Evaluating Tubuloglomerular Outcome by Measuring Proteinuria and Neutrophil Gelatinase Associated Lipocalin after Induction of Low-Dose Cyclophosphamide among Patients with Class III/IV Lupus Nephritis
Background: In lupus nephritis (LN), glomerular dysfunction is evident by proteinuria. Urinary Neutrophil Gelatinase Associated Lipocalin (NGAL) has emerged as a promising biomarker to detect tubular dysfunction. Objective: To evaluate the tubulo-glomerular outcome after induction of Euro-Lupus regimen by measuring proteinuria and NGAL. Methods: This was a quasi-experimental study. Patients were included based on American College of Rheumatology (ACR) criteria. A total of 19 diagnosed lupus nephritis (class III & IV with or without class V) cases were evaluated. Their renal biopsy report was labelled according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS). All patients were treated with low-dose cyclophosphamide (Euro-Lupus regimen) for three months. Patients were assessed at baseline and then monthly up to 3 months of induction. The observed major variables were complete blood count (CBC), lupus serology (ANA, anti-dsDNA, C3, C4, anti-phospholipid), 24-hour urinary total protein (UTP), spot urinary protein creatinine ratio (PCR), spot urinary NGAL, urinary NGAL creatinine ratio, serum creatinine, serum albumin and estimated glomerular filtration rate (e-GFR). The activity index (AI), chronicity index (CI) and disease activity over time (SLEDAI) were assessed accordingly. Results: Mean age of the study population was 29 ± 10 years, where 95.5% were female. After 3 months of induction with low-dose cyclophosphamide (Euro-Lupus regimen), hemoglobin, eGFR, and serum albumin level had significantly increased from baseline (p < 0.05), while serum creatinine, UTP, PCR, urinary NGAL and disease activity score were significantly decreased (p < 0.05). Complete response was seen in 26.3% study patients and partial response in 36.8% patients after 3 months of induction. Response did not differ significantly in this short period of treatment among different histological types of LN. Conclusion: Induction in lupus nephritis by low-dose cyclophosphamide (Euro-Lupus regimen) reduces proteinuria and urinary NGAL significantly after three months of therapy. This regimen is effective in improving glomerular and tubular dysfunctions of LN.
References
[1]
Prasher, P., Varma, P., Baliga, K., Uppal, S. and Saini, J. (1999) Lupus Nephritis-A Critical Analysis of 17 Patients. Medical Journal Armed Forces India, 55, 126-128. https://doi.org/10.1016/s0377-1237(17)30267-8
[2]
Sedhain, A., Hada, R., Agrawal, R.K., Bhattarai, G.R. and Baral, A. (2018) Low Dose Mycophenolate Mofetil versus Cyclophosphamide in the Induction Therapy of Lupus Nephritis in Nepalese Population: A Randomized Control Trial. BMC Nephrology, 19, Article No. 175. https://doi.org/10.1186/s12882-018-0973-7
[3]
Yu, F., Wu, L., Tan, Y., Li, L., Wang, C., Wang, W., et al. (2010) Tubulointerstitial Lesions of Patients with Lupus Nephritis Classified by the 2003 International Society of Nephrology and Renal Pathology Society System. Kidney International, 77, 820-829. https://doi.org/10.1038/ki.2010.13
[4]
Tesar, V. and Hruskova, Z. (2015) Lupus Nephritis: A Different Disease in European Patients? Kidney Diseases, 1, 110-118. https://doi.org/10.1159/000438844
[5]
Fatoye, F., Gebrye, T. and Mbada, C. (2022) Global and Regional Prevalence and Incidence of Systemic Lupus Erythematosus in Low-and-Middle Income Countries: A Systematic Review and Meta-Analysis. Rheumatology International, 42, 2097-2107. https://doi.org/10.1007/s00296-022-05183-4
[6]
Illei, G.G., Takada, K., Parkin, D., Austin, H.A., Crane, M., Yarboro, C.H., et al. (2002) Renal Flares Are Common in Patients with Severe Proliferative Lupus Nephritis Treated with Pulse Immunosuppressive Therapy: Long‐Term Followup of a Cohort of 145 Patients Participating in Randomized Controlled Studies. Arthritis & Rheumatism, 46, 995-1002. https://doi.org/10.1002/art.10142
[7]
Ward, M.M. (2009) Changes in the Incidence of Endstage Renal Disease Due to Lupus Nephritis in the United States, 1996-2004. The Journal of Rheumatology, 36, 63-67. https://doi.org/10.3899/jrheum.080625
[8]
Rathi, M., Goyal, A., Jaryal, A., Sharma, A., Gupta, P.K., Ramachandran, R., et al. (2016) Comparison of Low-Dose Intravenous Cyclophosphamide with Oral Mycophenolate Mofetil in the Treatment of Lupus Nephritis. Kidney International, 89, 235-242. https://doi.org/10.1038/ki.2015.318
[9]
Appel, G.B., Contreras, G., Dooley, M.A., Ginzler, E.M., Isenberg, D., Jayne, D., et al. (2009) Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis. Journal of the American Society of Nephrology, 20, 1103-1112. https://doi.org/10.1681/asn.2008101028
[10]
Mok, C. (2012) Understanding Lupus Nephritis: Diagnosis, Management, and Treatment Options. International Journal of Women’s Health, 4, 213-222. https://doi.org/10.2147/ijwh.s28034
[11]
Mok, C.C. (2016) Con: Cyclophosphamide for the Treatment of Lupus Nephritis. Nephrology Dialysis Transplantation, 31, 1053-1057. https://doi.org/10.1093/ndt/gfw068
[12]
Touma, Z. (2016) Proteinuria: Assessment and Utility in Lupus Nephritis. Orthopedic Research & Physiotherapy, 2, 1-8. https://doi.org/10.24966/orp-2052/100027
[13]
Satirapoj, B., Kitiyakara, C., Leelahavanichkul, A., Avihingsanon, Y. and Supasyndh, O. (2017) Urine Neutrophil Gelatinase-Associated Lipocalin to Predict Renal Response after Induction Therapy in Active Lupus Nephritis. BMC Nephrology, 18, Article No. 263. https://doi.org/10.1186/s12882-017-0678-3
[14]
Fang, Y.G., Chen, N.N., Cheng, Y.B., Sun, S.J., Li, H.X., Sun, F., et al. (2015) Urinary Neutrophil Gelatinase-Associated Lipocalin for Diagnosis and Estimating Activity in Lupus Nephritis: A Meta-analysis. Lupus, 24, 1529-1539. https://doi.org/10.1177/0961203315600244
[15]
Wagener, G., Jan, M., Kim, M., Mori, K., Barasch, J.M., Sladen, R.N., et al. (2006) Association between Increases in Urinary Neutrophil Gelatinase-Associated Lipocalin and Acute Renal Dysfunction after Adult Cardiac Surgery. Anesthesiology, 105, 485-491. https://doi.org/10.1097/00000542-200609000-00011
[16]
Xin, C., Yulong, X., Yu, C., Changchun, C., Feng, Z. and Xinwei, M. (2008) Urine Neutrophil Gelatinase-Associated Lipocalin and Interleukin-18 Predict Acute Kidney Injury after Cardiac Surgery. Renal Failure, 30, 904-913. https://doi.org/10.1080/08860220802359089
[17]
Tuladhar, S.M., Püntmann, V.O., Soni, M., Punjabi, P.P. and Bogle, R.G. (2009) Rapid Detection of Acute Kidney Injury by Plasma and Urinary Neutrophil Gelatinase-Associated Lipocalin after Cardiopulmonary Bypass. Journal of Cardiovascular Pharmacology, 53, 261-266. https://doi.org/10.1097/fjc.0b013e31819d6139
[18]
Haase-Fielitz, A., Bellomo, R., Devarajan, P., Bennett, M., Story, D., Matalanis, G., et al. (2009) The Predictive Performance of Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) Increases with Grade of Acute Kidney Injury. Nephrology Dialysis Transplantation, 24, 3349-3354. https://doi.org/10.1093/ndt/gfp234
[19]
Weening, J.J., D’Agati, V.D., Schwartz, M.M., Seshan, S.V., Alpers, C.E., Appel, G.B., et al. (2004) The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. Journal of the American Society of Nephrology, 15, 241-250. https://doi.org/10.1097/01.asn.0000108969.21691.5d
[20]
Hahn, B.H., McMahon, M.A., Wilkinson, A., Wallace, W.D., Daikh, D.I., FitzGerald, J.D., et al. (2012) American College of Rheumatology Guidelines for Screening, Treatment, and Management of Lupus Nephritis. Arthritis Care & Research, 64, 797-808. https://doi.org/10.1002/acr.21664
[21]
Anić, F., Žuvić-Butorac, M., Štimac, D. and Novak, S. (2014) New Classification Criteria for Systemic Lupus Erythematosus Correlate with Disease Activity. Croatian Medical Journal, 55, 514-519. https://doi.org/10.3325/cmj.2014.55.514
[22]
Houssiau, F.A., Vasconcelos, C., D’Cruz, D., Sebastiani, G.D., Garrido, E.d.R., Danieli, M.G., et al. (2002) Immunosuppressive Therapy in Lupus Nephritis: The Euro‐lupus Nephritis Trial, a Randomized Trial of Low-Dose versus High-Dose Intravenous Cyclophosphamide. Arthritis & Rheumatism, 46, 2121-2131. https://doi.org/10.1002/art.10461
[23]
Moroni, G., Raffiotta, F., Trezzi, B., Giglio, E., Mezzina, N., Del Papa, N., et al. (2014) Rituximab vs Mycophenolate and vs Cyclophosphamide Pulses for Induction Therapy of Active Lupus Nephritis: A Clinical Observational Study. Rheumatology, 53, 1570-1577. https://doi.org/10.1093/rheumatology/ket462
[24]
Noor, R.A.A., Eissa, M., Okda, H.I., Abdelnabi, H.H., Ahmed, S.A., Mohammed, E.F., et al. (2021) Comparison between High-Dose, Low-Dose Cyclophosphamide and Mycophenolate Mofetil in Treatment of Proliferative Lupus Nephritis (an Egyptian Multicenter Retrospective Study). Journal of the Egyptian Society of Nephrology and Transplantation, 21, 174-183. https://doi.org/10.4103/jesnt.jesnt_13_21
[25]
Sigdel, M.R., Kafle, M.P. and Shah, D.S. (2016) Outcome of Low Dose Cyclophosphamide for Induction Phase Treatment of Lupus Nephritis, a Single Center Study. BMC Nephrology, 17, Article No. 145. https://doi.org/10.1186/s12882-016-0361-0
[26]
Mehra, S., Usdadiya, J.B., Jain, V.K., Misra, D.P. and Negi, V.S. (2018) Comparing the Efficacy of Low-Dose vs High-Dose Cyclophosphamide Regimen as Induction Therapy in the Treatment of Proliferative Lupus Nephritis: A Single Center Study. Rheumatology International, 38, 557-568. https://doi.org/10.1007/s00296-018-3995-3
[27]
Dooley, M.A., Hogan, S., Jennette, C., Falk, R. and for the Glomerular Disease Collaborative Network, (1997) Cyclophosphamide Therapy for Lupus Nephritis: Poor Renal Survival in Black Americans. Kidney International, 51, 1188-1195. https://doi.org/10.1038/ki.1997.162
[28]
Roccatello, D., Sciascia, S., Naretto, C., Alpa, M., Fenoglio, R., Ferro, M., et al. (2021) A Prospective Study on Long-Term Clinical Outcomes of Patients with Lupus Nephritis Treated with an Intensified B-Cell Depletion Protocol without Maintenance Therapy. Kidney International Reports, 6, 1081-1087. https://doi.org/10.1016/j.ekir.2021.01.027
[29]
El Shahawy, M.S., Hemida, M.H., Abdel-Hafez, H.A., El-Baz, T.Z., Lotfy, A.M. and Emran, T.M. (2018) Urinary Neutrophil Gelatinase-Associated Lipocalin as a Marker for Disease Activity in Lupus Nephritis. Scandinavian Journal of Clinical and Laboratory Investigation, 78, 264-268. https://doi.org/10.1080/00365513.2018.1449242
