Just as the morphologic spectrum of endocarditis-associated glomerulonephritis has evolved, our own findings in infective endocarditis [49] confirm and extend observations emphasized in recent reviews documenting the evolution in clinical findings in bacterial infection-related GN in adults over the past three decades [51–53]. This evolution occurring in recent decades includes the change in demographics from younger to older patients, the frequency of comorbidities such as diabetes and HIV, and the change in predominance of infectious agents from primarily Streptococcal to a broader array of organisms with predominance of Staphylococci [33, 51, 54, 55].

Infective endocarditis carries a mortality rate of 40–50% [56]. Over the past decades, infective endocarditis outcomes have not improved, and infection rates are steadily increasing [56]. Recent case series and reviews of infective endocarditis have compared findings from current and previous eras, confirmed similar changes in the demographics of the disease and updated the clinical and pathologic features in both adults and children [16, 57]. However, few of these recent reports have focused primarily on infective endocarditis-related renal lesions, and much of the data currently available still includes predominately autopsy-derived information [16, 48].

In keeping with the overall trends in infection-related glomerulonephritis, findings in infective endocarditis in the current era involve predominately adult males with a 2.6:1 male predominance, older mean age at biopsy (mean age 47 years) with 25% elderly patients, and increased prevalence of Staphylococcal rather than Streptococcal infection (Tables 4.1 and 4.2) [49]. In general, postinfectious and infection-associated glomerulonephritis typically present with the acute nephritic syndrome and hypocomplementemia [23]. The most common presentation of infective endocarditis-associated glomerulonephritis is acute renal failure in which there was doubling of the serum creatinine (82%) (Table 4.1) [49]. This observation that the most common presentation is acute renal failure rather than acute nephritic syndrome differs from overall findings in infection-related glomerulonephritis [23, 51] and may be unique to this patient population with compromised cardiac function. In our material, only 8% presented with the typical acute nephritic syndrome of hematuria, hypertension, and renal failure and only about sixty percent with low serum complement levels. Other clinical syndromes at presentation include rapidly progressive glomerulonephritis (5%), and nephrotic syndrome with nephrotic range proteinuria (>3.5 g/day), hypoalbuminemia (serum albumin <3 g/dL), and peripheral edema (5%) (Table 4.1). The unique manifestations of endocarditis-associated glomerulonephritis are possibly related to the fact that these infections are often persistent and ongoing at the time of the kidney biopsy rather than being a classic postinfectious phenomenon [51]. Furthermore, the diagnosis of glomerulonephritis could prompt investigations that lead to a diagnosis of infective endocarditis. Indeed, cases of rapidly progressive ANCA-positive glomerulonephritis have been reported as the presenting feature of infective endocarditis [58, 59].

Conditions favoring endocarditis are noted in a majority (64%) of our patients, including intravenous drug use (37%), prosthetic valves (16%), and prior valvular disease (11%), yet this leaves over 50% of patients with no known prior cardiac disease (Table 4.1) [49]. A minority of patients had associated comorbid conditions, with the most common being hepatitis C infection (24%) and diabetes mellitus (18%) (Fig. 4.4). Less common predisposing states or coexisting conditions included coronary artery disease, chronic obstructive pulmonary disease, congestive heart failure, autoimmune disease, recent surgery, and malignancy [49].

In general, bacterial infections can trigger the production of various autoantibodies, such as antinuclear antibodies (ANA), anticardiolipin antibodies, cryoglobulins, rheumatoid factor, and anti-neutrophil cytoplasmic antibodies (ANCA) [37, 60]. In our renal biopsy study of endocarditis-associated glomerulonephritis [49], the average serum creatinine was 3.8 mg/dL (range 1.0–12.0) (Table 4.1). Hematuria was present in almost all cases. Daily proteinuria averaged 2.1 g (range 0.5–15). Twenty-eight patients had an ANA test, 86% of which were negative. ANCA testing was carried out in over half of patients and was positive in 25%. ANCA specificities included both pANCA and cANCA, as well as cases with dual positivity (Table 4.1) (Fig. 4.5) [49]. In general, ANCA specificity associated with endocarditis was initially thought to be anti-PR3, but cases with dual ANCA positivity and MPO-ANCA positivity have also now been reported in association with endocarditis [37, 49, 61–63]. Testing for cryoglobulins have varied reports of positivity from 17 to 95% positive, though many of these studies have limited renal histologic correlation [60] and the cryoglobulin test is frequently false negative. Similarly, large amounts of serum immunoglobulins and circulating immune complexes may be formed as a result of bacteremia, but this does not necessarily imply deposition within the kidney by immunofluorescence [47]. Just over half of patients (60%) had hypocomplementemia in our renal biopsy series, which was most commonly (35%) low C3 (complement component 3) with normal C4 (complement component 4); since only a few patients had reduction in C4 this suggests most had activation of the alternative complement pathway.

Infective endocarditis can involve any one of the four cardiac valves. In our current expanded study of 62 patients, endocarditis leading to glomerulonephritis most commonly involved the tricuspid valve (44%), followed by the mitral (38%), aortic (24%), and pulmonic (4%) valves (Table 4.2); infection of more than one valve was seen in 10% of patients (Fig. 4.6). In our study, 84% represented patients with community-acquired infective endocarditis in native valves, 94% of which had positive blood cultures compared to 90% positive blood cultures in the patients with prosthetic valve endocarditis [49]. One of the major Duke’s criteria to the diagnosis of infective endocarditis is vegetations noted by echocardiogram; these were noted in greater than two-thirds of patients in our renal biopsy study [49]. Of note, because transthoracic echocardiogram may not be able to detect small vegetations, transesophageal echocardiogram may be needed [64]. The most commonly noted sign of cardiac involvement in patients without vegetations on echocardiogram was new valvular regurgitation/murmur; the most common other criteria for diagnosis of infective endocarditis in these patients included fever, septic pulmonary emboli, and predisposing heart condition or injection drug use. For the entire cohort, the most common vascular phenomena was septic pulmonary infarcts, with only a minority of patients with the finding of intracranial hemorrhage, and rare patients with findings including conjunctival hemorrhages, nail splinter hemorrhages, or evidence of mycotic aneurysm [49].

Several studies note a similar rate of culture-negative endocarditis at about 8–9% [49, 65, 66]. Over half of patients with culture positive endocarditis are classified as having acute rather than subacute endocarditis. In our experience, the agent found on culture in the acute group is most often S. aureus (58%), with methicillin resistance in almost half (44%); the second most common pathogens found are Streptococcus species (21%) (Table 4.2) [49]. Less common causes of endocarditis noted include Gemella species, Gonococcus, and gram-negative bacteria such as C. burnetii, B. henselae, and Brucella [2–5, 49], as well as the HACEK group of oral cavity commensals (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) [1]. The most common cause of endocarditis in patients with history of IV drug abuse is Staphylococcal infection (86%), affecting the tricuspid valve or tricuspid and pulmonic valves in 74%, followed by mitral or aortic valves in 26% [49].

One has to pay attention to and look for and evaluate glomeruli with no or small crescents to avoid over-interpreting nonspecific staining secondary to glomerular necrosis and crescent formation. Deposits by immunofluorescence appear granular, with the location most often either a combination of mesangial and capillary loop (53%) (Fig. 4.11) or within the mesangial region only (39%) (Fig. 4.12) (Table 4.3). Though completely negative staining by immunofluorescence for immunoglobulins and complement is rare (5% of biopsies), up to 44% of biopsies in our study of 62 patients met criteria for pauci-immune staining intensity of immunoglobulins. Almost half of these (12 patients) had crescentic glomerulonephritis by light microscopy (Table 4.4). Of these 12 patients, ANCA was positive in 3, negative in 5, and not done in 4. In 2000, Majumdar et al. [48] also found that two-thirds of patients with endocarditis-associated glomerulonephritis have a pauci-immune pattern. Pauci-immune was defined as staining 0–2+ or less intensity for all immunoglobulins (IgG, IgM, and IgA) on a scale of 0–4+ [70]. Most pathologists using a 0–3+ scale, pauci-immune is usually defined as positivity of 1+ or less. Though the staining properties of C3 can be controversial and inconsistently interpreted as immune complex type or not, in our study of endocarditis-associated glomerulonephritis, the definition of pauci-immune disease is defined by immunoglobulin staining only, and does not account for the intensity of complement staining in glomeruli. This also seems prudent given that large case series have shown glomerular C3 deposition is not uncommon in pauci-immune, ANCA-associated glomerulonephritis [70, 71].