MALE LUPUS NEPHRITIS: A COMPREHENSIVE ANALYSIS OF CLINICAL FEATURES, SEROLOGICAL MARKERS, AND TREATMENT OUTCOMES

Introduction:

Systemic lupus erythematosus (SLE) is an autoimmune systemic disorder, more common in females of reproductive age‑group as compared with males with ratio 9:1.  There are very few studies regarding lupus nephritis (LN) in males. SLE can involve any organ, and when it affects the kidneys, it is known as “lupus nephritis” (LN). LN can manifest with minimal renal involvement in the form of mild proteinuria to severe end‑stage kidney disease (ESKD). Nearly 5% to 22% of these patients progress to ESRD as per the US Renal Data System database from 1995 to 2010, 18% of patients with ESKD due to LN were male. Given the severity of disease in males and availability of various treatment regimens, it is imperative to know the epidemiology, clinical profile and outcomes of different treatment modalities in male lupus nephritis.  This study aimed at analysis the Clinical features, Serological profile, and Treatment Outcomes of the male patients with lupus nephritis.

Methods:

This retrospective, single-centre study, conducted in tertiary care centre in south India, and received approval from the Institutional Review Board (IRB) vide minute number 0624144 dated 12.06.2024. The study encompassed all male patients with biopsy-confirmed lupus nephritis, observed between January 1, 2010, and December 31, 2018. Data retrieval occurred from electronic medical records within the departments of Nephrology and Nephropathology. The data was collected in Epidata version 4.6 and the results were analysed in SPSS ver.16. The data included clinical features, serological profile, induction protocols and maintenance immunosuppression regimens used in the treatment of male lupus nephritis. The outcomes of the patients with various induction and maintenance treatment protocols (as per KDIGO guidelines), in terms of clinical remission and serological remission were studied at 6 months, 12 months, 36 months and 60 months. The clinical remission was defined as 24 hour proteinuria <500 mg/dl, no hematuria (Red Blood Cells in urine- less than 5 per high power field) and serum creatinine less than 1.2 mg/dl. The serological remission was defined as normalisation of serum complements levels (C3 more than 100 mg/dl and C4 more than 10mg/dl), double stranded deoxyribonucleic acid (dsDNA) less than 100 IU/ml. Relapse was defined re appearance of hematuria (Red Blood Cells in urine- less than 5 per high power field, proteinuria (24 hour urine protein more than 1.5 gram/day) and deranged serum creatinine more than 1.2 mg/dl. Additionally the data of the adverse effects of various immunosuppressive regimens was collected. The categorical variables presented as frequencies and proportions, and continuous variables expressed as mean with standard deviation or median with interquartile range. The Comparative analyses was done by the Chi-squared test for categorical variables.

Results:

During the study period, 9243 patients underwent native kidney biopsies at this centre, among whom 1442 (15.6%) were diagnosed to have lupus nephritis, out of which 166 (11.5%) were male patients. The mean age of the patients was 31.1+ 11.2 years.

The most common presentation was Nephrotic syndrome (NS) in 43 ( ), Hematoproteinuira with deranged creatinine in 39 (23.4%), NS with deranged creatinine in 33 (20%), multisystem involvement in 31 (19 %), Rapidly Progressive glomerulonephritis in 10 (6%), musculoskeletal involvement in 6 (3.6%) and cutaneous presentation in in 4 (2.4%) patients. The multisystem involvement was defined as the patients who had cutaneous, haematological, renal and neurological involvement at presennation. The serological markers at diagnosis were low C3 in 132 (79.5%), low C4 in 66 (39.7%) and high dsDNA in 144 (86.7%). The most common class of lupus nephritis in this study was class 4 in 91 (54.8%) patients. The other classes include class 5 in 38 (22.8%), class 3 in 28 (16.8%) patients, combined class 4&5 in 7 (4.2%) patients and class 6 in 2 (1.2%) patients. The crescentic glomerulonephritis is seen in 28 (16.8%) patients. At diagnosis 15 (9%) of patients required hemodiaylsis and in 12 (7.2%) patients required both hemodialysis & plasmaphersis.

All these patients were initially managed with Methylprednisolone pulse at the dose of 500 mg/day for three days followed by oral prednisolone at the dose of 0.5mg/kg body weight. The steroids were gradually tapered and reduced to 5 mg/day at the end of 6 months and continued at 2.5 to 5 mg/day till 60 months. Two treatment regimens for intravenous Cyclophosphamide ware used, National Institutes of Health (NIH) which included 500-750mg/m2 monthly once for 6 months and Euro Lupus which included 500mg/m2 once in two weeks for 3 months.

The Mycophenolate was given at the dose of 1-1.5 gm twice daily with equivalent mycophenolate sodim preparation 720-1080 mg/day. The MPA Area under curve (AUC) was measured by High-Performance Liquid Chromatography (HPLC) after two weeks of starting therapy and the level maintained 45-60 mg.h/L at induction which was adopted from kidney transplant protocols. For maintenance therapy Mycophenolate and Azathioprine were used. The Mycophenolate was given at the dose of 500-1000 mg/day with target MPA AUC of 35-50 mg.h/L and Azathiproine was given at the dose of 1.5 to 2 mg/kg body weight with close monitoring of total leucocyte count.

The induction agent Mycophenolate (MPA) was used in 88 (53%) patients and Cyclophosphamide in 78 (47%) - National institutes of health (NIH regimen) in 35 and Euro Lupus regimen in 52 patients. At the end of six months of induction, 69 (78.4%) had follow up in Mycophenoate (MPA) group, among which 35 (50.7%) and 40 (50.8%) patients attained complete clinical and serological remission respectively. The mean MPA AUC 40.2+ 16.2 mg.h/L. A total of 57 (73%) of patients had follow up at the end of six months in Cyclophosphamide group among which 24 (42.1%) and 34 (59.6) patients attained complete clinical and serological remission respectively. There was no statistical significance between MPA and Cyclophosphamide in attaining clinical (p value- 0.21) and serological remission (p value – 0.49. But the infectious complications were more common in Cyclophosphamide group 13 (22.8) when compared to MPA group with p value-0.06. The leucopenia was more common in MPA group 18 (26%) when compared to 14 (24.5%) with p value 0.41. Two patients died in the cyclophosphamide group due to gram negative sepsis and septic shock within two months of diagnosis. Steroid induced hyperglycemia was seen in 22 (17.4%) of patients in both groups

At 36 months, in the MPA maintenance group, 53 (42%) patients had follow up, among which 41 (77.3%) and 48 (90.5%) attained complete clinical and serological remission respectively. At 60 months, 48 (50.5%) patients had follow up, among which 38 (79.1%) and 42 (87.5%) attained complete clinical and serological remission respectively. The dose of MPA was adjusted as per AUC and the mean MPA AUC was 38.2+ 14.4 mg.h/L. The Tacrolimus was added in in 05 patients at 36 months and 03 patients at the end of 60 months in view of persistent proteinuria. The Tacrolimus Co was maintained at 4-6 ng/ml.  . In the Azathioprine (AZA) group, 42 (33.3%) patients had follow up, among which 26 (62%) and 31 (73.8%) attained complete clinical and serological remission respectively. Rituxmab was used as add on agent in 3 patients who had persistent leucopenia with higher doses of MPA, where the minimum dose of MPA given.  At 60 months, 38 (40%) patients had follow up, among which 22 (57.8%) and 20 (52.6%) attained complete clinical and serological remission respectively.

At 60 months, the number of relapses were more in Azathioprine group when compared to MPA group with statistically significant p value of 0.013. The number patients progressed to end stage kidney disease was higher in AZA group when compared to MPA group with with statistically significant p value of 0.015.

In both groups, a total of 37 patients had relapse with the mean duration of relapse from date of kidney biopsy was 42.4+10.8 months. A total of 16 (43.2%) patients underwent repeat kidney biopsy and only 7 (43.7%) had class switch which required induction therapy followed by maintenance therapy. In other patients, the dose of steroid was increased with adjustement of MPA as per AUC concentration. The rates infections and leucopenia in both groups were not statistically significant. At the end of 60 months, 30.2% of patients did not attain clinical remission, but had stable mean creatinine of 3.2+ 1.4 mg/dl and mean urine protein creatinine ratio of 1.62+0.8. In our study, 27.9% of patients were not attained serological remission at 60 months. 

Conclusions:

This is one of the largest retrospective studies on male lupus nephritis from India, comparing various induction and maintenance regimens over a 60-month follow-up period, with MPA dosages adjusted according to therapeutic drug monitoring. In male patients presenting with nephrotic syndrome and renal dysfunction, lupus nephritis should be considered as a differential diagnosis, even in the absence of other systemic symptoms, as our study indicates. Male lupus nephritis is not as rare as previously thought and demands early diagnosis and optimal immunosuppressive therapy. Our findings show no significant differences between the inductions agents used; however, MPA may be more effective than AZA in preventing relapses during maintenance therapy. Both induction and maintenance therapies were associated with infections and leukopenia as major side effects.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.