SYSTEMIC DISEASE AND THE KIDNEY

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Lupus Nephritis

Despite immunosuppressive therapy, lupus nephritis

remains a strong predictor of ESRF and death in SLE

Jane Cross
David Jayne

Mycophenolate mofetil is a newer immunosuppressive

with an emerging role in lupus nephritis

Systemic lupus erythematosus (SLE) is a multisystem autoimmune

disease of unknown cause (see MEDICINE 30:10, 6). In the UK,
the prevalence is 27/100,000; the disease predominantly occurs
in women under the age of 40 years, though any age group may
be affected. Overt renal disease occurs in at least one-third of SLE
patients and is the most common severe manifestation. It is one of
the eleven diagnostic criteria proposed by the American College of
Rheumatology, four of which are required to support a diagnosis
of SLE. Development of nephritis is closely linked to survival and
morbidity; 20% of patients die and 25% reach end-stage renal
failure (ESRF) within 10 years. However, there is considerable
variation in presentation, pathology, course and outcome. Lupus
nephritis responds to corticosteroid and immunosuppressive
therapy, but the toxicity of current drugs contributes to morbidity
and mortality.

glomerular sclerosis. Extraglomerular features of lupus nephritis

include tubulo-interstitial nephritis (70% of patients), renal vein
thrombosis and renal artery stenosis. Thrombotic manifestations
are associated with autoantibodies to phospholipids, which are
detectable as circulating anticardiolipin autoantibodies or the
lupus anticoagulant.

Clinical features and investigations

Only 25% of SLE patients present with renal disease as the first
manifestation of the condition. In 5% of cases (usually men
> 40 years), it is several years before other criteria or serological abnormalities develop. Patients may present with asymptomatic urinary abnormalities such as microscopic haematuria or
proteinuria detected on routine testing in established SLE, with
hypertension, or with nephrotic syndrome (40%). Less commonly,
lupus nephritis presents as acute renal failure with symptoms of
renal impairment, in which case other severe manifestations (e.g.
myocarditis, cerebritis) may also be present.
The following factors influence the course of lupus nephritis
and its outcome, and should be considered in the evaluation of
patients:
demography (age, sex, race, duration of SLE and nephritis)
renal function (glomerular filtration rate, urinary abnormalities,
blood pressure)
serology (autoantibodies, complement, immunoglobulins,
albumin)
histopathology (light microscopy, immunofluorescence)
extrarenal organ involvement and drug exposure.
The histological appearances of glomerular disease have been
classified according to the pattern and extent of immune deposition and inflammation (Figure 1). Transformation to a more
severe or less severe histological class is well documented and
may result from treatment or be part of the natural history of the
disease. The activity and chronicity of renal biopsy specimens
are used to assess whether treatment should be intensified, and
chronicity indices may predict the long-term renal outcome. Interpretation of renal biopsy is subject to observer bias, however, and
is influenced by the sample size.

Pathology
Immune deposits in the glomeruli and mesangium are characteristic of SLE, and stain positive for IgG, IgM, IgA and the complement components C3, C1q and C4 on immunofluorescence. Circulating autoantibodies to cellular antigens (particularly anti-dsDNA,
anti-Ro and anti-C1q) and complement activation with correspondingly reduced serum C3, C4 and C1q levels are typical of lupus
nephritis. Following the appearance of immune complexes, an
inflammatory reaction develops with mesangial cell proliferation,
expansion of the mesangial matrix and infiltration of inflammatory
leucocytes. Other pathogenic mechanisms include infarction of
glomerular segments, thrombotic microangiopathy, vasculitis and

Jane Cross is a Renal Registrar at Addenbrookes Hospital, Cambridge,

UK. She qualified from the Royal London Hospital, London, and has
trained in the South West Thames region. Her interests include systemic
lupus erythematosus and trial design.

Management

David Jayne is Consultant Physician and Director of the Vasculitis and

Lupus Clinic at Addenbrookes Hospital, Cambridge, UK. He qualified
from the University of Cambridge and St Thomas Hospital, London,
and trained in general medicine and nephrology. His research interests
include immunotherapy and clinical trials in vasculitis and systemic
lupus erythematosus.

MEDICINE

No large, prospective randomized trials have been performed in

lupus nephritis; data are derived from retrospective studies and
from smaller trials with an average of 20 patients per treatment
arm. Most data suggest that WHO class II lupus nephritis has a
benign course, and treatment in the absence of other indications

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Survival to end-stage renal failure or death in lupus

nephritis according to histological grade

Modified WHO classification of lupus nephritis

Class 0
Normal

Class II
1.0

Class I
Light microscopy normal, immune deposits on immunofluorescence

Class V

0.8

Class II
A mesangial deposits
B mesangial hypercellularity

Class III
Class I

Survival

0.6

Class III
Focal segmental proliferative glomerulonephritis (< 50% glomeruli)
with leucocyte infiltration; immune deposits in the mesangium and
subendothelium

Class IV
0.4

Class IV
As class III, but diffuse (> 50% glomeruli); may also see glomerular
crescents and fibrinoid necrosis; includes membranoproliferative
variant

0.2

Class VI

Class V
Membranous nephropathy with uniform thickening of the capillary
walls and subepithelial immune complex deposition
A membranous nephropathy alone
B membranous nephropathy + class II
C membranous nephropathy + class III
D membranous nephropathy + class IV

10

15

20

Time after biopsy (years)

Histological grade predicts subsequent development of renal failure in
lupus nephritis. The current grading system does not take into account the
full range of lupus manifestations in the kidney, but remains the most
widely used tool. Glomerulofibrosis is the most important predictor of renal
failure, which is reflected in the poor outcome in WHO class VI nephritis.
(By courtesy of Dr A Howie and Dr D Adu, Queen Elizabeth II Hospital,
Birmingham.)

Class VI
Glomerulosclerosis
2
1

suppression and infection are lower than with cyclophosphamide,

but there is an increased risk of skin malignancy after prolonged
exposure.
Treatment-related death and morbidity from infection are significant problems in SLE, and newer, less toxic agents are sought.
Mycophenolate mofetil is used for both induction of remission and
maintenance therapy. Autologous peripheral stem cell transplantation is under evaluation for refractory and relapsing disease.

is usually not required. The outcome and treatment of class V

disease is debated, reflecting differences in interpretation of the
histological criteria.
The decision to treat active WHO class III and IV lupus nephritis
is less controversial. Systematic review of the available trials supports treatment with corticosteroids and an immunosuppressive
agent. The choice of immunosuppression is less clear; traditionally,
cyclophosphamide or azathioprine is used, but neither has been
shown to be superior to the other. In the UK, pulsed intravenous
cyclophosphamide with corticosteroids is the most widely used
first-line therapy to induce remission of active nephritis. Early
withdrawal of immunosuppression increases the relapse rate, so
cyclophosphamide is either continued or substituted by the less
toxic azathioprine. The optimum duration of therapy is debated;
continuing treatment for a significant disease-free period such as
2 years is recommended. Ciclosporin is an alternative immunosuppressive agent, used particularly in children.
Both cyclophosphamide and azathioprine have severe adverse
effects. Cyclophosphamide is associated with premature menopause in up to 50% of women, myelosuppression, an increased
risk of severe infections and bladder malignancy. Azathioprine
is associated with hypersensitivity reactions. The risks of myelo-

MEDICINE

Prognosis
Development of renal disease is the strongest predictor of ESRF and
early mortality in SLE. Renal histology and renal function are the
most important renal prognostic factors at presentation (Figure 2).
Following treatment, normalization of proteinuria and the absence
of relapse of nephritis are the best predictors of a good outcome.
Negative prognostic factors include male gender, black race and
haematological features of SLE.

Pregnancy and lupus nephritis

The effect of pregnancy on the activity of SLE is debated, but
disease activity at conception is important fetal loss is greater in
women with active disease at this time. Renal impairment per se

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is also associated with fetal loss and premature delivery. Management by a specialist team before conception and during pregnancy
is important in optimizing fetal and renal outcome.
u

Drugs and
Renal Insufficiency

REFERENCES
Balow J E, Boumpas D T, Fessler B J et al. Management of Lupus Nephritis.
Kidney Int 1996; 49: (Suppl. 53): 8892.
Bansal V K, Beto J A. Treatment of Lupus Nephritis: A Meta-analysis of
Clinical Trials. Am J Kidney Dis 1997; 29(2): 1939.
Hochberg M C. Updating the American College of Rheumatology Revised
Criteria for the Classification of Systemic Lupus Erythematosus.
Arthritis Rheum 1997; 40(9): 1725.
Korbet S M, Lewis E J, Schwartz M M et al. Factors Predictive of
Outcome in Severe Lupus Nephritis. Am J Kidney Dis 2000; 35(5):
90414.

Jeffrey K Aronson

Renal insufficiency alters both the disposition of drugs in the body

(pharmacokinetics) and tissue responses to drugs (pharmacodynamics), and nephrotoxic drugs can impair renal function.
Pharmacokinetic changes include the following.
Drugs that are excreted by the kidneys in an active form or
as active metabolites are eliminated at a reduced rate. Reduced
clearance causes accumulation of the drug, which can cause adverse effects. Renal replacement therapy can also alter the rate of
elimination of drugs.
Altered protein binding occurs. Displacement (e.g. phenytoin)
increases the unbound fraction of drug available for distribution
to the tissues and enhances its action.
Diuretics that act on the luminal side of the renal tubule do
not reach their site of action in sufficiently high concentrations;
increased doses are therefore required.

FURTHER READING
Davison A M, Cameron J S, Grnfeld J-P et al., eds. Oxford Textbook of
Clinical Nephrology. Vol. 2. 2nd ed. Oxford: Oxford University Press,
1998.
(Includes an excellent review of all aspects of lupus nephritis.)
Balow J E, Austin H A. Progress in the Treatment of Proliferative
Lupus Nephritis. Curr Opin Nephrol Hypertens 2000; 9(2):
10715.
(Reviews potential newer therapies for lupus nephritis.)

Pharmacodynamic changes include the following.

The sensitivity of the brain to the effects of some psychoactive
drugs is increased.
Tissue sensitivity to the effects of some endogenous hormones
(including growth hormone, vitamin D analogues and insulin) is
reduced.
Sensitivity to the effects of acetylcholinesterase inhibitors is
increased.

Changing drug regimens in renal insufficiency

A drug dosing regimen is a recipe for drug administration, intended to produce the desired therapeutic effect with a minimum
of unwanted effects. It is described in terms of the dose of drug,
the frequency and route of administration, and the formulation
used.
It is usual to start drug therapy using the published recommendations, generally beginning at the lower end of the recommended dose range and monitoring for a therapeutic effect. If the
desired effect does not occur, increase the dose gradually, until

Practice points
Lupus nephritis is common in patients with SLE and may be
asymptomatic
Clinical features do not predict severity on renal biopsy
Development of lupus nephritis strongly predicts renal and
patient survival
Current treatment is with cortciosteroids and an
immunosuppressive agent such as intravenous
cyclophosphamide or azathioprine
Large trials are required to confirm optimum therapy and assess
newer, less toxic treatments

MEDICINE

Jeffrey K Aronson is Clinical Reader in Clinical Pharmacology at the

University of Oxford, UK, and Honorary Consultant Physician in the Oxford
Radcliffe Hospitals Trust. He trained in general medicine and clinical
pharmacology in Glasgow and Oxford. His research interests include
adverse drug reactions, control of ion transport systems in response to
drugs and diseases, and the clinical pharmacology of cardiovascular
drugs.

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