The clinical evaluation of kidney disease in systemic lupus erythematosus

Introduction

Kidney disease is common in patients with systemic lupus erythematosus (SLE). This is most often due to lupus nephritis (LN). LN is one of the major causes of morbidity and mortality in SLE patients and is associated with poorer outcomes than in those patients with no kidney involvement. This poor prognosis is explained only in part by the risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), suggesting that LN is a manifestation of a more severe form of SLE.

In LN anti-double stranded DNA and other autoantibodies bind to self-antigens, including chromatin released during glomerular cell injury, and form immune complexes that accumulate in all compartments of the glomeruli. Immune complex deposits in the mesangium or subendothelial space lead to activation of the classical pathway of complement and initiate an inflammatory response that can also involve the renal interstitium. This process may result in injury to the entire kidney parenchyma (Chapter 35). Clinically, this is often manifested by an active, inflammatory urine sediment (described as follows), proteinuria, and sometimes renal insufficiency. Immune complex deposits can also accumulate in the subepithelial space, which is separated from the blood by the glomerular basement membrane. Subepithelial immune deposits primarily damage the glomerular epithelial cells (podocytes), leading to proteinuria, but generally do not result in in flammatory findings on urinalysis and most often kidney function is preserved. Besides LN, other mechanisms may lead to kidney damage in SLE, such as thrombotic microangiopathy, lupus podocytopathy, or superimposed ANCA associated glomerulonephritis. Kidney biopsy plays a crucial role in discerning underlying pathology and in choosing an appropriate treatment regimen. LN is often treatable. The best outcomes occur with early recognition and prompt treatment. Early recognition requires a high index of suspicion and the appropriate use of screening tests for kidney involvement followed by confirmatory tests and a kidney biopsy.

The scope of lupus nephritis

Examination of kidney tissue from SLE patients who had no clinical signs of kidney disease suggested that LN may be present in up to 90% of lupus patients. Most of this clinically silent LN was associated with very mild histologic changes, but about 15% of patients had moderate to severe pathology, many of whom did eventually develop proteinuria, an abnormal urine sediment, or renal insufficiency. Silent LN may represent the earliest stage in the natural history of LN.

The incidence of clinically overt kidney disease in all lupus populations is about 38%, but this varies greatly among racial and ethnic groups. The incidence of LN in non-white SLE patients is 50% or more, whereas only 12%-33% of white patients (European, European Americans) develop LN. LN is reported in 40%-69% of black patients (African American, Afro-Caribbean), and 47%-53% of Asian patients, and occurs frequently (36%-61%) in Hispanic patients.

Adverse kidney outcomes, such as ESKD or doubling of serum creatinine (a surrogate marker of ESKD), are also more frequent in black and Hispanic patients as compared to white patients. The incidence of ESKD attributed to LN in adults is 4.9 cases per million in the general population, but is 17-20 per million in black patients and 6 per million in Hispanics compared to 2.5 per million in white patients. According to the 2018 United States Renal Data System report, about 1.9% of the prevalent patients receiving renal replacement therapy have ESKD attributable to LN, but in children with ESKD lupus accounts for 5.6% of ESKD.

Beyond ESKD, the prevalence of CKD in patients with LN is difficult to quantify. However, if it is assumed that, at a minimum, a complete clinical renal response after treatment is needed to prevent CKD from developing, the prevalence of CKD is likely to be high, as many LN patients achieve only a partial renal response. Defining CKD as a serum creatinine greater than 1.0 mg/dL with estimated glomerular filtration rate (eGFR) less than 60 mL/min/m ² , the prevalence of CKD was estimated to be 4.5%. CKD in LN is important because it may progress to ESKD. Currently, progression to ESKD 5, 10, and 15 years after the diagnosis of LN occurs in about 11%, 17%, and 22% of patients in developed countries and 12%, 19%, and 26% in developing countries. Progression to ESKD is higher among black, Asian, and Hispanic patients compared to white patients. CKD is also a nontraditional risk factor for cardiovascular morbidity, as is lupus itself. The highest mortality in LN is seen in patients with chronic kidney damage.

The diagnosis of lupus nephritis

The systemic lupus international collaborating clinics (SLICC) proposed that the diagnosis of SLE can be made with a kidney biopsy showing LN in the presence of antinuclear or antidouble-stranded DNA antibodies. This facilitates the diagnosis of the kidney disease as LN. The SLICC criteria are more sensitive of the diagnosis of lupus than the American College of Rheumatology criteria (100% vs. 94%), but less specific (91% vs. 100%). However a kidney biopsy cannot be diagnosed as LN in isolation. Rather, a biopsy can show immune-complex mediated glomerulonephritis consistent with LN in the appropriate clinical setting.

The early diagnosis and treatment of LN is critical to preserve kidney function. The key to early diagnosis is maintaining a high index of suspicion for renal involvement in every SLE patient. Patients who present with LN when SLE is first diagnosed have higher rates of prolonged remission and a lower frequency of chronic kidney damage than those whose LN presents later. This may be because of early recognition, but only about half of LN patients have the evidence of kidney disease at the initial presentation of SLE. An algorithm to identify kidney involvement in SLE patients is shown in Fig. 42.1 .