Introduction

Endocarditis may have various renal manifestations, from microhematuria and/or proteinuria, to renal embolisms with arterial hypertension, macro-hematuria or renal failure in up to 30% of cases. Renal failure is a significant predictor of mortality^[1].

The case of a patient with necrotizing crescentic glomerulonephritis due to endocarditis associated with positive anti-proteinase 3 ANCA is presented. At the same time, the literature on the subject is reviewed.

Case report

A 72-year-old man was referred to Nephrology from the General Surgery service for elevated creatinine and edema. He reported weight loss from a cholecystectomy due to acute cholecystitis four months earlier. In the bile culture, Enterococcus faecalis was isolated and treated with piperacillin-tazobactam and with amoxicillin-clavulanate upon discharge. Three months after cholecystectomy serum creatinine increased from 1.4 to 2.4 mg/dl, accompanied by edema in the lower limbs. No fever, macrohematuria or other symptoms were associated. His medical history included hypertension on treatment with losartan, type 2 diabetes mellitus on treatment with metformin, and mild-moderate mitral regurgitation.

Physical examination revealed blood pressure of 140/70 mmHg, heart rate of 112 beats per minute, temperature of 35.7 °C, a III/VI pansystolic murmur in the mitral area and edema to the level of the knees.

Analytically, normocytic normochromic anemia, leukocytes: 5090 cells/|il and neutrophils: 80%, hypoalbuminemia, Cr: 2.7 mg/dl, urea: 139 mg/dl and creatinine clearance: 28 ml/min, were observed. Urine showed proteinuria of 1 g/24h, micro-albuminuria of 194 mg/dl, and 50-100 RBCs/HPF. The proteinogram was compatible with polyclonal hypergammaglobulinemia. Viral serologies for hepatitis B, hepatitis C and HIV were negative. In the immunological tests, there was a slight elevation of anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (anti-PR3 ANCA) (3.20 U/ml, normal <2 U/ml), a decrease in C3 (58 mg/dl) and C4 in the lower limit (12 mg/dL). Other immunological results (ANA, anti-MPO ANCA, anti-MBG, anti-DNA, cryoglobulins) and tumor markers were negative.

Various imaging tests were requested. Renal ultrasound showed normal kidneys and, in thoraco-abdominal CT, homogenous splenomegaly was observed. During admission, the patient exhibited a state of confusion, so cerebral magnetic resonance imaging (MRI) was requested where small vessel ischemic lesions were observed in both cerebral hemispheres. For examination of the systolic murmur, a transesophageal echocardiogram was performed, showing an image suggestive of endocarditis in the mitral valve with very severe failure (Figure 1).

Figure 1 Transesophageal echocardiogram. Vegetation in the auricular face of the mitral valve (left). Very severe mitral regurgitation with Color Doppler technique (right). 

Due to the persistence and progressive deterioration of renal function, a renal biopsy was performed (Figure 2). In the histological sections, lesions corresponding to focal necrotizing crescentic glomerulonephritis, fibrinoid necrosis foci of glomerular capillaries and mesangiolysis, acute tubular necrosis and moderate myointimal hyperplasia without signs of vasculitis were visualized. Immunofluorescence showed granular mesangial positivity for C3, weaker for IgM and more focal for C1q (Figure 3).

Figure 2 Histology of renal biopsy. Jones' silver methenamine stain of renal glomerulus, capillary rupture and cellular crescents due to extracapillary proliferation (left). Hematoxylin and eosin stain of urinary cast 

Figure 3 Direct immunofluorescence: Granular mesangial IgG, C3 and C1q deposits 

Enterococcus faecalis grew in the blood cultures and was initially empirically treated with vancomycin and gentamicin, which were subsequently changed according to antibiogram results for ampicillin and ceftriaxone.

Despite the antibiotic treatment, a progressive deterioration of renal function with active urinary sediment persisted; thus, treatment with methylprednisolone boluses and, later, oral prednisone (0.5 mg/kg for 4 weeks with subsequent dose decrease) was initiated.

Finally, mitral valve replacement was performed. After surgery, renal function began to improve and levels of anti-PR3 ANCA and C3 returned to normal, but the patient died of nosocomial pneumonia.

Discussion

The patient presented rapidly progressive glomerulonephritis with mildly positive anti-proteinase 3 ANCA. This combination may lead to suspicion of ANCA glomerulonephritis. However, hypocomplementemia does not characterize ANCA glomerulonephritis and its presence together with polyclonal hypergammaglobulinemia, splenomegaly, and new onset of murmur allowed to suspect endocarditis. This diagnosis was confirmed by echocardiography and blood culture.

Absence of fever could be misleading. However, up to 16% of endocarditis may occur without fever^[2] or leukocytosis, even blood cultures may be negative in some cases^[3,4].

Coexistence of necrotizing glomerulonephritis, ANCA and endocarditis allows to discuss the pathogenesis of nephropathy and the therapeutic approach.

The literature collected 16 cases of positive ANCA in patients with endocarditis and acute glomerulonephritis in renal biopsy (Table 1), ten of which are positive anti-PR3 ANCA^[5,13], two anti-myeloperoxidase^[11,14] and five unspecified^[15,19] Anti-PR3 ANCAs can be elevated in connective tissue diseases and chronic infections such as bacterial subacute endocarditis, tuberculosis, or hepatitis B or C5 virus infection, as well as in the elderly. In this regard, endocarditis could be one of the infectious stimuli that would activate neutrophils to express antigens recognized by ANCAs15. ANCAs may be one of multiple autoantibodies whose levels increase in the context of polyclonal hypergammaglobulinemia, a characteristic of endocarditis. The debate is centered on whether ANCAs contribute decisively to the pathogenesis of tissue injury in endocarditis or are an epiphenomenon^[20].

Table 1 Cases of glomerulonephritis associated with ANCA and endocarditis 

Renal histological lesions may range from focal segmental proliferative glomerulonephritis, with or without fibrinoid necrosis, and intracapillary thrombi, to diffuse exudative proliferative glomerulonephritis, with or without extracapillary proliferation^[21]. There may or may not be immunoglobulin deposits21. Absence of immune deposits could support a pathogenic role of ANCAs, which characteristically produce necrotizing or pauci-immune crescentic glomerulonephritis.

Regarding the evolution of renal function, out of the 16 reported cases of endocarditis with associated glomerulonephritis, three did not recover renal function and two patients required acute hemodialysis.

One of the dilemmas that arise in the coexistence of endocarditis, positive anti-PR3 ANCA and acute glomerulonephritis is the treatment to be followed. Among the reported cases, ten patients were treated with steroids and antibiotics in combination, two of which died. Six were treated with antibiotics alone and five underwent valve replacement.

There is, therefore, no clear consensus on the treatment of endocarditis with anti-PR3 ANCA. Some authors propose as a treatment the combination of immunosuppression and antibiotics11, while others prefer antibiotic treatment alone, without immunosuppression22.

As shown in the table compiled, exclusive antibiotic treatment was associated with lower mortality, but it could also be used in patients with milder nephropathy, as there is currently no strong evidence to support immunosuppression alone5, 23. In any case, it seems reasonable to delay immuno-suppressive treatment until, at least, patient stabilization and infection control. At this point, C3 and anti-PR3 ANCA values tend to normalize1, 5, 16, as occurred in our patient.

On the other hand, it is important to propose and choose the right time to perform a valve replacement when the patient does not show rapid improvement. Without infection control, surgical intervention is too risky, and septic emboli may spread across the rest of the body. However, the risk of complications and consequences for the patient increases over time, and may lead to an unfortunate prognosis.

The KDIGO24 guidelines state that prognosis of post-endocarditis glomerulonephritis is generally favorable and is directly related to the speed with which the infection is eradicated.