Postinfectious glomerulonephritis (PIGN) may occur in association with bacterial, viral, fungal, protozoal, and helminthic infections. The classic association of glomerulonephritis (GN) with infection is poststreptococcal GN, usually developing after streptococcal pharyngitis (see Poststreptococcal Glomerulonephritis).[1, 2] However, in recent decades the spectrum of postinfectious GN has changed. The incidence of poststreptococcal GN, particularly in its epidemic form, has progressively declined in industrialized countries with early use of effective antibiotics.[3]
Glomerulonephritis associated with methicillin-resistant Staphylococcus aureus (MRSA) infection has become recognized as a more severe manifestation, which is 3 times more common in older patients in developed countries.[4] The majority of patients have diabetes mellitus and present with acute kidney injury, hematuria, and heavy proteinuria. Comorbid diabetes is a predictor of poor outcome; in one series 65% of adults and 55% of older patients with diabetes developed end-stage renal disease (ESRD) after PIGN.[5]
Viral-induced GN manifests in significantly different histologic forms of glomerular injury, depending on the duration of viral activity. For example, a patient with a recent self-limited acute varicella-zoster infection may develop diffuse proliferative glomerulonephritis (DPGN), wherease a subacute Epstein-Barr infection lasting weeks or months may result in collapsing focal segmental glomerulosclerosis (cFSGS) or membranous glomerulopathy (MN). Chronic persistent infections, such as with hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), result in a wide spectrum of glomerular disorders.[6]
A relationship of GN with occult viral disease has also been reported. Occult HCV infection has been detected in 30%–50% of patients with idiopathic membranous nephropathy, IgA nephropathy, FSGS, antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis, and membranoproliferative GN (MPGN). Occult HBV infection has been described in selected cases of idiopathic membranous nephropathy and IgA nephropathy. There is anecdotal evidence that antiviral therapy has been effective in cases of occult HCV- or HBV-associated GN initially diagnosed idiopathic glomerular disease.[7]
The incidence of glomerulonephritis in malaria is estimated to be around 18%[8] and in schistosomaisis, approximately 15%.[9]
For patient education information, see Hepatitis B, Hepatitis C, and Blood in the Urine as well as the Infections Center and Digestive Disorders Center.
Most glomerular diseases associated with infection are mediated by immune complexes. The classic example observed in poststreptococcal GN involves an antigen-antibody reaction, which may occur in the circulation or in the glomerulus. Deposition in the glomerulus results in activation of the complement cascade, which may involve either the classic or alternative pathway. The immune complexes may activate endogenous glomerular cells. The reduction of chemotactic factors results in the accumulation of leukocytes and platelets within the glomerulus and, consequently, the inflammatory response.
The pathogenesis of glomerulonephritis related to staphylococcal infection is not fully understood. Bacterial superantigens may play a key role in the pathological change. A staphylococcal antigen (eg, enterotoxins C and A and toxic shock syndrome toxin [TSST]-1) act as a superantigen and it can bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. This complex then binds to the T-cell receptor without MHC restriction. The interaction results in massive T-cell activation and a subsequent cytokine burst. The cytokines cause polyclonal B-cell activation that induces the production of IgA, IgG, and IgM. These components have a natural specificity for staphylococcal antigens such as those on the cell envelope.[4]
Several possible pathogenic events occur in viral diseases associated with glomerular injury, including the following:
Formation of circulating immune complexes involving viral antigens and antibodies
Formation of circulating immune complexes induced by the release of antigens following virally induced cellular injury
Formation of in situ antigen-antibody reactions or cell-mediated injury
Autoimmune reactions to glomerular structures induced by the virus
In protozoal infections, such as malaria, antibodies are formed against malarial antigens. The circulating immune complexes activate complement and macrophages. The complexes are primarily deposited in subendothelial areas. A cell-mediated immune response may also occur.
Postinfectious glomerulonephritis (PIGN) may occur in association with bacterial, viral, protozoal, and helminthic or fungal infections. See Table 1. below.
Table 1. Infectious agents associated with PIGN
View Table
See Table
Bacterial endocarditis: PIGN occurs more commonly in subacute rather than acute endocarditis. Currently, S aureus is the most common pathogen recognized.[10] Shunt nephritis may be associated with ventriculovascular, ventriculoperitoneal, peritoneovascular, or vascular shunts.[11]
The various causes of infection-related GN have different prevalence rates. In endocarditis, associated GN may occur in up to 20% of cases.[12] Staphylococcus aureus has become a more common cause of GN than Streptococcus in developed countries.[4] GN associated with hepatitis C is becoming a far more commonly recognized cause of GN.[13, 14] It is estimated that 35–60% of patients with chronic hepatitis C will develop renal manifestations including type I membranoproliferative glomerulonephritis (MPGN), mesangial glomerulonephritis, and focal and segmental glomerulonephritis.[15]
Although specific incidence statistics are not available, in certain developing areas of the world, hepatitis B, HIV disease, malaria, and schistosomiasis are major causes of glomerulopathy. The incidence of GN in malaria is estimated to be around 18%.[8] GN is present in approximately 15% of patients with schistosomiasis.[9]
In most GNs associated with infection, no racial or sexual predilection exists. However, HIV-associated GN is far more common in males. Although classic postinfectious GN primarily occurs in childhood, it has been documented in all age groups. Glomerulonephritis associated with methicillin-resistant Staphylococcus aureus (MRSA) infection is 3 times more common in older patients in developed countries.[4]
Depending on the etiology, the outcome of GN associated with infection can be quite variable. Complete recovery occurs in most patients, even those patients with crescents observed in kidney biopsy tissue. The outcome depends on the duration of infection before specific antibacterial or other antiinfective therapy is initiated.
The prognosis for shunt nephritis is good with early diagnosis and treatment of the infection. Approximately 30% of ventriculovascular shunts become infected and GN develops in 0.7–2% of the infected shunts. Ventriculoperitoneal shunts are rarely complicated with GN. Staphylococcus epidermidis or S aureus are the most common pathogens. A late diagnosis delays antibiotic therapy and removal of the shunt, resulting in a worse renal prognosis.[3]
In schistosomal infections, progression of renal disease is common, even after treatment.
Age >65 years and comorbid diabetes are independent risk factors of poor prognosis for GN related to staphylococcal infection.[4]
In GN associated with bacterial endocarditis, renal function returns after treatment with antibiotics. The GN usually resolves after the infection has cleared, with renal function beginning to improve within 1-2 weeks, complement levels normalizing within 6 weeks, and hematuria normalizing in approximately 6 months.[12]
The course of GNs associated with viral infection is more variable, although patients with HIV nephropathy commonly progress to end-stage renal disease.[16]
Hypertension may be due to renal failure. Edema due to nephrotic syndrome is unusual but can develop in as many as 30% of cases associated with shunt nephritis. Rash may be maculopapular or purpuric. Lymphadenopathy is a reported finding. Hepatosplenomegaly may be palpable.
Findings of subacute bacterial endocarditis (SBE) may include the following:
The presentation in patients with postinfectious glomerulonephritis (PIGN) may vary from asymptomatic hematuria to a full-blown acute nephritic syndrome consisting of proteinuria, edema, hypertension, and renal failure. Hematuria may be gross or microscopic and edema may be present. Patients may report fever, night sweats, and rigors. Weight loss is a possible complaint and patients may report arthralgias. Abdominal, chest, or back pain may be caused by a visceral abscess.
Patients may have history of shunt placement for hydrocephalus, or they may have a vascular graft that has become infected.
Patients with hepatitis B or C may have a history of intravenous drug abuse, needle stick injury, blood transfusions, or sexual promiscuity.
Patients with HIV infection may have history of intravenous drug abuse, hemophilia, receipt of blood transfusion from 1977-1985, unprotected sex with multiple partners, or tuberculosis.
Urinalysis in patients with postinfectious glomerulonephritis (PIGN) may reveal hematuria, pyuria, red blood cell casts, and proteinuria. Findings are very helpful for determining whether glomerulonephritis (GN) is primarily of a nephrotic or nephritic type.
In patients with an acute bacterial infection, the complete blood cell count (CBC) may show an elevated neutrophil count. Eosinophilia may be observed in patients with GN associated with subacute bacterial endocarditis (SBE) or a parasitic infection. Depending on the duration of disease and severity of renal dysfunction, anemia may be observed due to chronic kidney disease.
The blood urea nitrogen (BUN) and serum creatinine levels are commonly elevated in patients with infection-related GN. However, levels may be normal early in the course of these disorders.
Hyperkalemia or evidence of metabolic acidosis may be observed in patients with chronic renal insufficiency.
Liver function tests in patients with hepatitis-associated GN commonly result in an elevated aspartate aminotransferase level.
Rheumatoid factor results are commonly positive in patients with GN associated with bacterial endocarditis.[17]
Serum complement levels (C3, C4, CH50) levels are commonly are low in patients with infection-related GN, more so in those with certain diseases. Low complement levels indicate an immune complex disease and are not necessarily diagnostic because they can be present in patients with other immune complex diseases (eg, lupus nephritis).
Hepatitis is a common cause of infection-related GN. Depending on the clinical presentation, a hepatitis serology panel (hepatitis B surface antigen, hepatitis C antibody) can be performed .
Cryoglobulins are commonly present in patients who have GN associated with hepatitis C.
HIV testing should be performed on all patients with GN and risk factors for HIV infection.
Depending on the clinical presentation, drawing blood for viral titers (cytomegalovirus, parvovirus B19, mumps, varicella, Epstein-Barr virus, Hantavirus) may be important in order to help identify the cause of the GN.
Stool for ova and parasites should be performed if the patient has been in areas endemic to diseases such as schistosomiasis or filariasis.
Depending on the clinical presentation, any of the following may be performed as part of the evaluation to help identify the cause of the GN:
Antistreptolysin-O titer
Antineutrophil cytoplasmic antibody assay
Antiglomerular basement membrane antibody
Serum protein electrophoresis
Urine protein electrophoresis .
In appropriate clinical circumstances, peripheral blood smears to test for malaria may be helpful.
Renal ultrasound is routinely obtained in patients presenting with abnormal renal function to help rule out obstructive causes of nephropathy, and findings demonstrate certain anatomic abnormalities. It is also useful to confirm the presence of 2 functioning kidneys prior to performing percutaneous renal biopsy.
CT scan of the chest, abdomen, or pelvis may be indicated if visceral abscess is suggested.
A transthoracic echocardiogram should be performed if bacterial endocarditis is a possible cause. If findings are inconclusive, a transesophageal echocardiogram is indicated to help rule out valvular vegetations.
In most cases, the treatment of postinfectious glomerulonephritis (PIGN) is based on treating the underlying infection. In certain instances, immunosuppressive agents such as corticosteroids may be employed to reduce glomerular inflammation. Inpatient care depends on the severity of infection, and the need for hospitalization depends on the clinical condition of the patient (eg, the patient may require dialytic support or IV fluids and antibiotics). If bacterial endocarditis or a shunt infection does not respond to antibiotics, then surgical intervention is indicated.
Oral antibiotics can be continued in an outpatient setting, with frequent monitoring of kidney function. Outpatient dialysis, if necessary, may need to be arranged.
The majority of patients are infected with methicillin-resistant Staphylococcus aureus (MRSA) and antbiotics are the typical treatment for most cases.[4]
Treatment of shunt infections and visceral abscesses is usually is based on culture sensitivity results.
Viral
Chronic hepatitis B
Treatment is indicated if associated liver dysfunction is present. Current first-line agents are pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), and tenofovir disoproxil fumarate (TDF). For complete discussion, see Hepatitis B.
Chronic hepatitis C
Guidelines for the treatment of patients with hepatitis C, including viral genotype–specific therapy and recommendations for patients with renal impairment, have been issued by the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (ISDA) and are available at https://www.hcvguidelines.org/ Current recommendations vary for patients with an estimated glomerular filtration rate (eGFR) of >90 to >30 mL/min (ie, chronic kidney disease [CKD] stages 1-3) versus those with eGFR < 30 mL/min or end-stage renal disease [ESRD]). For more information, see Hepatitis C.
In addition to antiviral therapy, treatment may include B-cell depletion therapy with rituximab to prevent formation of immune complexes and cryoglobulins, or nonspecific immunosuppressive therapy targeting inflammatory cells to prevent the synthesis of immune complexes and treat cryoglobulin-associated vasculitis.[18]
HIV
Highly active antiretroviral therapy (HAART) is the standard of care for patients with HIV, with or without nephropathy.[19] Treatment is based on findings from viral titers, the history of previous therapy, and, preferably, on the advice of an infectious diseases specialist. There is evidence that HAART therapy may slow the progression of HIV associated nephropathy to ESRD. Patients should also be started on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), as this may slow the progression of disease.
Syphilis
Nephropathy is usually observed in secondary syphilis because this phase is associated with high levels of immune complexes. If central nervous system or ocular involvement is not present, treatment is similar to primary syphilis (ie, a single intramuscular dose of benzathine penicillin 2.4 million U). If the patient is allergic to penicillin, use doxycycline (100 mg PO bid) or erythromycin (500 mg PO qid) for 2 weeks.
Other viral agents
Nephropathy associated with cytomegalovirus, parvovirus, and polyomavirus infections is observed in immunocompromised individuals and those who have undergone renal transplantation. Treatment is with specific antiviral agents (ie, ganciclovir for cytomegalovirus, cidofovir for polyomavirus [JC and BK virus]) and temporary withdrawal of immunosuppression therapy.
Parasitic
Malaria
Antimalarial drugs are the cornerstone of treatment of falciparum malaria. For more information, see Malaria.
Treatment of malaria-associated GN involves supportive measures such as hydroelectrolytic disturbances corrections, fluid replacement, and dialysis.[9] Dialysis is required in 46-76% of cases, and complete renal function recovery is reported to occur in approximately 64% of cases in both Plasmodium falciparum and P vivax malaria. Early initiation of dialysis has been associated with better outcomes.[8]
Schistosomiasis
Usually, treatment with praziquantel does not slow the progression of nephropathy. Sometimes, if schistosomiasis is associated with co-infection with Salmonella species, treatment of the Salmonella infection improves the nephropathy. Patients may benefit from either cyclosporine or cyclophosphamide, with remission reported in a third of cases.[9]
Leishmaniasis
Agents used in leishmaniasis treatment include antimony compounds (eg, sodium stibogluconate) and amphotericin B, pentamidine, and paromomycin. For more information, see Leishmaniasis. Diethylcarbamazepine and ivermectin are used for treating filariasis.
Fungal
For aspergillosis, treatment is based on the site of infection and usually includes amphotericin. For more information, see Aspergillosis>.
Consultation with a nephrologist is indicated in patients with GN associated with infection. Consultation with an infectious diseases specialist may be appropriate if the infectious etiology is unclear.
In its clinical practice guidelines for glomerulonephritis (GN), Kidney Disease: Improving Global Outcomes (KDIGO) recommends treatment of the infectious disease and standard approaches to management of the kidney manifestations for poststreptococcal GN, infective endocarditis–related GN, and shunt nephritis.[3]
For hepatitis C virus (HCV)–associated GN, the guidelines make the following recommendations[3] :
Chronic kidney disease (CKD) stages 1 and 2: Combined antiviral treatment using pegylated interferon and ribavirin; dosage of ribavirin should be titrated according to the patient's tolerance and level of renal function.
CKD Stages 3, 4, or 5 and not yet on dialysis: Monotherapy with pegylated interferon adjusted to the level of kidney function
For patients with mixed cryoglobulinemia (IgG/IgM) and nephrotic proteinuria or evidence of progressive kidney disease or an acute flare of cryoglobulinemia, treatment with plasmapheresis, rituximab, or cyclophosphamide, in conjunction with IV methylprednisolone, and concomitant antiviral therapy are recommended.[3]
For hepatitis B virus (HBV)–associated GN the guidelines recommend standard treatment with interferon-alpha or with nucleoside analogues, with the dosage adjusted to the degree of kidney function. For patients with biopsy-confirmed HIV-associated nephropathy, antiretroviral therapy should be initiated regardless of CD4 count.[20]
For patients with GN and concomitant malarial, schistosomal, or filarial infection, treatment is recommended with an appropriate antiparasitic agent to eradicate the organism. Corticosteroids or immunosuppressive agents should not be used for treatment of schistosomal-associated GN. A blood culture for Salmonella should be considered in patients with hepatosplenic schistosomiasis who show urinary abnormalities and/or reduced GFR. A positive blood culture for Salmonella necessitates anti-Salmonella therapy.[3]
Clinical Context:
Indicated for hepatitis B. Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.
Clinical Context:
Increases cell membrane permeability in susceptible worms, resulting in loss of intracellular calcium, massive contractions, and paralysis of musculature. In addition, produces vacuolization and disintegration of schistosome tegument. This is followed by attachment of phagocytes to parasite and death. Tabs should be swallowed whole with some liquid during meals. Keeping tabs in mouth may reveal bitter taste, which can produce nausea or vomiting.
Clinical Context:
For parasitic infections. Synthetic organic compound highly specific for several common parasites. Does not contain toxic metallic elements. Not recommended as DOC because of more severe adverse effects. Recommended if therapy with mebendazole fails or is not available.
Clinical Context:
DOC for the treatment of leishmaniasis in United States. May be administered IV or IM. Intravenous use is preferred because large volumes are required. Available at 100 mg/mL. Dilute each mL in 10 mL of 5% dextrose water and administer over 15 min to prevent thrombophlebitis.
Clinical Context:
Inhibits growth by concentrating within acid vesicles of parasite, which increases internal pH of organism. Also inhibits hemoglobin utilization and metabolism of parasite.
Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.
Clinical Context:
Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).
Clinical Context:
Nucleoside analogue approved by the FDA for chronic hepatitis B treatment. Now considered first-line therapy, eclipsing interferon. Inhibits hepatitis B viral DNA polymerase. Use should be considered in patients with ongoing hepatitis B viral replication, elevated aminotransferase activity, and histologic evidence of liver injury. Consider for cases that failed, are unlikely to respond to interferon, or patients who cannot tolerate interferon. Discontinue lamivudine only when repeated assays demonstrated HBeAg loss or seroconversion to HBeAb. Emergence of resistance is the major drawback of nucleoside analogue monotherapy. Proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because resistant strains of HBV seem to be attenuated and are associated with only mild liver injury.
Note that the available dosage forms differ between Epivir and Epivir-HBV (formula specific for hepatitis B virus). Epivir-HVB is available as a 100 mg tab or oral solution 5 mg/mL, whereas Epivir contains 150 mg/tab or 10 mg/mL in oral solution.
James W Lohr, MD, Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences
Disclosure: Received research grant from: GSK<br/>Partner received salary from Alexion for employment.
Coauthor(s)
Quresh T Khairullah, MBBS, MD,
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital
Disclosure: Nothing to disclose.
Chief Editor
Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
