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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 32
| Issue : 6 | Page : 595-599 |
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A long-term follow-up study of lupus nephritis in a single tertiary care centre
Ajay I Rathoon1, Venu Gurusamy2, Vasanth Ganesan2, S Arivazhagan2, Chelikani Yaswanth2
1 Department of Nephrology, SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India
2 Department of Nephrology, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India
| Date of Submission | 02-Dec-2021 |
| Date of Acceptance | 09-Jan-2022 |
| Date of Web Publication | 16-Jul-2022 |
Correspondence Address:
Ajay I Rathoon
Department of Nephrology, SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu - 603 211
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijn.ijn_501_21
Introduction: Lupus nephritis (LN) is an immune complex glomerulonephritis, which is a very serious complication of systemic lupus erythematosus (SLE) as it can progress to end-stage kidney disease (ESKD). Methods: In this study of 92 renal biopsy-proven LN, the patients were followed up for a minimum period of 2 years with a mean follow-up period of 5.4 ± 3.4 years. Results: The mean serum creatinine of our study population was 1.4 ± 1.53. Our study population included 2 patients with class I lesions, 5 with class II, 22 with Class III, 53 with Class IV, and 10 with Class V lesions. Our therapeutic approach included only oral steroids for class I and class II lesions; for class III, IV, and V lesions, our approach included pulse steroids followed by oral steroids with either intravenous (IV) monthly cyclophosphamide (CYC) or mycophenolate mofetil (MMF). For maintenance, azathioprine or MMF were used along with low-dose oral steroids after 6 months of CYC or MMF. In CYC induction group containing 78 patients (84.7%), 66 patients (84.6%) attained remission (CR + PR), relapse in five patients (6.4%), ESRD on HD in five patients (6.4%), and death in two patients (2.6%). Conclusion: At the end of the study, in all groups, 79 patients (85.86%) were in remission (CR + PR), six patients (6.5%) were in relapse, five patients (5.4%) had reached the ESKD stage on HD, and two patients (2.2%) died.
Keywords: Cyclophosphamide, lupus nephritis, SLE
How to cite this article:
Rathoon AI, Gurusamy V, Ganesan V, Arivazhagan S, Yaswanth C. A long-term follow-up study of lupus nephritis in a single tertiary care centre. Indian J Nephrol 2022;32:595-9 |
How to cite this URL:
Rathoon AI, Gurusamy V, Ganesan V, Arivazhagan S, Yaswanth C. A long-term follow-up study of lupus nephritis in a single tertiary care centre. Indian J Nephrol [serial online] 2022 [cited 2023 Feb 3];32:595-9. Available from: https://www.indianjnephrol.org/text.asp?2022/32/6/595/351271 |
| Introduction | |  |
Lupus nephritis (LN) is a frequent and potentially serious complication of systemic lupus erythematosus (SLE).[1] LN causes morbidity and mortality both directly and indirectly through the complications of its therapy. SLE is more common in females, with a ratio of 10:1, although males with SLE have the same rate of renal disease as females.[2] SLE peaks between the age of 15–45 years, and more than 85% of the patients are younger than 55 years of age. SLE is more commonly associated with severe nephritis in children and males and is milder in older adults.[3] Diagnosis of SLE is established by the presence of clinical and laboratory findings defined by EULAR/ACR 2019 criteria according to which ANA positive status is mandatory.[4]
In patients with SLE, abnormalities of immune regulation lead to a loss of self-tolerance, autoimmune responses, and the production of a variety of autoantibodies and immune complexes.[1],[2] LN is an immune complex glomerulonephritis which is a very serious complication of SLE as it can progress to ESKD.[2],[3]
| Methods | | |
This is a retrospective cohort descriptive study of 92 biopsy-proven LN patients who were followed up for a period ranging from a minimum of 2 years to a maximum of 15 years from January 2005 to December 2019. LN was defined by EULAR/ACR 2019 criteria, according to which ANA-positive status was considered mandatory. Only biopsy-proven LN cases were included. Pathologically, LN class was diagnosed according to ISN/RPS 2003 classification.[5]
Inclusion criteria
- ANA at a titer of ≥1:80 on HEp-2 cell line platform at least once
- Renal biopsy-proven LN
- A minimum follow-up period of 2 years
- All age groups included
Exclusion criteria
- ANA-negative status
- Follow-up period less than 2 years
- LN Class VI
All the patients were followed up for a minimum of 2 years since the day of diagnosis of LN with renal biopsy. Clearance was obtained from the Institutional Human Ethical Committee.
Therapeutic protocol
For classes I and II, oral prednisolone at 1 mg/kg was given which was tapered to 10 mg/day within 6 months and continued during follow-up. For classes III, IV, and V, methylprednisolone pulse of 500 mg/day intravenously for 3 days followed by 1 mg/kg oral prednisolone, which was tapered to 10 mg/day over 6 months, and intravenous (IV) monthly cyclophosphamide (CYC) or mycophenolate was used as the primary induction agent after explaining the potential side effects. Our CYC protocol is explained in [Figure 1].
IV CYC was used at the dose of 500 mg/month for 6 months when patient weight was less than 40 kg and 750 mg/month if weight was more than 40 kg. The remaining patients who had a less severe form of disease or were not willing for CYC were started on mycophenolate mofetil (MMF) at a dose of 1.5 g/day as an induction agent in addition to steroids. Azathioprine at a dose of 1–2 mg/kg per day or MMF at a dose of 1 g/day were used as maintenance treatment along with low-dose oral steroid after 6 months of CYC or MMF.
Therapeutic response was assessed at 6th, 12th, 18th, and 24th month. KDIGO criteria were used to define complete remission, partial remission, no response, and relapse,[6] which are noted in [Table 1]. The primary endpoint of the study was to look for the percentage of remissions or relapses or ESKD on HD or death during the follow-up period.
| Results | | |
We analyzed 92 patients with baseline serum creatinine <1.40 mg/dL in 71 patients (77.2%) and >1.41 mg/dl in 21 patients (22.8%). Urine spot PCR of 0.5–3.0 in 63 patients (68.5%) and >3.0 in 29 patients (31.5%) were noted. Basic characteristics of the study population are listed in [Table 2]. Antiphospholipid antibodies (APLAs) were positive in seven patients (7.6%), thrombotic microangiopathy (TMA) was seen in two patients (2.1%) who had class IV, and class transfer proved by repeat renal biopsy was seen in three (3.2%) patients.
IV CYC induction was used in 78 patients (84.7%), and MMF induction in seven (7.6%). Only oral steroids were given for LN Class I and II, which was in seven patients (7.6%). The cumulative CYC dose used was 4.5 g in 49 patients (53.3%), 3 g in 27 patients (29.3%), and 1.5 g in two patients (2.2%), in whom due to infection further doses were not given. For maintenance, we used azathioprine along with low-dose oral steroids in 77 patients (81.5%), MMF along with low-dose oral steroids in nine patients (9.8%), and only oral steroids in eight patients (8.7%).
At the end of 6 months, 37 (40.2%) patients attained complete remission, 37 (40.2%) partial remission, and 18 (19.6%) no remission. At the end of 12 months, 54 (58.7%) patients attained complete remission, 24 (26.1%) partial, and 14 (15.2%) no remission. At the end of 18 months, 60 (65.2%) patients attained complete remission, 22 (23.9%) partial, and 10 (10.9%) no remission. At the end of 24 months, 65 (70.7%) patients attained complete remission, 20 (7.6%) partial, and seven (7.6%) no remission. A total of 85 patients (92.3%) attained remission at the end of 2 years of follow-up. One patient attained complete remission at the 26th month of follow-up. Response in various classes is shown in [Figure 2].
In patients with creatinine >1.4 mg/dL (21 patients), 10 (47.6%) patients attained complete remission, seven (33.3%) partial, and four (19%) no remission. In the CYC induction group of 78 patients (84.7%), at the end of 24 months, 55 (70.5%) patients attained complete remission, 17 (21.8%) partial, and 6 (7.7%) no remission, which is shown in [Figure 3]. At the end of the study, 66 (84.6%) patients attained remission, of which 51 patients complete and 15 partial, relapse in five patients (6.4%), ESKD on HD in five patients (6.4%), and death in two patients (2.6%), which is shown in [Figure 4].
The mean duration at which remission was achieved was 7.4 ± 6.2 months. The range of attaining complete remission was 1–22 months with a mean of 7.4 ± 5.4 months. The range of attaining partial remission was 3–27 months with a mean of 9.5 ± 7.9. The mean duration of remission was 4.6 ± 3.3 years with a maximum remission period of 15 years.
Relapse was seen in 15 patients (16.3%), and 77 patients did not have relapse till the end of their follow-up period. We treated relapse by switching the maintenance drug from azathioprine to MMF. If a patient did not attain remission with this, then rituximab was used as a rescue drug. We used rituximab in 4 such patients, of which 3 patients attained remission and one patient did not attain remission and progressed to ESKD. Two patients presented with LN with TMA, who were started on IV CYC 750 mg/month six doses with five sessions of plasmapheresis, of which one patient improved and attained partial remission and the other patient progressed to ESKD on HD.
The minimum follow-up duration was 2 years, and maximum 15 years. The mean years of follow-up were 5.4 ± 3.4 years. Further, 51 patients (55.4%) had a follow-up duration of less than 4 years, 25 (27.2%) 5–9 years, and 16 (17.4%) 10–15 years. Of 92 patients in the study, 61 patients (66.3%) are still on regular follow-up. At the end of the study, 79 (85.86%) patients were in remission (CR + PR), 6 (6.5%) in relapse, 5 had reached the ESKD stage on HD, and 2 (2.2%) died.
Adverse events such as pneumonia were seen in 4 patients, acute bronchitis in 7, fungal skin infection in 2, herpes zoster in 5, leukopenia in 2, abscess in 1, and deep-vein thrombosis (DVT) in 1 patient.
| Discussion | | |
This is a single-center retrospective cohort study that was conducted in a tertiary care center in South India. We included all patients who were ANA positive with a renal biopsy-proven LN and a minimum follow-up period of 2 years to a maximum period of 15 years. The male:female ratio in our study population was 1:7.3. We defined remission, relapse, and treatment failure according to the KDIGO guidelines.[6]
In our study, we used IV CYC at a dose of 500 mg/once a month for 6 months when patient weight was less than 40 kg and 750 mg/once a month for 6 months when patient weight was more than 40 kg for class III, IV, and V lesions compared to NIH regimen where CYC dose of 0.5–1 g/m2 was given once a month for 6 months followed by quarterly for 2 years,[7] and according to Euro-lupus regimen, a CYC dose of 500 mg was given once in 2 weeks for 3 months irrespective of the weight of the patient.[8] In these two regimens, CYC was not used in class V patients.
Our CYC protocol was used in 78 (84.7%) patients out of the total 92 patients of the study population, of which 66 (84.6%) attained remission; relapse was noted in five (6.4%) patients, 5 (6.4%) progressed to ESKD on HD, and 2 (2.6%) died. Of 22 class III patients, CYC was used in 19 patients, of which 18 (94.7%) patients attained remission. Of 53 class IV patients, CYC was used in 51 patients, of which 40 (78.4%) patients attained remission.
Our protocol had a better remission rate of 84.6% with CYC when compared to ALMS multicenter study, where the remission rate was 56.2% in the MMF group and 53.0% in the CYC group.[9] In the American study by Ginzler et al.[10] published in 2005, the remission rate for MMF was 52.1% and for CYC was 30.4%, rates which were less when compared to our study. In the NIH trial, the methylprednisolone and CYC group attained a remission rate of 85%,[7] and in a multicenter Chinese study,[11] the remission rates for CYC as per NIH protocol was 82.1%, which was similar to our results.
Our cumulative CYC dose range (3–4.5 g), is less than the NIH regimen and the same as or slightly higher than the EURO-LUPUS regimen. However, our duration of treatment was over 6 months when compared to 3 months in the EURO-LUPUS trial.[8] Our CYC regime exposes the patients of LN to a lower cumulative dose of CYC over a longer duration; thus, the side effects, especially infections and leukopenia, were less without sacrificing efficacy. Comparison of basic characteristics and outcome of various studies is listed in [Table 3]. The adverse events in our study and their comparison with other studies are listed in [Table 4]. | Table 3: Comparison of baseline characteristics, induction treatment regimen, and renal outcomes
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The limitations of this study are that it was a single-center observational study with no control group. The MMF induction population was very small. The study population belonged to a single ethnic group.
| Conclusion | | |
In our study according to the treatment protocol discussed above, we reached a comparable or even better remission rate with a very less toxicity profile. However, a larger, multicenter, multi-ethnic, randomized, controlled study is required to provide stronger evidence.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| 10. | Ginzler EM, Buyon J, Wallace DJ. Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus Nephritis. N Engl J Med 2005;353:2219-28. |
| 11. | Jayaprakash V, Dineshkumar T, Dhanapriya J, Rajasekar D, Sakthirajan R, Balasubramaniyan T, et al. End of induction treatment outcomes with a novel cyclophosphamide-based regimen for severe lupus nephritis: Single-center experience from South India. Indian J Rheumatol 2020;15:100-5. [Full text] |
| 12. | Rathi M, Goyal A, Jaryal A, Sharma A, Gupta PK, Ramachandran R, et al. Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int 2016;89:235-42. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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