A 55-year-old Japanese man was referred and admitted to our hospital with rapidly progressive glomerulonephritis (RPGN) and nephrotic syndrome in December 2012. His serum creatinine (SCr) level was 0.63 mg/dL in 2011 (Table). Seven weeks earlier, he had been admitted to another hospital with hemorrhagic gastric ulcer and renal failure [SCr, 3.50 mg/dL; serum albumin, 2.7 g/dL; urine protein to creatinine ratio (UPCR), 12.3 g/gCr; and moderate hematuria] (Table), which gradually worsened until the referral. His medical history included obsolete tuberculosis, hypertension, and an emergent operation for perforated peptic ulcer at the ages of 31, 53, and 54, respectively. There was no family history of kidney disease. On admission, his body weight, height, and blood pressure were 64.1 kg, 174 cm, and 169/105 mmHg, respectively, and he was afebrile. The laboratory findings (Table) were as follows: hemoglobin, 9.6 g/dL; white blood cell count, 9,020 /muL; platelet count, 46.2x104/muL; serum total protein, 5.5 g/dL; albumin, 1.7 g/dL, total cholesterol, 166 mg/dL, creatinine, 7.60 mg/dL; sodium, 144 mEq/L; potassium, 3.4 mEq/L; chloride, 110 mEq/L; C-reactive protein, 0.14 mg/dL; IgG, 1,330 mg/dL; IgA, 136 mg/dL; IgM, 82 mg/dL; kappa-light chain, 179.0 mg/L (normal range, 2.42-18.92); lambda-light chain, 78.40 mg/L (normal range, 4.44-26.18); kappa/lambda ratio, 2.283 (normal range, 0.248-1.804). A urinalysis revealed heavy hematuria with proteinuria at 13.6 g/gCr and a variety of casts. Anti-streptolysin O and anti-streptokinase antibodies were not elevated. Anti-nuclear and anti-neutrophil cytoplasmic antibodies as well as HBcAb, HBsAg, and serum cryoglobulins were negative. Serum or urine paraproteins were not detected by immunofixation electrophoresis. Chest X-ray showed bilateral pleural effusions, and echocardiography showed no vegetations.
The first kidney biopsy was performed on hospital day 2 (Fig. 1). Light microscopy showed 35 glomeruli, including one glomerulus with global sclerosis. Numerous circumferential cellular crescents and diffuse endocapillary and mesangial proliferation with double contour formation along the capillary walls were observed (Fig. 2A and B). Immunofluorescence showed granular IgG, IgG1, kappa light chain, and C3 deposits predominantly along the capillary walls, with undetectable IgM, IgA, C1q, IgG2-4, and lambda light chain (Fig. 3A-H). Electron microscopy (EM) showed subepithelial and subendothelial deposits, including hump-like shaped deposits (Fig. 4A and B). Positive immunofluorescent staining for nephritis-associated plasmin receptor (NAPlr) and positive in situ zymography for plasmin (Fig. 5A and B) suggested a preceding infection as the etiology of glomerulonephritis, which could partially explain the spontaneous recovery of the renal function later observed in this case, similar to that observed in PIGN.
PIGN usually involves activation of the complement pathway, especially the alternative pathway (AP), and previous reports have shown persistent and irreversible renal impairment in PIGN cases with defects in the AP. Thus, a comprehensive genetic study was performed using the patient's blood sample to investigate potential mutations of AP regulatory genes, including C3, CFH, CFHR1, CFHR3, CFHR5, CFI, CFB, and CD46, which revealed a heterozygous missense variant, c.2392G>A, p.D798N in CFH. The patient provided his written informed consent, and the detailed methods are described in greater detail elsewhere. This mutation is a very rare variant (rs55931547) with the allele frequency being 0.00003307 in ExAC (), and no published functional data are available given the novel variant in relation to the disease. However, according to the CADD database (), which is the in silico protein function prediction program, the score is 12.4 (>10), suggesting that this variant may cause the dysfunction of CFH.
Symptomatic therapy with no corticosteroids or immunosuppressants was started due to the repeated hemorrhagic ulcer and ameliorated decline in the renal function. On day 13 after admission, hemodialysis was initiated due to oliguria and congestion despite high-dose intravenous diuretics (Fig. 1). However, a gradual decrease in SCr with an increase in urine volume was observed two weeks after hemodialysis initiation, resulting in cessation of hemodialysis on day 52. After discharge on hospital day 66, SCr and urinary protein decreased to 1.2 mg/dL and <1 g/gCr, respectively. One year after discharge, the patient developed nephrotic-range proteinuria (Table). A second kidney biopsy performed at that time showed markedly increased sclerotic or collapsing glomeruli (approximately 70% of all glomeruli) with fibrous crescents (15-20%), moderate tubular atrophy, and fibrosis (Fig. 2C). The remaining glomeruli showed mesangial proliferation with double contour formation along the capillary walls (Fig. 2D). Predominant C3 deposits with weak deposits of IgG1 and kappa light chain and subendothelial deposits were observed (Fig. 3I-L, 4C); however, NAPlr and plasmin deposits were absent (Fig. 5I and J). Nephrotic-range proteinuria spontaneously resolved, and the UPCR and SCr levels were within the ranges of 1-2 g/gCr and 1.2-1.5 mg/dL, respectively, for one year following discharge. Repeated serum and urine electrophoresis showed no paraproteins (Fig. 6).