• Antinuclear and anti-DNA antibodies.
  
• Depressed complement components, C3 and C4.
  
• Deposition of nephritogenic immune complexes.
  
• Spectrum of hematuria, proteinuria, hypertension, and renal insufficiency.
  
• Major pathologic classes of lupus nephritis (LN): Class I, minimal mesangial LN; Class II, mesangial proliferative LN; Class III, focal LN; Class IV, diffuse LN (segmental/global); Class V, membranous LN; and Class VI, advanced sclerosis LN.
  
• Variable acute and chronic renal vasculopathy and tubulointerstitial damage.

Evidence of pathogenic autoimmunity within the kidney is manifest in the majority of patients with systemic lupus erythematosus (SLE). The clinical and pathologic effects of the disordered autoimmune processes range from mild and indolent to severe and progressive glomerulonephritis.

The immunologic basis for autoimmunity in SLE is complex and incompletely understood, but there is evidence of dysregulation of both humeral and cellular immune pathways. Autoantibodies to a range of constitutive nuclear antigens are cardinal elements in the definition of SLE. Of these, anti-DNA antibodies appear to be the most nephritogenic, although other autoantibodies are clearly involved in many cases.

Immune complexes of several types appear to be involved. The classic paradigm involves deposition of preformed circulating immune complexes, initially in the mesangial interstices with eventual spillover into the subendothelial space manifested by progressive stages of mesangial and endocapillary proliferative disease. An alternative model posits that circulating nuclear remnants of excessive apoptotic cellular breakdown are bound to glomerular capillary sites with subsequent binding of autoantibodies to the “planted” antigens and local formation of immune complex aggregates.

Observations in the Heymann nephritis animal model and in rare congenital forms of human membranous nephropathy indicate that autoantibodies are capable of reacting with constitutive antigens of the glomerular podocytes. This in situ production and accumulation of immune complexes along the external (subepithelial) aspect of the glomerular capillary has not been definitively proven to be operant in human membranous LN.

Autoimmunity based on direct cell-mediated injury to various components of the nephron have been proposed, based primarily on the high frequency of mononuclear cell infiltration in various forms of LN. Despite the common presence of infiltrating lymphoid cells, there is no direct proof of a pathogenic mechanism (analogous to the nephron damage of cell-mediated renal allograft rejection) in human LN.

The natural history of SLE is known most precisely from studies of murine models where death from progressive LN regularly occurs unless interdicted by effective immunosuppressive regimens. Evidence of a comparably ominous natural history of human LN is occasionally evidenced by severe damage and renal failure in misfortunate patients lacking access to modern medical therapies. It is gratifying that numerous therapeutic advances have dramatically improved the prognosis of LN over the past few decades.

The clinical manifestations of SLE are extremely protean. In the context of clinical practice, diagnosis of SLE should be suspected when there is evidence of multisystemic disease along with autoantibodies to nuclear antigens. Ideally, the diagnosis of SLE should be based on the presence of four or more criteria defined by the American College of Rheumatology, but it should be emphasized that these criteria are intended to standardize eligibility criteria for inclusion of subjects in SLE research studies, rather than to establish diagnostic criteria for SLE in clinical practice.

Symptoms and Signs

Glomerulonephritis is uncommonly the sentinel manifestation of SLE. An exception to this principle is membranous LN wherein up to 25% of patients present with no extrarenal manifestations and diagnosis of SLE may emerge only during extended follow-up.

The key challenge for diagnosticians is to detect clinically significant LN prior to overt symptoms. Patients with a likely or proven diagnosis of SLE should be carefully queried for what they may ordinarily consider to be trivial changes in urine color, nocturia, and foam-producing urination, each of which may mark the onset of occult LN.

Laboratory Findings

Evidence of hematuria, proteinuria, or pathologic urine sediment on screening urinalysis usually confirms the presence of LN. However, the astute clinician should be mindful that false-negative urinalyses, particularly urine sediment abnormalities, are relatively common in high-throughput clinical laboratories. It is judicious to “flag” urinalyses from patients with SLE for special scrutiny by laboratory personnel.

Proteinuria is traditionally quantified by 24-hour urine collection. However, spot urine protein/creatinine ratio (the value of which approximates the number of grams per day of proteinuria) is becoming widely accepted as the more convenient alternative for patients, particularly for monitoring changes in proteinuria over time.

Serologic testing includes antinuclear, anti-DNA, and antiphospholipid antibodies, which are useful for the diagnosis of SLE and its complications. The clotting diathesis conferred by the antiphospholipid syndrome may compound the thromboembolic risk of persistent nephrotic syndrome. Elevated anti-DNA titers and depressed levels of C3 and C4 complement levels correlate with active proliferative LN; changes in levels of these serologies tend to be more useful than their absolute levels for monitoring activity of nephritis during follow-up.

Special Tests

Renal biopsy is primarily valuable for staging the type and severity of LN. The classification scheme has recently been revised and updated (Table 32–1). Discordances among clinicopathologic findings are common over time and repeat renal biopsy may be needed to stage (or potentially reclassify) the renal disease.