Postinfectious Glomerulonephritis: Introduction
This chapter deals with nephritis associated with bacterial infections. A variety of bacterial infections are associated with renal disease, among which are Streptococcus (group A and C), Staphylococcus (aureus and epidermidis), Salmonella (typhi and paratyphi), Treponema pallidum, and Brucella abortus sui. We will limit our considerations to three specific disease entities: Poststreptococcal glomerulonephritis, glomerulonephritis associated with infective endocarditis, and glomerulonephritis associated with infected atrioventricular shunts.
Poststreptococcal Glomerulonephritis
- Acute nephritic syndrome (hematuria, edema, hypertension, ± oliguria), occasionally nephrotic syndrome, and rarely rapidly progressive azotemia.
- No evidence of systemic disease.
- Recent streptococcal infection (serology or culture).
- Reduced serum complement (CH50 and C3).
The incidence of acute poststreptococcal glomerulonephritis (APSGN) has decreased dramatically in most industrialized countries. The association with alcoholism in adult patients has been noticed in central Europe. Nevertheless, in other countries, such as Singapore, Trinidad, and Venezuela, a poststreptococcal etiology is the causative factor in more than 70% of the children admitted to the hospital with glomerulonephritis. The reason for these geographic variations in epidemiology may be the accessibility to early medical care and antibiotic treatment resulting from improvements in living standards. In addition, a lack of hygiene and sanitation prevalent in underdeveloped countries may predispose to a Th1 type of response (characteristic of APSGN) in contrast to the Th2 response that tends to favor minimal change disease in the industrialized countries with higher standards of hygiene. APSGN presents as sporadic cases, clusters of cases, or epidemics that follow streptococcal infections of the throat or the skin. The original epidemics were all due to group A streptococci, but the most recent large epidemic was due to the consumption of unpasteurized milk and cheese from cows with mastitis caused by Streptococcus zooepidemicus.
Streptococci of M types 47, 49, 55, and 57 are frequently the etiologic agents of pyodermitis-associated nephritis while types 1, 2, 4, and 12 correspond to upper respiratory streptococcal infections causing nephritis. There is a wide variability in the incidence of nephritis following a nephritogenic streptococcal infection, but the incidence among siblings is close to 40%, which indicates a familial predisposition to the disease; however, a genetic marker of susceptibility for APSGN has not been found.
APSGN is an immune complex-mediated disease. Humoral and cellular immune mechanisms are involved. Immune complexes formed in the circulation or in situ induce the local activation of the complement (preferentially by an alternative pathway) and coagulation systems (platelet consumption and activation) and the recruitment of inflammatory cells. Infiltration of helper T lymphocytes is an early feature and increased levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and platelet-derived growth factor (PDGF) have been demonstrated. In addition, there is evidence of autoimmune reactivity attributed in part to neuraminidase-induced desialization of normal components. Antineutrophil cytoplasmic antibody (ANCA), cryglobulins, serum rheumatoid factor titers, C3eNef, and antiimmunoglobulin (Ig) G renal deposits have all been demonstrated. These manifestations of autoimmune reactivity have undefined clinical significance except for the demonstration of ANCA that is more frequent in cases of greater severity.
The nature of the nephritogenic streptococcal antigen is still controversial. At present, streptococcal plasmin receptor [nephritis-associated plasmin receptor (NAPlr) or glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] and streptococcal cationic exotoxin B and zymogen precursor (SPE B) are actively being investigated. Serum antibody response to these antigens has been found in 70–90% of the patients and both GAPDH and SPE B have been detected in renal biopsies obtained early in the course of the disease. Multicentric studies show that the antizymogen antibody titer is the best marker of nephritogenic streptococcal infection. Recently, evidence of colocalization of NAPlr and glomerular plasmin-like activity has been found, suggesting that the ability to bind to plasmin plays a critical pathogenetic role in APSGN.
APSGN induces long-term protective immunity as demonstrated by the fact that repeated attacks of the disease are extremely rare.
APSGN is usually, but not exclusively, a disease of children and adolescents: The highest incidence occurs in patients between the ages of 4 and 15 years. Less than 5% of the patients are younger than 2 years and about 10% in most large series are older than 40 years.
The diagnosis of APSGN requires the demonstration of antecedent streptococcal infection in a patient who presents with acute glomerulonephritis. Nephritis may follow 7–15 days after streptococcal tonsillitis and 4–6 weeks after impetigo. It is not unusual for the active pyodermitis to have subsided at the time of APSGN but telltale skin scars and decoloration are present. Impetigo frequently complicates scabies and a clue to this association may be obtained by examination of the siblings of the patient.
The acute nephritic syndrome, characterized by edema, gross or microscopic hematuria, hypertension, and frequently oliguria, is the usual clinical presentation of APSGN and renal histology shows acute endocapillary glomerulonephritis with mesangial and capillary granular immune deposition. Hematuria, gross or microscopic, is almost universally present. The edema occurs in 80–90% of the patients, is usually the primary complaint, and varies in severity from swollen eyelids to anasarca, but in contrast with nephrotic syndrome, ascites is rarely present. Hypertension is found in 80% of the patients. The severity of hypertension is correlated with the degree of fluid retention and the volume-sensing hormonal systems reflect primary sodium retention with expansion of extracellular fluid volume: Suppressed renin–angiotensin–aldosterone system and stimulated secretion of atrial natriuretic peptide. The clinical manifestations of acute nephritic syndrome usually last less than 2 weeks.
Less than 4% of the children with APSGN have massive proteinuria and these patients usually have thick, garland-like immune deposits and large numbers of prominent “humps” as revealed by electron microscopy. Occasionally, a patient develops rapidly progressive azotemia and crescentic glomerulonephritis.
Asymptomatic cases, manifested by microscopic hematuria, reduction of the complement levels, and sometimes hypertension after a recent streptococcal infection, are in prospective studies four or five times more frequently than clinically apparent disease.
The clinical manifestations of APSGN in children are different from those in adult patients, who frequently have a more protracted course, higher incidence of complications, and a consistently poorer prognosis.
The positivity of cultures in cases of APSGN has significant variability: 10–70% of the cases during epidemics and about 25% in sporadic cases. Most frequently, the poststreptococcal etiology is established by increasing titers of antistreptolysin O (ASO)(reported in 33–80% of the cases of APSGN that follow throat infections), anti-DNase B (increased in 73% of the postimpetigo cases), and the streptozyme test that measures antibodies to four antigens: DNase B, ASO, hyaluronidase, and streptokinase (positive in about 80% of the cases). Anti-NAPlr, anti-SPE B, and antizymogen (SPE B precursor) antibody titers are more sensitive (positive in close to 90% of the APSGN patients), but their determination is not generally available.
The complement system is preferentially, but not exclusively, activated by the alternative pathway. C4 levels are usually normal and CH50 and C3 are depressed in more than 90% of the cases and return to normal in less than 1 month. A normal serum complement in the acute phase as well as hypocomplementemia lasting longer than 1 month should raise the suspicion of a diagnosis different than APSGN. Serum IgG and IgM are usually elevated and IgA is normal. Cryoglobulins are present in one-third of the patients.
The urine sediment shows red blood cell casts and dismorphic erythrocytes, characteristic of glomerular hematuria. The fractional excretion of sodium is frequently less than 0.5 and increases with the reestablishment of diuresis.
Renal biopsy is not indicated in APSGN unless there are characteristics that make the diagnosis doubtful or have prognostic significance and therapeutic implications (see Differential Diagnosis below).
The initial approach to the patient with acute nephritic syndrome should indicate if a systemic disease is associated with the acute glomerulonephritis or if the clinical picture results from a primary renal disease. The lack of fever, gastrointestinal and pulmonary manifestations, arthralgias, or vasculitis skin lesions suggests primary renal disease. The serum complement levels are helpful as a first-line laboratory test because fewer than 10% of the patients with APSGN have a normal serum complement and such a findings should raise the possibility of other diseases such as IgA nephropathy, vasculitis, hemolytic uremic syndrome, or anti-glomerular basement membrane disease. In addition, the serum complement returns to normal levels in less than a month in APSGN and a persistently low C3 should make the clinician consider membranoproliferative glomerulonephritis (types 1 or 2) or lupus erythematosus.
