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October 11, 2019

Disease Week: Infection-Associated Glomerulonephritis and Endocarditis-Associated Glomerulonephritis

A paradigm shift has occurred in the epidemiology, bacteriology, and clinical and pathologic findings of infection-associated glomerulonephritis over the past few decades.  The incidence of acute Streptococcal glomerulonephritis has declined, in part due to improved socioeconomic conditions and the advent of antibiotic therapy in developed countries.  An increase in methicillin-resistant and sensitive Staphylococcal infections ranging from superficial skin infections to deep-seated occult infections such as visceral abscess, osteomyelitis, and endocarditis has been noted.  This increase is seen in the expanding elderly population who have increasing comorbidities of diabetes and heart disease and increased use of cardiac devices, indwelling catheters and central lines. It is also seen in the younger patient group who has seen a rise in intravenous drug use.  These infections are usually active during the occurrence of glomerulonephritis, rather than occurring after an infection-free latent period as was seen in the past with prototypical post-streptococcal glomerulonephritis.  This temporality introduces a difficult treatment dilemma for clinicians, where immunosuppression therapy to treat glomerulonephritis may be contraindicated in the context of an active infection. 

Furthermore, the clinical diagnosis of infection can be challenging, and may coincide or even occur after the discovery of renal disease.  The incidence of overt nephritic syndrome has decreased, and more often, acute renal failure, along with hematuria and proteinuria, is noted.  In elderly patients, this clinical presentation may be attributed to worsening of underlying comorbidities of diabetes and heart disease rather than to infection.  Fever may be absent.  Blood cultures may be negative.  Imaging studies may be required to identify the source of infection.  Renal biopsy findings are heterogeneous and non-pathognomonic, and morphologic mimics are abundant.  Laboratory findings have exceptions as well.  Complement levels can be normal.  Positive ANCA serologies are noted in a subset of patients with infection-associated glomerulonephritis.  It is therefore critical for the treating clinician and pathologist alike to be mindful of the changing landscape of infection-associated glomerulonephritis, inclusive of mimics and diagnostic pitfalls, and to maintain a high index of suspicion.

Despite these mimics and pitfalls, clinical features that might suggest the possibility of an infection-associated glomerulonephritis include risk factors for infection, such as diabetes, intravenous drug use, indwelling intravenous catheters, recent surgical or invasive procedure, prosthetic heart valve or other devices, poor dentition, or non-healing ulcers and surgical wounds.  Hypocomplementemia, when present, should be noted.  While a spectrum of morphologic patterns of glomerular injury can be noted by light, immunofluorescence and electron microscopy, certain biopsy features, or often the constellation of findings, can raise suspicion for infection.  For example, despite the light microscopy findings, and despite presence or absence of immunoglobulins by immunofluorescence, strong C3 staining is typically noted in cases of infection-associated glomerulonephritis.  Presence of prominent subepithelial humps on electron microscopy, while not pathognomonic, should raise concern for possible infection; their absence, however, does not exclude infection.  IgA nephropathy with presence of crescents and/or presence of endocapillary hypercellularity by neutrophils can raise the possibility of IgA-dominant infection-associated glomerulonephritis.  A crescentic glomerulonephritis by light microscopy, that otherwise looks like typical ANCA-related disease with presence of C3 or other immunoglobulins (especially IgM) that are of greater amount and intensity than typically seen in pauci-immune disease, together with electron-dense deposits by ultrastructural examination, should raise concern for infective endocarditis.  Even for a pauci-immune crescentic glomerulonephritis, in the appropriate clinical context, underlying infection should be excluded as the etiology.  Given the vastly different therapy required for this differential diagnosis, a thorough evaluation may be warranted.