Extreme Nephrotic-Range Proteinuria in Mixed Lupus Nephritis with Low Histologic Activity: Potential Contribution of Obesity-Related Hyperfiltration in a Triple Autoimmune Overlap Syndrome

By Vilma CADRI, Ilda NASUFI, Nisrin HASA, Irda RRUGEJA, Ervin RRAPUSHI

Abstract
Background: Mixed lupus nephritis (LN), combining proliferative and
membranous lesions, is frequently associated with substantial proteinuria and increased risk of kidney injury. However, the occurrence of massive nephrotic-range proteinuria despite minimal histologic activity, persistently negative anti-double stranded DNA (anti-dsDNA) antibodies, and preserved serum creatinine represents an uncommon diagnostic challenge. The coexistence of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriatic arthritis (PsA) in a single patient is exceptionally rare and further complicates disease assessment and management. Case Presentation: We report a 39-year-old man with an 18-year history of triple autoimmune overlap syndrome (SLE, RA, and PsA) who presented with severe nephrotic-range proteinuria (10.7 g/24 h), urinary albumin-to-creatinine ratio (UACR) of 23,538 mg/g, hypoalbuminemia, persistent hypocomplementemia, pancytopenia, and severe obesity BMI 39.2 kg/m². Despite preserved serum creatinine (0.8 mg/dL), measured creatinine clearance was markedly elevated at 216 mL/min, consistent with extreme glomerular hyperfiltration. Serological evaluation demonstrated positive antinuclear antibodies (ANA) but persistently negative anti-dsDNA antibodies. Kidney biopsy revealed mixed lupus nephritis Class III+V according to the 2018 ISN/RPS classification, with full-house immunofluorescence, a low activity index (2/24), and minimal chronicity (0–1). The marked discrepancy between massive proteinuria and limited histologic activity raised the possibility that obesity-related hyperfiltration contributed to urinary protein losses in addition to immune-complex-mediated renal injury. Following treatment with pulse methylprednisolone, mycophenolate mofetil, hydroxychloroquine, and supportive nephroprotective therapy, the patient achieved substantial clinical and biochemical improvement. After nine months of follow-up, proteinuria decreased to 3.8 g/24 h, UACR declined to 238 mg/g, serum albumin improved to the lower limit of normal, and complement levels normalized, while body weight remained unchanged. Conclusion: This case highlights three important clinical messages. First, active lupus nephritis may occur despite persistently negative anti-dsDNA antibodies. Second, severe nephrotic-range proteinuria may be observed in mixed Class III+V lupus nephritis even when histologic activity appears limited. Third, obesity-related glomerular hyperfiltration may amplify proteinuria and contribute to clinicopathological discordance. The marked renal improvement despite unchanged body weight suggests that lupus nephritis represented the principal pathological process, whereas hyperfiltration acted as an important disease modifier. Kidney biopsy remains indispensable for diagnosis and therapeutic decision-making in complex autoimmune overlap syndromes.
Keywords: lupus nephritis; mixed lupus nephritis; overlap syndrome; systemic lupus erythematosus; rheumatoid arthritis; psoriatic arthritis; nephrotic syndrome; glomerular hyperfiltration; obesity-related kidney disease; mycophenolate mofetil.