Prepared by: Prof. Dr. Younis Abdul Redha Al-Khafaji<br /><br />Abstract<br />In recent years, numerous studies have provided new evidence regarding the diagnosis, management, and monitoring of patients with lupus nephritis (LN). The observed disconnect between clinical and histological findings has led to a reevaluation of the role of kidney biopsy as both a diagnostic and monitoring tool. In terms of treatment, four evidence-based immunosuppressive regimens are now available as first-line therapy. Current challenges include selecting the optimal immunosuppressive approach for each patient, the unmet need for non-invasive biomarkers to monitor disease activity and guide therapy, the necessity for comprehensive patient management in this complex multisystem disease, and the development of more targeted therapies that modulate key molecular pathways driving glomerular inflammation and injury, aiming to improve treatment responses. This review discusses the diagnostic and therapeutic approaches to LN, in addition to evaluating treatment response and disease monitoring.<br /><br />Introduction<br />Renal involvement in systemic lupus erythematosus (SLE), known as lupus nephritis (LN), occurs in up to 60% of patients. Renal symptoms often present concurrently with or shortly after the diagnosis of SLE and can range from subtle urinary abnormalities (e.g., hematuria, proteinuria) to rapidly progressive nephritic syndrome. Despite advances in SLE and chronic kidney disease management, 10–30% of LN patients progress to kidney failure within ten years of diagnosis. LN is also associated with increased mortality, with standardized mortality ratios of 2.2, 3.6, and 9.20 for patients with renal involvement, kidney damage, or kidney failure, respectively, compared to SLE patients without renal involvement. LN further contributes to increased cardiovascular risk, infections, metabolic complications, and reduced health-related quality of life.<br /><br />Recent Advances<br />New medications have shown short-term benefits in LN outcomes, with two of them receiving regulatory approval for use as initial therapy alongside standard care. As novel therapies emerge, clinicians face the challenge of choosing the most beneficial treatment combinations while minimizing immunosuppression-related risks. Additionally, these treatments have reshaped our interpretation of clinical outcomes, biomarkers, and histopathological findings during disease monitoring. This review provides an updated overview of the diagnosis, management, and follow-up of LN patients.<br /><br />Diagnosis of Lupus Nephritis<br />The most concise definition of LN is immune complex-mediated glomerulonephritis in SLE patients. LN should be suspected in patients presenting with hematuria, proteinuria, and/or a persistent unexplained decline in renal function (measured via estimated glomerular filtration rate, or eGFR). In practice, proteinuria—alone or in combination with hematuria and/or decreased eGFR—is the primary trigger for renal biopsy.<br /><br />Non-Immunosuppressive Treatment<br />Although not discussed in detail in this review, non-immunosuppressive therapy plays a crucial role in preserving kidney function and preventing complications. Key supportive and preventive interventions in LN management are summarized in Table 1.<br /><br />Immunomodulation with Antimalarials<br />Antimalarial drugs (hydroxychloroquine and chloroquine) offer several benefits in both SLE and LN. They reduce the risk of...<br /><br />Current Tools for Assessing Treatment Response<br />Treatment response in clinical trials is often measured using the concepts of "complete" or "partial" response. These involve stabilization of serum creatinine, reduction of proteinuria, and occasionally resolution of hematuria and lowering of glucocorticoid doses below a certain threshold. Among these variables, only serum creatinine and proteinuria are correlated with long-term kidney function preservation.<br /><br />The Need for Long-Term Therapy in Lupus Nephritis<br />Even after achieving remission (ideally both clinical and histological), LN patients remain at risk of relapse. Reported relapse rates range from 22% to 66%. Each flare contributes to nephron loss, reduced treatment responsiveness, and poorer long-term renal outcomes.<br /><br />Development of Future Targeted Therapies for Pathogenic Pathways in LN<br />Although new therapies used alongside standard care have improved LN outcomes, significant challenges remain in clinical and translational research. A disease classification beyond histopathology and more rooted in pathophysiology is needed to apply current treatments effectively and develop novel drugs that increase complete response rates while minimizing side effects.<br /><br />Conclusion<br />Recent years have seen a growing body of evidence supporting LN management. Tools such as biomarkers and renal biopsy are valuable at various disease stages. Four immunosuppressive regimens are currently supported by clinical trial data. However, selecting the best approach for each patient remains a major challenge. There is an ongoing need for specific biomarkers to guide treatment and disease monitoring, as well as for more precise and effective therapeutic options.<br /><br />Al-Mustaqbal University is the First in Iraq <br/><br/><a href=https://www.linkedin.com/company/college-of-health-medical-techniques/posts/ target=_blank>linkedin College of Health and Medical Techniques</a>