Chronic kidney disease in patients with lupus nephritis—Important but underrecognized

Lupus nephritis (LN) affects 30%–60% of patients with systemic lupus erythematosus (SLE) and is a leading cause of severe acute glomerulonephritis among Asians. Despite significant advances in LN management over the past decades, progression to end-stage kidney disease (ESKD) has remained largely unchanged over the last two decades and still occurs in 10%–20% of LN patients.¹ As LN has a relapsing cause, chronic kidney disease (CKD) is prevalent due to repeated episodes of acute nephritis, which lead to progressive attrition of kidney reserve. CKD in LN is often underrecognized since serum creatinine can remain within the “normal range” despite significant reduction in kidney function, especially in Asian females with small body size. Additionally, the presence of CKD has important implications on clinical management, including the choice and optimum dose of immunosuppressive medications.

The reported prevalence of CKD in LN patients ranges from around 10% to approaching 50%.^2-9 Multiple factors contribute to the marked variation in reported prevalence rates, including variations in the duration of follow-up (4–14 years), differences in baseline patient characteristics, different definitions of abnormal kidney function, and different treatments. As CKD is progressive, longer follow-up durations are associated with higher prevalence rates. Reports on Caucasian patients stated seemingly lower CKD prevalence rates of 19%–24%,^{2, 7, 8} compared with 11.5%–47.6% in reports from Asia, Middle East, and South America.^{3-6, 9} In addition to differences in genetic background and disease severity, access to health care and medications, and socioeconomic factors including adherence to clinical management, are likely confounding factors.

Recognizing the presence of CKD and identifying risk factors for CKD progression in LN patients are of paramount importance in clinical management, as the ultimate aim is to prolong kidney survival. As we and others have demonstrated previously, kidney survival is a major determinant for patient survival.^{10, 11} Over the past few decades, several groups of medications have been demonstrated to reduce the rate of CKD progression, irrespective of the original cause of kidney damage. These include renin-angiotensin system (RAS) blockers, sodium-glucose co-transporter-2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid antagonists, and endothelin inhibitors. The effect of the different “renoprotective” medications in patients with LN remains to be investigated. We have previously shown that RAS blockade could reduce residual proteinuria in patients with quiescent LN.¹² It is well-established that the level of proteinuria correlates with the rate of CKD progression, and long-term follow-up data from the Euro-Lupus and MAINTAIN studies showed that persistent proteinuria of >0.8 g/day at 1 year from baseline was associated with less favorable long-term kidney survival.^{13, 14} In another study, time-averaged proteinuria ≥2 g/day was associated with a 6–7 times more rapid decline in eGFR compared to patients with proteinuria <2 g/day.²

Risk factors for the development or progression of CKD include abnormal kidney function at LN diagnosis and also delayed diagnosis and treatment.^{2, 4-6, 8} It has been reported that delayed diagnosis by 6 months or longer after onset of nephritic symptoms was associated with a ninefold higher risk of ESKD during follow-up.¹⁵ Histological class of LN by itself did not show a good correlation with subsequent CKD development, but the presence of extensive tubulointerstitial chronic lesions portends an unfavorable kidney survival.^3-8 In this context, an Italian group reported that a total Chronicity Index (CI) score >2 and all individual components of CI were predictive of CKD development.⁸ Other studies also demonstrated that a higher tubular atrophy score and the presence of >25% interstitial fibrosis/tubular atrophy (IFTA) were associated with CKD development, respectively.^{3, 7} Hypertension, hyperlipidemia, and diabetes mellitus are important risk factors for CKD, and these comorbidities are common in LN patients.¹⁶ Hypertension at the time of LN diagnosis was reported by several groups as a risk factor for CKD.^{3-5, 8, 9} Blood pressure optimization is therefore essential in all patients with CKD to prevent superimposed hypertensive nephrosclerosis. Nephron injury occurs at each nephritic flare. Not surprisingly, CKD was associated with a higher cumulative number of renal flares.^{3, 4, 6} In this regard, we have reported that long-term maintenance treatment with mycophenolate was associated with a lower flare rate.¹⁷ Recent post hoc analysis of the BLISS-LN trial data also showed that adding belimumab to background immunosuppression with glucocorticoid and mycophenolate or cyclophosphamide in patients with active LN was associated a lower renal flare rate.¹⁸ In addition, a report from Brazil showed an association between CKD development and economic deprivation, which could be attributed to premature discontinuation of medications.⁹ Calcineurin inhibitors (CNIs) have demonstrated efficacy and are increasingly used in the management of LN.^{19, 20} CNIs exert a direct effect on the podocyte cytoskeleton, which contribute to the reduction in proteinuria. Due to its potential nephrotoxicity, CNIs should be used with caution with lower target drug exposure in patients with CKD and should be avoided in patients with severe CKD.

Patients with LN can be under the care of nephrologists, rheumatologists, or general physicians. Clinicians must be vigilant of CKD progression by perusing the serial levels of serum creatinine, and be alert to factors that could reduce the serum creatinine level (such as reduced muscle mass), thereby creating an illusion of stable kidney function. The prevention of CKD should be inherent in the holistic management of patients with LN, and as discussed previously, there are multiple ways to reduce the risk of CKD progression and life-time risk of kidney failure.

All authors contributed to the preparation of the manuscript, and TMC had leadership and supervisory role in this work.

T.M.C received grant/research support from Astellas and AstraZeneca, consulting fees from GSK and Novartis, and was an advisor/review panel member for GSK, Kezar, Novartis, and Visterra. D.Y.H. Yap received grant/research support/consulting fees from AstraZeneca, Gilead, BI, GSK, Bayer, Baxter, Fresenius Kabi, Otsuka, and Kirin.