This was a retrospective observational study comprising a total of 201 patients with biopsy-proven LN treated between 1990 and 2016 at Nagasaki University Hospital and affiliated community hospitals. Two expert nephropathologists (M.K. and T.T.) classified the biopsy specimens separately based on the International Society of Nephrology/Renal Pathology (ISN/RPS) classification to obtain the LN patients' pathological information , regardless of the patients' previous World Health Organization (WHO) or ISN/RPS classification.
Patients with advanced comorbidities or other diseases associated with impaired renal function (e.g., diabetic or primary renal disease) were excluded. Patients with inadequate medical records and patients with <12 months of follow-up were also excluded. All patients were followed up at 1- to 3-month intervals and at ≥12 months from the date of their renal biopsy.
We divided the 201 patients into two groups: early-onset LN and late-onset LN. As described [10, 11, 16], early-onset was defined as the development of LN within 5 years of the patient's SLE diagnosis, and late-onset was defined as the development of LN >5 years after the patient's SLE diagnosis. Some of the patients provided written informed consent for the use of their data, and the opt-out strategy was used by the remainder of the patients. Patients who declined to give informed consent were excluded. The study was reviewed and approved by the Medical Ethics Committee of Nagasaki University Hospital (approval nos. 12012397 and 17082129).
The patients' baseline characteristics were collected on the dates of their renal biopsies. The demographic data included the patient's age at the onset of SLE, gender, duration of SLE (from the diagnosis of SLE to renal biopsy), comorbidities of Sjögren's syndrome (SS)/antiphospholipid syndrome (APS), and the induction treatment used. We analyzed the patients' laboratory data, including the white blood cell (WBC) count, lymphocyte count, hemoglobin, platelet counts, albumin, proteinuria, urine protein/creatinine ratio (Up/Ucr), serum creatinine (Cr), blood urea nitrogen (BUN), and estimated glomerular filtration rate (GFR). Immunological parameters were also measured, including complement 3 (C3), complement 4 (C4), total hemolytic complement (CH50), immunoglobulin (Ig)G, IgA, IgM, anti-nuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), anti-Smith (Sm) antibody, and anti-ribonucleoprotein (RNP) antibody. The histological characteristics of activity and chronicity scores were determined as described .
Treatment and the definition of complete renal remission
Based on the clinical judgment of the rheumatologist and the treatment guidelines/recommendations for LN published by the American College of Rheumatology (ACR) and the EULAR/ERA-EDTA [18, 19], the patient was treated with immunosuppressive agents. Treatment consisted of prednisolone (PSL) with intravenous cyclophosphamide (IVCY; 500–1,000 mg/m2 body surface area 1´/month for 6 months), or PSL in combination with a first-line immunosuppressive regimen used for the treatment of LN, followed by IVCY or oral immunosuppressive agents quarterly; PSL was administered at doses of 0.5–1 mg/kg/day with or without intravenous methylprednisolone (mPSL) pulse therapy (50–1,000 mg/day × 3 days). Plasma exchange (PE) was performed in patients who were refractory to other treatments.
At the discretion of the attending physician, induction therapy was performed for approx. 6 months. We defined CR at 6 and 12 months as an Up/Ucr ratio <50 mg/mmol (roughly equivalent to proteinuria <0.5 g/24 hr) and a normal or near-normal GFR (within 10% of the patient's normal GFR if previously abnormal). We defined partial renal response (PR) as a normal or near-normal GFR with a ≥50% reduction in proteinuria to subnephrotic levels [18, 20, 21].
Mortality, the occurrence of ESKD, and predictors of CR attainment at 6 and 12 months
The primary outcome was mortality from any cause in both the early- and late-onset LN groups. The secondary outcome was ESKD, defined as dialysis dependence for >3 months. We also determined the predictors of CR attainment at 6 and 12 months after the start of induction therapy. Data were collected until either the patient's last follow-up or until December 31, 2019, whichever was later.
A nonparametric Wilcoxon rank-sum test was used for intergroup comparisons of multiple variables. Fisher's exact test was used to test for possible associations between each variable factor and the treatment response. To identify independent predictors of CRs, all variables with p<0.15 in a univariate analysis were entered into a multivariable regression model in which nonsignificant variables were sequentially removed. The interaction between the variables in the final model was tested, and the resulting significant variables were extracted as independent predictors of CR. A Cox proportional hazards model was used to examine the risk of ESKD and mortality. Data regarding the length of time to ESKD or mortality after induction therapy were analyzed using the Kaplan-Meier method with a log-rank test. Patients were censored if they were lost to follow-up or reached the end of the study. All statistical analyses were performed using JMP® Pro15 software (SAS Institute, Cary, NC). The significance level was set at p<0.05.