The effectiveness and safety of corticosteroid therapy for IgA nephropathy with crescents: a prospective, randomized, controlled study

This was a prospective, randomized, controlled, non-blind study. IgAN patients with crescents were enrolled between January 2017 to December 2019 in our clinic medical center.

The inclusion criteria were: 1) Age 14–65 years, regardless of sex; 2) Clinical evaluation and renal biopsy diagnostic for primary IgAN, presenting with crescents; 3) Mean urinary protein excretion of 0.5–3.5 g/24 h on two successive examinations; 4) eGFR≥50 ml/min/1.73 m²; 5) Willingness to sign an informed consent. The exclusion criteria were: 1) Secondary IgAN, such as systemic lupus erythematosus, Henoch-Schonlein purpuric nephritis and hepatitis B-associated nephritis; 2) Proportion of crescent ≥50%; 3) Pure fibrous crescents; 4) biopsies with the number of glomeruli < 8; 5) Current or recent (within 30 days) exposure to high-dose of steroids or immunosuppressive therapy; 6) Date of renal biopsy exceeded more than 30 days; 7) Cirrhosis, chronic active liver disease; 8) History of significant gastrointestinal disorders (e.g. severe chronic diarrhea or active peptic ulcer disease); 9) Any active systemic infection or history of serious infection within 1 month; 10) Other major organ system disease (e.g. serious cardiovascular diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma requiring oral steroid treatment or central nervous system diseases); 11) Active tuberculosis; 12) Malignant hypertension that was difficult to be controlled by oral drugs; 13) Known allergy, contraindication or intolerance to the steroids; 14) Pregnancy or breast feeding at the time of entry or unwillingness to comply with measures for contraception; 15) Malignant tumors; 16) Mental aberrations; 17) Current or recent (within 30 days) exposure to any other investigational drugs.

The statistical software SAS® 9.4 (SAS Institute) was used to generate the assignment list and the random numbers were placed in separate sealed envelopes by the statistical assistant in our medical center. We screened all the patients meeting the eligibility criteria and enrolled the participants. The randomization and allocation procedures were carried out the research assistant based on the random number obtained from the sealed envelopes. All the enrolled participants were randomly assigned in a 1:1 ratio to the 1–2-3 group (received methylprednisolone intravenous infusion at the 1st-2nd-3rd months) or the 1–3-5 group (received methylprednisolone intravenous infusion at the 1st-3rd-5th months). Treatment allocation was not masked.

Patients in the 1–2-3 group received methylprednisolone 0.25 g/d intravenously for 3 consecutive days in the 1st-2nd-3rd month, and oral prednisone 0.5 mg/kg/d on consecutive days for 6 months and those in 1–3-5 group were treated with methylprednisolone 0.25 g/d intravenously for 3 consecutive days in the 1st-3rd-5th month, and oral prednisone 0.5 mg/kg/d on consecutive days for 6 months. During the 6-month therapy period, patients were recommended to receive blockers of the renin-angiotensin system for comprehensive supportive care and to reduce blood pressure to the target of below 125/75 mmHg. No patient in this study received any other immunosuppression, such as mycophenolate, cyclophosphamide, or cyclosporine A.

This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board of our hospital (approval no. 2014ZSLYEC-009). Written informed consent was obtained from the patients before enrollment. The trial in the current study was registered to the ClinicalTrials.​gov (NCT02160132).

Proteinuria was defined as urine protein for 24 h on two successive examinations during every follow-up. Serum creatinine was tested by sarcosine oxidase method. Estimated glomerular filtration rate (eGFR) = 175 × serum creatinine (mg/dl)^-1.234 × age (year)^-0.179 [if female,× 0.79], MDRD equation [15]. Renal biopsy was performed in every patient and the biopsy specimens were reviewed by one pathologist who was unaware of clinical details of the patients. All the samples were divided into three parts for light, immunofluorescence and electron microscope examinations. Total number of glomeruli, mesangial proliferation, endocapillary hypercellularity, segmental glomerulosclerosis, interstitial inflammatory infiltration had been recorded for the MEST score. Cellular and/or fibrocellular crescents were recorded and taken to MEST-C score classification; but fibrous crescents were not considered [6]. Lee’s grade was divided into grades II, III, IV, V according to Lee’s glomerular grading system [16].

All participants were followed up for 6 months. The primary outcome measure was remission of proteinuria (complete or partial); while the secondary outcome measures were deterioration of renal function (evidenced by a 50% rise from baseline serum creatinine levels, or a 25% decline from baseline eGFR levels, or onset of end-stage renal disease). Treatment outcomes included complete remission (CR), partial remission (PR), and no response (NR). CR was defined as proteinuria< 0.3 g/24 h, without active urinary sediment, serum albumin≥35 g/L, serum creatinine stable within 15% of the basal level. PR was defined as proteinuria decreased by more than 50% of the basal level, serum albumin≥30 g/L, and serum creatinine stable within 15% of the basal level. NR was defined as the decrease of proteinuria not exceeding 50% of the basal level, and the serum albumin< 30 g /L. Steroid therapy-related side effects were recorded, including steroid diabetes, upper respiratory tract infection, pneumonia and skin-related infection. Steroid diabetes was defined as no previous history of diabetes, and an increase in blood sugar level that meets the diagnostic criteria for diabetes during corticosteroid therapy.

Per protocol set (PPS) was used for analysis of effectiveness and safety set (SS) was used for analysis of safety. Continuous data with normal distribution (eg. age, proteinuria and serum creatitine) were indicated with mean ± standard deviation (SD) while categorical data were indicated with number and percentage (%). Student’s independent t-test was used to compare the mean differences between 1 and 2-3 and 1–3-5 groups. Categorical variables were compared using the Chi-square test or Fisher’s exact test (if the expected value ≤5 was found). Data without normal distribution (eg. crescents) were presented as the median (quartile) and were compared with non-parametric tests. Repeated measurement ANOVA was used to investigate the significances of changes in proteinuria, serum creatinine, and eGFR over time. Kaplan-Meier survival function and log-rank test were used to compare the developing trends of total remission (CR + PR) and CR-only between two groups. To further investigate the association between group variable and outcome index, proteinuria, serum creatinine, and eGFR, a linear regression under generalized estimating equation (GEE) model was used. All patient’s results were measured at 6 time-points: month 1, 2, 3, 4, 5, and 6. An autoregressive (lag1) correlation matrix was adopted for the repeated measure data. The linear regression coefficient B was reported.

This clinical trial adheres to CONSORT guidelines. A completed CONSORT checklist has been provided as Appendix.

There were initially 74 patients who participated in the pulse therapy session, including 36 cases in the 1–2-3 and 38 cases in the 1–3-5 group. However, 2 patients in the 1–2-3 voluntarily withdrew from therapy due to steroid diabetes and without remission after 3-month treatment, while 4 patients in the 1–3-5 groups withdrew due to pneumonia (n = 2), steroids diabetes (n = 1), and frequent upper respiratory tract infection during treatment (n = 1). (Fig. 1) Therefore, 68 patients (mean age = 31.74 ± 10.34 years; 33 males and 35 females) were included for analyses, 34 cases for each group. All 68 patients were followed up for 6 months. As shown in Table 1, there was no difference in proteinuria, serum albumin, serum creatinine, eGFR, MEST-C score, crescent proportion, and blood pressure between the 1–2-3 and 1–3-5 groups.

The levels of urine protein, serum creatinine, and eGFR from month 1 to month 6 were compared between groups. As shown in Table 2 and Fig. 2, there was no significant difference in the three parameters at all time points between the 1–2-3 and 1–3-5 groups (all P > 0.05). However, the changes over time within-group or all patients were all significant (all P < 0.05, Table 2). As shown in Fig. 2, urine protein and serum creatinine had a decreasing trend, while eGFR had an increasing trend. Although there was no significance, the 1–2-3 group had descriptively lower creatinine and higher eGFR than the 1–3-5 group.

The linear regression estimations of group factor to urine protein, serum creatinine, and eGFR including 6 time-points results under GEE models were performed. As shown in Table 3, there was no significant difference in urine protein, serum creatinine, and eGFR between the 1–2-3 and 1–3-5 groups (all P > 0.05). However, the estimated B value of serum creatinine (8.75) and eGFR (− 10.86) reflected the descriptive difference between groups as shown in Fig. 2.

During the period of therapy, there were no patients that crossed-over to different arms. Table 4 shows the clinical outcomes after pulse therapy. Overall, there were 26 (38.24%) CR, 29 (42.65%) PR, and 13 (19.12%) NR of all patients. Remission (or total remission) was defined as CR + PR. The rates of remission in the 1–2-3 group and 1–3-5 group were 85.3 and 76.47%, respectively (P = 0.644). The mean period of remission was 4.04 ± 1.52 months, but that in the 1–2-3 group seemed shorter. No patient had serum creatinine increasing over 50% after 6-month therapy, and 2 patients had eGFR decreasing over 25% after therapy The Kaplan-Meier survival curve analysis also indicated that there was no difference in total remission (P = 0.200) and CR (P = 0.210) between the two groups (Fig. 3).

Ten (13.51%) patients had different complications during the treatment period of all the patients. (Table 5) Six patients (8.11%) had encountered infections, including upper respiratory tract infection, pneumonia and herpes zoster. All the infections had happened during the second month during follow-up and been cured within 2 weeks. Four patients (5.41%) had got steroid diabetes which happened during the second or third month, and their doses of oral prednisone had been reduced to 0.25 mg/Kg/d on the third month of therapy. There was no significant difference in the rates of adverse events between groups.