A case of non-lupus full-house nephropathy diagnosed by kidney biopsy but observed IgA nephropathy on second biopsy

Abstract

We describe a case of full-house nephropathy without any underlying disease, including systemic lupus erythematosus. A 40-year-old woman was referred to our hospital with mild proteinuria and microscopic hematuria. The patient was diagnosed with immune complex-mediated glomerulonephritis with a predominant mesangioproliferative pattern based on renal histopathological results using full-house immunofluorescence staining. She showed no clinical criteria for the diagnosis of systemic lupus erythematosus, except for kidney disorders, and tested negative for antinuclear antibodies throughout her clinical course. However, in the second kidney biopsy, no C1q or C4 were detected in the immunofluorescence study, suggesting an immunoglobulin A nephropathy-like pattern. The patient responded favorably to corticosteroid treatment. We found a heterozygous CFHR3-CFHR1 deletion. The association between full-house nephropathy and CFHR3-CFHR1 deletion is unknown, but its influence on the histological pattern in our case is suspected. This indicates the diversity in the pathogenesis of non-lupus full-house nephropathy and warrants further investigation.

Introduction

Non-lupus full-house nephropathy (FHN) is a glomerular disease that displays a full-house pattern in immunofluorescence studies in the absence of autoantibodies and other symptoms of systemic lupus erythematosus (SLE) [1]. Only a few patients develop symptoms suggestive of SLE during follow-up [2], and many pass without any clinical or serological evidence of SLE. Therefore, the diagnosis of non-lupus FHN is challenging. In addition, non-lupus FHN is considered to have a high degree of similarity with lupus nephritis, and these two diseases are thought to have similar pathogenic mechanisms. However, the pathogenesis and prognosis of non-lupus FHN are poorly understood.

Here, we present a case that was diagnosed as non-lupus FHN based on the first kidney biopsy. However, it was subsequently confirmed as immunoglobulin A (IgA) nephropathy (IgAN)-like findings on the second kidney biopsy and a heterozygous CFHR3-CFHR1 gene deletion. We discuss the association between non-lupus FHN, IgAN, and the CFHR3-CFHR1 gene deletion.

Case report

A 40-year-old woman was referred to our hospital with mild proteinuria and microscopic hematuria. Her family and medical histories were unremarkable. She had two children with normal deliveries. She was not on regular medication. The physical examination findings were as follows: height 156.0 cm, weight 45.5 kg, body mass index 18.7 kg/m², blood pressure 108/68 mmHg, pulse rate 60 beats/min, and body temperature 36.6 °C. The remainder of her physical examination findings were unremarkable, with no sign of ascites or pretibial edema. No lymphadenopathy or skin lesions were observed. No discernible neurological abnormalities were observed.

Urinary protein was 30 mg/dl and 0.6 g/day. The urinary sediment showed 10–19 erythrocytes, 1–4 leukocytes per high-power field. The hematocrit was 36.3%, the hemoglobin concentration was 12.3 g/dl; the platelet counts were 236,000/mm³, leukocyte count was 5,140 /mm³, lymphocyte count was 1,440 /mm³. The serum urea nitrogen level was 14.4 mg/dl, that of creatinine (Cre) was 0.58 mg/dL; the estimated glomerular filtration rate (eGFR) was 90.3 mL/min/1.73 m²; the uric acid was 4.4 mg/dL; the total cholesterol was 186 mg/dL; the total protein was 6.9 g/L; and albumin was 4.5 g/dL. Urinary N-acetyl-beta-D-glucosaminidase level was 6.42 U/L (6.0 U/g Cre) and β2 macroglobulin level was 93.46 μg/L. The C-reactive protein level was 0.05 mg/dL; immunoglobulin (Ig) G was 1,165 mg/dL; IgA was 249 mg/dl; and IgM was 220 mg/dL. Hemoglobin A1c was 5.4%. The total complement level (CH50) was 28.00 (reference values: 30–45) IU/L; C3 93 (80–140) mg/dl; C4 21.5 (11–34) mg/dL; C1Q 3.1(< 1.5) μg/mL. Anti-body assays were negative. All other laboratory test results were within the normal limits. Additional laboratory data are presented in Table 1. Chest radiography and electrocardiographic findings were normal. Renal ultrasonography and computed tomography revealed normal kidney structure.

Table 1.

Laboratory data upon the first admission.

Examination (hematology)	Value	Reference range	Examination (coagulation)	Value	Reference range	Examination (infectious marker)	Value	Reference range
WBC (/µL)	5140	3450–9790	aPTT (second)	35.5	23.0–37.0	HBs Ag	–
RBC (104/µL)	400	372–494	PT (%)	103.5	70–130	HBs Ab	–
Hb (g/dL)	12.3	10.8–14.9	FDP（µg/mL）	1.8	<5	HCV Ab	–
Ht (%)	36.3	34.4–45.2	D dimer (µg/mL）	0.4	<1	HIV Ab	–
Plt (× 103/µL)	23.6	14.6–33.9				TPHA	–
			(Serology)			STS	–
(Biochemistry)			CPR (mg/dL)	0.05	<0.27
Total protein (g/dL)	6.9	6.5–8.2	Ferritin (ng/dL)	<8.0	8–74	(Urinalysis)
Albumin (g/dL)	4.5	3.8–5.0	RF(IU/mL)	5	<20	Protein	1+
Total bilirubin (mg/dL)	0.65	0.15–1.24	IgG (mg/dL)	1165	870–1700	Protein (g/gCr)	0.31
ALT (U/L)	15	13–33	IgA (mg/dL)	249	110–410	(g/day)	0.25
AST (U/L)	11	6–27	IgM (mg/dL)	220	34–220	Glucose	–
LDH (U/L)	130	124–226	C3 (mg/dL)	93	80–140	Ketone	–
ALP (U/L)	153	104–338	C4 (mg/dL)	21.5	11–34	Occult blood	3+
γ-GTP (U/L)	17	10-50	CH50 (U/mL)	28.0	30.0–45.0	Sediments
BUN (mg/dL)	14.4	7.5–20.4	IC-1q (µg/mL)	3.1	<3.0	Red blood cells (/hpf)	20–29
Cre (mg/dL)	0.58	0.45–0.94	ANA (titer)	<40	<80	White blood cells (/hpf)	1–4
UA (mg/dL)	4.4	2.5–6.9	Anti SS-A (U/mL)	0.5	<6.9	NAG (U/L)	6.42	0.97–4.17
Na (mEq/L)	139	135–147	Anti SS-B (U/mL)	0.5	<6.9	B2MG (µg/L)	93.46	13.0–301.2
K (mEq/L)	4.2	3.5–5.0	Anti Sｍ (U/mL)	1.2	<7
Cl (mEq/L)	106	98–108	Anti-dsDNA IgG (IU/mL)	3.4	<19.9
Ca (mg/dL)	9.7	8.7–11.0	Anti U1 RNP(U/mL)	0.5	<3.4
iP (mg/dL)	3.6	2.4–4.5	Anti CLGPI (U/mL)	1.3	<3.4
Glucose (mg/dL)	87	70–139	aPL IgG (U/mL)	1	<9
HbA1c (%)	5.4	4.9–6.0	Cryoglobulin	–
Total cholesterol (mg/dL)	186	128–219
HDL-cholesterol (mg/dL)	86	40–96
LDL-cholesterol (mg/dL)	80	70–139
Triglyceride (mg/dL)	34	30–149

WBC white blood cell, RBC red blood cell, Hb hemoglobin, Ht hematocrit, Plt platelet, ALT alanine aminotransferase, AST aspartate aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, γ-GTP γ-glutamyltranspeptidase, BUN blood urea nitrogen, Cre creatinine, UA uric acid, Na sodium, K potassium, Cl chlorine, Ca calcium, iP inorganic phosphorus, HbA1c hemoglobin A1c, HDL-cholesterol high-density lipoprotein cholesterol, LDL-cholesterol low-density lipoprotein cholesterol, aPTT activated partial thromboplastin time, PT prothrombin time, FDP fibrin/fibrinogen degradation products, CRP C-reactive protein, RF rheumatoid factor, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, C3 complement 3, C4 complement 4, CH50 total complement immunoassay, IC-C1q immune complex C1Q binding assay, ANA antinuclear antibody, Anti DNA anti-DNA antibody, Anti SS-A anti-SS-A antibody, Anti SS-B anti-SS-B antibody, Anti Sm anti-Smith antibody, Anti-dsDNA IgG anti-double stranded DNA IgG antibody, Anti U1 RNP anti-ribonucleoprotein antibody, Anti CLGPI anti-cardiolipin antibody, aPL anti-phospholipid antibody, HBs Ag hepatitis B surface antigen, HBs Ab hepatitis B surface antibody, HCV Ab hepatitis C antibody, HIV Ab human immunodeficiency virus antibody, TPHA Treponema pallidum hemagglutination assay, STS serologic test for syphilis, hpf high-power field, NAG N-acetyl-β-D-glucosaminidase, B2MG β2 microglobulin

On the second hospital day, a kidney biopsy was performed to investigate the cause of mild proteinuria and microscopic hematuria. Light microscopy revealed 20 glomeruli (Fig. 1a); three of them were obsolete. The remaining glomeruli exhibited diffuse mesangial proliferative changes and moderate expansion of the mesangial and paramesangial matrix (Fig. 1b). Three glomeruli showed adhesion of the Bowman’s capsule or small fibrocellular crescents. Several large periodic acid-Schiff (PAS)-positive deposits were observed in the mesangial and paramesangial areas (Fig. 1c). Thickening of the glomerular basement membrane or double contour sign was not observed (Fig. 1d). No endarteritis or arteriosclerosis were observed in the patient. Tubular atrophy with mild interstitial cellular infiltration was observed. Immunofluorescence analysis revealed prominent fine granular IgG, IgA, IgM, C1q, C3, and C4 (IgG, IgA > IgM, C1q, C3 > C4) deposition in the mesangium but not in the peripheral capillary walls and tubular basement membrane (Fig. 2). Congo red staining results were negative. The full-house immunofluorescence staining in our patient resembled the pathological features of lupus nephritis. Electron microscopy revealed several large and very large mesangial and paramesangial electron-dense deposits (Fig. 3, 4). No organized fibrillar or microtubular structures were observed. Tubulovesicular structures or virus-like particles were not observed.

Fig. 1.

Microscopic findings of the first kidney biopsy: a Under light microscopy, the first kidney biopsy sample contained 20 glomeruli. (periodic acid-silver methenamine stain, original magnification × 40). b Light microscopy demonstrated diffuse mesangial proliferative changes and moderate expansion of mesangial and paramesangial matrix (periodic acid-Schiff stain, original magnification × 200). c Several large periodic acid-Schiff-positive deposits were observed in the mesangial and paramesangial areas (periodic acid-Schiff stain, original magnification × 400). d Thickening of the glomerular basement membrane or double contour sign was not noted. (periodic acid-silver methenamine stain, original magnification × 400)

Fig. 2.

Immunofluorescence analysis of the first kidney biopsy: immunofluorescence analysis revealed prominent fine granular IgG, IgA, IgM, C1q, C3, and C4 (IgG, IgA > IgM, C1q, C3 > C4) deposition in the mesangium

Fig. 3.

a,b Electron microscopic findings in the first kidney biopsy: electron microscopy revealed many relatively large and very large mesangial and paramesangial electron-dense deposits.

Fig. 4.

Microscopic findings of the second kidney biopsy: several large periodic acid-Schiff-positive deposits were observed in the mesangial and paramesangial areas, as in the first biopsy (periodic acid-Schiff stain, original magnification × 400)

Based on the clinical and histopathological findings, she was initially treated with 30 mg of oral corticosteroids daily. The patient showed gradual improvement in mild proteinuria and microscopic hematuria. After 3 months of treatment, serum C1q levels returned to normal, and proteinuria and microscopic hematuria improved. After 6 years, corticosteroids were tapered to 5 mg every other day, and a second kidney biopsy was performed to investigate the treatment options.

Light microscopy revealed 14 glomeruli, one of which was obsolete. Like the first biopsy, the remaining glomeruli showed diffuse mesangial proliferative changes with moderate expansion of the mesangial and paramesangial matrix. Several large PAS-positive deposits were observed in the mesangial and paramesangial areas (Fig. 5). Tubular atrophy with mild interstitial cellular infiltration improved and was nearly absent. Immunofluorescence analysis revealed prominent fine granular IgG, IgA, IgM, and C3 (IgA and IgG > IgM and C3) in the mesangium (Fig. 6). The C1q and C4 deposits disappeared. Unlike the first biopsy, the immunofluorescence study of the second kidney biopsy revealed the pathological features of IgAN. Electron microscopy images revealed several relatively large mesangial and paramesangial electron-dense deposits, as observed in the first biopsy (Fig.7).

Fig. 5.

Immunofluorescence analysis of the second kidney biopsy: immunofluorescence analysis revealed prominent fine granular IgG, IgA, IgM, and C3 (IgA, IgG > IgM, C3) in the mesangium

Fig. 6.

Electron microscopic findings in the second kidney biopsy: electron microscopically, many relatively large mesangial and paramesangial electron-dense deposits were observed, as in the first biopsy

These findings, including mild proteinuria, microscopic hematuria, mild hypocomplementemia, positive immunocomplex, and renal histopathological results, led to a diagnosis of immune complex-mediated glomerulonephritis with a predominant mesangioproliferative pattern using full-house immunofluorescence staining. Although the full-house immunofluorescence staining pattern was characteristic and not specific of lupus nephritis, the patient showed no clinical criteria for the diagnosis of SLE, except for kidney disorders. Her ANA and anti-dsDNA tests were both negative. Hence, we first diagnosed the patient with idiopathic non-lupus FHN. However, in the second kidney biopsy, C1q and C4 disappeared on immunofluorescence staining, suggesting IgAN.

To further examine the genetic involvement of the complement system, we performed extensive diagnostic tests to identify the cause of the hypocomplementemia. Prednisone (5 mg/day) was administered at the time of testing. Plasma C3, C4, CH50, soluble C5b-9 complement, complement factor Ba, complement factor H (CFH), complement factor I, and complement 5a levels were normal. The enzyme-linked immunosorbent assay for anti-CFH IgG was negative. After obtaining informed consent, we collected DNA from the patient. Genomic DNA was extracted from whole blood, and targeted next-generation sequencing of candidate genes for complement disorders was performed. Sequencing of the exonic regions of 136 genes conducted by the Japanese Association for Complement Research revealed a heterozygous CFHR3-CFHR1 gene deletion.

Repeated tests for ANA and anti-dsDNA were negative, and no clinical features of SLE were observed throughout the clinical course. After 12 years, she was taking 5 mg prednisolone every other day, and her renal function remained normal (eGFR; 70.7 mL/min/1.73 m²), with no hematuria. Her proteinuria was 0.1 g/g Cre and she still had mild hypocomplementemia (CH50; 21 IU/L).

Discussion

Clinical recognition of non-lupus FNH as a diagnostic category is very important. Here, we report a case of non-lupus FNH with mild hypocomplementemia. The present case displayed a relatively favorable prognosis after corticosteroid treatment. However, a subsequent post-treatment kidney biopsy revealed congruent observations with the characteristics of IgAN within the purview of the immunofluorescence study. Genetic testing of the complement system revealed a heterozygous CFHR3-CFHR1 deletion. Here, we discuss the association between non-lupus FHN, IgAN, and CFHR3-CFHR1 deletion.

Full-house immunofluorescence staining is a characteristic pathological finding in lupus nephritis [3]. The main differential diagnoses for non-lupus FHN are lupus nephritis, atypical presentation of membranous nephropathy, IgAN, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (GN), post-infectious GN, and C1q nephropathy [1]. Non-lupus FHN cases are rarely evaluated histologically before or after treatment. In our case, a second post-treatment kidney biopsy showed an IgAN-like pattern on immunofluorescence staining. Earlier, Jones et al. reported five cases of FHN with focal proliferative glomerulonephritis [4], whereas Miura et al. found such a full-house pattern in approximately 10% of cases of IgAN, indicating that the differentiation of these cases from IgAN is difficult when based on immunofluorescence studies only [5]. Patients with mesangial proliferative glomerular lesions and dominant or codominant IgA on immunofluorescence studies, as in the present case, are the second most common group of patients with non-lupus FHN [6, 7]. In contrast, Hongyan et al. reported patients with SLE who had full-house nephritis with mainly IgA deposits and speculated that it was a specific clinical subtype of SLE [8]. Recently, the complement system has been suggested to be involved in the pathogenesis of IgAN. In such cases, C1q is infrequently deposited in IgAN, and leptin and alternative pathways are thought to be involved in its pathogenesis [9]. However, approximately 10–40% of IgAN cases are positive for C1q [10]. Accumulating clinical, genetic, and biochemical evidence suggests that the complement system plays an important role in the pathogenesis of IgAN [11]. Several clinical trials of complement inhibitors for the treatment of IgAN are currently underway [9].

In the present case, genetic testing of the complement system revealed a heterozygous CFHR3-CFHR1 deletion. Human CFH-related proteins (CFHRs) comprise a family of five proteins that are structurally related to CFH [12]. Genetic variants of CFHRs are associated with an increased risk of certain diseases; however, the specific functional roles of these proteins are not completely understood [12]. In our patient, FHN and heterozygous CFHR3-CFHR1 deletions may have coexisted by chance, but an association between these two conditions was observed. A heterozygous CFHR3-CFHR1 deletion was recognized as a copy number variation. This deletion is relatively common, although its association with certain diseases varies by race [13]. The common CFHR3-CFHR1 deletion haplotype is associated with several complex genetic diseases [13]. For example, CFHR3-CFHR1 deletions are associated with protection against age-related macular degeneration [14]; however, they are also associated with a risk of SLE [15] and atypical hemolytic uremic syndrome (aHUS) [16]. In addition, heterozygous CFHR3-CFHR1 deficiency may be associated with the development of transplant-associated thrombotic microangiopathy [17] and drug-induced aHUS [18]. With respect to IgAN, a genome-wide association study showed that CFHR3-CFHR1 deletion is associated with IgAN, and complement activation by the alternative complement pathway is speculated to be involved in the onset and progression of IgAN [19]. In cases of CFHR3-CFHR1 deletion, CFH action is enhanced and the deposition of IgA, IgG, and C3 in the mesangial region is attenuated [20]. The presence of this allele reduces the risk of developing IgAN by 26% in heterozygosity and 45% in homozygosity [21]. In contrast, a French study reported that CFHR3-CFHR1 deletion was not associated with IgAN progression [22]. This deletion’s contribution to the histological findings observed in the present case remains unclear. The deletion of CFHR3-CFHR1 has been reported as a possible risk factor for SLE [15]. Interestingly, our case did not meet the criteria for SLE but presented with non-lupus FHN characteristics.

The patient responded relatively well to steroid therapy. Several studies have examined the clinicopathological features of patients with non-lupus FHN. Rijnink et al. reviewed 32 cases of non-lupus FHN among 149 FHN cases [6]. Clinically, these individuals present with lower-range hematuria, more proteinuria, and less complement consumption in the classical pathway than patients with lupus FHN. In contrast to our case, non-lupus FHN was associated with unfavorable renal survival [6]. Responsiveness to treatment may indicate a diversity of non-lupus FHN cases.

In conclusion, we report a case of non-lupus FHN with hypocomplementemia. Our patient had a relatively favorable course of corticosteroid treatment. We identified a heterozygous CFHR3-CFHR1 deletion in our patient. The association between FHN and CFHR3-CFHR1 deletion is unknown, but some influence on the histological findings of our cases is suspected. A post-treatment kidney biopsy revealed an IgAN-like pattern. This indicates the diversity in the pathogenesis of non-lupus FHN and warrants further investigation.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Informed consent

Informed consent was obtained from the patient in the case report.