Acute postinfectious glomerulonephritis (PIGN), generally synonymous with acute poststreptococcal glomerulonephritis, was initially described in the early 1800s by Wells1 and Blackall2 when they observed gross hematuria and anasarca as dramatic side effects of postscarlatinal dropsy. Patients with scarlet fever, another streptococcus-associated entity, were also noted to have occasional bouts of acute glomerulonephritis. Since these studies, the randomness of occurrence of the glomerulonephritis with streptococcal infections has to a degree been explained by the presence of nephritogenic strains of the bacterium that appear most capable of causing PIGN. However, this is not the complete story because many patients with these strains do not develop PIGN, regional and geographical differences in prevalence are found with the same strains, and other causes of PIGN aside from streptococcus have been described (eg, other bacteria, viral agents). There is no evidence of bacterial seeding in the kidney by the bacteria and the glomerulonephritis typically develops after the primary infection has resolved.
Full-blown PIGN is characterized by glomerular hypercellularity principally due to a proliferation of endogenous mesangial and endocapillary cells. There is also a significant infiltration by cells involved in immune responses, including polymorphonuclear leucocytes, lymphocytes, and occasional plasma cells. Crescent formation and tubulo-interstitial inflammation may be present. Immunofluorescence microscopy studies have revealed prominent capillary loop and mesangial deposition of IgG and C3 with the intensity of these effector molecules diminishing as the illness subsides. Ultrastructural examination shows characteristic epithelial electron-dense deposits (“humps”) that correspond to the immunofluorescence evidence of immune complex deposition. PIGN that progresses can show chronic injury to glomeruli (eg, sclerosis) while resolving disease tends to be devoid of the initial changes present when the illness is most apparent.
The clinical manifestations of the illness (eg, hematuria, proteinuria) are as impressive as the histopathological changes and similarly tend to be self-limiting, with rare individuals progressing to chronic glomerulonephritis. However, the belief that acute PIGN carries a good prognosis and is innocuous in relation to future renal function is currently under dispute. Specifically, recent papers have demonstrated reduced renal functional reserve 10 years after the onset of PIGN.3 Also, the intriguing fact that subclinical disease is up to 4 times more frequent than overt disease has stimulated the search for more sensitive morphologic and immunologic markers. In this issue of Human Pathology, Haas presents significant findings that further address the issue of subclinical PIGN.4 He found that a notable number of cases (5.6%) among 1012 renal biopsies showed ultrastructural evidence of immune complexes characteristic of PIGN. These patients demonstrated no clinical manifestations of acute PIGN and some patients (eg, diabetics) had an increased frequency of characteristic deposits, suggesting the possibility of silent episodes of PIGN. These morphologic observations further substantiate the contention that PIGN occurs more frequently than is clinically appreciated. Among the unanswered questions with this form of PIGN that appears to be clinically silent but pathologically manifest is whether it is also related to enduring functional injury to the kidney.
The inference has long been that this infection-associated inflammation more than likely involves an immune response directed at or affecting the kidney, and that PIGN is an immune complex glomerulonephritis. However, there remain numerous questions when explaining how the relationship between the host immune system and infectious agent leads to varying clinical and pathologic manifestations of this renal disease.
It is acknowledged that the immune response to common pathogens can vary significantly within a given mammalian species. With reference to PIGN, it is crucial to understand the frequency, form and scale of the immune response to nephritogenic pathogens among different individuals. In the earliest stages it is advantageous for the host to possess a level of “protective immunity” that prevents any significant infiltration by exogenous organisms into tissues. Certainly, an efficient set of “nonspecific”, unprimed cells within the innate immune system (eg, macrophages) and preexisting antibodies and primed T cells combine to guard an individual from the daily exposure one encounters with potentially pathogenic organisms. Microbes that escape this initial interaction and colonize are then dealt with by a primary immune response, the latter critically dependent on immune response (Ir) genes of the host. In humans, these Ir genes are located at various loci with the best known examples mapping in the human leukocyte antigen (HLA) region. HLA haplotype association with certain diseases and infections has been demonstrated5 and this assuredly has relevance to organisms involved in the pathogenesis of PIGN. For instance, Kotb and colleagues have demonstrated that certain HLA class II haplotypes bestow protective immunity to human hosts from severe complications of infection with group A streptococcal organisms, whereas certain HLA class II polymorphisms were associated with a reduced propensity to develop severe disease.6 Paradoxically, it is the lack of an immune response that is associated with less severe disease. In this case, it is the absence or reduced affinity of the receptor on HLA class II molecules for bacterial superantigens that confers protection on the host. In PIGN, bacterial superantigens may be among the virulence factors released from the offending pathogen that bind to specific ligands on host molecules, subsequently inducing nonspecific inflammatory changes.
Components of the specific immune response (antibodies, effector T cells) are also crucial participants in the pathogenesis of PIGN. Antigen-antibody immune complexes in the kidney stimulate and maintain nonspecific cellular and soluble inflammatory processes. For the best studied and most prevalent form of PIGN, it appears that the erythrogenic toxin type B (ETB) produced by the streptococcus may be a component of the immune complexes that develop,6 although the prevalence of this molecule is variable. It remains to be determined whether there is passive deposition of circulating immune complexes or if microbial molecules bind to receptor sites in the kidney and thereafter recognized by specific antibodies. To date, no reliable candidate antigens from other pathogens have been described as a component of the immune complexes.
There is also heterogeneity with specific immunity, and Ir genes can influence the degree of antibody or cellular immunity a host can manifest to antigens released by microbial organisms. Differences within the antibody response to PIGN-inducing antigens doubtless influence the character, duration, and consequences of the local inflammatory response during PIGN. In all of this, the role of T cells in PIGN remains an enigma that has multiple possibilities in how subpopulations of these cells could manifest their influence on PIGN development. For example, a skewing of anti-pathogen helper T cell populations to either a TH1 (eg, more classical inflammatory cell responses) or to a TH2 (eg, increased antibody, more suppressive cytokines) population can impart a remarkably different character to the immune response. Regulatory T cells specific to these microbes at genetically predetermined or environmentally influenced levels could modify how the immune response evolves. Finally, effector T cells may be potent or inefficiently generated and anergic to the pathogenic substances.
Does the lack of an efficient immune response (once the pathogen and its molecules have implanted in the kidney) benefit the host by not promoting a destructive local inflammation in the kidney? Or rather, does an inefficient smoldering immune response result in a protracted inapparent form of injury? One can envision a subclinical but pathologically evident PIGN that could cause or potentiate chronic renal injury such as chronic glomerulonephritis. If the latter scenario proves correct, are there certain patient populations at higher risk for developing this form of PIGN, such as immunocompromised individuals? In that regard, the study by Haas not only demonstrates an increased frequency of silent PIGN, but also points to certain patient groups at potentially higher risk for this particular condition. As we attempt to understand what is the “true” prevalence and the long-term ramifications of this multifaceted immune-mediated disease, we must also develop a greater understanding of the immunopathological mechanisms in all forms of PIGN. Accomplishing these goals will pave the way to a rational approach in the prevention and treatment of this highly complex disorder.
FULL TEXT