The Official Patient's Sourcebook on Lupus (10 page)

complete remission, and 14 percent had a partial remission, as compared

with 76 percent and 14 percent, respectively, of the 21 patients in Group

2. The improvements in the degree of proteinuria (protein in the urine)

and the serum albumin (protein levels in the blood) and creatinine

concentrations were similar in the two groups. One patient in each group

discontinued treatment because of side effects. Infections were noted in

19 percent of the patients in Group 1 and in 33 percent of those in Group

2. Other adverse effects occurred only in group 2; they included

amenorrhea (23 percent), hair loss (19 percent), leukopenia (10 percent),

and death (10 percent). The rates of relapse were 15 percent in Group 1,

Studies 49

and 11 percent in Group 2. The authors conclude that for the treatment of

diffuse proliferative lupus nephritis, the combination of mycophenolate

mofetil and prednisolone is as effective as a regimen of

cyclophosphamide and prednisolone followed by azathioprine and

prednisolone, with similar levels of toxicity. 2 figures. 4 tables. 15

references.

·
Natural History and Treatment of Lupus Nephritis

Source: Seminars in Nephrology. 19(1): 2-11. January 1999.

Contact: Available from W.B. Saunders Company. Periodicals

Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-

2452.

Summary: Renal involvement occurs in most patients with systemic

lupus erythematosus (SLE). This article discusses the natural history and

treatment of lupus nephritis. Contemporary therapeutic regimens for

immunosuppression and for the treatment of hypertension,

hyperlipidemia, infections, and seizures have likely contributed to

improvements in the prognosis of these patients over the past four

decades. Corticosteroids usually ameliorate the manifestations of lupus

nephritis but achieve less complete and sustained remissions than

cytotoxic drugs. Among the cytotoxic drugs, pulse cyclophosphamide

has one of the best profiles of efficacy and toxicity. Because each episode

of lupus nephritis exacerbation results in cumulative scarring, atrophy,

and fibrosis, the authors recommend continued maintenance treatment

for 1 year beyond the point of complete remission of proliferative lupus

nephritis. Studies are in progress to determine whether innovative

treatment strategies will enhance efficacy and minimize toxicity

associated with cytotoxic drug therapies. Lupus membranous

nephropathy poses a lower risk of renal failure, but persistent nephrotic

syndrome confers risks of cardiovascular events; this form of lupus

nephritis is usually treated with less intensive regimens of

corticosteroids, cytotoxic drugs, or cyclosporine. The prognosis and

overall success of treatment for lupus nephritis seem to vary widely

among geographically and racially diverse populations. The causes for

the apparently worse prognosis and poorer responses to treatment of

lupus nephritis in African American patients are currently unexplained

and require further study. Until such data are available, caution is clearly

warranted in extrapolating evidence, particularly about the prognosis

and effects of treatment among different populations of patients with

lupus nephritis. 4 figures. 2 tables. 85 references. (AA).

50 Lupus Nephritis

·
Renal Vascular Lesions in Lupus Nephritis

Source: Medicine. 76(5): 355-368. September 1997.

Contact: Available from Lippincott Williams and Wilkins. 227 East

Washington Square, Philadelphia, PA 19106. (800) 638-6423.

Summary: This article reports on a study of a series of 169 kidney

biopsies performed between 1980 and 1994 in 132 patients with lupus

nephritis (LN). The biopsies were performed to obtain a comprehensive

clinical and histologic description of the intrarenal vascular lesions in LN

and, more specifically, to clarify two incompletely resolved issues: first,

to outline the clinical manifestations associated with the different types of

renal vascular lesions and the prognostic significance of each; second, to

better understand the so-called lupus vasculopathy (also called

noninflammatory renal microangiopathy, renal angiitis, and other

names). The terms used suggest that blood clotting and endothelial

lesions are involved; however, the research reported in this article does

not support these mechanisms. The authors favor the hypothesis that

lupus vasculopathy could in fact be due to formation of immunoglobulin

microvascular casts. The authors call for a better description of the

clinical significance of these renal vascular lesions in LN, with particular

attention to lupus vasculopathy. The most common vascular lesions were

nonspecific sclerotic changes, found in 37 percent of the biopsies; the

other common vascular lesions were immunoglobulin microvascular

casts (24 percent of biopsies). Vasculitis and thrombotic microangiopathy

were rare lesions (2.4 percent and 0.6 percent of cases, respectively). The

authors conclude that, taken as a whole, their data confirm that the

presence of active and severe forms of diffuse proliferative LN (WHO

class IV) carries a worse prognosis compared with the other forms of LN.

The long term renal survival of patients with class IV LN was

significantly worse than that of patients with other forms of LN, with a 10

year renal survival of 70 percent compared with 85 percent, respectively.

However, the data do not support the conclusions of some previous

studies that the presence of intrarenal vascular lesions is a marker of poor

renal prognosis in LN. 4 figures. 8 tables. 43 references. (AA-M).

·
Reliability of Histologic Scoring for Lupus Nephritis: A Community-

Based Evaluation

Source: Annals of Internal Medicine. 119(8): 805-811. 1993.

Summary: This article reports on a research study undertaken to

determine the reliability of the National Institutes of Health (NIH)-

modified semiquantitative histologic scoring system for lupus nephritis.

Five pathologists, all experienced in reading renal biopsy specimens,

Studies 51

assessed 25 specimens that had been obtained from patients with a

clinical diagnosis of systemic lupus erythematosus and showed diffuse

proliferative glomerulonephritis. Biopsy specimens were scored

independently and blindly by pathologists for components of nephritis

chronicity and activity. Reliability was measured by percentage

agreement, intraclass correlation coefficient or kappa statistic, and

individual reader effect on the group arithmetic mean. The results show

that, in a nonreferral setting, the NIH-modified scoring system for lupus

nephritis is only moderately reproducible. The authors stress that, if this

system is used to predict renal outcome, it may result in erroneous

predictions of risk for renal failure and response to therapy. 2 figures. 5

tables. 39 references. (AA-M).

·
Treatment of Lupus Nephritis: A Work in Progress (editorial)

Source: New England Journal of Medicine. 343(16): 1182-1183. October

19, 2000.

Summary: Until the pathogenesis (development of disease state) of

nephritis (kidney infection) due to systemic lupus erythematosus (SLE) is

unraveled, optimal treatment for patients with this disease remains an

elusive goal. This article outlines one option for treatment of lupus

nephritis, serving as an introduction to a separate article in this issue of

the Journal. The author first reviews the differing presentations of SLE,

noting that in some patients the kidneys are not involved but in others,

there is rapidly progressive destructive kidney disease. This difference

may be due in part to genetic risk factors, to environmental factors (such

as exposure to ultraviolet light, infectious pathogens, and silica dust),

race, or socioeconomic factors. In general, the treatment of lupus

glomerulonephritis depends on the severity of the disease. Intravenous

cyclophosphamide is given, in addition to oral glucocorticoids, for the

aggressive forms of the disorder. However, the adverse effects of these

therapies have prompted the search for alternative treatments. The

author then comments on the accompanying article which presents the

results of a study in which patients with diffuse proliferative lupus

nephritis were successfully treated with prednisolone and

mycophenolate mofetil. The editorial author notes that there are several

reasons for caution before generalizing these findings to other patients

with proliferative lupus glomerulonephritis, notably underrepresentation

of patients with poor prognosis and certain demographic characteristics.

10 references.

52 Lupus Nephritis

Federally-Funded Research on Lupus Nephritis

The U.S. Government supports a variety of research studies relating to lupus

nephritis and associated conditions. These studies are tracked by the Office

of Extramural Research at the National Institutes of Health.
20 CRIS
P

(Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally-funded biomedical research projects conducted at

universities, hospitals, and other institutions. Visit the CRISP Web site at

http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket
.

You can

perform targeted searches by various criteria including geography, date, as

well as topics related to lupus nephritis and related conditions.

For most of the studies, the agencies reporting into CRISP provide

summaries or abstracts. As opposed to clinical trial research using patients,

many federally-funded studies use animals or simulated models to explore

lupus nephritis and related conditions. In some cases, therefore, it may be

difficult to understand how some basic or fundamental research could

eventually translate into medical practice. The following sample is typical of the type of information found when searching the CRISP database for lupus

nephritis:

·
Project Title: ACE Inhibitors In Lupus Nephritis--TGFB and

Autoantibody Production

Principal Investigator & Institution: Singh, Ram R.; Associate Professor;

Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh

45229

Timing: Fiscal Year 2001; Project Start 5-MAR-2001; Project End 8-FEB-

2006

Summary: Angiotensin-converting enzyme inhibitors (ACEIs), such as

captopril, are widely used to control hypertension in patients who have

chronic renal disease. ACEIs improve renal function in patients with

chronic renal disease, however, than would be expected from their

suppression of hypertension. ACEI-induced improvement in renal

function is associated with decreased renal TGF-beta expression and

matrix deposition. We anticipate that ACEIs may have a similar effect on

TGF-beta production, renal fibrosis and end stage renal disease in

patients with lupus. However, because TGF-beta can inhibit T and B cell

20 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services

Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

Studies 53

activation and auto-antibody productions, an ACEI-induced decrease in

TGF-beta may exacerbate auto-antibody-mediated disease in lupus by

enhancing auto-antibody production. Consequently, this proposal will

explore potential therapeutic and damaging effects of ACEIs in SLE,

inflammatory component of lupus nephritis, its continued presence

enhances renal matrix deposition and fibrosis. To test this hypothesis we

will: 1) evaluate autoantibody responses and renal disease in lupus-prone

mice treated with ACEIs; and 2) generate and characterize mice that have

kidney-specific deletion of the Tgfb1 gene. These mice will be used in

future to determine the effect of TGF-beta deletion on lupus nephritis.

Lupus-prone and control mice will be treated with captopril or a control

anti-hypertensive agent; the effect on blood pressure, renal functions,

renal histology, renal immune and collagen deposition will be

determined. These changes will be correlated with TGF-beta expression

in kidneys and spleens, and serum auto-antibodies. We will then

generate mice that have renal-specific Tgfb1 gene deletion, and

characterize their phenotype, specifically for any inflammatory changes

in kidneys and other organs. The broad objectives of this proposal are to

understand the role of TGF- beta in the pathogenesis of lupus nephritis,

to explore how manipulation of in vivo TGF-beta can influence lupus,

and to elucidate the mechanism and clinical utility of ACEIs in lupus.

Delineation of pathways that cause matrix deposition in kidneys, but do

not affect T and B cell activation, may lead to treatment strategies that

improve end stage renal disease in SLE.

Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

·
Project Title: Antic5 Therapy of Lupus Nephritis