ORIGINAL ARTICLES
Year : 2022 | Volume
: 22 | Issue : 3 | Page : 148--153
Safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 lupus nephritis: a retrospective study
Girish P Vakrani1, Nambakam Tanuja2, Sania Saba2,
1 Department of Nephrology, Vydehi Institute of Medical Sciences and Research Centre, RGUHS University, Whitefield, Bengaluru, Karnataka, India
2 Department of General Medicine, Vydehi Institute of Medical Sciences and Research Centre, RGUHS University, Whitefield, Bengaluru, Karnataka, India
Correspondence Address:
Dr. Girish P Vakrani
Department of Nephrology, #82, Vydehi Institute of Medical Sciences and Research Centre, RGUHS University, Whitefield, Bengaluru 560066, Karnataka
India
Abstract
Background Renal involvement in systemic lupus erythematosus is known as lupus nephritis (LN). LN presents with varied renal features. Class 4 and 5 LN are traditionally treated with prolonged standard high doses of prednisolone with various immunosuppressants such as cyclophosphamide and mycophenolate. These high doses of prednisolone are associated with numerous side effects. There is deficient data on the dose, duration of glucocorticoid therapy, and also paucity of data on comparison between the standard dose versus low-dose glucocorticoid therapy. Hence, this study can help in evaluating the use of low-dose glucocorticoids, its impact on renal outcome, and looking at side effects. Materials and methods It was a retrospective observational study conducted to look at the safety and efficacy of low-dose glucocorticoid regimen in induction phase treatment of class 4, 5 LN. Results On treatment, it was found that the resolution of microscopic hematuria, and improvement of low C4, and hypoalbuminemia were statistically significant in the low-dose steroid group. The resolution of proteinuria was seen in both groups and the resolution of renal failure was noted in both groups but was statistically significant in the standard dose group. Increased incidence of steroid-related complications was seen in the standard dose steroid group. Conclusions These findings possibly indicate that low-dose steroid therapy is good enough to treat LN with proteinuria, but a standard dose steroid is required in the presence of renal failure in LN, though increased incidence of steroid-related complications was seen in the standard dose steroid group.
How to cite this article:
Vakrani GP, Tanuja N, Saba S. Safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 lupus nephritis: a retrospective study.J Egypt Soc Nephrol Transplant 2022;22:148-153
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How to cite this URL:
Vakrani GP, Tanuja N, Saba S. Safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 lupus nephritis: a retrospective study. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Jun 10 ];22:148-153
Available from: http://www.jesnt.eg.net/text.asp?2022/22/3/148/351710 |
Full Text
Introduction
Renal involvement in systemic lupus erythematosus, an autoimmune disease, is known as lupus nephritis (LN) with an incidence of 50–60% [1,2].
LN presents with varied features ranging from microscopic to macroscopic hematuria, milder proteinuria to nephrotic range of proteinuria, hypertension and acute kidney injury to chronic kidney disease [2].
The International Society of Nephrology/Renal Pathology Society Classification identifies six independent histologic classes in LN [3]. Class 4 and 5 are most commonly seen and are traditionally treated with mainstay medication like pulse parenteral glucocorticoid methylprednisolone followed by prolonged standard high doses of prednisolone 1 mg/kg/day with various immunosuppressants such as cyclophosphamide and mycophenolate [4,5]. These high doses of prednisolone are associated with numerous side effects such as infections, glucose intolerance, hypertension, avascular necrosis, myopathy, Cushingoid habitus, etc., along with saturation of both its steroid receptor and its anti-inflammatory action [5–7]. High doses of glucocorticoids are considered by clinicians due to fear of relapse of disease [8]. Many studies have been conducted not only to look at the efficacy of treatment with low-dose glucocorticoids in attaining disease remission but also to minimize the side effects of therapy at the same time [1,2,7].
Though LN is common, there is deficient data on the dose, duration of glucocorticoid therapy, and also paucity of data on comparison between standard dose versus low-dose glucocorticoid therapy. Hence, this study can help in evaluating the use of low-dose glucocorticoids, its impact on renal outcome, and its side effects, compared with the standard dose steroid therapy.
Aims and objectives
The objectives of te study were as follows:
(1) To look at the safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 LN.
(2) To assess the safety and complications in both low-dose and standard steroid dose treatment groups.
Methodology
Study area
This study was conducted using medical records of class 4 and class 5 LN diagnosed patients, who were either treated with a standard dose of prednisolone (1 mg/kg/day) or low dose of prednisolone (0.5 mg/kg/day) after three doses of 500 mg pulse methylprednisolone along with injection cyclophosphamide 500 mg/sqm monthly as per the NIH regimen or mycophenolate 2 g/day as induction therapy at Vydehi Institute of Medical Sciences and Research Centre, which is a tertiary care hospital in Bangalore.
Data collection
Data was collected regarding:
Patient’s demography: age, sex.
Clinical features: blood pressure, weight, body surface area.
Biochemical parameters: serum creatinine, serum albumin, spot urine protein–creatinine ratio, urine RBC, C3, C4, ANA, dsDNA at baseline, 3, and 6 months.
Kidney biopsy histopathological findings.
Disease remission
Remission of LN was described as:
Complete remission of proteinuria with attaining target urine protein–creatinine ratio less than 0.2, with stabilization of serum creatinine to less than 1.5 mg/dl, if deranged previously or partial remission of proteinuria by more than 50% from baseline but not attaining urine protein–creatinine ratio less than 0.2, with improvement of serum creatinine but not less than 1.5 mg/dl, if deranged previously [2,4].
Side effects of glucocorticoid: steroid-induced diabetes mellitus, acne, pneumonia, esophageal candidiasis, menstrual irregularities, urinary tract infection, seizures, herpes, gastrointestinal tract bleed, Cushingoid habitus, myopathy, osteoporosis, leucopenia, gastritis, sepsis, and other parameters like death and chronic kidney disease.
Data analysis regarding comparison of clinical and biochemical parameters between both groups upon treatment was done.
Inclusion criteria
All patients diagnosed as kidney biopsy-proven class 4, 5 LN in Vydehi Hospital between January 2015 and September 2020.
Exclusion criteria
Patients with prior treatment with immunosuppressants.
Class 1, 2, 3, 6 LN.
Study design
This retrospective observational study was conducted to look at the safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 LN.
Type of study design: observational.
Outcomes/endpoints observed: to look at the safety and efficacy of low-dose glucocorticoid regimen in the induction phase treatment of class 4, 5 LN.
Statistical analysis of the study
The data was collected, entered, and analyzed with SPSS, version 27 (IBM, Chicago, IL, USA). Continuous variables were presented as mean±SD. Categorical variables were presented as frequency and percentage. χ2 test or Fisher’s exact test was performed to see the association between any two categorical variables. Mann–Whitney test was performed when comparing 1 independent variable with two levels (groups). A P value of less than 0.05 was considered statistically significant.
Results
In total, 50 LN patients were enrolled: twenty-one (42%) and 29 (58%) were treated with low-dose and standard dose steroid, respectively. Seventeen (81%) and 25 (86%) were females in low-dose and standard dose steroid groups, respectively. Hypertension was found in five (23.8%) and three (10.3%) patients in low-dose and standard dose steroid, respectively, at baseline.
At baseline ([Table 1]), proportions of microscopic hematuria (P=0.286), high urine protein–creatinine ratio (proteinuria P=0.241), types of histopathological LN classes (P=0.419), severity of activity and chronicity index (P=0.706), low complement 3 (C3), low complement 4 (C4) levels, ANA positivity, use of cyclophosphamide, mycophenolate (P=0.464), and hydroxychloroquine were found similar in both groups, but the proportion of ACEI and ARB medications use (P=0.017), hypalbuminemia (P<0.001), and renal failure(high serum creatinine with P=0.007) was higher in low dose group.{Table 1}
In intensive treatment ([Table 2]), it was found that the resolution of microscopic hematuria was statistically significant in low-dose steroid at the end of 6 months of treatment (P=0.009). The resolution of urine protein–creatinine ratio (proteinuria) was seen in both groups though it was not statistically significant when compared in both groups at the end of 6 months of treatment (P=0.058). Attaining complete remission of proteinuria was higher compared with partial proteinuria remission in both groups at the end of 6th month. The resolution of hypoalbuminemia was statistically significant in the low-dose group (P=0.027. The resolution of renal failure (decline in serum creatinine) was noted in both groups but was statistically significant in the 3rd month (P=0.001) and 6th month (P=0.006) in the standard dose group.{Table 2}
Hypocomplementemia of C3 showed mild improvement equally in both groups at the end of 6 months (P=0.84). Hypocomplementemia of C4 showed statistically significant improvement in the low-dose group at the end of 6 months than the high dose group (P=0.001), attaining ANA negativity that showed statistical significance in the high-dose group at the end of 6 months (P=0.001), attaining anti-dsDNA negativity that showed statistical significance in the low-dose group at the end of 6 months (P=0.001).
Among complications ([Table 3]), the low incidence of new-onset diabetes mellitus (P=0.38), acne from skin lesions (P=0.57), oro-esophageal candidiasis (P=1), urinary tract infections (P=0.383), herpes skin lesions (P=1), gastrointestinal bleeding (P=0.254), myopathy (P=1), osteoporosis (P=1), and sepsis (P=1) were noted in both groups equally, but increased incidence of hypertension (P=0.44), pneumonia (P=0.033), menstrual irregularities (P<0.001), Cushingoid features (P=0.03), and acid-peptic disorder (P=0.002) attained statistical significance (with P<0.05) in the high-dose group.{Table 3}
Discussion
Up to 50% of systemic lupus erythematosus will have kidney involvement. Many earlier trials have aimed at disease activity remission with minimum side effects of medications [1]. Complete remission is defined as normalization of serum creatinine and decline in PCR to less than 50 mg/mmol. Partial remission is improvement in creatinine though not to normal range and proteinuria to less than 300 mg/mmol [2].
In this study, the baseline characteristics were similar in the distribution of number of patients, sex-wise patients, and presence of hypertension among both low-dose and standard dose steroid intervention groups, similar to the Bharati et al. study [3]. Further, in this study proportions of microscopic hematuria, proteinuria, types of histopathological classes of LN, severity of activity and chronicity index, low C3, low C4 levels, ANA positivity, use of cyclophosphamide, mycophenolate, and hydroxychloroquine were found similar in both intervention groups like in the Bharati et al. [3] study, though the proportion of ACEI and ARB medications use, hypalbuminemia, and renal failure was higher in the low-dose group.
On treatment, it was found that the resolution of microscopic hematuria was statistically significant in the low-dose steroid group. Unlike partial proteinuria remission, the complete proteinuria remission was higher in both groups though it was not statistically significant, unlike in the Bharati et al. [3] group. The resolution of hypoalbuminemia was statistically significant in the low-dose group unlike in the Bharati et al. [3] group. The resolution of renal failure was noted in both groups but was statistically significant in the standard dose group unlike in the Bharati et al. [3] study.
The higher resolution of hypoalbuminemia in the low dose group, in contrast to higher resolution of renal failure in the standard dose group, possibly could be related to higher use of ACEI, ARBs in the low-dose group, or to mere reflection of higher numbers of low-dose group having renal failure at baseline or indicates that low-dose steroid is enough to treat LN with proteinuria but high dose steroid is required in the presence of renal failure in LN. LN is traditionally treated intensively for 6 months with pulse intravenous steroids followed by high-dose oral steroids, which is tapered from 8 weeks therapy in conjunction with other immunosuppressants [1].
In the study by Bomback and Appel [1], it was noted that therapy with low-dose steroid along with cyclophosphamide in proliferative LN was effective and also prevented relapses. These findings are similar to this study. Steroid alone or low-dose steroids were also used to treat LN in combination with other immunosuppressants in a study by Zakharova et al. [2]. Although the study had not specifically noted the efficacy of various immunosuppressant combination therapies, it noted good renal disease remission results with low-dose steroid therapy as well [2]. These findings were similar to this study. Zeher et al. [9] noted that low-dose steroids with mycophenolic acid was equally effective in remitting proliferative LN compared with a standard dose steroid with mycophenolic acid, though patients were already on maintenance immunosuppressants before enrollment into the study [9].
In contrast to the above findings, only in one study by Bharati et al. [3] comparing low-dose versus high-dose steroid therapy in conjunction with other immunosuppressants, it was noted that significant changes in urine protein and serum albumin improvement occurred in standard dose steroids though serum creatinine did not change in both standard and low-dose steroid groups. Further, there are no clear-cut guidelines about dose and duration of steroid therapy [5].
Hypocomplementemia of C3 showed mild improvement equally in both groups and hypocomplementemia of C4 showed statistically significant improvement in the low-dose group than the high-dose group, possibly related to persistent hypocomplementemia of C4 that is noted more than that of C3 even after LN remission [10] or possibly related to higher incidence of infection in the high-dose group [10,11] or possibly related to a larger range of normal values of C4 compared with C3 in LN leading to decreased diagnostic specificity [10] or it may indicate low C4 not returning to normal after therapy could be related to the underlying C4 deficiency rather than consumption of C4 [12]. As such low C3 and C4 both returning to normal on treatment of LN is gradual [10]. Attaining ANA negativity showed statistical significance in the high dose group, attaining anti-dsDNA negativity that showed statistical significance in the low-dose group. With treatment of LN, autoantibodies may disappear in varying percentages [13,14]. Early changes in autoantibodies with treatment may not distinguish responders from nonresponders [12]. So, autoantibodies’ complement response toward therapy may not be that significant than that compared with response of renal function parameters after intensive therapy in LN.
Higher proportions of complications such as hypertension, pneumonia, menstrual irregularities, Cushingoid features, and acid-peptic disorder were seen in high-dose steroid groups like in other earlier studies [1–3,6,9]. This shows that high-dose prolonged use of steroids was associated with increased incidence of complications such as hypertension than that with low-dose steroids. This finding supports recommendations for use of low-dose steroids.
These findings suggest that either low-dose steroids or early steroid tapering and discontinuing can be tried in LN like in other earlier studies [2]. Steroids interfere with genomic transcription of inflammatory molecules, which is saturated at 30–40 mg/day. At higher doses, there is no anti-inflammatory effect but rather leads to side effects. Nongenomic effects by methylprednisolone led to lower dose and faster tapering of oral prednisolone. A combination of pulse methylprednisolone with low-dose prednisolone 30 mg/day is more effective and safer than high-dose prednisolone in the induction phase [7]. Mild to moderate doses like 30 mg/day of steroids for a short course help treat aggressive diseases including lupus flares and are as effective as high-dose steroids with less toxicity, and added modern immunosuppression helps to use low-dose steroids [15-18].
Limitations
First, as it is a retrospective study, there is limitation of data collected. Second, as the hospital is a tertiary referral center, it may not depict the real spectrum of kidney diseases in all age groups. Third, the study groups are less and hence the results cannot be generalized. It needs a larger study group for the results to be generalized.
Conclusions
On treatment, it was found that the resolution of microscopic hematuria, improvement of hypocomplementemia of C4, and hypoalbuminemia was statistically significant in the low-dose steroid group. The resolution of proteinuria was seen in both groups; the resolution of renal failure was noted in both groups but was statistically significant in the standard dose group. Autoantibodies’ complement response toward therapy may not be that significant than that compared with response of renal function parameters after intensive therapy in LN. Higher rates of steroid-related complications were seen in the standard dose steroid group. These findings possibly indicate that low-dose steroid therapy is good enough to treat LN with proteinuria but a high-dose steroid is required in the presence of renal failure in LN.
Acknowledgements
The author acknowledges Ms Supriya and Dr Hemavarneshwari, Department of Community Medicine in helping him with the statistics for this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
| 1 | Bomback AS, Appel GB Updates on the treatment of lupus nephritis. J Am Soc Nephrol 2020; 21:2028–2035. |
| 2 | Zakharova EV, Makarova TA, Zvonova EV, Anilina AM, Stolyarevich ES Immunosuppressive treatment for lupus nephritis: long-term results in 178 patients. Biomed Res Int 2016; 2016:1–7. |
| 3 | Bharati J, Rathi M, Ramachandran R, Sharma A, Kumar V, Kohli HS, et al. Comparison of two steroid regimens in induction therapy of proliferative lupus nephritis: a randomized controlled trial. Indian J Nephrol 2019; 29:373–375. |
| 4 | Jaryal A, Vikrant S Current status of lupus nephritis. Indian J Med Res 2017; 145:167–178. |
| 5 | Acharya N Glucocorticoids in maintenance of systemic lupus erythematosus: is complete withdrawal a possibility?. Lupus Open Access 2021; 5:100153. |
| 6 | Sahay M, Saivani Y, Ismal K, Vali PS. Mycophenolate versus cyclophosphamide for lupus nephritis. Indian J Nephrol 2018; 28:35–40. |
| 7 | Porta S, Danza A, Saavedra MA, Carlomagno A, Goizueta MC, Vivero F, Irastorza GR Glucocorticoids in systemic lupus erythematosus. Ten questions and some issues. J Clin Med 2020; 9:2709. |
| 8 | Bose B, Silverman ED, Bargman JM Ten common mistakes in the management of lupus nephritis. Am J Kidney Dis 2014; 63:667–676. |
| 9 | Zeher M, Doria A, Lan J, Aroca G, Jayne D, Boletis I, et al. Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis. Lupus 2011; 20:1484–1493. |
| 10 | Hebert LA, Cosio FG, Neff JC Diagnostic significance of hypocomplementemia. Kidney Int 1991; 39:811–821. |
| 11 | Wang H, Liu M Complement C4, infections, and autoimmune diseases. Front Immunol 2021; 12:1–15. |
| 12 | Dallera M, Stone D, Levesque V, Cisternas M, Wofsy D Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide. Arthritis Care Res 2011; 63:351–357. |
| 13 | Cameron JS Lupus nephritis. JASN 1999; 10:413–424. |
| 14 | Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T, the LJP 394 Investigator Consortium. Relationship between anti–double-stranded DNA antibodiesand exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheumat 2005; 52:1129–1137. |
| 15 | Amissah-Arthur MB, Gordon C Contemporary treatment of systemic lupus erythematosus: an update for clinicians. Ther Adv Chronic Dis 2010; 1: 163–175. |
| 16 | Tseng C-E, Buyon JP, Kim M, Belmont HM, Mackay M, Diamond B, et al. The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006; 54: 3623–3632. |
| 17 | Ruiz-Irastorza G, Danza A, Perales I, Villar I, Garcia M, Delgado S, et al. Prednisone in lupus nephritis: how much is enough. Autoimmun Rev 2013; 13:2. |
| 18 | Ponticelli C, Glassock RJ, Moroni G Induction and maintenance therapy in proliferative lupus nephritis. J Nephrol 2010; 23:9–16. |
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