Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt

KIDNEY DISEASE IN INFECTIVE ENDOCARDITIS — Patients with infective endocarditis (IE) can develop several forms of kidney disease: a bacterial infection-related immune complex-mediated glomerulonephritis (GN), renal infarction from septic emboli, and renal cortical necrosis [1-3]. In addition, drug-induced acute interstitial nephritis or acute kidney injury from antibiotics such as aminoglycosides can develop as a result of treating the infection. (See "Renal infarction" and "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)

The frequency of kidney involvement was illustrated in a retrospective study of over 200 consecutive episodes of bacterial endocarditis [4]. Approximately one-third of patients developed acute kidney injury (of any cause), a complication observed most often among older patients and those with Staphylococcus aureus infection. In a separate series of patients with IE-associated GN, acute kidney injury was the most common clinical presentation [5].

Clinical features and kidney biopsy findings — The most common organism in IE-associated GN is S. aureus, which is seen in 56 percent of cases (see "Staphylococcus-associated glomerulonephritis in adults"); Streptococcus species are the next most common. Less common organisms include Bartonella henselae, Coxiella burnetii, Cardiobacterium hominis, and Gemella. In 9 percent of patients with IE-associated GN, no organism could be cultured. One-half of affected patients do not have a known risk factor; in the remainder, common comorbidities included cardiac valve disease (30 percent), intravenous drug use (29 percent), hepatitis C (20 percent), and diabetes (18 percent). The cardiac valve infected was tricuspid in 43 percent, mitral in 33 percent, and aortic in 29 percent of patients in the largest series described [5]. There are a few case reports of patients with IE and GN who developed pulmonary hemorrhage, potentially mimicking other systemic diseases such as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis and antiglomerular basement membrane (anti-GBM) autoantibody disease [6,7]. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Positive ANCA testing has been reported in some cases of IE, which may lead to diagnostic confusion [5,8]. Bartonella endocarditis appears to be associated with particularly high rates of ANCA positivity. In a literature review of 54 cases of Bartonella IE-associated glomerulonephritis, 78 percent were ANCA positive by indirect immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA), and 67 percent were positive for proteinase 3 (PR3)-ANCA [9]. The significance of ANCA is unclear. However, in one series, positive ANCA testing may have been associated with a subacute form of IE leading to multiple valve involvement and more frequent kidney function impairment [10].

Acute kidney injury is the most common clinical presentation (79 percent), and almost all patients have hematuria (97 percent) [5]. Features of the acute nephritic syndrome were seen in a minority (10 percent), as was nephrotic syndrome (6 percent); 53 percent of patients had reduced C3 complement, and 19 percent had reductions in C4 complement, suggesting activation of the alternative complement pathway. ANCA (usually directed at myeloperoxidase or lactoferrin) may be positive in up to one-third of patients [5]; some patients also have a positive rheumatoid factor, and rare patients are positive for anti-GBM autoantibodies.

In the largest series, crescentic GN was the most common pattern seen on kidney biopsy specimens by light microscopy (53 percent) (picture 1) [5]. Diffuse proliferative GN was also a common finding (33 percent), and focal proliferative GN and mild mesangial proliferative GN were seen in a few patients. In addition to GN, the majority of patients showed tubular injury (86 percent) and interstitial inflammation (88 percent). By immunofluorescence microscopy, C3 was present in 94 percent of cases, immunoglobulin staining was observed in less than one-third of biopsies, and immunoglobulin A (IgA)-dominant (or codominant with IgG) staining was seen in 17 percent. A significant proportion of biopsies met the criteria for pauci-immune GN by immunofluorescence (44 percent). On electron microscopy, 90 percent of biopsies showed deposits, most commonly in the mesangial area (84 percent), followed by the subendothelial area (45 percent). Only a minority had subepithelial "humps," which are deposits that are classically seen in infection-related GN (14 percent).

In another series of 78 patients with staphylococcal infection-related GN, there was marked variability in the degree of IgA staining in the kidney biopsy: trace in 25 percent, mild in 19 percent, moderate in 44 percent, and strong in 12 percent of the cases [11]. A pauci-immune pattern of immunofluorescence was seen in 13 percent of patients. Of the 41 patients who were tested for ANCA, nine (22 percent) were positive. Subepithelial humps were observed in only 31 percent of biopsies.

Diagnosis — The presence of IE is usually suggested from the history, cardiac examination, and positive blood cultures. The diagnosis of IE is presented elsewhere. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)

In patients with IE and acute kidney injury or an abnormal urinalysis, GN is suspected based upon urinary findings. However, GN must be distinguished from other kidney diseases that can occur in the setting of endocarditis:

●Drug-induced interstitial nephritis, usually with a penicillin, cephalosporin, or quinolone, shares many of the clinical findings of acute GN: hematuria (occasionally, but not usually, with red cell casts), mild proteinuria, and kidney function impairment. Pyuria and white cell casts can be seen in both disorders but are typically the major finding in acute interstitial nephritis.

The distinction between these disorders can usually be made from the timing of the kidney manifestations. Glomerular involvement is typically near or at its peak of severity just before the institution of appropriate antimicrobial therapy. By contrast, acute interstitial nephritis is a later event, generally requiring 10 or more days of drug treatment [12,13]. If present, eosinophilia and eosinophiluria also point toward this disorder. Recurrent fever may be seen and may erroneously suggest failure of antibiotic therapy. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

●Aminoglycoside-induced acute tubular necrosis also occurs late (after at least five to seven days of therapy) and is associated with different urinary findings from either the GN or interstitial nephritis. The urinalysis can vary from a bland sediment to one showing multiple muddy brown granular casts, renal epithelial cells, and epithelial cell casts. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)

●Renal emboli, which can occur as late as several months after bacteriologic cure, should be suspected if there is acute, often unilateral flank pain or evidence of other peripheral emboli. The diagnosis can be confirmed by the finding of focal perfusion defects on a radionuclide scan.

●Libman-Sacks endocarditis associated with systemic lupus erythematosus (SLE) and lupus nephritis may present with a clinical picture resembling that of infection-related GN. Serologic abnormalities typically associated with SLE (anti-DNA antibodies) and kidney biopsy showing a "full house" staining pattern are suggestive of SLE [14,15]. (See "Nonbacterial thrombotic endocarditis".)

●ANCA-associated vasculitis may be misdiagnosed in patients with endocarditis who present with fevers, systemic symptoms such as GN, vasculitic skin lesions, and a positive test for ANCA and may receive inappropriate immunosuppressive therapy [16]. Blood cultures and an echocardiogram should be performed in such patients. Not infrequently, the diagnosis of infection-related GN is established by kidney biopsy, which shows pauci-immune necrotizing and crescentic GN in ANCA-associated vasculitis but immune deposits (C3, IgG, IgM, IgA, C1q) in infection-related GN. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Infections'.)

Treatment and outcome — Treatment of IE-associated GN includes immediate institution of antimicrobial therapy to promptly eradicate the infection [17]. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis" and "Right-sided native valve infective endocarditis".)

However, control of the infection may not be associated with a favorable outcome. In the series of patients reported above, 21 percent of patients died; of the surviving patients, 10 percent progressed to end-stage kidney disease, 37 percent had persistent kidney function impairment, and only 32 percent had complete kidney recovery [5].

Glucocorticoids alone or in combination with cyclophosphamide have been used in several patients with persistent kidney function impairment despite the use of antibiotics [5,18]. However, there is no conclusive evidence that immunosuppressive therapy improves the outcome of IE-associated glomerulonephritis. In one series that included 15 patients treated with both antibiotics and immunosuppression, four of the 15 patients died, one developed end-stage kidney disease, six had permanent kidney function impairment, and four had complete recovery [5].

KIDNEY DISEASE WITH INFECTED VENTRICULAR SHUNTS — Shunt nephritis may complicate infected ventricular shunts used for the treatment of hydrocephalus. The frequency of shunt nephritis has markedly declined since ventriculoperitoneal shunts have largely replaced ventriculovascular shunts; shunt nephritis with ventriculoperitoneal shunts is rare [19,20]. In patients with infected ventriculoatrial shunts, shunt nephritis was reported to occur in 0.7 to 2 percent of cases [21,22]. The mechanism of kidney injury probably involves persistent antigenemia derived from an infectious agent with subsequent immune complex formation [23]. The presence of immune complexes induces classical pathway complement activation, which in turn mediates direct injury to glomerular cells (via the C5-9 complex) and generates chemotactic peptides (C3a, C5a) that perpetuate local inflammation.

Clinical manifestations and histopathology — Shunt nephritis typically occurs within five years of surgery to place the shunt but can occur decades later, and the diagnosis can sometimes be delayed up to several years after the first clinical manifestation [24]. Patients typically show systemic symptoms and signs (eg, recurrent fever, hepatosplenomegaly, vasculitic skin rash, anemia, and cerebral symptoms). Hypertension is common. The spectrum of kidney function impairment may range from normal kidney function to a rapidly progressive glomerulonephritis (GN) picture [25,26].

Laboratory testing shows hematuria (sometimes, gross hematuria) and proteinuria (occasionally, nephrotic range). Decreased C3 complement levels and positive cryoglobulins, antineutrophil cytoplasmic autoantibodies (ANCA), rheumatoid factor, and antinuclear antibodies are frequent serologic findings. Cultures of blood and cerebrospinal fluid show mainly S. epidermidis (which might be mistaken for a contaminant in blood cultures). Other bacteria include S. aureus, E. coli, Corynebacterium bovis, Corynebacterium xerosis, Pseudomonas aeruginosa, Pseudomonas cepacia, diphtheroids, Listeria monocytogenes, Bacillus subtilis, Bacillus cereus, Serratia, Cutibacterium acnes, Peptococcus, Mycobacterium gordonae, Micrococcus, Moraxella nonliquefaciens, Moraxella bovis, Acinetobacter, alpha-hemolytic Streptococcus species, and the fungus, Fusarium. However, cultures may be negative, especially if antibiotics were prescribed before obtaining the cultures [22,25,26].

Kidney biopsy patterns by light microscopy include endocapillary proliferation, membranoproliferative changes, and endocapillary and extracapillary proliferation with crescents. Immunofluorescence microscopy demonstrates granular subendothelial and mesangial deposits containing polyclonal immunoglobulins (immunoglobulin M [IgM] and immunoglobulin G [IgG]) and complement (mainly, C3) [22,26].

Evaluation — Although rare, the diagnosis of shunt nephritis should be considered in patients with a history of ventriculovascular shunt placement who present with proliferative GN. In some adult patients, a history of ventriculovascular shunt placement may not be forthcoming, because the shunt placement might have occurred during infancy or childhood.

In addition, systemic symptoms and a positive ANCA in patients with shunt nephritis may suggest ANCA-associated vasculitis [19], and other positive serologies could suggest lupus nephritis or cryoglobulinemic nephritis [27]. The presence of vasculitic skin lesions may be confused with those of immunoglobulin A vasculitis (Henoch-Schönlein purpura).

Thus, in patients presenting with proliferative GN who have positive blood cultures, it is important to exclude the presence of a ventriculovascular shunt and, if present, obtain cultures of the cerebrospinal fluid. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Treatment and prognosis — Antibiotic treatment of the underlying infection and shunt removal are essential to kidney recovery; delayed removal or lack of removal of the infected shunt, even if appropriate antibiotics are administered, may be associated with progressive kidney function impairment leading to end-stage kidney disease [26]. Although there are limited data on the role of immunosuppression for shunt nephritis, a short course of glucocorticoids has been used after the shunt has been removed and antibiotics have been initiated [22].

SUMMARY

●Kidney disease in infective endocarditis – Patients with infective endocarditis (IE) can develop a bacterial infection-related immune complex-mediated glomerulonephritis (GN), renal infarction from septic emboli, and renal cortical necrosis. In addition, a drug-induced acute interstitial nephritis or acute kidney injury (AKI) from antibiotics such as aminoglycosides can develop as a result of treating the infection. (See 'Kidney disease in infective endocarditis' above.)

•Clinical features – AKI is the most common clinical presentation in IE-associated GN, and almost all patients have hematuria. Features of the acute nephritic syndrome or the nephrotic syndrome are seen but are uncommon. More than one-half of patients have reduced C3 complement; reductions in C4 complement are less frequent. Antineutrophil cytoplasmic autoantibodies (ANCA) may be positive in up to one-third of patients. The most common organism in IE-associated GN is S. aureus, which is seen in 56 percent of cases; Streptococcus species are the next most common. (See 'Clinical features and kidney biopsy findings' above.)

•Pathology – Crescentic GN is the most frequently observed pattern seen on kidney biopsy specimens by light microscopy (53 percent) (picture 1), followed by diffuse proliferative GN. The majority of patients also have evidence of tubular injury and interstitial inflammation. By immunofluorescence microscopy, C3 is the predominant finding, and immunoglobulin is present in less than one-third of biopsies. Dominant, or codominant, immunoglobulin A (IgA) staining may be seen in up to one-third of patients. On electron microscopy, subepithelial "humps" were seen in only a minority of patients. A significant proportion of biopsies meet criteria for pauci-immune GN. (See 'Clinical features and kidney biopsy findings' above.)

•Diagnosis – The presence of IE is usually suggested from the history, cardiac examination, and positive blood cultures. In patients with IE and AKI or an abnormal urinalysis, GN is suspected based upon urinary findings. However, other kidney diseases can also occur in the setting of endocarditis, and a kidney biopsy establishes the diagnosis. (See 'Diagnosis' above.)

•Treatment – Treatment of IE-associated GN includes immediate institution of antimicrobial therapy to promptly eradicate the infection. However, a minority of patients have complete kidney recovery. (See 'Treatment and outcome' above.)

●Kidney disease with infected ventriculovascular shunts – Shunt nephritis may complicate infected ventricular shunts used for the treatment of hydrocephalus. The frequency of shunt nephritis has markedly declined since ventriculoperitoneal shunts have largely replaced ventriculovascular shunts. (See 'Kidney disease with infected ventricular shunts' above.)

•Clinical features – Shunt nephritis typically occurs within five years of surgery to place the shunt, and the diagnosis can sometimes be delayed up to several years after the first clinical manifestation. Patients typically show systemic symptoms and signs (eg, recurrent fever, hepatosplenomegaly, vasculitic skin rash, anemia, and cerebral symptoms). Hypertension is common. The spectrum of kidney function impairment may range from normal kidney function to a rapidly progressive GN. (See 'Clinical manifestations and histopathology' above.)

Laboratory testing shows hematuria (sometimes, gross hematuria) and proteinuria (occasionally, nephrotic range). Decreased C3 complement levels and positive cryoglobulins, antineutrophil cytoplasmic autoantibodies (ANCA), and antinuclear antibodies are frequent serologic findings. Cultures of blood and cerebrospinal fluid show mainly S. epidermidis (which might be mistaken for a contaminant in blood cultures). Kidney biopsy patterns by light microscopy include endocapillary proliferation, membranoproliferative changes, and endocapillary and extracapillary proliferation with crescents. Immunofluorescence microscopy demonstrates granular subendothelial and mesangial deposits containing polyclonal immunoglobulins and complement. (See 'Evaluation' above.)

•Evaluation – Although rare, the diagnosis of shunt nephritis should be considered in patients with a history of ventriculovascular shunt placement who present with proliferative GN. In some adult patients, this history may not be forthcoming, because the shunt placement might have occurred during infancy or childhood. In patients presenting with proliferative GN who have positive blood cultures, it is important to exclude the presence of a ventriculovascular shunt and, if present, obtain cultures of the cerebrospinal fluid. (See 'Evaluation' above.)

•Treatment – Antibiotic treatment of the underlying infection and shunt removal are essential to kidney recovery; delayed removal or lack of removal of the infected shunt, even if appropriate antibiotics are administered, may be associated with progressive kidney function impairment leading to end-stage kidney disease. (See 'Treatment and prognosis' above.)