Keywords

Introduction

The association between acute renal disease and infection is well known and was first described in the modern era by Sir Richard Bright in 1827, as part of the cluster of a glomerulonephritis (GN) that was called “Bright’s disease” (Stratta et al. 2014). The disease, known today as postinfectious glomerulonephritis (PIGN), was first described secondary to streptococcal infection (pharyngitis or scarlet fever) and is an immune-complex-mediated disease. The condition is triggered by foreign pathogens, usually a bacterial infection, that cause secondary complement-mediated renal injury.

Table 1 Infective agents that might cause an acute postinfectious glomerulonephritis (PIGN) (Stratta et al. 2014; Jain et al. 2011; Garty et al. 2009; Asano et al. 2016; Kanodia et al. 2016; Kanjanabuch et al. 2009; Watanabe et al. 2003)
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Until recently, most of the PIGN in the pediatric population was secondary to streptococcal throat or skin infections, and named post-streptococcal glomerulonephritis (PSGN) (Chadban and Atkins 2005). However, during the last few years, more bacterial and viral pathogens cause IRGN, of which Staphylococcus aureus infection (Usui et al. 2016) is the most common PIGN in the elderly population.

Epidemiology

PIGN-like PSGN is more common during the winter season, and primarily affects children at the age of 3–12 years. Although uncommon, it can occur in infants younger than 2 years (Dagan et al. 2016).

The incidence of Streptococcal-related PIGN in the pediatric population in developing and developed countries is 24.3 and 6 per 100,000 person years, respectively, and in adults and children the incidence is 2 and 0.3, respectively (Nasr et al. 2013; Carapetis et al. 2005; Kanjanabuch et al. 2009). Acute PIGN, once a common pediatric disease, has almost completely disappeared from the developed (industrialized) countries, mainly because of antibiotic treatment and improvement in the socioeconomic status (Stratta et al. 2014). The accurate incidence of PIGN is unknown while that of PSGN occurs with an estimated 472,000 cases per year, worldwide, of which 97% is in developing countries (Steer et al. 2007). In developed countries, PSGN is less common than Staphylococcus aureus PIGN, which is considered a disease of the elderly population, and associated with alcoholism and diabetes mellitus (Montseny et al. 1995).

Adult data on acute PIGN suggests male predominance, with male-to-female ratio 1.4–3:1, and the disease is more common in Caucasian and Asians populations (Nasr et al. 2013).

Pathogenesis

The glomerular damage in PIGN is the result of circulating immune complexes deposition and/or in situ formation of immune complexes containing bacterial antigens. In typical PIGN, the pathogenic endotoxin which circulates and binds to the glomeruli initiates activation of the complement alternative pathway through the mannose-binding lectin which induce an antibody response (Couser and Johnson 2014). The atypical PIGN is caused by deregulation of the complement alternative pathway (De Vriese et al. 2015).

The pathogenesis of most acute PIGN resembles that of acute PSGN, and both have an immune complex pathogenesis. While in acute PSGN nephritogenic toxins have been identified, in acute non-streptococcal PIGN, little is known on the specific immune-mediated pathogenesis of the renal injury (Rodríguez-Iturbe and Batsford 2007).

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-associated GN are not considered a PIGN but rather an IRGN because the genesis of HCV- and HIV-associated glomerular disease share a total dependence on the presence of active viral replication to sustain renal injury (Kupin 2017).

Clinical Characteristics

Acute nephritic syndrome, or glomerulonephritis (GN), is characterized by hematuria, proteinuria (nephrotic range or non-nephrotic range), edema, and often by hypertension and a mild degree of acute kidney injury (Kanjanabuch et al. 2009). The classic PIGN clinical presentation is a young child usually 3–7 years old, who abruptly develops eyelid edema followed by smoky and scant dark cloudy urine and increasing blood pressure a few days after a nonrenal infection. Anuria and nephrotic range proteinuria are occasionally observed, and a urine volume usually increases 4–7 days after hospital admission, indicating resolution of the glomerulonephritis.

PSGN usually presents 7–15 days after a throat infection and 3–5 weeks after a skin infection (Rodríguez-Iturbe and Batsford 2007). Most of the reports of PIGN show a latent period that resembles the latent period of the PSGN throat infection. PIGN develops 13 days after the presentation of P. vivax malaria (Kanodia et al. 2016), 12 days after Parvo B-19 (Marco et al. 2016) but only 2 days after the presentation of Influenza (H1N1) (Jain et al. 2011). The urinary volume increase is rapidly followed by resolution of the edema and normalization of blood pressure. Microscopic hematuria takes several months to resolve and can persist for 1 year after the acute attack (Kanjanabuch et al. 2009).

A quarter of all PIGN cases will have a subclinical GN (Yoshizawa et al. 1996). The patients usually present with acute, trivial, and self-limited infections develop subclinical glomerular disease, as indicated by low-grade proteinuria (<1 gram per day), pyuria, and microscopic hematuria (Kanjanabuch et al. 2009).

Laboratory

The classic serologic finding of PIGN is a reduction of C3 serum complement levels that occurs in 90% of the cases (Rodríguez-Iturbe and Batsford 2007). In regard to PIGN secondary to staphylococcal infection, the majority of cases will have IgA deposits in the renal biopsy and serum levels of IgA and IgG are elevated; other serological tests including complement, ANCA, cryoglobulins, and rheumatoid factor are usually in the normal range while small elevation in ANA can be seen (Zeledon et al. 2008).

Pathology

Most of the cases of PIGN are diagnosed by the clear clinical and laboratory signs obviating the need for a renal biopsy (Rodríguez-Iturbe and Mezzano 2016). In cases where renal biopsy is performed, the histology is characterized by extracapillary proliferation (Stratta et al. 2014), or in the case of a Streptococcus aureus infection, IgA-dominant deposition (Koyama et al. 2017). In most cases, enlarged hypercellular glomeruli with prominent endocapillary proliferation and infiltration with neutrophils and mononuclear cells, with variable degrees of immunoglobulin and complement deposits. The histologic picture consists of diffuse or focal, mesangial or mesangiocapillary proliferation with, in few instances, fibrocellular crescents.

Deposits of IgA, IgG, and C3 have been observed in both the mesangium and the peripheral capillary walls with subendothelial deposits have been reported, while sub-epithelial “humps” characteristic of PIGN are unusual (Zeledon et al. 2008; Fogo 2016). The granular deposition of complement C3 is often coupled with IgG and occasionally with IgM. IgA deposition is rare, except in patients with diabetes and secondary staphylococcal infection. “Full house” immunostaining (IgG, IgM, IgA, C3, C4, C1q) that resembles the pathologic finding of lupus nephritis is frequently reported (Kanjanabuch et al. 2009). The dominant IgA staining in staphylococcal PIGN can be distinguished from IgA nephropathy by electron microscopy (EM) appearance of the deposits (Usui et al. 2016; Fogo 2016; Nasr et al. 2007).

The histologic picture changes over the course of the disease with glomerular endocapillary proliferative GN in the active stage, mesangial proliferative GN in the healing stage, or both types during the subclinical stage, with C3-dominant deposits. In severe disease, crescents are present and rapidly progressive glomerulonephritis is expected. Under EM, small immune deposits are commonly present in the mesangial and subendothelial areas of the kidney with acute PIGN. However, the characteristic finding is large “humps” (dome-shaped deposits) under the effaced epithelium, particularly in the mesangial notch or waist region. The proliferative and exudative changes associated with non-streptococcal acute PIGN are not prominent as those observed in the classic PSGN (Kanjanabuch et al. 2009; Rodríguez-Iturbe and Mezzano 2016).

Treatment

A patient with PIGN suffers from two main problems: a postinfection (bacterial or viral) state and an acute nephritis syndrome (hypertension, acute kidney injury, edema). While managing the patient, these two problems need to be taken into consideration.

Pathogen Treatment

The first question to be considered related to the diagnosis of non-streptococcal PIGN is what is the causative pathogen and what is the best antibiotic (or anti-viral) treatment needed. While in PSGN the treatment of choice will be penicillin (or in cases of penicillin allergy – erythromycin), in the case of non-streptococcal PIGN, the cornerstone of the antibiotic treatment is to identify the correct pathogen. In cases of IgA-dominant GN secondary to staphylococcal infection, the antibiotic treatment depends on the bacterial sensitivity (MRSA vs. MSSA). In cases of other pathogens, the antibiotic or anti-viral treatment needs to be tailored to the specific pathogen (Rodríguez-Iturbe and Mezzano 2016).

Corticosteroid treatment is contraindicated while there is active infection, and can be use in selected cases of RPGN when active infection is no longer present (Rodríguez-Iturbe and Mezzano 2016).

Acute Nephritis Treatment

When treating a patient with glomerulonephritis secondary to a recent infection, the first thing to be considered is whether the patient needs to be admitted to an inpatient facility or is able to receive sufficient treatment as an outpatient. A patient with subclinical nephritic syndrome with good urine output and without hypertension might benefit from outpatient treatment. In contrast, any patient with acute nephritic syndrome needs to be hospitalized (Rodríguez-Iturbe and Mezzano 2016), mainly for the follow up of any possible exacerbation of hypertension.

The cornerstone for managing of acute nephritis is bed rest, fluid restriction, and low salt diet (Rodríguez-Iturbe and Mezzano 2016). In cases of apparent fluid overload, that manifested as severe edema, elevated blood pressure, and circulatory congestion, the administration of loop diuretics orally or parenterally (Furosemide, 40 mg every 12 hours) is warranted. Antihypertensive medications are required in cases of severe hypertension that is not well controlled with diuretics in order to prevent hypertension-induced seizures. It is recommended to start with nifedipine (5 mg every 4–6 h) or parenteral hydralazine (Rodríguez-Iturbe and Mezzano 2016).

Prognosis and Complications

The overall prognosis of acute PIGN resembles that of acute PSGN , and in the short term, both share an excellent prognosis. Furthermore, the complications that was described during the acute phase are rare (Rodríguez-Iturbe and Mezzano 2016).There are, however, a few rare medical complications that affect the patients during the acute attack: acute kidney injury (Ayoob and Schwaderer 2016); severe hypertension with clinical sequela such as hypertensive encephalopathy, hyperkalemia, and pulmonary edema that might require acute dialysis; cerebral venous thrombosis (Morkhandikar et al. 2016); and posterior reversible leukoencephalopathy (Fux et al. 2006) that resembles hypertensive encephalopathy and manifests as mental disturbances, headaches, visual hallucinations, and convulsions. The last two are extremely rare, severe complications with grave prognoses.

Rapidly progressive glomerulonephritis (RPGN) that presents as dramatic loss of renal function over a few weeks to months is a rare but severe complication of PIGN. Approximately, half of the RPGN cases are associated with PIGN (Piyaphanee et al. 2016), and about one-third of the patients that develop RPGN will deteriorate to end-stage renal disease (ESRD) (Piyaphanee et al. 2016) over the course of time.

The long-term prognosis of acute PIGN in the pediatric population is much better than in the adult population, and deterioration to ESKD in children was reported in less than 1% of the cases (Rodríguez-Iturbe and Mezzano 2016). Non-nephrotic proteinuria was found in 7.2%, hypertension and microhematuria were found in 3% and 5.4%, respectively (Rodriguez-Iturbe and Musser 2008), and the history of PIGN has strong association with reduced glomerular filtration rate (<60 mL/min/1.73 m2) in later life (Hoy et al. 2012).