Version May 2024
INTRODUCTION — Kidney involvement is common in systemic lupus erythematosus (SLE). An abnormal urinalysis with or without an elevated plasma creatinine concentration is present in a large proportion of patients at the time of diagnosis of lupus nephritis (LN).
An overview of the epidemiology, pathogenesis, diagnosis, and classification of LN will be presented here. The approach to therapy in the different types of LN is discussed separately:
●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)
EPIDEMIOLOGY — Most patients with systemic lupus erythematosus (SLE) will have clinical evidence of kidney disease, usually an abnormal urinalysis, at some point in the course of their disease [1-4]. Lupus nephritis (LN) typically develops early in the disease course [5]. Clinically evident kidney disease eventually occurs in up to one-half of patients with SLE, and up to 10 percent of patients with LN will develop end-stage kidney disease (ESKD) [1,6-18]. In one cohort of 1827 patients with newly diagnosed SLE, LN occurred in 700 (38 percent) patients followed for a mean of 4.6 years [19]. The overall 10-year incidence of ESKD was 4 percent and, in patients with LN, 10 percent. In this cohort, LN was also associated with a threefold increased risk of death. Study-to-study variations in prevalence estimates of LN may be due in part to racial differences in disease prevalence and/or risk of nephropathy, as well as varying definitions and/or disease ascertainment [14,18,20,21].
There is a higher incidence of LN among patients with SLE in the United States as compared with Europe, which may in part reflect racial and ethnic differences [12,15-17]. The incidence of LN is higher in Black patients with SLE (34 to 51 percent), Hispanic patients (31 to 43 percent), and Asian patients (33 to 55 percent) than it is in White patients (14 to 23 percent) [5-9,21]. Black patients and Hispanic patients also tend to present with more severe underlying histopathology, higher serum creatinine concentrations, and more proteinuria than White patients [5,22]. In addition, Black patients, Hispanic patients, and those living in poverty have a worse prognosis than White patients and those with a higher socioeconomic status. However, the higher frequency of LN in Black populations persists even after correction for socioeconomic factors [21-23].
The time course for the development of LN varies with sex, age, and ethnicity. In a retrospective study in the United States, males, younger patients (eg, less than 33 years of age at diagnosis), and patients who are not White were at enhanced risk of developing nephritis earlier in the course of the disease [13]. A number of patient characteristics place patients with LN at greater risk for progressive kidney disease including African or Hispanic ancestry, male sex, pediatric onset, frequent relapses or incomplete remission, and proteinuria >4 g/day at diagnosis [24].
PATHOGENESIS — Although lupus nephritis (LN) is considered to be a classic form of immune complex glomerulonephritis, the pathogenesis of LN is complicated. The pathogenesis may involve the expression of genes, both in the peripheral blood as well as in the kidneys, leading to neutrophil activation and increased expression of interferon and upregulation of myeloid cell and proinflammatory transcriptomes [1,25-27]. Neutrophils and dying neutrophils may release neutrophil extracellular traps (NETs) composed of chromatin, histones, and immunostimulatory proteins that become a source of nuclear antigens allowing antigen-specific autoantibody production [28]. NET degradation has been found to be decreased in patients with systemic lupus erythematosus (SLE) and especially in those with LN [29]. Complement activation in LN may damage the kidney through endothelial damage and enhancement of kidney inflammation [30].
The pattern of glomerular injury seen in SLE (and in other immune complex-mediated glomerular diseases) is generally related to the site of formation of the immune deposits, which are primarily due to anti-double-stranded DNA (anti-dsDNA or anti-DNA) antibodies. These antibodies bind DNA in various forms, such as DNA in the form of nucleosomes, which consist of double-stranded DNA (dsDNA) wound around a core histone octamer [10].
●Anti-dsDNA immune complex formation – These immune complexes are primarily composed of DNA and anti-dsDNA. However, immune complexes may also have as their components chromatin, C1q, laminin, Sm, La (SS-B), Ro (SS-A), ubiquitin, ribosomes, and glomerular elements including the parts of the glomerular basement membrane (GBM) and mesangium [31-38]. The immune deposits in LN can occur in the mesangium, subendothelial, and/or subepithelial compartments of the glomerulus.
The site of immune complex formation is related to the characteristics of both the antigen and antibody:
•Mesangium and subendothelial space – Large, intact immune complexes or anionic antigens (which cannot cross the anionic charge barrier in the glomerular capillary wall) are deposited in the mesangium and subendothelial space [31,32]. These deposits are proximal to the GBM and are therefore in communication with the vascular space. As a result, activation of complement (typically via the classical pathway) with the generation of the chemoattractants, C3a and C5a, results in the influx of neutrophils and mononuclear cells. These changes are manifested histologically by a mesangial, focal, or diffuse proliferative glomerulonephritis and clinically by an active urine sediment (red cells, white cells, and cellular and granular casts), proteinuria, and, often, an acute decline in kidney function.
The degree and nature of immune deposition as well as the response to the deposits determine whether the patient develops mild disease limited to the mesangium or a more severe focal or diffuse proliferative glomerulonephritis. (See "Mechanisms of immune injury of the glomerulus".)
•Subepithelial space – Experimental studies suggest that there are two primary mechanisms by which subepithelial deposits may form: a cationic antigen that can cross the GBM and fix in a subepithelial location with subsequent antibody complexing or an autoantibody may be directed against an endogenous epithelial cell antigen [39]. Although deposits in the subepithelial space can also activate complement, there is no influx of inflammatory cells, since the chemoattractants are separated from the circulation by the GBM. Thus, injury is limited to the glomerular epithelial cells, and the primary clinical manifestation is proteinuria, which is often in the nephrotic range. Histologically, these patients most commonly have membranous nephropathy.
Immune complex deposition can activate other arms of the inflammatory response:
•Upregulation and activation of adhesion molecules on endothelium can result in the recruitment of proinflammatory leukocytes and the initiation of autoimmune injury [40]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)
•Activated mesangial cells, infiltrating macrophages, and B and T cells produce inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, tumor growth factor-beta, interferon-gamma, chemokines, and platelet-derived growth factor. All of these inflammatory mediators have the potential to extend kidney injury [41-44]. Activated platelets may also contribute to mesangial cell proliferation [45].
Although kidney disease is primarily due to anti-dsDNA complexes, some data suggest that autoantibodies against C1q, a complement component, may correlate with LN [46-48]. These antibodies may promote disease by binding to C1q that has been fixed on immune complexes on the GBM [49]. The binding of anti-C1q antibodies to C1q activates complement, resulting in an influx of inflammatory cells.
●Other mechanisms – The induction of nephritis by anti-dsDNA may not require immune complex formation. Anti-dsDNA antibodies appear to bind to human mesangial cells in vitro and induce production of proinflammatory substances [50,51]. In an in vitro system, for example, anti-dsDNA isolated during active LN induced mesangial cell production of IL-1 (and other proinflammatory substances), which in turn increased synthesis of hyaluronan (an extracellular matrix component that accumulates during tissue injury and recruits lymphocytes) [51]. The plasma cells that secrete these autoantibodies have been located not just in the spleen and bone marrow but also in the tubulointerstitium of the cortex and outer medulla of the kidney [52]. Thus, the kidney may be a major site of autoreactive plasma cells in LN.
Neutrophils and NETs may add to antigen-specific autoantibody production facilitating inflammation, endothelial damage, and local interferon alpha production in the kidney [1,28,29].
●Genetics – A variety of genes and genetic factors reportedly predispose patients to the development of SLE and influence the clinical picture of kidney disease in SLE [53]. A meta-analysis of studies evaluating the relationship between polymorphisms of HLA-DRB1 alleles and SLE found that some genotypes (HLA-DR4 and -DR11) conferred protection from LN while others were associated with an increased risk of LN (HLA-DR3 and -DR15) [54]. Another meta-analysis found a stronger association between the genes for platelet derived growth factor receptor alpha (PDGFRA) and solute carrier family 5 member 11 (SLC5A11) and LN compared with human leukocyte antigen (HLA) loci [55]. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Genetic factors'.)
The increased frequency and severity of LN among African Americans has led to the examination of genetic factors that might predispose them to LN [56-61]. Polymorphisms in the immunoglobulin receptor alleles Fc-gamma-RIIa-H131, present on macrophages, have been associated with susceptibility to LN in some studies [56,60], although conflicting data exist [57]. Other studies have noted an association between polymorphisms in the Fc-gamma-RIIIa-F158 receptor allele and Fc-gamma-RIIIb and LN [58,59].
These polymorphisms result in alterations of the binding avidity of the receptors to their specific immunoglobulin G (IgG) subclasses [58]. It is hypothesized that this change permits the inappropriate deposition of circulating immune complexes in the kidney (and elsewhere) due to inadequate clearance by hepatic and splenic macrophages [56]. These differences may contribute to a worse prognosis in LN. As an example, African Americans have higher frequencies of certain Fc-gamma-RIIa-R131 alleles associated with phagocytosis of IgG2 immune complexes [56].
Two APOL1 gene variants (APO L1 G1 and G2) that are found almost exclusively in African Americans have been associated with glomerulosclerosis and disease progression in a number of disorders including LN [62,63]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis" and "HIV-associated nephropathy (HIVAN)".)
CLINICAL FEATURES — Kidney disease is typically detected in most patients with systemic lupus erythematosus (SLE) by an abnormal urinalysis with or without an elevated plasma creatinine concentration. The most frequently observed abnormality in patients with lupus nephritis (LN) is proteinuria [1,4,5,64]. Other common clinical manifestations include microscopic hematuria with or without red cell casts, kidney function impairment, nephrotic-range proteinuria or nephrotic syndrome, and hypertension [1]. As a result, all patients with SLE should be routinely monitored for kidney disease. (See 'When to suspect LN' below.)
Most kidney abnormalities emerge soon after the diagnosis of SLE is made (commonly, within the first 6 to 36 months) [1,13,65]. In some cases, manifestations of LN are the presenting features of SLE [66]. An elevated plasma creatinine concentration eventually develops in approximately 30 percent of all patients with SLE.
Rarely, patients may have silent LN, in which significant abnormalities are observed on kidney biopsy without any clinical signs of kidney involvement. Studies in which a kidney biopsy is performed in patients without any clinical evidence of kidney disease have found mesangial, focal, or diffuse proliferative glomerulonephritis in some patients [67-70]. As an example, a cohort study evaluated the kidney pathology of 195 patients with SLE, 86 of whom had no clinical kidney involvement; among those without clinical kidney involvement, 13 (15 percent) had either class III or IV LN, and 9 (10 percent) had class V (membranous) disease [70].
The kidney disease in patients with silent LN often remains clinically silent and is associated with a benign kidney outcome [67,70]. Some patients, however, progress to overt nephritis [68].
EVALUATION AND DIAGNOSIS
When to suspect LN — The presence of lupus nephritis (LN) should be suspected in patients with known systemic lupus erythematosus (SLE) who develop an active urinary sediment with persistent hematuria (five or more red blood cells, most of which are dysmorphic, per high-power field) and/or cellular casts, proteinuria, and/or an elevated serum creatinine (or decrease in estimated glomerular filtration rate [eGFR]) [2,3]. Elevated anti-double-stranded-DNA (anti-dsDNA) titers and low complement (C3 and C4) levels often indicate active SLE, particularly LN, although the utility of serological assessment differs among patients.
All patients with known SLE should undergo laboratory testing to assess for kidney involvement at regular intervals. The frequency with which monitoring laboratory tests are performed is tailored to each patient and is discussed in detail separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Monitoring response to therapy'.)
There are some patients for whom signs and symptoms of LN are the predominant presenting symptoms resulting in the diagnosis of SLE. The approach to diagnosing SLE in such patients is reviewed in a separate topic. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation'.)
Establishing the diagnosis — The diagnosis of LN is ideally confirmed by a kidney biopsy [2,3,71]. A kidney biopsy is important to define the nature of kidney involvement, exclude other causes of kidney injury, and determine the histopathologic subtype of LN. Biopsies are also important to assess disease activity and chronicity. (See 'Histopathologic classification of LN' below.)
Role of kidney biopsy — A kidney biopsy should be performed in most patients with SLE who have clinical or laboratory evidence of kidney involvement (eg, abnormal proteinuria, active urine sediment, elevated serum creatinine and/or decreased glomerular filtration rate [GFR]) to establish the correct diagnosis and determine the histologic subtype of LN. However, as with any other invasive procedure, an individualized risk-benefit assessment is required prior to performing the procedure. (See "The kidney biopsy", section on 'Appropriate use of kidney biopsy'.)
We generally perform a kidney biopsy in patients who have one or more of the following clinical manifestations:
●Urine protein excretion greater than 500 mg/day.
●An active urinary sediment with persistent hematuria (five or more red blood cells per high-power field, most of which are dysmorphic) and/or cellular casts. The urine may be contaminated with vaginal blood in menstruating women or with bladder red cells with urinary tract infections. Red cells from these sources are not dysmorphic.
●A rising serum creatinine that is not clearly attributable to another mechanism.
Our approach is consistent with the indications for kidney biopsy included in the joint European Alliance of Associations for Rheumatology (formerly known as European League Against Rheumatism)/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) guidelines [72].
Determining the nature and class of LN is important for the following reasons:
●Treatment is guided by the histologic subtype (ie, the International Society of Nephrology/Renal Pathology Society [ISN/RPS] class, the degree of activity and chronicity) and by complicating lesions such as interstitial nephritis and thrombotic microangiopathy.
●Biopsy may also identify entities other than LN. Some patients with SLE and nephrotic-range proteinuria will have a lupus podocytopathy without major immune complex deposition but with effaced foot processes as seen in minimal change disease. Others with kidney disease may have a thrombotic microangiopathy or predominant tubulointerstitial involvement rather than major glomerular involvement.
●The clinical presentation may not accurately reflect the severity of the histologic findings. As an example, infrequently, proliferative lupus may be present even if the patient has minimal proteinuria and normal serum creatinine.
We generally do not perform a kidney biopsy in patients with proteinuria that is less than 500 mg/day and a bland urine sediment. Such patients are unlikely to have focal or diffuse LN or lupus membranous nephropathy. They may have minimal mesangial or mesangial proliferative disease, neither of which requires immunosuppressive therapy. Such patients should still be monitored for evidence of progressive disease such as increasing proteinuria, emergence of an active sediment, and/or an increase in serum creatinine. These manifestations suggest transformation to a more severe lesion and warrant kidney biopsy. Data supporting close monitoring of patients with low-grade proteinuria are provided by a study of 151 patients with SLE and proteinuria ≥0.2 and <0.5 g/g, which found that half progressed to a urine protein-to-creatinine ratio of ≥0.5 g/g within one to two years [73]. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Laboratory evaluation' and "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Monitoring response to therapy'.)
Characteristic histopathologic findings — The histopathology of LN can be quite varied, and at times, LN may be confused with other immune complex-mediated glomerulonephritides. However, some histopathologic features are highly characteristic of LN. These include:
●Glomerular deposits that stain dominantly for IgG and contain codeposits of immunoglobulin A (IgA), immunoglobulin M (IgM), C3, and C1q, the so-called "full house" immunofluorescence pattern. Less commonly, the "full house" immunofluorescence pattern may also be seen in patients with endocarditis [74], HIV [75], hepatitis C [76], a portosystemic shunt [77], and poststreptococcal glomerulonephritis. In addition, intense staining for C1q has also been shown to have a similar sensitivity and specificity for LN as the "full house" staining pattern [78].
●Glomerular deposits simultaneously seen in the mesangial, subendothelial, and subepithelial locations.
●Extraglomerular immune-type deposits within tubular basement membranes, the interstitium, and blood vessels.
●Tubuloreticular inclusions in the glomerular endothelial cells (picture 1). These inclusions are composed of ribonucleoprotein and membrane, and their synthesis is stimulated by alpha-interferon [79]. The only other circumstances in which these structures are prominent are in HIV nephropathy (associated with chronically high levels of circulating alpha-interferon) and treatment with alpha-interferon. However, patients with HIV nephropathy typically have collapsing focal segmental glomerulosclerosis without evidence of immune complexes rather than a proliferative glomerulonephritis with immune complex deposition. (See "HIV-associated nephropathy (HIVAN)".)
Timing of initial biopsy — Ideally, a kidney biopsy is performed promptly (ie, within days to weeks) in patients who have an appropriate indication. Prompt diagnosis after the onset of LN and subsequent initiation of appropriate therapy are associated with improved outcomes, regardless of the histologic class [80-82]. A rapidly rising serum creatinine and/or the development of new nephrotic-range proteinuria are indications for urgent kidney biopsy so that an accurate diagnosis can be established, and appropriate treatment can be initiated as soon as possible.
The potential magnitude of the increase in risk with delayed kidney biopsy was illustrated in a study of 91 patients with LN who were followed for a median of six years. Patients who had clinically recognized kidney disease for six or more months prior to biopsy had a much higher rate of end-stage kidney disease (ESKD; 47 versus 14 per 1000 patient-years for those who had an earlier biopsy; hazard ratio 9.3, 95% CI 1.8-47.0) [80]. Similar findings were noted in another report in which the relative risk for subsequent kidney function impairment was 4.9 in patients with a delay between the time of detection of kidney disease and first kidney biopsy [81].
When to repeat the biopsy — The indications for a repeat biopsy include the emergence of an active sediment in someone with previously quiescent disease, a new elevation in serum creatinine, and/or worsening of proteinuria despite treatment [83-86]. In a report from a single institution, transformation from one histologic pattern to another (most frequently from focal to diffuse LN or from diffuse to advanced sclerosing LN) was noted in more than one-half of patients who underwent repeat kidney biopsy [84].
The utility of repeat biopsy depends in part upon the histologic diagnosis obtained on the initial biopsy. Among patients with lupus membranous nephropathy, a repeat biopsy is warranted for those who develop an active sediment or a rising serum creatinine since these findings suggest transformation to a class III or IV lesion, which usually requires different treatment. In a retrospective study of 29 patients with lupus membranous nephropathy, the probability of a transition from membranous to class III or IV nephritis at 10 years was 35 percent [83]. By contrast, recurrence of proteinuria generally is not an indication for repeat biopsy in lupus membranous nephropathy, since relapse of isolated proteinuria is common, especially after immunosuppressive therapy with cyclosporine [87]. (See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
The value of a repeat biopsy has been debated. Some feel a repeat biopsy may not be necessary in patients with successfully treated diffuse LN who develop a recurrent active sediment that almost certainly represents recurrent diffuse disease. Kidney biopsy is unlikely to provide any additional data that would affect treatment in most such patients. Others feel that there may be a discordance between the clinical findings suggesting remission and persistent histologic activity in the repeat biopsy [88-91]. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
Settings in which repeat kidney biopsy is helpful include:
●Increasing proteinuria. In one report, increasing proteinuria was the indication for repeat biopsy in 45 of 57 patients with LN who had at least two kidney biopsies [86]. Also, new or worsening nephrotic syndrome in patients with treated class III or IV LN may reflect a concurrent membranous lesion, which may require a different approach to therapy.
●An active urine sediment and a rapidly rising serum creatinine. This might reflect crescentic disease that may warrant more aggressive initial therapy, such as pulse glucocorticoids.
●Slowly rising serum creatinine or persistent proteinuria. The goal of repeat biopsy is to distinguish active LN from advanced sclerosing LN (class VI) alone, which would not be treated with immunosuppressive therapy.
●Suspicion of possible kidney disease unrelated to LN (eg, drug-induced acute interstitial nephritis).
●Helping to guide the tapering or withdrawal of immunosuppressives in patients on long-term maintenance therapy who are in clinical remission. In a single-center study, 44 patients with LN underwent a repeat kidney biopsy and withdrawal of maintenance immunosuppression after they were in clinical remission for at least 12 months and on maintenance immunosuppression for at least 36 months [92]. Forty-four percent of the patients had persistent histologic activity on repeat kidney biopsy despite being in a clinical remission on maintenance therapy. After withdrawal of maintenance immunosuppression, LN flared in 35 percent of patients. Ninety-one percent of flares occurred in patients with active histopathology on repeat biopsy.
There is no consensus among the authors and editors of this topic on when to perform repeat kidney biopsy in patients with slowly progressive chronic kidney disease. Such patients may have nonimmunologic injury induced by nephron loss from previous inflammatory disease, with subsequent intraglomerular hypertension and hyperfiltration. Clinical manifestations in these patients may include a gradual increase in protein excretion (non-nephrotic), a bland urine sediment without hematuria (although residual hematuria can occasionally be seen), and a gradual increase in serum creatinine. In a study of 45 patients who had a repeat kidney biopsy for the evaluation of increasing proteinuria, the most common finding was a decrease in active lesions and an increase in chronic changes [86]. Treatment in these patients generally does not involve immunosuppressive therapy, but continued monitoring for signs of active kidney disease is recommended. However, possible indications for repeat kidney biopsy include the presence of antiphospholipid antibodies (which can cause kidney disease with a bland urine sediment), active extrarenal lupus, and markedly elevated anti-dsDNA antibody titers with or without hypocomplementemia. (See "Antiphospholipid syndrome and the kidney", section on 'Kidney disease in APS associated with systemic lupus erythematosus'.)
Histopathologic classification of LN — Based upon clinicopathologic correlations derived from kidney biopsy, a lupus nephritis (LN) classification system was developed by a group of kidney pathologists, nephrologists, and rheumatologists in 2004 (the ISN/RPS classification) and revised in 2018 [93-96]. The revised ISN/RPS classification system divides glomerular disorders associated with SLE into six different patterns (or classes) based upon kidney biopsy histopathology [93,94,96]. LN activity and chronicity indices have also been proposed to provide more granularity to the diagnosis of active and chronic lesions [96]. (See 'Activity and chronicity' below.)
Although the different classes tend to have distinct histologic, clinical, and prognostic characteristics, there is substantial overlap due in part to variations in sampling. In addition, a significant percentage of patients evolve from one class of LN to another, sometimes after therapy and sometimes spontaneously [84,93,97-100]. The evolution from one class of nephritis to another is not surprising, since the different histologic types represent nonspecific responses to immune complex deposition.
Although various serologic and urine markers have been examined as potential noninvasive determinants of histologic class [101-104], no serum or urine marker of disease activity provides the degree of information that is gained by histopathology. Thus, classification of LN is determined by kidney biopsy [96].
Minimal mesangial LN (class I) — This class of lupus nephritis (LN) is rarely, if ever, diagnosed because these patients typically have a normal urinalysis, no or minimal proteinuria, and a normal serum creatinine. As a result, a biopsy is not usually performed. Patients with class I disease have only mesangial immune deposits that are identified by immunofluorescence alone or by both immunofluorescence and electron microscopy, but such patients do not have light microscopic abnormalities. Minimal mesangial LN (class I) represents the earliest and mildest form of glomerular involvement.
Mesangial proliferative LN (class II) — The histologic changes with class II disease are manifested clinically by microscopic hematuria and/or proteinuria. Hypertension is uncommon, and nephrotic syndrome and kidney function impairment are virtually never seen.
Light microscopy with class II disease reveals mesangial hypercellularity (of any degree) or mesangial matrix expansion (picture 2). A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy. Visible subendothelial deposits on light microscopy or any global or segmental glomerular scars (which are thought to be the result of previous endocapillary hypercellularity, necrosis, or crescents) are inconsistent with the diagnosis of class II LN. Such findings would indicate either class III or IV disease. Extensive podocyte effacement with nephrotic syndrome can rarely be seen, resembling minimal change disease if there is an associated podocytopathy.
The kidney prognosis with mesangial proliferative LN is excellent, and no specific therapy is indicated unless the patient progresses to more advanced disease or has evidence of extensive podocyte effacement and nephrosis. (See 'Lupus podocytopathy' below.)
Focal LN (class III) — Patients with class III lupus nephritis (LN) usually have hematuria and proteinuria, and some patients will also have hypertension, a decreased GFR, and/or nephrotic syndrome. Class III disease is defined histologically by the following:
●Less than 50 percent of glomeruli are affected by light microscopy. If more than 50 percent are involved, then the disease would be defined as diffuse LN (class IV). Although less than 50 percent of glomeruli are affected on light microscopy, immunofluorescence microscopy (for IgG and C3) reveals almost uniform involvement [105].
●Active or inactive endocapillary or extracapillary glomerulonephritis is almost always segmental (ie, involves less than 50 percent of the glomerular tuft) [94]. Electron microscopy usually reveals immune deposits in the subendothelial space of the glomerular capillary wall as well as the mesangium.
Determining prognosis in class III disease may be limited by the inability to accurately determine the percent of glomeruli involved. This latter feature relates to possible sampling error induced by the relatively small number of glomeruli that are obtained on a typical percutaneous kidney biopsy. (See "The kidney biopsy".)
The treatment of focal LN is discussed separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
Diffuse LN (class IV) — Class IV LN is the most common histologic pattern seen on biopsy and most severe form of lupus nephritis (LN) [106]. Hematuria and proteinuria are present in virtually all patients with active class IV disease, and nephrotic syndrome, hypertension, and reduced GFR are all frequently seen. Affected patients typically have significant hypocomplementemia (especially C3) and elevated anti-dsDNA levels, especially during active disease [107].
Class IV LN is defined histologically by the following:
●More than 50 percent of glomeruli are affected by light microscopy (picture 3). If less than 50 percent are involved, then the disease would be defined as focal LN (class III).
●Affected glomeruli display endocapillary with or without extracapillary glomerulonephritis. Mesangial abnormalities may also be observed. Electron microscopy reveals subendothelial deposits, at least during the active phase (picture 1). The presence of diffuse wire loop deposits, but with little or no glomerular proliferation, is also considered class IV disease.
With active disease, hypercellular, necrotizing lesions, and crescent formation all may be present, affecting more than 50 percent of glomeruli on light microscopy [105,106]. The marked deposition of immunoglobulins (especially IgG) and complement (especially C3) in this setting (picture 4) results in thickening of the glomerular capillary wall (picture 1) and a pattern on light microscopy that is similar to that in membranoproliferative glomerulonephritis. These lesions are characterized by the marked influx of proinflammatory cells (monocytes, suppressor/cytotoxic T cells), sometimes resulting in cellular crescents [108,109].
The treatment of diffuse LN is discussed separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
Lupus membranous nephropathy (class V) — Lupus membranous nephropathy is present in 10 to 20 percent of patients with LN [97,110,111]. Patients with class V LN typically present with signs of the nephrotic syndrome, similar to that in primary membranous nephropathy [31,97,111]. Microscopic hematuria and hypertension may also be seen at presentation, and the creatinine concentration is usually normal or only slightly elevated.
Class V disease is characterized by diffuse thickening of the glomerular capillary wall on light microscopy (picture 5) and by subepithelial immune deposits (either global or segmental involvement) on immunofluorescence or electron microscopy (picture 6) [94,111,112]. Mesangial involvement may also be seen.
Although sparse subendothelial deposits can be seen by immunofluorescence or electron microscopy with class V disease alone, the presence of such deposits as detected by light microscopy warrants a combined diagnosis of classes III and V disease or of classes IV and V disease. In this setting, the additional designation of class III or IV is based upon the distribution of the deposits.
Lupus membranous nephropathy may present with no other clinical or serologic manifestations of SLE (eg, complement levels may be normal, and anti-dsDNA antibodies may not be detectable) [87,111,113-115]. There are, however, several findings on electron and immunofluorescence microscopy that, if present, strongly suggest underlying lupus rather than primary membranous nephropathy. These issues and the treatment of lupus membranous nephropathy are discussed elsewhere. (See "Lupus nephritis: Therapy of lupus membranous nephropathy".)
The presence of significant hematuria and cellular casts with or without an elevated serum creatinine suggests concurrent proliferative disease, which is not uncommon and is associated with a much worse prognosis than class V alone. In a review of 79 patients with lupus membranous nephropathy, 36 had pure membranous lesions, 15 had endocapillary proliferation and/or necrosis in less than 50 percent of glomeruli, and 28 had endocapillary proliferation and/or necrosis in more than 50 percent of glomeruli [116].
Advanced sclerosing LN (class VI) — Patients with advanced sclerosing glomerulonephritis usually display slowly progressive kidney dysfunction in association with proteinuria and a relatively bland urine sediment. Class VI disease is characterized by global sclerosis of more than 90 percent of glomeruli. It represents healing of prior inflammatory injury, as well as the advanced stage of chronic class III, IV, or V lupus nephritis (LN). Active glomerulonephritis should not be observed. A retrospective study found that 4 percent of 169 kidney biopsies from patients with LN were classified with type VI disease [117]. Identification of this lesion is important since immunosuppressive therapy is unlikely to be beneficial.
Activity and chronicity — Most biopsies of patients with LN are classified not only by LN class but also with an index of "activity" and of "chronicity."
●Active lesions are generally inflammatory or proliferative and potentially reversible. These include endocapillary hypercellularity, neutrophils and karyorrhexis, fibrinoid necrosis, hyaline wire loops, cellular or fibrocellular crescents, and interstitial inflammation.
●Chronic lesions imply irreversible damage and would not generally mandate immunosuppression. These include glomerulosclerosis, fibrous crescents, interstitial fibrosis, and tubular atrophy.
The activity and chronicity indices are defined by a summation of scoring of the above findings weighted for more severe components.
OTHER FORMS OF LUPUS KIDNEY DISEASE — In addition to the glomerulopathies, there are other forms of lupus kidney disease, including tubulointerstitial nephritis, vascular disease, lupus podocytopathy, collapsing glomerulosclerosis, and kidney disease infrequently associated with drug-induced lupus [5]. Many of these patterns of kidney damage can only be diagnosed with a biopsy. The investigators responsible for the International Society of Nephrology/Renal Pathologic Society (ISN/RPS) classification system of lupus nephritis (LN) emphasize that the presence and severity of tubulointerstitial and vascular involvement should be noted in any biopsy specimen [93,94,96].
Tubulointerstitial lesions — Tubulointerstitial disease (interstitial infiltrate, tubular injury) with or without immune deposits along the tubular basement membrane is a common finding in LN and is almost always associated with concurrent glomerular disease [118,119]. The severity of the tubulointerstitial involvement is an important prognostic sign, correlating positively with the presence of hypertension, an elevated plasma creatinine concentration, and a progressive clinical course [119-121]. In a study of 313 patients with LN, for example, the presence of tubulointerstitial nephritis was significantly associated with a twofold higher risk of developing end-stage kidney disease (ESKD) or a doubling of serum creatinine after controlling for other prognostic indicators [121]. As expected, both tubular atrophy and interstitial fibrosis were also associated with an increased risk. By contrast, the presence of tubular basement membrane deposits alone correlates with the serologic activity of the disease but not the prognosis [119].
In a few cases, tubulointerstitial disease is the only manifestation of LN. This possibility should be suspected when a patient with systemic lupus erythematosus (SLE) presents with a rising plasma creatinine concentration and a urinalysis that is relatively normal or shows only a few red cells and/or white cells [122,123]. These changes may be accompanied by signs of tubular dysfunction such as metabolic acidosis due to type 1 (distal) renal tubular acidosis, hyperkalemia due to impaired distal potassium secretion, or hypokalemia due to salt wasting and secondary hyperaldosteronism [124,125]. Idiopathic hypokalemia distinct from that associated with renal tubular acidosis has also been observed in a small cohort of patients with LN [126]. Autoantibodies directed against the acid-secreting intercalated cells in the collecting tubule may be responsible for the acid secretory defect in at least some patients [127]. A review of the mechanisms by which distal acid secretion can be altered is discussed elsewhere. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)
Vascular lesions — Involvement of the kidney vasculature is not uncommon in LN, and its presence can adversely affect the prognosis of the kidney disease [117,128,129]. The most frequent manifestations are immune complex deposition (which is typically associated with immune deposits in the glomeruli), immunoglobulin microvascular "thrombi," a thrombotic microangiopathy leading to a syndrome similar to thrombotic thrombocytopenic purpura (TTP), vasculitis, or atheroembolic disease and atherosclerosis [117,128,130-132].
Vascular immune deposits are usually located beneath an intact endothelium. They typically produce no inflammation; however, fibrinoid necrosis with vascular narrowing can be seen in severe cases, often in association with moderate to severe hypertension [129]. It is unclear in this setting whether the hypertension contributes to the vascular injury and/or whether the vascular narrowing exacerbates the hypertension via activation of the renin-angiotensin system. Regardless of the pathogenesis, patients with necrotizing vasculopathy tend to have a worse kidney prognosis than those with isolated glomerular disease.
Rarely, patients with LN develop renal vein thrombosis [133]. These patients are typically nephrotic or have high antiphospholipid antibody levels, and the pathogenesis and treatment of the renal vein thrombosis are similar to that in patients without SLE. (See "Hypercoagulability in nephrotic syndrome".)
Other patients present with glomerular and vascular thrombi. These lesions may involve a diverse group of thrombotic microangiopathies [132]. Some are in association with antiphospholipid antibodies such as the lupus anticoagulant (LA) and anticardiolipin antibodies, or antibodies against the von Willebrand factor convertase (ADAMTS13). The name "LA" refers to the ability of these antibodies to produce in vitro prolongation of the partial thromboplastin time. In vivo, however, antiphospholipid antibodies promote coagulation, leading to venous and arterial thromboses, thrombocytopenia, livedo reticularis, and in women, frequent miscarriages. (See "Antiphospholipid syndrome and the kidney".)
Lupus podocytopathy — Some investigators have demonstrated that a glomerular podocytopathy due to kidney involvement in lupus can be associated with diffuse epithelial cell foot process effacement without immune complex deposition. This is the classic histologic finding of minimal change disease [134-136]. It is estimated such lesions occur in 1 to 2 percent of nephrotic patients with SLE [5,137]. Such lesions have been termed "lupus podocytopathy" [138]. In a retrospective study of 470 kidney biopsies from patients with SLE, biopsies with normal light microscopy or a histologic diagnosis of either focal segmental glomerulosclerosis or mesangial proliferative glomerulonephritis were further evaluated [134]. The absence of endocapillary hypercellularity or necrosis, or of electron-dense glomerular basement membrane deposits, was found in 18 such biopsies, of which eight were from patients with nephrotic-range proteinuria. At least 80 percent foot process effacement was observed in all but one of these eight patients.
There is a possibility that these observations reflect the chance occurrence of SLE and either minimal change nephropathy and/or focal segmental glomerulosclerosis. However, this should occur in less than 1 in 10,000 cases, a frequency that is much less than that observed in this study (7 of 470). In addition, the onset of podocytopathy in these patients is seen most commonly at the onset of SLE or in the setting of a disease flare.
The presence of severe foot process effacement in the absence of deposits in the glomerular capillary wall implies a mechanism that is independent of immune complex deposition, presumably similar to the mechanism of primary minimal change disease or primary focal segmental glomerulosclerosis. Proposed explanations include direct antibody binding to podocyte slit diaphragm proteins, production of a cytokine or lymphokine toxic to podocytes, or podocyte injury driven by T cell dysfunction. A number of lupus podocytopathy cases have been linked to nonsteroidal antiinflammatory drug (NSAID) use for SLE [134,136,138].
Patients with a lupus-related podocytopathy often respond to a short course of high-dose glucocorticoids, similar to patients with isolated minimal change disease [139]. (See "Minimal change disease: Treatment in adults".)
Collapsing glomerulosclerosis — Collapsing glomerulosclerosis is histologically characterized by the collapse of the glomerular capillary tuft with epithelial cell proliferation in the Bowman's space and is clinically characterized by the nephrotic syndrome, kidney function impairment, and rapid progression to ESKD. Collapsing glomerulosclerosis is most often associated with HIV or COVID-19-associated nephropathy, especially in patients of African descent with two risk alleles for APOL1. However, collapsing glomerulosclerosis can also be seen in patients with SLE, usually during an active flare [140]. In addition, such patients may have concurrent LN. These issues are described in detail elsewhere. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)
Drug-induced lupus — A variety of drugs can induce a lupus-like syndrome, such as minocycline, hydralazine, isoniazid, and historically, procainamide. Kidney involvement is an uncommon feature of drug-induced lupus, but a proliferative glomerulonephritis or the nephrotic syndrome can occur. (See "Drug-induced lupus".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Systemic lupus erythematosus".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Lupus and kidney disease (The Basics)")
SUMMARY
●Epidemiology – Most patients with systemic lupus erythematosus (SLE) will have clinical evidence of kidney disease, usually an abnormal urinalysis, at some point in the course of their disease. When present, lupus nephritis (LN) typically develops earlier in the disease course. (See 'Epidemiology' above.)
●Pathogenesis – Although LN is considered to be a classic form of immune complex glomerulonephritis, the pathogenesis of LN can involve a variety of mechanisms. These mechanisms include the expression of genes leading to neutrophil activation, increased expression of genes for interferon and other pro-inflammatory mediators in myeloid and other immune cell populations, release of neutrophil extracellular traps (NETs), and complement activation. The pattern of glomerular injury seen in SLE (and in other immune complex-mediated glomerular diseases) is generally related to the site of formation of the immune deposits, which are primarily due to anti-double-stranded DNA (anti-dsDNA or anti-DNA) antibodies. (See 'Pathogenesis' above.)
●Clinical features – Kidney disease is typically detected in most patients with SLE by an abnormal urinalysis with or without an elevated plasma creatinine concentration. The most frequently observed abnormality in patients with LN is proteinuria. Other common clinical manifestations include microscopic hematuria with or without red cell casts, kidney function impairment, nephrotic-range proteinuria or nephrotic syndrome, and hypertension. (See 'Clinical features' above.)
●When to suspect LN – The presence of LN should be suspected in patients with known SLE who develop an active urinary sediment with persistent hematuria (five or more red blood cells, most of which are dysmorphic, per high-power field) and/or cellular casts, proteinuria, and/or an elevated serum creatinine (or decrease in estimated glomerular filtration rate [eGFR]). Elevated anti-dsDNA titers and low complement (C3 and C4) levels often indicate active SLE, particularly LN, although the utility of serological assessment differs among patients. There are some patients for whom signs and symptoms of LN are the predominant presenting symptoms resulting in the diagnosis of SLE. (See 'When to suspect LN' above.)
●Diagnosis – The diagnosis of LN is ideally confirmed by histologic findings in a kidney biopsy. A kidney biopsy is important to define the nature of kidney involvement, exclude other causes of kidney injury, and determine the histopathologic subtype of LN. Biopsies are also important to assess disease activity and chronicity. (See 'Establishing the diagnosis' above.)
●Histopathologic classification – A widely used classification system of LN divides glomerular disorders associated with SLE into six different patterns or classes based upon kidney biopsy findings including minimal mesangial LN (class I), mesangial proliferative LN (class II), focal LN (class III), diffuse LN (class IV), lupus membranous nephropathy (class V), and advanced sclerosing LN (class VI). (See 'Histopathologic classification of LN' above.)
●Other forms of lupus kidney disease – In addition to the glomerulopathies, there are other forms of lupus kidney disease, including tubulointerstitial nephritis, vascular disease (including thrombotic microangiopathy), lupus podocytopathy, collapsing glomerulosclerosis, and kidney disease infrequently associated with drug-induced lupus. Many of these patterns of kidney damage can only be diagnosed with a biopsy. (See 'Other forms of lupus kidney disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to earlier versions of this topic review.
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