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A wolf in sheep’s clothing

Sir, Lupus podocytopathy is an increasingly recognised histological variant of lupus nephritis proposed to describe a subset of patients with systemic lupus erythematosus (SLE) presenting with nephrotic-range proteinuria and share most histological characteristics with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) except for immune deposits in the mesangial region. To the best of our knowledge this is the first description of lupus podocytopathy as the presenting manifestation of clinical SLE. A 30-year-old Caucasian female was referred to the nephrology unit with acute-onset nephrotic syndrome. She presented to her general practitioner with a two-week history of dizziness and frothy urine when a urine dip stick revealed 4þ protein but no blood. She denied fever, rash, joint pains and was on no regular medications including nonsteroidal anti-inflammatory drugs. Her physical examination was unremarkable with the exception of pitting pedal edema. Investigations were notable for gross proteinuria with urine albumin creatinine ratio (ACR) at 1138mg/mol (normal <3.5mg/mol), normal renal functions (serum creatinine 54mmol/L; eGFR >90ml/min), mild hypoalbuminemia of 24 g/L (normal 35 52 g/L) and normal full blood count. Anti-nuclear antibody (ANA) was positive in a titre of 1:320 with elevated anti-double-stranded DNA antibodies at 29 IU/ml (Farr radioimmunoassay, normal <7 IU/ml) but normal C3 (1.01, normal 0.82 1.93 g/L) and C4 (0.17, normal 0.15 0.57 g/L). Renal biopsy (Figure 1) appearances were near normal by light microscopy. Immunofluorescence (IF) showed weak (1þ) predominantly granular mesangial staining for several analytes. Electron microscopy revealed diffuse effacement of foot processes with no subendothelial or subepithelial immune deposits but small-to-medium size paramesangial dense deposits. Treatment for ‘minimal change disease’ with oral prednisolone at 50mg/day resulted in rapid clinical and biochemical remission (urine ACR <1.6mg/mol) within two weeks of treatment. She remained in remission for four months. Following steroid withdrawal she presented with mild proteinuria (urine ACR 27.8mg/mol) accompanied by severe debilitating symmetrical arthritis involving small and medium joints. Prednisolone, mycophenolate mofetil and hydroxychloroquine have kept her in remission since. This patient’s initial clinical presentation with isolated nephrotic-range proteinuria and a renal biopsy diagnosis of ‘minimal change disease’ did not meet the classification criteria for systemic lupus erythematosus (SLE) despite some serological evidence. However, her subsequent presentation with arthritis was associated with markedly elevated anti-double-stranded DNA antibodies at >100 IU/ml (previously 29 IU/ml); low C3 and C4 (previously normal) and ANA of >1:2560 (previously 1:320). Renal functions remained normal with urine demonstrating minimal proteinuria but no haematuria. The manifestation of clinical SLE resulted in a revised renal pathological diagnosis of lupus podocytopathy as she met the requirements of the proposed criteria (Table 1). Lupus podocytopathy is not a recognised class of lupus nephritis in the currently used 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) nomenclature. Historically, nephrotic syndrome in SLE is characteristic of proliferative lupus nephritis (class III, class IV) or membranous (class V). The association of SLE with MCD/FSGS has been described in isolated case reports and the relevance of this association is still debated. However, the frequency of these cases and the observation that the onset of the nephrotic syndrome frequently correlates with the onset of clinical systemic features of SLE implies that the podocytopathy is more likely the result of active lupus than the coexistence of two separate but concurrent diseases, SLE and MCD/FSGS. The pathogenesis of podocyte injury in lupus nephritis remains elusive, though aberrant T-cell function, interleukin (IL) 13 pathway and circulating toxin hypothesis have been implicated. The rapid response to glucocorticoid therapy with a median time to remission of four weeks is particularly characteristic. Correspondence to: B Chacko, Nephrology and Transplantation Unit, John Hunter Hospital, Newcastle, NSW 2310, Australia. School of Medicine and Public Health University of Newcastle, NSW, Australia. Email: Bobby.Chacko@hnehealth.nsw.gov.au Received 3 January 2018; accepted 27 March 2018