Lupus Nephritis

Abstract

The importance to practicing nephrologists of lupus nephritis (1, 2, 3) is that, although rare, it is a serious disease whose prognosis can usually be improved dramatically by treatment, but for which the treatment is potentially toxic, prolonged, complex, and difficult to plan and carry out. Lupus is defined by its clinical picture, together with antibodies directed against one or more nuclear components, particularly anti-double-stranded DNA (dsDNA). It is best regarded as a syndrome, in which a variety of immunologic events may lead to a similar final common pathway, and thus present a similar clinical picture (4). One important distortion that occurs through the usual style of reporting of lupus in the literature is that by defining “typical” or “core” patients with a positive antinuclear antibody and/or dsDNA antibodies, a considerable number of patients are excluded who belong to the lupus “family” of diseases, but do not satisfy current strict criteria. These patients are in practice as important to recognize and treat as those with “classical” lupus. Many with a clinical lupus syndrome but a negative antinuclear antibody have low titers of anti-Ro antibody; this subset of patients rarely has significant renal disease, but often has a high incidence of antiphospholipid antibodies and associated thromboses and abortions (see below), as well as inherited complement deficiencies. Origins of Autoimmunity and the Immunologic Abnormalities of Lupus How autoimmunity and the lupus syndrome may arise remains the subject of speculation (5). In lupus, a generalized autoimmunity is present with autoantibodies directed against a variety of self components (6), and the role of the autoantibodies in generating the organ damage is unclear. This contrasts with organ-specific autoimmunity such as that found in myasthenia gravis or anti-glomerular basement membrane nephritis, in which clearly pathogenic autoantibodies are directed against a single self epitope. Genetic factors are important in lupus, with a strong racial preponderance. For instance, the prevalence and mortality of lupus are both ten times higher in black (American) women than whites; however, it is relatively rare in the progenitors of Afro-Americans in West Africa. Familial clustering of lupus is present also, and monozygotic twins show a 25% concordance. In addition, patients with lupus may have healthy family members who show antinuclear and other autoantibodies. However, only weak associations have been noted with MHC loci, the strongest being with genes for C4A or C4B or low production of tumor necrosis factor. A few lupus patients also have genetic deficiencies of complement components. Acquired complement deficiencies are also associated with lupus, for example of the complement receptor CR-1. A female phenotype is the major risk factor for the development of lupus. The female:male ratio rises from 2:1 in prepubertal children up to 4.5:1 in adolescence to the 8 to 12:1 reported in series of adult onset patients, falling back to 2:1 in patients over 60 yr of age. These data are in accord with murine models of lupus, in which estrogens are precipitating factors in the emergence of lupus, while androgens protect. Lupus is distinctly rare before puberty, although onset in the first year of life has been recorded. Overall incidence is much lower in children compared with adults. Infective agents, including historically tuberculosis and more recently retroviruses, have been considered as candidates for the provocation of the lupus syndrome; however, there is no convincing evidence of their participation in human disease. Medicines, of which hydralazine and procainamide are prototypes, may precipitate a lupus syndrome, but they rarely affect the kidney. Pathogenesis and Mediation of Disease Immune aggregates are present at sites of injury in glomeruli, and in the tubules also in about two-thirds of renal biopsies, as are complement components. Whether these are derived from circulating complexes or from in situ combination of antigen and antibody is still unclear. Deficiencies in the handling of immune complexes and other foreign material have been described, perhaps inherited in association with the MHC haplotype HLA-A1-B8-DR3. This deficiency may be worsened by “saturation” of the monocyte-phagocytic system by immune aggregates, either free in the circulation or fixed to CR-1 receptors stripped from erythrocytes. Typically, there are multiple autoantibodies in lupus directed against nucleic acids and proteins concerned with intracellular transcriptional and translational machinery (6): The main targets are nucleosomes (DNA-histone) (7) or even quaternary antigens on the chromatin itself, small nuclear ribonucleoproteins and small cytoplasmic ribonucleoproteins. Patients with lupus nephritis usually show antibodies directed against dsDNA, Sm, and C1q (see below). It remains uncertain whether the DNA- anti-DNA antibody system, so characteristic of lupus, has a direct role in pathogenesis. There is no reason to believe that the effector mechanisms of renal damage (complement, polymorphs, monocytes, cytokines, eicosanoids, etc.) are different in lupus from primary glomerulonephritis, but the interstitial cellular infiltrates in lupus often show an excess of CD8+ cytotoxic T lymphocytes over CD4+, compared with the usual majority of CD4+ T-helper lymphocytes and monocytes seen in primary glomerulonephritis. Why do only some patients with lupus develop clinically evident nephritis? Those with nephritis usually have antibodies directed against dsDNA as well as single-stranded DNA, and have at most low titers of anti-Ro and anti-La antibody. They also have high avidity anti-DNA antibodies that activate complement strongly. Higher avidity anti-DNA antibodies also occur in proliferative more than membranous lupus nephritis, and cationic antibodies appear to be more pathogenic. Antibodies directed against C1q are more frequent in those with nephritis also. Renal Manifestations of Lupus Nephrologists often forget that only 25 to 50% of unselected patients with lupus have abnormalities of urine or renal function early in their course, although up to 60% of adults and 80% of children may develop overt renal abnormalities later. In those over 50 yr of age at onset, less than 5% have nephritis initially. The dominant feature of renal lupus is proteinuria (Table 1), present in almost every patient and commonly leading to the nephrotic syndrome. Microscopic hematuria is almost always present, but never in isolation; macroscopic hematuria is rare. Surprisingly, hypertension is not overall more common in those with nephritis than in those without; but, as expected, those with more severe nephritis are more commonly hypertensive. About half will show a reduced GFR, and occasional patients present with acute renal failure. Renal tubular function is disturbed, which is not surprising in view of the finding of both immune aggregates in tubular basement membranes and the presence of interstitial nephritis (see below). In a high proportion of patients, urinary excretion of light chains and β2-microglobulin are both increased. Recently, hyperkalemic renal tubular acidosis has been emphasized as a manifestation of lupus (8).Table 1: Clinical features of patients with lupus nephritisaExtrarenal Manifestations in Lupus Nephritis Because lupus is a systemic disease, the management of the nephritis must be seen as part of the whole management of the lupus syndrome. In some patients, the effects of the extrarenal disease will dominate, and all nephrologists need to be skilled in the early recognition, diagnosis, and treatment of lupus affecting other body systems. The initial complaints are usually nonrenal, even in patients who later develop severe nephritis, although a small number of patients develop what initially appears to be an idiopathic nephritis and then develop lupus. The major features of lupus in other organ systems are described in detail in texts on lupus in The most important and serious is lupus in Lupus Nephritis Antibodies antibodies, particularly those against dsDNA and the are associated with the presence of nephritis (Table The antibody is but present only in to 50% of patients with nephritis, more in patients than in may antibodies from the while the on the antinuclear antibody The of etc.) are not in lupus from other antinuclear present in patients with of is but a positive for antibodies can be only in a of patients with lupus, and severe are not often to is with 50% of patients a while is found in of The of the are from of of in the and and/or of circulating by of both antiphospholipid antibodies and immune complexes with circulating Antibodies and the The is on the presence of antiphospholipid antibodies, directed against the than the These antibodies in but in are associated with The in mechanisms are but what in remains antibodies can be in to of patients with lupus nephritis, and have been associated with renal and as well as and It is important to that the in of it is to do in the presence of antiphospholipid in a of that on with is the of a lupus and will with These may be antibodies directed against factors leading to such as factor and but also less commonly factors and risk factors of and also of of free and factor The of lupus is usually but about half of patients with lupus are initially of a disease other than lupus, most commonly and of in in such as a nephrotic or idiopathic membranous in a It be to all patients for antinuclear Nephritis has been reported in a of patients with disease but of the antinuclear antibody for the anti-Ro and anti-La antibodies of and the of antibodies the usually not show systemic but on proteinuria will be by one of the in its treatment and in of these patients on to develop clinical and immunologic lupus. The presence of and a lupus but not may be the of lupus may be and can affect the lower and a few patients with lupus may have in their renal with Lupus may on be by a which of with other of cytoplasmic antibodies may to be present (see Immunologic and the of Lupus are to a of lupus nephritis some antinuclear antibodies in the to with dsDNA patients with negative antinuclear antibody show or no renal disease, although there are and more than 80% of this have antiphospholipid antibodies The proportion of positive not only on the but also on the The only high avidity also up low avidity antibodies, as the with the presence and of nephritis are best with high avidity antibodies the but for the has it will in some patients in the is but who do have lupus. antibodies are almost for lupus, but are found only in about of patients, and thus have a low is found at in more than of patients with lupus, and is more common with evident The of and C1q to be more than which complement the is almost never seen in idiopathic nephritis or acute glomerulonephritis, although common in However, of and factor are also through of the The of cytoplasmic antibodies is difficult in the presence of antinuclear antibodies, and may be as a positive However, the finding of multiple together with complement in the glomeruli, and a than a no Immune complexes can be in the of the majority of patients with lupus, those with nephritis, and the in rises and with of clinical However, their in is so other show immune complexes of and immune is no in clinical In addition, for have been to not immune complexes but autoantibodies. Renal Renal is in all patients with lupus who have urine and/or reduced renal function it and initial treatment (see below). The characteristic of lupus nephritis is its patients, biopsies, and even The of lupus nephritis (Table and A through and 2, A through on light is but at best it only a of to be proliferative and is a of it such a of there is a in the proportion of patients to in different series from all over the more than half show or nephritis 2, A and severe which most treat The proportion of is about the in all to 2, and The of lupus of lupus 1: of a in patient with lupus nephritis, of of of in lupus of a with and proliferative characteristic of glomerulonephritis. of of from patient with lupus of is in the presence of tubular membrane often in lupus of of of lupus of in from patient with lupus of the of membranous glomerulonephritis. of in lupus of is almost always the dominant with and being however, a few patients show or complement components such as and C1q are usually present, with The finding of for all of together with and C1q is present in about of patients with lupus, and almost never in disease. immune such as complement components and are also present in by is often present in but rare in other Nephritis In about 50% of patients with nephritis, less in those with but in up to of those with immune aggregates are present in the tubular basement membrane In an occasional tubular is of The interstitial cellular is T lymphocytes and monocytes, with only a few and the T both CD4+ and CD8+ are present, with the being and of tubules is seen in disease. In more disease, the is with a of In a few patients, an acute nephritis is seen in the of disease and may present as acute renal immune aggregates, and and with and of the may all be more rarely of these are of a prognosis (see below), and thus are important to patients show overt on and criteria. have been the presence of antiphospholipid antibodies and by some is rare in lupus, with the that of proteins such as A and do not in the of in lupus. disease and have been reported in lupus in occasional show that is common is from proliferative to a membranous renal function proteinuria may these A number of have noted that lupus patients clinical of nephritis in renal biopsies, significant disease. There have been few on such patients, but one that the majority clinical nephritis for However, it is that all patients with clinically evident nephritis must have through a of or disease before this particularly as the proportion of patients with nephritis at onset is so of these patients a for a is not more severe of nephritis have a to in more severe clinical renal be with from the clinical In patients, is a of However, this is no patients with more severe nephritis are more treatment (see below). and interstitial well with at the of as well as with of antibody similar in patients in all but have noted not clinically the a renal is the patient will almost have some treatment, which will the and in Patients with Lupus Nephritis The clinical of lupus can no be considered from the of treatment (1, or more few patients with severe nephritis more than a year or and half of those with even less severe of nephritis to yr (Table There has been in the for patients with biopsies, which from lupus nephritis as a There that this has been the of management of the disease, and this has to almost all patients with lupus nephritis treatment, including those with the However, the data of must not be In the patients with lupus and proteinuria who treatment, and in the proteinuria or for lupus, lupus nephritis, and nephritis over the most patients there is a to early treatment, by relatively disease that can be common is the patient who The and of not only on the disease, but on the and of lupus is a disease, the not of only on what to renal that this is by and are compared with yr and However, those reduced renal function renal is the of proteinuria in the of disease How can treatment be to of of patients with lupus to overall of in lupus (Table are much more than in other of primary glomerulonephritis, in which renal is the dominant It must be that the data in this a considerable and that they may not in to such as to of patient with lupus nephritis renal and is the of in lupus lupus affecting the system or are and almost half of all lupus are to excess particularly from in renal this is usually the first of The proportion of patients in renal disease who have lupus has been patients on still to other of patients and of lupus nephritis in the is rare and its incidence has been the have not often strict for lupus nephritis in of in lupus with in to and There has been more than which features be associated with a in lupus nephritis and data to the are Clinical factors in some not age at onset than onset, black and of clinical number of present at onset, and the number of clinical also in some renal there is or no in different of nephritis in patients, although and to a as do the number of and T in the have also been to a as in other of nephritis, but disease is relatively in lupus. the and have been associated with also, although the has been of and the of to of high and low risk for a and also and not to treatment, although these data are not by all other complement of circulating and have been but are not in The strongest of is with and a DNA at onset all with a of Lupus Nephritis In the treatment of lupus nephritis, are with the treatment of severe acute disease, often affecting systems and usually the onset of the the of the disease is and the treatment and management of more or less disease, which from the effects of treatment more and more important The evidence for all but the of lupus nephritis with is but no a with one not so has been is such a to be in the In most patients with or urine the will be the and treatment Whether treatment with at this of severe disease has never been There is evidence that early treatment of those with but urine but renal function and is the evidence on whether the of membranous improved treatment, although most treat patients with this a proportion of such patients renal failure. it is in those with proliferative nephritis of or severe proliferative nephritis to have the most to however, no have been to whether is by the treatment to the in this However, it is difficult to with the in described in the The in high with 60 carry a in of believe together with to can the incidence of these particularly on This is of that treatment is to a of to effects described of high of or even through and hypertension may be and acute of these to be more common in children and with lupus. It is difficult to whether are in of and than with the only reported thus concerned patients with lupus, and only small and this subject and to the that there is no evidence that the of cytotoxic agents, such as or in the acute the most still a cytotoxic in the acute of severe lupus nephritis and this is by of has the in the that it is a much more of than and the of autoantibodies is reduced to and most it for Whether there is in by the the acute is is commonly although it not to a which for one of its is as the has to be before it is so that there is no the patient is usually in the at this not be an there is an for in lupus, a role in acute severe lupus nephritis has not been The no of the of a times over cytotoxic and and to show with the to antibody have even more of for to but it is whether this treatment be in patients with associated severe syndrome, or however, to it as a treatment of all has A for the treatment of the acute of lupus nephritis as in the is in treatment of lupus the acute disease will be or although occasional patients may have a and of The of to or disease and the effects of the to this are a number of and a of the of treatment in the as well as the acute no of other have been the effects of be to to or and have not been compared in lupus, but the are often in children to of have been but the and of this have never been has been almost although effects of to be less in other in of an clinical of cytotoxic to in the is that the data from the have less of renal at to yr in those with a cytotoxic than in those with although it not to in this the cytotoxic or the of In these only with improved in to a of only with it is important to that there no in clinical those with either or and the in the and those with not more than yr of been be for than about of and and the acute it has no in then has been for of up to yr or as noted the in and to those with even there no from those However, it has evident that the treatment, a considerable risk of with and early a finding in a and with This may be a particularly important in the children with lupus, who the treatment damage in be by the so that a is not be such treatment, although it may be at a later in those who do not The risk of such may not be evident for from that in the remains present of of is However, a major of the is that in patients it low with effects on and the treatment can be in of to has in the although is common and higher will this the acute of the disease but in the have initial and then patients to (Table There is evidence that the of not on and almost have a has only a small can be and is and are rare. In lupus nephritis, as or than the best with by can be by initial by and In a of cytotoxic is In view there is no evidence as that a ratio in the than and no these has been has been on as an but its effects and than has been recently in clinical with however, more data are be to patients with lupus of its on T through of evidence that a of to a in some patients, although a often of There is no in antibody not appear to be particularly in acute lupus, but can have a role in the as a and for its in proteinuria in nephrotic has been in a number of small series of patients with lupus, including those to with How it is but of by the antibodies and effects on are the most usual and have been for up to or is seen in renal function may its in nephrotic patients, the in some of the of the of Immunologic Patients with severe lupus have been have been with for but the of this on prepubertal or more have been in disease with major treatment including and These are still as are less immunologic including the of antibodies and to of immune which in have a major role to in of antibody may be associated with a number of patients for and there is a and In the main of DNA is that usually of treatment the complement are of the acute in severe clinical and data are almost always for Lupus Nephritis A number of other have been for lupus nephritis, but have not a major on clinical the patient with a surprising of and have reported even in severe This treatment has also been in lupus, but in view of the in in lupus nephritis and the of this of to interstitial nephritis, this has not or receptor have not been to be against lupus nephritis, either or to and The has been to from lupus nephritis, with a in antibody a high the disease. A of in human lupus effects on and titers not has been on on and are particularly in view of the disease reported in women with lupus, which is a major of and in Lupus The of management in patients with lupus nephritis is of disease with effects of This is not but to the of patients can renal may whether a in renal function with proteinuria is the of glomerulonephritis, or of which at the to renal of and immunologic are of occasional patients will more than yr from onset of disease treatment is it is often to treatment yr or more even in patients with severe lupus at onset, whose disease will have although a proportion may of Lupus and its (Table will be seen in up to half of patients with lupus. such as and are more common in lupus, and the treatment the are those of the treatment of is by the most common seen and is to the of not is particularly common in early treatment with always be to can be a major and be excluded in lupus patients with The is not in of lupus from there is usually only a with of disease. However, with in has as a major of later have been reported in patients, in the of risk factors for in lupus and hypertension even in and in a the of renal disease. present in about of patients, and their a for antiphospholipid antibodies and other in the body may be but thromboses the However, an antiphospholipid antibody is present, thromboses may be seen more with being particularly is and is perhaps the or renal is frequent also, in the of membranous A number of patients with a picture of lupus and have been described, who may develop acute renal and in have a is rare in The excess of may be and of the of lupus and its treatment