such as myocarditis and cerebritis, might also be present.The wide range of presentations bears little relationship to renal biopsy findingsand it is recommended that all patients with abnormal urinalysis or with reducedrenal function have a renal biopsy performed to assess the nature of involvementmore closely.

Assessment by renal biopsy

Renal biopsies have some limitations as only a very small sample of tissue is obtainedand lupus nephritis, like many glomerulonephritides, does not affect the kidneyuniformly. However, biopsy provides significantly greater information than urinalysisand serum creatinine alone.

Classification of lupus nephritis

Different classification systems for lupus nephritis have been suggested but the WHOclassification, published in 1982 and subsequently revised in 1995, has in the past beenthe most widely used. The WHO system classifies glomerular involvement according tothe extent and pattern of immune deposits and inflammation, which are detected byimmunohistochemistry on light microscopy. The finding of positive staining forimmunoglobulin (Ig) G, IgM and IgA, together with staining for C1q, C3 and C4, isknown as ‘full house’ and is present in up to 25% of patients with lupus nephritis andalmost never in patients with non-lupus disease.

The WHO system does not assess glomerular activity, involvement of the renaltubules, blood vessels or chronicity of interstitial damage. The limitations of theWHO system have led to modifications recently being suggested by theInternational Society of Nephrology/Renal Pathology Society (ISN/RPS).7 Thisnewer classification incorporates definitions of biopsy activity and chronicity andencourages the separate additional reporting of significant vascular and tubulo-interstitial pathology. As with the WHO system, it is based on glomerularpathology but differs in that class I disease now denotes minimal mesangial lupusnephritis. The ISN/RPS classification is summarised in Table 1. These modificationsshould provide better standardisation for future studies and ensure improvedreproducibility between centres. The classification is now being used in ongoingstudies and trials worldwide. We would recommend that this system is now usedto report renal biopsies.

These classification systems do not quantify the extent of chronicity or damage.Howie et al developed a morphometric index that assesses chronic damage in lupusnephritis biopsies. They have found that this index predicts time to renal failure anddeath (P!0.001) but not death before dialysis; these findings are independent of WHOclassification.8

Table 1. International society of nephrology/renal pathology society classification of lupus nephritis

(2003) (from Ref. 7).

Class Description

Class I Minimal mesangial lupus nephritis

Normal at light microscopy

Mesangial deposits on immunofluorescence

Class II Mesangial proliferative lupus nephritis

Mesangial hypercellularity or expansion with mesangial immune deposits

Some subepithelial or subendothelial deposits on immunofluorescence by electron

microscopy

Class III Focal lupus nephritis

Involves !50% glomeruli. Active or inactive lesions typically with subendothelial deposits

A: Active lesions; focal proliferative lupus nephritis

A/C: Active and chronic lesions; focal proliferative and sclerosing lupus nephritis

C: Chronic inactive lesions with glomerular scars; focal sclerosing lupus nephritis

Class IV Diffuse lupus nephritis

Involves O50% glomeruli. Active or inactive diffuse, segmental or global endo- or

extracapillary glomerulomephritis. Typically with subendothelial deposits. Divided into

diffuse segmental (S) when O50% of involved glomeruli have segmental lesions and diffuse

global when O50% of involved glomeruli have global lesions

S(A): Active lesions; diffuse segmental proliferative lupus nephritis

G(A): Active lesions; diffuse global proliferative lupus nephritis

S(A/C): Active and chronic lesions; diffuse segmental proliferative and sclerosing lupus

nephritis

G(A/C): Active and chronic lesions; diffuse global proliferative and sclerosing lupus nephritis

S(C): Chronic inactive lesions with scars; diffuse segmental sclerosing lupus nephritis

G(C): Chronic inactive lesions with scars; diffuse global sclerosing lupus nephritis

Class V Membranous lupus nephritis

Global or segmental subepithelial immune deposits by light microscopy and immuno-

fluorescence or electron microscopy, with or without mesangial changes

Class V lupus nephritis can occur in combination with class III or class IV disease in which

case both are diagnosed

Class V disease can show advanced sclerosis

Class VI Advanced sclerosis lupus nephritis

O90% of glomeruli globally sclerosed without residual activity


Repeat renal biopsy

Repeat biopsy at times of deteriorating renal function, new microscopic haematuria orproteinuria provides useful information and can be useful in helping to determine renalprognosis.9 It can help:

† to confirm the presence of a clinically suspected renal flare† in the assessment of chronic damage and progression† in guidance of treatment duration, and to assess whether proteinuria is due to

ongoing disease activity or chronic damage.

Assessment of resolution of previous activity and lack of progression of chronicdamage all provide useful data for monitoring the effectiveness of drug therapy. WHOclass switching is well documented.


The limitations of the WHO system and the need for the newer modifications ishighlighted by the differing prognostic data that have been generated from previousstudies correlating WHO class with long-term outcome, especially with class Vdisease.10,11 Universal use of the ISN/RPS classification of lupus nephritis will lead toimprovement in comparability of data generated in trials.

PROGNOSIS

The natural outcome of lupus nephritis is difficult to predict because many patients willhave already received corticosteroids or other immunosuppressants. Long-termfollow-up studies have demonstrated that, with treatment, patient survival is 72% at 10years and 61% at 20 years, this compares with 5-year survival rates of 17% in the 1950sof patients with class IV disease.12 Preservation of renal function is less encouraging,with reports of 5-year renal survival with treatment of 46–95%.13 Retrospective studieshave suggested prognostic factors at disease presentation to identify those patients atrisk of development of ESRD. These factors can be divided into renal or non-renal.

Non-renal factors

These include male sex and concomitant haematological features of SLE, such asthrombocytopenia and leucopenia.13 Younger age at diagnosis of renal disease predictsmortality, with male patients over 25 years of age and female patients under 25 yearshaving a decreased overall survival rate.14 Persistent hypocomplementaemia and raisedanti-dsDNA antibodies after treatment have been found to predict renal relapse.15

Antiphospholipid antibodies have been found to be strongly associated (PZ0.01) withthe development of chronic renal disease.16 African–American and Hispanic patientshave a worse outcome for ESRD. Poorer socioeconomic background, independent ofother factors, is associated with a worse prognosis.17

Renal factors at presentation

Abnormal renal function at presentation is associated with a worse prognosis. Delaybetween the detection of renal disease and time to first renal biopsy significantlypredicts renal failure and death from renal disease. This is likely to be due to the delay instarting immunosuppressive therapy.18,19 Long-term follow-up is required to assessrenal outcome accurately, although most patients who subsequently develop ESRD doso within 10 years of initial renal presentation.12

Renal response during treatment

Response to treatment has been found to be an important predictor of outcome.Failure to achieve clinical remission of lupus nephritis is associated with a worse long-term renal survival. A 10-year follow-up of patients with proliferative lupus nephritis,treated with cyclophosphamide, demonstrated a 94% renal survival at 10 years forthose patients who had achieved renal remission, compared with 31% renal survival forthose who had no renal remission.13 Up to 45% of patients are likely to develop renalflares. Those patients who achieve a partial renal remission have more rapid andrecurrent flares than those that fully respond to initial therapy.20 Patients with renal


flares have been found to have a 27 times greater likelihood of doubling of serumcreatinine at 10 years than those patients who do not have flares.21 Type of renal flare isalso important and in those patients with nephritic flares, new haematuria is a predictorof doubling of serum creatinine.21,22 Change in proteinuria after 1 year of treatment hasbeen found to be a statistically significant predictor of development of renal failure (PZ0.001) and death (PZ0.001).23

These findings, and the data demonstrating the effect of delaying renal biopsy,support the early use of immunosuppressives to induce renal remission. Those patientswho achieve only partial renal remission, with grumbling low-grade activity, have aworse renal and overall prognosis.

WHO AND HOW TO TREAT?

WHO class II disease

The outcome of class II disease is good and the majority would suggest initial therapywith a tapering course of steroids.24 No randomised trials are available for thetreatment of class II disease. If clinical markers of renal involvement deteriorate thenescalation of treatment, to include immunosuppressive therapy, would be advised, asoutlined below.

WHO class VI disease

Class VI disease has a uniformly poor prognosis for renal survival, reflecting chronicdamage; immunosuppressive treatment is not recommended. Instead, therapies aimingto optimise blood pressure control and stabilise proteinuria with the use ofantihypertensives, angiotensin converting enzyme inhibitors and angiotensin receptorblockers are used to optimise renal survival.25

WHO class V disease

A main area of contention remains the treatment of class V disease, partly becauseof differences in histological classification.10 Some retrospective data suggest abenign course for the condition. In a study in which pure lupus membranousnephropathy, with no additional features of class III or class IV disease, was treatedwith azathioprine and steroids, there was a 67% complete remission rate at 1 year,with 22% achieving partial remission and 11% being resistant to therapy.26

Mycophenolate mofetil treatment of 13 patients with lupus membranousnephropathy for 6 months obtained complete or partial remission in 77%.27

Methylprednisolone and chlorambucil have also been used as treatment regimensfor membranous nephropathy not associated with lupus disease.28 The presence ofadditional class III or class IV disease implies a more aggressive course and mostwould treat these patients according to regimens for class III or class IV disease.24

This debate will continue until prospective studies over at least a 5- to 10-yeartime span, with standardised reporting of renal biopsies, are performed.


Proliferative lupus nephritis (WHO class III and IV disease)

The need for treatment of class III and class IV disease is less controversial. Therapeuticdecisions in lupus nephritis are based on a limited number of randomised controlledtrials. A recently published 2004 Cochrane systematic review analysed all publishedtherapeutic trials for proliferative lupus nephritis and found that 25 of 920 articles wereeligible for consideration, with a total of 909 patients across all therapeuticcombinations.29 The review found that the use of cyclophosphamide with steroidsreduced the risk of doubling serum creatinine, compared with steroids alone, but hadno impact on overall mortality. The risk of ovarian failure was significantly increasedwith the use of cyclophosphamide. Azathioprine with steroids reduced the risk of deathbut had no effect on renal outcomes compared with steroids alone. As trials from 1971to 2002 were included, interpretation of the review is limited by the variable range ofdrug doses used over this time period. Routine dosages of steroids have beensignificantly reduced during this time. Trials using both oral cyclophosphamide andintravenous cyclophosphamide regimens were pooled, with large variations incumulative doses of cyclophosphamide administered. Despite these provisos, the useof cyclophosphamide with steroids to preserve renal function in patients with diffuse,proliferative, lupus nephritis was recommended.

Long-term treatment with cyclophosphamide for patients with proliferative lupusnephritis is associated with adverse effects, including an increased risk of infection (10–18% per year). Oral cyclophosphamide is associated with an increased risk of herpes of19%, compared with 9% for intravenous cyclophosphamide regimens, and with anincreased risk of ammenorrhoea in 50% compared with 29% for intravenouscyclophosphamide therapy.30 Cumulative doses of cyclophosphamide over 9 g,particularly in women over the age of 32 years, are associated with ovarianfailure.31,32 Reversible alopecia can occur in 20% of patients treated withcyclophosphamide.33 Bladder toxicity (in 14–17%) is well reported particularlywith the older treatment regimes but now occurs less frequently, particularly withthe use of pre-treatment hydration.33,34 The aim of treatment therefore, is to induceand maintain remission of active nephritis with minimum toxicity.

Therapeutic regimens to treat proliferative lupus nephritis can be divided into thosetherapies aiming to induce remission of renal disease and those maintaining the renalremission achieved.

INDUCTION THERAPY

The aim of treatment is to achieve a rapid clinical renal remission, as this is associatedwith an improved long-term renal prognosis.

Cyclophosphamide

Cyclophosphamide, as outlined above, can be used for this phase of treatment. Mostunits now use intravenous regimens because this reduces the cumulative doseadministered. The later lupus nephritis trials at the National Institutes of Health (NIH)used pulsed intravenous cyclophosphamide at 0.5–1 g/m2 given monthly for 6 months,then every 3 months for a further 2 years.35 This regimen was subsequently used bymany for the treatment of active proliferative lupus nephritis. Recently, dosing regimens


have been adjusted by many units with 6–12 months of therapy using 6–8 pulses ofcyclophosphamide now commonly being used, assuming renal remission is achievedduring this time.

In the Euro-Lupus trial of 90 patients, a shorter course of cyclophosphamide therapyof 0.5 g fortnightly for six doses was compared with the 20-month intravenouscyclophosphamide regime. After a median follow-up period of 73 months, no differencewas found between the two groups for the end-points of ESRD or doubling of serumcreatinine. All patients included in this trial had proliferative glomerulonephritis butonly 22% of them presented with renal impairment, and 28% with nephrotic syndrome.Also few Black or Afro-Caribbean patients, whose prognosis is poorer, were included inthe study.36

Cyclophosphamide is an effective induction agent in the majority of cases but 22% ofpatients might have disease refractory to cyclophosphamide.37 Adverse effects ofcyclophosphamide, particularly infertility, are of concern as most patients with lupusnephritis are of child-bearing age. There is, therefore a need for alternative agents fordisease induction or for cases refractory to cyclophosphamide.

Mycophenolate mofetil (MMF)

MMF is an immunosuppressant that is successfully used in solid organ transplantationand has been used to good effect in the treatment of lupus nephritis and other immune-mediated glomerular disorders.38 MMF has been used for induction therapy in newlydiagnosed active lupus nephritis and also for those patients with lupus nephritisrefractory to cyclophosphamide therapy. Prospective trials for remission induction inlupus nephritis are summarised in Table 2.39–46 A large multicentre international trial isdue to start in 2005, which will compare cyclophosphamide with MMF, both withsteroids, in the induction of remission of active lupus nephritis This trial has beenpowered to produce statistically significant data and will have appropriate duration offollow-up of 5–10 years. MMF is teratogenic in animal studies and is thereforecontraindicated during pregnancy but there is no current consensus on preconceptionadvice for women on MMF wanting to become pregnant.

MAINTENANCE THERAPY

The aim of this phase in treatment is to maintain renal remission without compromisingpatient long-term morbidity. Renal flare or relapse is associated with a worse longer-term renal outcome. Optimum duration of maintenance therapy is unclear.

Azathioprine

Azathioprine is most commonly used for maintenance therapy in lupus nephritis. Therecent systematic review found that azathioprine with steroids did not improve renaloutcomes compared with steroids alone in the treatment of diffuse, proliferative, lupusnephritis.29 A prospective trial comparing azathioprine with cyclophosphamide isunderway in the Netherlands.47 A European trial (EULAR) randomised 32 patients withdiffuse, proliferative, lupus nephritis to either pulse intravenous cyclophosphamide withmethylprednisolone for 24 months compared with pulsed intravenous cyclopho-sphamide followed by azathioprine. Two patients in the azathioprine group reached

Table 2. Prospective trials in lupus nephritis using mycophenolate mofetil.

Trial (ref. no.) and no.

patients Treatment regimen Endpoints Adverse effects MMF Follow-up results

Chan et al 2000(39,

40) 51 patients

MMF 2 g/day for 6 months then

1 g/day for 6 months versus oral

CYC (2.5 mg/day) for 6 months

then AZA for 6 months Steroid

doses equal in both limbs

CR: 81% MMF, 76% CYC, PR:

14% MMF, 14% CYC at 12

months

1 GI upset, 11 infection At 3 years: relapse rate: 46%

MMF, 17% CYC, significantly

lower infection rate in MMF

group

Kingdon et al 2001

(41) 13 patients

MMF 1 g/day for 25 months 69% serological improvement,

23% withdrawn, 8% relapse

23% infections

Karim et al 2002 (42)

21 patients

MMF 2 g/day for 14 months Proteinuria decreased (PZ0.02) 2 infections

Li et al 2002 (43) 75

patients

0.5–2 g MMF/day for at least 6

months

Proteinuria decreased at 6

months (P!0.01) improvement

in serum creatinine

16% infection, 10% GI

Appel et al 2003 (44)

140 patients

MMF 1–3 g/day for 6 months

versus, IV CYC 0.5–1 g/m2CR: 22% MMF, 5.8% CYC,

PR: MMFZCYC

GI upset: 20% MMF, 3%CYC,

Infection: MMFZCYC,

3 deaths CYC

Kapitsinou et al 2004

(45) 18 patients

MMF 2 g/dayCsteroids for 15

months

CR: 55%, PR: 22% 11% GI upset, 1 infectious

meningitis

Cross et al 2005 (46)

24 patients

MMF 2 g/day for 12 months CR: 83%, PR: refractory disease

8.5%, withdrawn 21%

10 infections At 35 months: 5% relapse

AZA, azathioprine; CR, complete remission; CYC, cyclophosphamide; GI, gastrointestinal; IV, intravenous; MMF, mycophenolate mofetil; PR, partial remission.

Diagn

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ESRD and required dialysis; none in the pulsed cyclophosphamide group reached thisstage. Three deaths occurred in the continuous cyclophosphamide group and one inthe azathioprine group. No statistically significant differences between the tworegimens were found.48

MMF

Azathioprine has well-documented adverse effects and 10% of patients can produce ahypersensitivity reaction or be intolerant. MMF has therefore been used as analternative maintenance agent. Contreras et al reported a comparison of MMF,azathioprine and pulsed intravenous quarterly cyclophosphamide as maintenancetherapy in proliferative lupus nephritis.49 All 59 patients received monthly pulsedintravenous cyclophosphamide for a maximum of 7 months before being randomised toreceive the maintenance therapies. During treatment, four patients in the cyclopho-sphamide group and one in the MMF group died. ESRD developed in three of thecyclophosphamide group and in one each in the azathioprine and MMF groups.Interestingly, the relapse-free survival was higher in the MMF group than thecyclophosphamide group (PZ0.02) and the number of infections was lower in the MMFand azathioprine groups.49

The European Working Party on Systemic Lupus Erythematosus has recentlylaunched a new trial, MAINTAIN, to compare MMF with azathioprine as remission-maintaining treatment in diffuse, proliferative, lupus nephritis. A 3-month course of thelow-dose cyclophosphamide regime is administered initially.50

Ciclosporin

This agent has been used to treat membranous nephropathy associated with lupus(class V) and found to induce remission in all of the 24 patients over a 24-month period.High relapse rates on withdrawal of the ciclosporin were noted.51 Ciclosporin asadjunctive therapy in three patients with proliferative lupus nephritis, resistant tointravenous cyclophosphamide, with favourable outcome have been reported.52

Concerns as to nephrotoxicity have limited its routine use.

Mizoribine

This drug has the same mechanism of action as MMF. It was developed in Japan and hasbeen used in some patients with flares of proliferative lupus nephritis; it significantlyreduced proteinuria and anti-dsDNA levels. Repeat biopsies in these patientsdocumented histological improvement. At present its use is limited to Japan.53

ADJUNCTIVE THERAPIES

Rituximab

Rituximab is an mouse/human anti-CD20L antibody and is used in the treatment oflymphoma. CD20 is a 33–37 kDa, non-glycosylated phosphoprotein expressed on thesurface of almost all normal and malignant B cells but not on plasma cells. B-celldepletion is producing promising results in preliminary studies of SLE, including


refractory diffuse, proliferative, lupus nephritis. Typical regimens have employed fourinfusions of rituximab (375 mg/m2) over 1 month with intravenous pulsed cyclopho-sphamide.54 Phase I/II trials of rituximab in SLE have shown it to be well tolerated andsafe, with B-cell depletion being profound in the majority of patients. This wasassociated with an improvement in disease activity scores.55 Controlled trials ofrituximab in SLE and nephritis are awaited.

Anti-BLys therapy

B-lymphocyte stimulator (BLyS) is a protein discovered by Human Genome Sciences. Itis required for the development of B-lymphocyte cells into mature plasma B cells.LymphoStat, a human monoclonal aAnti-BLyS antibody, specifically recognizes andinhibits the biological activity of BLyS. Dysregulation of BLyS over extended periods oftime is common in patients with SLE.56 Phase I trials in SLE have documented areduction in B cells and anti-dsDNA levels without toxicity. A phase II study in SLE hascompleted recruitment, although this study precludes active lupus nephritis requiringcyclophosphamide or high-dose steroids.

OUTCOMES FOR CLINICAL TRIALS IN LUPUS NEPHRITIS

The most important requirement for lupus nephritis trials remains an adequate periodof follow-up—ideally for 5–10 years. Design and reporting of trials in lupus has beencriticised.57,58 For lupus nephritis trials, the following outcomes are commonly used:

† doubling of serum creatinine† time to renal remission† time to renal flare.

The definition of renal remission and flare varies between investigators but usuallyimplies stable renal function, inactive urinary sediment with no haematuria or pyuriaand proteinuria of less than 0.5 G/24 hours. Use of proteinuria as a separate endpoint isnot recommended because of the difficulties in differentiating persistent proteinuriadue to chronic damage from that due to persistent disease activity. Further outcomemeasures would include complication rates due to treatment, such as infectionsrequiring hospitalisation and change in overall lupus disease activity (for further detailson assessment of SLE disease activity the reader is referred to Section 1).

SUMMARY

Lupus nephritis remains the main determinant of mortality for patients with SLE. Thefuture challenge remains the design of therapeutic regimens incorporating existing andnewer therapies that will rapidly induce renal remission with minimum toxicity. Theremission achieved should then ideally be maintained with less toxic therapy. Improvingstandardisation and use of consensus measures in clinical trials and the introduction ofthe ISN/RPS classification should ensure that clinically significant data are generated.Although most centres currently offer courses of intravenous cyclophosphamide ofvarying length, there is increasing data supporting the use of low-dose, short-term


cyclophosphamide- or mycophenolate-mofetil-based protocols. The discovery ofeffective, specific, targeted therapies, such as, anti-CD20 and anti-BLyS monoclonalantibodies holds the potential for therapy without immune suppression in the future.

Practice points† urinalysis and estimation of GFR should be performed regularly in all patients

with SLE† renal biopsy is useful in all patients with abnormal urinalysis and impaired renal

function† renal biopsies should be reported according to the ISN/RPS classification† prompt treatment of active lupus nephritis improves renal survival† induction treatment is usually with intravenous cyclophosphamide or MMF† maintenance therapy is usually with azathioprine or MMF† renal involvement in lupus is a strong predictor of morbidity and mortality

Research agenda† large, multicentre trials in lupus nephritis using consensus outcome measures

will improve treatment regimens† outcomes for adjuvant therapies for patients with SLE and lupus nephritis are

awaited with interest

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