American Journal of the Medical Sciences:
Renal Disease In African Americans
Lupus Nephritis in African Americans
Lea, Janice P. MD
From the Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia.
Correspondence: Janice P. Lea, M.D., Emory University School of Medicine, 1639 Pierce Dr. WMB Rm. 338, Atlanta, GA 30322 (E-mail: firstname.lastname@example.org).
Lupus nephritis is more common and severe in African American women. Despite aggressive immunosuppressive therapies employed in lupus nephritis, African Americans have a higher incidence of progression to end-stage renal disease. The reasons for the racial disparities are not clear, but seem to be due to genetic, environmental, and socioeconomic factors. Hypertension and proteinuria are well-defined prognostic factors that significantly impact the course of renal disease progression for most forms of renal disease. However, clinical trials in lupus nephritis to date have not evaluated the role of aggressive antihypertensive or antiproteinuric therapies in retarding renal disease progression. Thus, additional studies are needed to better elucidate the natural history of lupus nephritis in African Americans and to optimize therapeutic strategies for those who are identified as being at high risk.
Systemic lupus erythematosus (SLE), an immune complex disease, is characterized by tissue deposition of circulating antigen-antibody complexes leading to release of inflammatory mediators and influx of inflammatory cells, resulting in clinically apparent kidney damage, most prominently glomerulonephritis (GN). Nephritis develops in up to 60% of the patients who have SLE and is a major cause of morbidity in these patients. Twenty percent of the patients who have lupus nephritis (LN) progress to end-stage renal disease (ESRD) within 10 years of its onset. Lupus nephritis is four times more common in African Americans than in whites. The basis for these differences is probably due to both genetic and environmental factors. African Americans are also at disproportionately increased risk for other types of renal disease, including those related to hypertension, diabetes, HIV infection, and focal segmental glomerulosclerosis.
The most frequent clinical sign of LN for all patients is proteinuria, and thus often progresses to the nephrotic syndrome. Microscopic hematuria is usually present; an increase in serum creatinine occurs in about 50% of patients. Persons with LN usually are hypocomplementemic and have antibodies directed against dsDNA, C1q, and the Smith(Sm) antigen. Renal biopsy is important in defining prognosis and therapeutic regimen. On kidney biopsy, LN is classified as: type 1, normal; type 2, pure mesangial changes; type 3, focal proliferative GN; type 4, diffuse proliferative GN (DPGN); type 5, membranous GN; and type 6, sclerosing GN. Types 3 and 4 are considered the more active and severe forms of LN associated with high-grade proliferation and warrant more aggressive therapy.
Epidemiology and Prognostic Factors
Studies of the natural history of LN have suggested that a number of demographic, clinical, and histological factors contribute to the prognosis of this disorder. Some, but not all, investigators have found that racial differences in mortality and loss of renal function may be accounted for by differences in socioeconomic status. 1,2 Several prognostic factors have emerged as high-risk features for patients with LN and include: black race, the presence of hypertension, azotemia, proteinuria, thrombocytopenia, anemia, hypocomplementemia, and the presence of cellular crescents, interstitial fibrosis, or glomerulosclerosis on renal biopsy. 3–6
The prognostic significance of race among patients with LN is illustrated in studies reported by the Glomerular Disease Collaborative Network or the National Institutes of Health. 7,8 At both centers, the risk of ESRD was significantly greater for African Americans than whites. In fact, a subset of African American patients in the Collaborative network progressed rapidly to ESRD despite intensive therapy with corticosteroids and pulse cyclophosphamide. 7 They found that variations in the severity of renal failure among racial groups were not caused by differences in baseline clinical features, renal pathology, or comorbid conditions. 7 Values of serum creatinine and the extent of chronic histological change identified before treatment did not suggest that the diagnosis had been delayed in African Americans because of limited access to health care, although the role of socioeconomic status was not evaluated in this study. 7
In a National Institutes of Health study of 166 patients with LN, 49 of whom were black, race, serum creatinine, and kidney pathology data were independent predictors of renal insufficiency. 8 Black patients in this study were more likely than others to have high-risk histological features, including extensive cellular crescents (>50%) and moderate to severe interstitial fibrosis before randomization. The presence or extent of subendothelial deposits did not identify patients at increased risk for worse renal outcomes; only 6 patients were reported to have fibrinoid necrosis, which may be an important prognostic factor. A 1977 to 1990 retrospective analysis from Cook County Hospital showed that DPGN had a poor prognosis in African Americans;3 however, prognosis in mild and moderate focal segmental proliferative lesions or with simple membranous glomerulonephritis was as good as had been reported in whites.
Dooley et al 7 reported that among white patients 95% still had renal function after year 5, whereas black patients showed a progressive yearly decline in this percentage: from 85% at year 1 to 79, 72, 62, and 58% by year 5. Racial differences in renal failure were independent of age, the duration of lupus, a history of hypertension, the degree of hypertension control during therapy, the type of antihypertensive therapy, or the activity and chronicity indices on renal biopsy. The major finding in this study was that even when there is a similar renal pathology, serum creatinine levels at baseline, and treatment regimens, African Americans with SLE-DPGN progress more rapidly to ESRD compared with white patients. 7 Despite the lack of correlation with hypertension and renal disease progression in this study, others have found that the degree of hypertension influences renal prognosis. 5,6 Bakir et al reported that moderate and severe hypertension was more common in groups with DPGN and crescentic GN than in groups with focal proliferative GN and membranous GN; whether hypertension played a role in the development of more aggressive renal lesions or was a consequence of more severe renal damage is unknown. 3
The usefulness of serological markers in predicting renal prognosis in LN for the general population remains controversial. 9,10 Studies have attempted to correlate the clinical manifestations of LN in African Americans with changes in DNA antibody titers or other autoantibodies. McCarty et al 11 reported a distinctive precipitin profile in black women with LN (positive anti-Sm, anti-nRNP, and anti-Ro/SS-A). These findings were not confirmed by Garcia et al. 12 They studied 94 black women with LN and 128 black women with SLE without nephritis and concluded that there was not a distinctive autoantibody profile in those with nephritis; however, women with LN had higher anti-dsDNA antibody titers. 12
Elevated IgG anticardiolipin antibodies have been found in a number of studies to predict the development of thromboembolic complications of the antiphospholipid syndrome. One study found that patients with either intracapillary thrombi or anticardiolipin antibody had significantly poorer renal function at presentation and tended to progress more rapidly. 13 In a report from Britain, investigators observed an independent effect of the presence of IgG anti-cardiolipin antibodies and the development of renal SLE. 1 However, in Garcia’s report, 12 anticardiolipin antibodies were similar in African American women with and without LN. Clinicians need to realize that serological tests are rarely reliable predictors of adverse course for LN, although DNA antibody titers tend to decrease after treatment; rising anti-dsDNA antibody titers along with falling serum complements warrant intensive surveillance for progressive renal damage. 10
Familial clustering of lupus does occur and monozygotic twins show a 25% concordance. In addition to SLE susceptibility genes, there may be nephropathy susceptibility genes predisposing to LN because there is familial clustering of ESRD in African Americans with LN. 14 Freedman et al 14 reported a series of 25 black patients with LN: 28% of them had relatives with ESRD and 12% of those had ESRD due to LN. Blacks with SLE but without renal disease had no family members with ESRD. Some of the genes that predispose patients to LN are known, including HLA-A1-, B8-DR3, complement, and Fc-receptor alleles leading to renal injury. There was an increased frequency of FcγRIIA-R131 in African American SLE patients with more marked skewing of the FcγRIIA gene distribution in the nephritis group compared with patients who were non-SLE (African American) control subjects. 15 The authors concluded that these findings suggest a model in which the inability to clear immune complexes by way of FcγR increases the risk of SLE and particularly LN.
Clinicopathologic studies have shown clearly that fibrosis involving the glomerular, vascular, and especially the interstitial compartments of kidney is the strongest marker for progressing to ESRD. Lupus nephritis results from an acute inflammatory and immunological response to renal immune complex deposition from the production of antibodies to DNA and other antigens. Once deposited in the kidney, immune complexes activate a number of inflammatory cascades, leading to complement activation, coagulation/fibrinolysis, chemotactic factor production, cytokine/growth factor generation, and reactive oxygen species generation. 16 Recent studies have demonstrated that reactive oxygen species function as signaling molecules in a variety of pathways that are relevant to progressive kidney damage in patients with LN, including proliferation, cytokine activation and production of second messengers. 17 Reactive oxygen species are capable of activating several transcription factors that are involved in expression of tumor growth factor-β (TGF-β) and collagen genes. TGF-β is well recognized as a potent stimulus for collagen production leading to extracellular matrix accumulation. 18
Overexpression of TGF-β in animal and human kidney disease results in mesangial cell proliferation and glomerulosclerosis as well as tubulointerstitial injury and renal failure, whereas therapy antagonizing TGF-β has an antifibrotic effect. 19 Elevated TGF-β is a characteristic feature of a number of progressive renal diseases, including lupus. 20–23 Interestingly, African Americans with ESRD due to various causes express higher levels of TGF-β than do white ESRD patients. 24 By extrapolation, TGF-β may play an important role in mediating renal disease in African Americans with LN.
Cardiovascular Risks, ESRD, and Transplantation
All patients with SLE are at increased risk for atherosclerotic vascular diseases. Among patients with ESRD caused by LN, cardiovascular and cerebrovascular disease account for 16 to 50% of the deaths. However, recent data from the United States Renal Data System do not indicate that women with ESRD due to LN are at higher risk for cardiovascular and cerebrovascular disease than are women with ESRD from other causes. 25 There was also no reported differences in outcomes based on race in the USRDS report. Even though conventional teaching is that lupus activity subsides with development of ESRD, recent studies show that clinical and serological signs of active lupus were present in the majority of SLE patients treated with chronic dialysis and this can contribute to mortality. 26 Possible contributors to increased cardiovascular risk other than the traditional factors, such as hypertension, dyslipidemias, obesity, etc, may be the presence of antiphospholipid antibodies, corticosteroid treatment, and systemic inflammation.
Although patients with ESRD due to LN, including those who are African American, have survival rates with cadaveric and living allografts that are similar to those of the general population with renal transplants, persons with LN and antiphospholipid syndrome seem to be at greater risk of graft loss. 27,28 Both black and white ESRD patients with LN were 20% less likely to receive a cadaveric transplant and were on the wait list longer than those with other causes of ESRD, according to the USRDS. 29 Recurrence of LN is reportedly rare in the allograft, although a recent study showed that 10% of patients with lupus undergoing renal transplantation had evidence of recurrence of LN. 30
Although the overall prognosis of all patients with proliferative LN has improved, subsets of high-risk patients (eg, African Americans) continue to have poor outcomes despite contemporary regimens of intensive immunosuppression. Intravenous cyclophosphamide given once a month for 6 months, followed by quarterly infusions until remission is obtained for at least 1 year, along with a course of steroid therapy, has become the standard of care for treating severe LN in all patients. Dooley et al 7 reviewed 89 patients with SLE-DPGN treated with intravenous cyclophosphamide between 1985 and 1995. Renal survival was significantly worse in 51 blacks compared with 38 whites: the rate of renal survival was 95% at 5 years among whites with diffuse proliferative GN; among similarly treated blacks, the rate was 79% at 1 year and 58% at 5 years. 7 The percentage of patients receiving bolus methylprednisolone therapy at the time of SLE-DPGN diagnosis was similar between the 2 races and no differences were seen in the tapering schedule of corticosteroids initially started at 60 mg/kg for 2 months then tapered over 12 months. The median cumulative intravenous cyclophosphamide dose was less for blacks than for whites, attributed to more blacks reaching ESRD during the 6-month course of intravenous cyclophosphamide.
In a National Institutes of Health study of severe DPGN, a 6-month course of monthly pulse methylprednisolone was less effective in African Americans than in whites. 8 A more intensive treatment of 30 months of pulse cyclophosphamide seemed to be equally efficacious for both African Americans and whites, 8 suggesting a role for more long-term treatment with pulse cyclophosphamide, especially in African Americans, to improve outcomes. A recent trial by Chan et al 31 reported that mycophenolate therapy combined with prednisolone was as effective as a regimen of cyclophosphamide and prednisolone in women from Hong Kong with LN (there were no African Americans in this study). Mycophenolate has been reported to reduce the incidence of acute rejection in black patients with a renal transplant, but the optimal dosage may be higher for blacks than for nonblacks. 32
Additional therapy of LN should include aggressive antiproteinuric strategies using angiotensin-converting enzyme inhibitors because they can slow the progression of a variety of renal diseases associated with proteinuria. 33–36 Because hypertension adversely effects renal function, aggressive antihypertensive therapy should also be employed: target blood pressures should be 125/75 mm Hg as recommended by the Joint National Committee based on data from the Modification of Diet and Renal Disease study. 37 The MDRD study established that more stringent blood pressure control reduced the rate of renal disease progression, particularly when proteinuria > 1 g/d is present, and particularly in African Americans. 37 Despite the benefit of lowering blood pressure observed in many patients with various renal diseases, there have not been any large-scale trials involving aggressive blood pressure control in African Americans with LN.
The goal of aggressive treatment in LN is to induce remission. Achieving a remission of LN predicts a more favorable renal and patient survival. 4 African Americans were less likely to achieve a remission in the Lupus Collaborative Study. The 5- to 10-year renal survival rates were 50 and 38% in black patients but 74 and 68% in white patients. 4 The incidence of treated ESRD due to LN increased in 1995 from 1982 despite the introduction of new treatment regimens. 38 These data suggest that newer treatment strategies have not been widely used, or that the benefits observed in clinical trials are not commonly replicated in clinical practice. Perhaps blood pressure and proteinuria have not been managed aggressively enough to delay the progression of renal disease. Additional studies are indeed necessary to better elucidate the natural history of LN in African Americans and to optimize therapeutic strategies for those who are identified as high risk.
It is difficult to compare outcomes between different clinical trials, mostly because of differences in treatment regimens and in degrees of renal damage; still, all observations suggest a more unfavorable renal prognosis in African Americans with LN. Whether these findings are a consequence of socioeconomic, genetic, or environmental factors is not clearly defined and more prospective studies are needed in both African Americans and whites to better determine reasons for the worse renal survival in African Americans. Because African Americans are more susceptible to renal damage induced by hypertension, future investigation should target aggressive blood pressure control in addition to immunosuppressive therapy with steroids and cytotoxic agents. Nonetheless, aggressive therapeutic regimens are warranted in this high-risk population of African Americans with LN to improve overall outcomes.
I thank Dr. William E. Mitch for his critical review of the manuscript.
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KEY INDEXING TERMS: Lupus nephritis; African Americans
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