Diagnostic dilemmas in a girl with acute glomerulonephritis: Answers

Based on the initial presentation of macroscopic hematuria, proteinuria, and renal failure following an episode of pharyngitis with a typical time lag of 2 weeks, the differential diagnosis consists primarily of acute post-infectious glomerulonephritis (PIGN), the first presentation of either immune complex, or complement-mediated membranoproliferative nephritis (MPGN), or IgA nephropathy (IgAN) triggered by an infection. Less likely, but not excluded, are ANCA vasculitis, lupus nephritis, anti-glomerular basement (GBM) glomerulonephritis, and toxicity-/medication-induced glomerulonephritis. The young age and lack of sinusitis or pulmonary symptoms make ANCA vasculitis less likely and there were neither physical nor anamnestic signs of systemic lupus erythematosus (SLE). Macroscopic hematuria and nephrotic proteinuria are less consistent with a toxic cause of acute kidney injury. Given the clinical course, the patient had suspected rapidly progressive glomerulonephritis (RPGN).

Additional laboratory investigations should be aimed at possible causes of RPGN [1]. The few available studies on pediatric RPGN report that it is caused in over 80% by a form of immune-complex-mediated glomerulonephritis, with MPGN, Henoch–Schönlein purpura (HSP)/IgA nephropathy and PIGN as the most frequent underlying causes [2‐5]. Lupus nephritis, C3 glomerulonephritis (C3GN), and ANCA vasculitis are more infrequent causes of pediatric RPGN [2‐5]. In our patient, additional serum measurements included anti-streptolysin titer (AST) and anti-DNAse B titer, mycoplasma, hepatitis B and C serology, ANA, anti-PR3 ANCA, anti-MPO ANCA, anti-GBM measurements, and a full complement cascade for assessment of both the classical and alternative pathways (C3, C4, C3d, AP50, CH50, C3 nephritic factor, C5b-9).

On the day after admission, the patient developed oliguria and a steep rise in creatinine level, indicating a rapid progression of renal failure. Although there was a high degree of suspicion regarding PIGN, serum complement C3 and C4 levels and AST and anti-DNAse B titer were not yet available. Generally, a renal biopsy is not mandatory when PIGN is suspected. However, certain features atypical of PIGN should prompt a biopsy. These include RPGN, extra-renal manifestations, a patient’s age <2 years, persistent gross hematuria, hypertension or nephritic syndrome, and hypocomplementemia lasting >6 weeks [6]. In view of the rapid course of the acute kidney injury in our patient, a renal biopsy was planned for the next available appointment, which was the next day.

There is little evidence regarding the treatment of RPGN in children and existing guidelines are based on studies in adults, in whom the underlying cause of the glomerulonephritis is usually different. For instance, adults have a higher likelihood of ANCA vasculitis [1]. Nevertheless, there is a general consensus that methylprednisolone pulse therapy with or without cyclophosphamide, is the first therapeutic regimen in RPGN [2‐5, 7]. In our patient, we refrained from immunosuppressive treatment before a biopsy had been obtained. At the time, there was a high degree of suspicion regarding either PIGN or MPGN (immune complex- or complement-mediated). Methylprednisolone pulse therapy was not started, as there is a lack of evidence for a beneficial effect of immunosuppressive therapy in PIGN [7, 8]. Also, we feared that high doses of steroids might influence the renal biopsy. “Blind” administration of eculizumab was also considered but rejected for lack of a diagnosis and in view of its high costs. Supportive treatment consisting of fluid restriction, diuretics, and antibiotics was continued, awaiting the serum complement results.

In our patient, the renal biopsy and serum complement results imposed a diagnostic dilemma, which is described below. On the third day of admission, a Monday, serum complement measurements were found to be normal (C3: 1.15 g/l, reference value 0.9–1.8 g/l; C4: 0.43 g/l; reference value 0.1–0.49 g/l). AST and anti-DNAse B titer were not yet available. Creatinine levels continued to rise to 640 μmol/l (7.2 mg/dl) and oliguria persisted. Because of the clinical picture of RPGN, together with the absence of hypocomplementemia characteristic of PIGN, this initial diagnosis was considered less likely, as was a complement-mediated MPGN. A renal biopsy was performed on the same day, combined with the placement of a central venous line for hemodialysis. Methylprednisolone pulse therapy (three daily pulses of 500 mg/m² body surface area) was started immediately after the renal biopsy. Histopathological evaluation of the renal biopsy showed crescentic glomerulonephritis in all 25 glomeruli (100% crescents), together with some endocapillary hypercellularity due to granulocyte infiltration. All crescents were cellular, with no signs of chronicity (Fig. 1a, b). There was also mild interstitial edema and tubules were dilated and filled with erythrocytes and granulocytes (Fig. 1c). Immunofluorescence was negative for IgG (Fig. 1d), IgM, IgA, kappa, lambda, and C1q, but revealed coarse granular C3c deposits along the capillary walls (2+), the so-called “starry-sky” pattern (Fig. 1e). C4d staining was negative and C5b9 staining was similar to C3c. Electron microscopy showed several (subepithelial) humps (Fig. 1f) and tiny subendothelial electron dense deposits. Intramembranous garland-like electron dense deposits compatible with dense deposit disease (DDD) were not observed. These findings could be associated with both C3GN and severe PIGN.

Intermittent hemodialysis was started on the fourth day after admission. AST and anti-DNAse B titer were still not available, nor were the bacterial and viral serology investigations. As renal biopsy findings were consistent with both PIGN and C3GN, a diagnosis of C3GN due to an intrinsic complement defect, triggered by an infection, could not be ruled out, despite the normal complement C3 level. In view of the severity of the clinical course, the biopsy findings with 100% crescents and recent publications reporting promising results of the complement inhibitor eculizumab for C3GN [9‐11], a single dose of eculizumab (375 mg/m² body surface area) was administered intravenously awaiting further results. Complement cascade diagnostic investigations had been undertaken before eculizumab administration to prevent difficulties in interpretation of the results. Over the following days, intermittent hemodialysis was continued. The AST returned highly positive (1,600 U/ml), as did the anti-DNAse B titer (>1,600 U/ml), indicative of a recent streptococcal infection. Mycoplasma and hepatitis B/C serology were negative. Complement cascade analysis showed mild complement alternative pathway route activation (114%; reference value: 40–110%), with elevated alternative complement byproduct C3d (4.8%; reference value: 0.5–3.1%) and normal C5b-9 (<1,2 AE/ml; reference value:<4 AE/ml). C3 nephritic factor was negative, as were ANA, ANCA, and anti-GBM antibodies. From the sixth day after admission onward, renal function improved rapidly and hemodialysis treatment was discontinued. The patient was discharged 11 days after admission, with a serum creatinine level of 106 μmol/l (1.2 mg/dl) and without medication. At last follow-up, 2 months after presentation, renal function had completely recovered (creatinine 42 μmol/l (0.5 mg/dl), eGFR according to Schwartz was 116 ml/min/1.73 m²), and proteinuria levels had declined significantly (protein to creatinine ratio: 55.2 mg/mmol Cr). This clinical course of rapid improvement favors the diagnosis of PIGN with RPGN presentation.