Background

Acute glomerulonephritis is a disease characterized by the sudden appearance of edema,

hematuria, proteinuria, and hypertension. It is a representative disease of acute nephritic
syndrome in which inflammation of the glomerulus is manifested by proliferation of cellular
elements secondary to an immunologic mechanism (see the following image).[1, 2]

Schematic representation of proposed mechanisms involved in the development of acute

poststreptococcal glomerulonephritis (APSGN).MES: mesangial cell; END: endothelial cell;
PMN: polymorphonuclear cell; M: macrophage; T: T lymphocyte; GMB: glomerular
basement membrane; C: complement; Anti-NAPlr-Ab: Anti-NAPlr-antibody.Courtesy of
open access article, "The Role of Nephritis-Associated Plasmin Receptor (NAPlr) in
Glomerulonephritis Associated with Streptococcal Infection." Oda T, Yoshizawa N,
Yamakami K, et al. Journal of Biomedicine and Biotechnology, 2012; doi: 10.1155/417675.
Acute poststreptococcal glomerulonephritis (APSGN) results from an antecedent infection of
the skin (impetigo) or throat (pharyngitis) caused by nephritogenic strains of group A betahemolytic streptococci.[3, 4, 5] The concept of nephritogenic streptococci was initially advanced
by Seegal and Earl in 1941, who noted that rheumatic fever and acute poststreptococcal
glomerulonephritis (both nonsuppurative complications of streptococcal infections) did not
simultaneously occur in the same patient and differ in geographic location.[6] Acute
poststreptococcal glomerulonephritis occurs predominantly in males and often completely
heals, whereas patients with rheumatic fever often experience relapsing attacks.
The M and T proteins in the bacterial wall have been used for characterizing streptococci.
Nephritogenicity is mainly restricted to certain M protein serotypes (ie, 1, 2, 4, 12, 18, 25, 49,
55, 57, and 60) that have shown nephritogenic potential. These may cause skin or throat

infections, but specific M types, such as 49, 55, 57, and 60, are most commonly associated
with skin infections. However, not all strains of a nephritis-associated M protein serotype are
nephritogenic.[7] In addition, many M protein serotypes do not confer lifetime immunity.
Group C streptococci have been responsible for recent epidemics of APSGN (eg,
Streptococcus zooepidemicus). Thus, it is possible that nephritogenic antigens are present and
possibly shared by streptococci from several groups.[2]
In addition, nontypeable group A streptococci are frequently isolated from the skin or throat
of patients with glomerulonephritis, representing presumably unclassified nephritogenic
strains.[7] The overall risk of developing acute poststreptococcal glomerulonephritis after
infection by these nephritogenic strains is about 15%. The risk of nephritis may also be
related to the M type and the site of infection. The risk of developing nephritis infection by M
type 49 is 5% if it is present in the throat. This risk increases to 25% if infection by the same
organism in the skin is present.
See also Acute Glomerulonephritis, Emergent Management of Acute Glomerulonephritis, and
Rheumatic Heart Disease.

Pathophysiology
Most forms of acute poststreptococcal glomerulonephritis (APSGN) are mediated by an
immunologic process. Cellular and humoral immunity is important in the pathogenesis of this
disease, and humoral immunity particularly in APSGN. Nonetheless, the exact mechanism by
which APSGN occurs remains to be determined. The 2 most widely proposed theories
include (1) glomerular trapping of circulating immune complexes and (2) in situ immune
antigen-antibody complex formation resulting from antibodies reacting with either
streptococcal components deposited in the glomerulus or with components of the glomerulus
itself, which has been termed molecular mimicry.
Additional evidence has also been presented to support the anti-immunoglobulin activity or
glomerular plasmin-binding activity of streptococcal antigens. The cross-reactivity of
streptococci and mammalian tissue implicating molecular mimicry in acute rheumatic fever
led to evidence of a similar mechanism involved in APSGN. However, the similar crossreactivity patterns of rheumatogenic and nephritogenic strains of streptococci argue against
molecular mimicry involving M proteins.

Immune complex-mediated mechanisms

An immune complexmediated mechanism is the most widely proposed mechanism leading
to the development of APSGN. Nephritogenic streptococci produce proteins with unique
antigenic determinants. These antigenic determinants have a particular affinity for sites
within the normal glomerulus. Following release into the circulation, the antigens bind to
these sites within the glomerulus. Once bound to the glomerulus, they activate complement
directly by interaction with properdin.
Glomerular-bound streptococcal antibodies also serve as fixed antigens and bind to
circulating antistreptococcal antibodies, forming immune complexes. Complement fixation
via the classic pathway leads to the generation of additional inflammatory mediators and
recruitment of inflammatory cells.

Zymogen (NSAP) and NAPlr

Two major antigens have presently been identified as the potential cause(s) of APSGN: A
zymogen precursor of exotoxin B (SPEB [streptococcal pyrogenic toxin B]) or nephritis
strainassociated protein (NSAP), and nephritis-associated plasmin receptor (NAPlr), a
glycolytic enzyme, which has glyceraldehydes-3-phosphate dehydrogenase (GAPDH)
activity with plasmin-binding capacity, a nephritogenic property that aids in circulating
immune complex deposition.[8, 9, 10, 11, 12]
NSAP is a 46- to 47-kd protein that is unique to the extracellular products of nephritogenic
streptococci. NSAP was demonstrated in glomerular deposits of 14 of 21 patients with
APSGN, but none in control biopsy samples from 5 patients with acute kidney injury and 11
with nonstreptococcal glomerulonephritis. NSAP was also detected in serum from 96% of
APSGN patients compared with 15-20% of patients with either acute kidney injury or
impetigo.[13] NSAP has antigenic, biochemical, and structural similarities to streptokinase
from group C streptococcal organisms, binds to plasmin, and is a plasminogen activator.
However, streptokinase cannot be demonstrated in glomerular deposits for patients with
APSGN, and serum levels of purified group A streptokinase were similar in patients with
APSGN and those with acute kidney injury. Thus, although NSAP and streptokinase have
similarities, they appear to be 2 distinct proteins.[13]
Yoshizawa et all isolated a 43-kd protein called preabsorbing antigen (PA-Ag) that is
putatively identical to endostreptosin.[14, 15] PA-Ag has the ability to preabsorb the antibody
in convalescent sera from patients with APSGN and thus prevent its deposition in glomeruli.
PA-Ag activates the alternative pathway.[15] This 43-kd protein was later identified by
Yamakami et al as NAPlr.[16] These researchers noted that NAPlr was present in 100% of the
early biopsy samples from in glomeruli of patients with APSGN.[17] The glomerular
distribution of NAPlr deposition and plasmin activity determined by in situ zymography are
identical.
The fact that NAPlr did not co-localize with C3 in glomerular deposits suggests that: (1)
complement was activated by NAPlr in the circulation rather than in situ, and (2) NAPlr
induced APSGN independently of complement activation by binding to the glomerular
basement membrane (GBM) and mesangial matrix via its adhesive character, subsequently
trapping and activating plasmin and causing in situ glomerular damage by degrading the
GBM or activating latent matrix metalloproteases.[17, 18]
SPEP is another group A streptococcal nephrogenic antigen most often isolated in Latin
America, the United States, and Europe. It is a cationic protease with plasmin-binding
properties. It localizes to glomeruli in patients with APSGN and is secreted as an exotoxin.
Corresponding serum anti-SPEP antibodies occur in most patients during convalescence.
SPEP titers correlate better with nephritis than either ASOT or anti-DNase B antibodies.
A proposed mechanism for acute poststreptococcal glomerulonephritis is that soluble,
released NAPlr binds to glomeruli and provide a mechanism to capture plasmin activated by
streptokinase. The activated plasmin bound to NAPlr associates with the GBM and
mesangium. Both NAPlr and NSAP are capable of inducing chemotactic (monocyte
chemoattractant protein 1) and interleukin (IL)6 moieties in mesangial cells, promoting
enhanced expression of adhesion molecules. Peripheral blood leukocytes also release other
cytokines such as tumor necrosis factor-alpha, IL-8, and transforming growth factor-beta,

which react with NSAP. These findings highlight the inflammatory potential of these
nephritogenic antigens.[19, 20, 21, 22]
Bound plasmin can cause tissue destruction by direct action on the glomerular basement
membrane or by indirect activation of procollagenases and other matrix metalloproteinases
(MMPs). NAPlr can also activate the alternate complement pathway, leading to accumulation
of polymorphonuclear cells and macrophages and local inflammation. In addition, the in situ
formed and circulating immune complexes can readily pass through the altered glomerular
basement membrane and accumulate on the subepithelial space as humps.
Complement activation from both serum profiles and immunofluorescence patterns for
glomerular deposits indicates that C3 activation in APSGN is predominantly via the
alternative pathway.[23, 24, 25] The immune deposits consist of immunoglobulin G (IgG), C3,
properdin, and C5.[25] These deposits rarely contain C1q or C4, both components of the classic
complement pathway. A recent study also showed evidence for activation of the lectinbinding pathway from deposition of membrane-bound lipoprotein in some patients with
APSGN.[26]
During the early phase of the diseases (first 2 wk), evidence of classical pathway activation is
seen, as demonstrated by transient depression of serum C1q, C2, and/or C4 concentrations.[27,
28, 29]
and the presence of circulating C1-inhibitor-C1r-C1s complexes or C4d fragments. It is
proposed that the circulating immune complexes in the acute stage of the disease due to
classic complement pathway activation is distinct from that seen in the glomerular immune
deposits. APSGN with typical findings on histopathology may occur in patients with no
evidence of complement activation, as manifested by depression of serum C3 concentrations.
[30, 31]

Hypocomplementemic patients differ from normocomplementemic patients by virtue of the

presence of factor B in the glomerular deposits and the absence of factor H, which is a
regulatory protein of the alternative pathway.[25] These findings suggest that the glomerular
immune deposits of C3bBb convertase may be due to ongoing complement activation in situ
rather than systemic activation. Crescentic APSGN may have an increased association with
normocomplementemia. The reason for this possible association of normocomplementemia
with crescent formation in APSGN is not clear.
Serum IgG levels are elevated in about 44% of patients with APSGN.[32] Less than 50% of
patients with elevated serum IgG levels, however, have glomerular deposits of IgG. Elevated
IgG levels were more likely to be found in patients with antistreptolysin O titers of greater
than or equal to 833 Todd units (P < .001). However, elevated serum IgG concentrations do
not correlate with severity of disease, age of the patient, or serum albumin or C3 levels. It
would appear that failure to form antibody to a glomerular-bound protein produced by
nephritogenic Streptococcus, is thought to be the origin of the IgG in glomerular deposits, is
in some way significantly associated with elevated serum levels of IgG and antibody to
streptolysin O.[32]
There is considerable evidence both for and against most putative nephritogenic antigens.
Genomic sequencing of nephritogenic strains of streptococci may lead to the discovery of
new nephritogenic antigen candidates in conserved and differing regions of the streptococcal
genome. This will lead to improved understanding of the pathogenetic mechanism(s) leading
to the development of APSGN.

Nonimmune complex-mediated mechanisms

Other nonimmune complex mediated mechanisms have been proposed for the development
of APSGN, such as delayed-type hypersensitivity, superantigens, and autoimmune
phenomena.
A role for delayed-type hypersensitivity has been implicated in the pathogenesis of this
disease. Early in the course of APSGN, resident endothelial and mesangial cells are
predominantly proliferated, and this is accompanied by infiltration with polymorphonuclear
leukocytes and monocytes. Macrophages are effector cells that cause resident cellular
proliferation. The infiltration of macrophages in the glomeruli is mediated by complementinduced chemotaxis and, most likely, by an antigen-specific event related to delayed-type
hypersensitivity mediated by helper/inducer T cells.
Streptococcal M proteins and pyrogenic exotoxins can act as superantigens. These cause a
marked expansion of T cells expressing specific T-cell receptor B-chain variable gene
segments. Massive T-cell activation occurs, with release of T-cellderived lymphokines such
as IL-1 and IL-6.
Autologous IgG in APSGN becomes antigenic and elicits an anti-IgG rheumatoid factor
response, leading to formation of cryoglobulins. Cryoglobulins, rheumatoid factors, and other
autoimmune phenomena occur in APSGN and are thought to play a role in the pathogenesis
of the disease together with streptococcal superantigens.

Epidemiology
Currently, approximately a quarter of APSGN is due to Streptococcus. In developed countries
such as the United States, APSGN more commonly affects elderly persons, with diabetes
mellitus, malignancy, alcoholism, human immunodeficiency virus infection, and intravenous
drug use being risk factors. The disease affects white males more frequently, often around the
fifth decade of life.
Over the last 2-3 decades, the incidence of acute poststreptococcal glomerulonephritis
(APSGN) has declined in the United States as well as in other countries, such as Japan,
Central Europe, and Great Britain. The estimated worldwide burden of APSGN is
approximately 472,000 cases per year, with approximately 404,000 cases being reported in
children and 456,000 cases occurring in less developed countries.[33] APSGN associated with
skin infections is most common in tropical areas where pyoderma is endemic, whilst
pharyngitis-associated APSGN predominates in temperate climates.[33]
However, in recent years, a slight increase in the incidence of the disease has been reported,
although the actual incidence is still unknown. This is particularly true in elderly persons,
especially in association with debilitating conditions such as alcoholism or intravenous drug
abuse.[34] The overall decline in APSGN may be due to the improvement in living conditions
with less crowding. However, other factors, including decreased prevalence or infectivity of
the nephritogenic streptococci, may also have contributed to the decline in incidence. The
recently observed increase in incidence is more difficult to explain. In the past 30 years, large
epidemics have been reported in middle-income countries, with clusters of cases in more

developed countries.[35] However, in poorly developed countries, it is likely that clusters of

cases of APSGN may go underreported.
Globally, as many as 50% of cases may be subclinical, although it is known that APSGN
continues to have a wide distribution. A high percentage of affected persons have mild
disease and are asymptomatic (estimates of the ratio of asymptomatic to symptomatic patients
vary from 2:1 to 3:1); thus, the actual incidence of the disease is not known.
In developing countries APSGN, usually occurs in children, predominately males and often
as epidemics. APSGN usually occurs as sporadic cases, but epidemic outbreaks have taken
place in communities with densely populated dwellings that have poor hygienic conditions
with a high incidence of malnutrition, anemia, and intestinal parasites. In certain regions,
epidemics may occur in cyclical outbreaks every 5-7 years for unknown reasons.
A strong seasonal variation is also noted; sporadic APSGN following upper respiratory tract
infection, pharyngitis, and tonsillitis is more common in winter and spring in temperate areas,
whereas skin infections are commonly found to precede APSGN in the more tropical and
subtropical areas, with a peak incidence during summer and autumn.
A nationwide study in New Zealand was conducted to define epidemiology and clinical
features of APSGN in children hospitalized with the illness. The study found higher incidence
in socio-economically deprived children as well as with Pacific and Maori children.[36]

Age-, race-, and sex-related demographics

The disease is more frequent in children aged 2-12 years, with a peak prevalence in
individuals aged approximately 5-6 years,[37] although it has been reported in infants as young
as 1 year and in adults as old as 90 years. However, in most large series, 5-10% of patients
are older than 40 years, and 5% are younger than 2 years. The most commonly affected age
group is those aged 5-20 years, although in the developed world, the disease is mostly seen in
white males, around the fifth decade of life.
Although a male predominance is noted in symptomatic cases (male-to-female ratio, 1.7-2:1)
for unknown reasons (APSGN is seen predominantly in males), when subclinical and clinical
disease is taken into account, the rates are the same in males and females.
No racial predilection is noted for acute poststreptococcal glomerulonephritis; the condition
is reported in all ethnic and cultural groups. In urban populations, a predilection toward
minority populations is observed; however, this may be related more to the socioeconomic
factor of overcrowding than to any racial predilection. In the developed world, APSGN
affects mainly elderly white males, more frequently around the fifth decade of life. In the
developing world, the disease is seen mainly in black children, predominantly males.

Prognosis
The course and prognosis for acute poststreptococcal glomerulonephritis (APSGN) is well
known and almost always favorable in children, but this is not so with nonstreptococcal
forms of the condition. In addition, for unknown reasons, the prognosis for individuals with
APSGN is not as good for adults (particularly elderly persons) as it appears to be for children.

In elderly patients with debilitating conditions (eg, malnutrition, alcoholism, diabetes, chronic
illness), the incidences of azotemia (60%), congestive heart failure (40%), and nephroticrange proteinuria (20%) are high. Death may occur in 20-25% of these patients.[38, 39]
Prolonged follow-up observation appears to be indicated. The ultimate prognosis in
individuals with APSGN largely depends on the severity of the initial insult.
Epidemic poststreptococcal acute glomerulonephritis appears to end in virtually complete
resolution and healing in all patients, and the prognosis is favorable for 95% of children with
acute sporadic poststreptococcal glomerulonephritis. The prognosis for persons with acute
glomerulonephritis secondary to other causes is less certain.
Edema usually resolves within 5-10 days, and the blood pressure usually returns to normal
after 2-3 weeks, even though persistence of elevated pressures for as many as 6 weeks is
compatible with complete resolution.
Urinary abnormalities resolve at various times after onset. Proteinuria may disappear within
the first 2-3 months or may slowly decrease over 6 months. Intermittent or postural
proteinuria has been noted for 1-2 years after onset.
Gross hematuria usually disappears within 1-3 weeks but may be exacerbated by physical
activity. C3 concentration returns to normal in more than 95% of patients by the end of 8-10
weeks. Microscopic hematuria usually disappears after 6 months, but its presence for as long
as 1 year should not cause undue concern, and even more prolonged hematuria (1-3 y) has
been observed in some patients who ultimately have demonstrated complete resolution of
their renal disease. Strongly consider the possibility of chronic renal disease when both
hematuria and proteinuria persist longer than 12 months.
In a few hospitalized patients, the initial injury is so severe that either persistent renal failure
or progressive renal failure ensues. However, histologic regression of the disease in most
patients is predictable, and the ultimate prognosis is good.
Although clinical resolution occurs in most patients, several authors report time-related
reduction in precise measurements of renal function, as well as diminished renal functional
reserve. These studies further support the thesis that any significant loss of nephrons leads to
hyperfiltration of the remaining units. Studies that have followed up children with APSGN
for 10-20 years have shown that approximately 20% of the patients have abnormal urine
analyses, with less than 1% having azotemia.[40]
Clinical manifestations of the disease rarely recur after the first 3 months, and second
episodes of acute glomerulonephritis are rare.

Complications
The most common acute complication is hypertension with or without central nervous system
(CNS) manifestations.
Anemia is common early in the disease and is primarily due to dilution, although in 2
instances, autoimmune hemolytic anaemia was documented in the early stages of APSGN.[41,
42]
Anemia tends to resolve with diuresis. A few patients may have diminished erythropoiesis
in the recovery phase and have some persisting anemia.

An occasional patient develops pulmonary edema because of the marked increase in vascular
volume that is present in the early phase of the disease.
Congestive heart failure is rare but has been reported. Definite myocarditis has also been
documented.
In most patients with moderate to severe APSGN, a measurable reduction in volume of
glomerular filtrate (GF) is present, and the capacity to excrete salt and water is usually
diminished, leading to expansion of the extracellular fluid (ECF) volume. The expanded ECF
volume is responsible for edema and, in part, for hypertension, anemia, circulatory
congestion, and encephalopathy. Persistence or worsening of azotemia is always troubling
and may suggest acute kidney injury. The presence of acute kidney injury may suggest an
alternate diagnosis (eg, membranoproliferative glomerulonephritis [MPGN], HenochSchnlein purpura [HSP], systemic lupus erythematosus [SLE]) or a severe or worsening
APSGN, such as observed in those with crescentic glomerulonephritis or rapidly progressive
glomerulonephritis.[43]
The renal survival of APSGN in the developed world is significantly worse than in the
epidemic form of APSGN seen in the developing world. A third to two third of patients in the
developed world develop chronic kidney disease that may progress to end-stage kidney
disease. These outcomes may be influenced by the susceptibility of patients in developed
countries, who are usually old and have comorbidities.

Patient Education
Clearly and specifically explain the nature of the disease, its course, and the eventual
prognosis of the condition to the child (if old enough to understand) and the parents and/or
caregivers. They need to understand that, although complete resolution is expected, a small
possibility exists for persistent disease, and that an even smaller possibility exists for
progression. This information is necessary for some patients to ensure that compliance with
the follow-up program occurs.
Clearly outline a follow-up plan and discuss the plan with the family. Blood pressure
measurements and urine examinations for protein and blood constitute the basis of the
follow-up plan. Perform examinations at 4- to 6-week intervals for the first 6 months and at
3- to 6-month intervals thereafter, until both hematuria and proteinuria have been absent and
the blood pressure has been normal for 1 year. Documenting that the low C3 has returned to
normal after 8-10 weeks may be useful.
For patient education information, see High Blood Pressure Center, as well as Blood in the
Urine and Chronic Kidney Disease.

History and Physical Assessment

A delay in the diagnosis of acute poststreptococcal glomerulonephritis (APSGN) is

sometimes related to the absence of a clear history of a preceding documented streptococcal
infections.[44] This may be due to more stringent definition criteria that require documented
evidence of past infection by streptococci. Typically, an acute nephritic syndrome develops 12 weeks after an antecedent streptococcal pharyngitis, whereas a lapse of 3-6 weeks is
common before a nephritic syndrome develops following streptococcal pyoderma.
Other factors contributing to a delay in the diagnosis of acute poststreptococcal
glomerulonephritis include the sporadic occurrence of disease, because this often requires a
high index of suspicion, as opposed to epidemics; the history of an upper respiratory tract
infection alone during the preceding month, which may not be diagnostically helpful, because
upper respiratory tract infections are common during winter; the misdiagnosis of severe
volume overload in a child as primarily due to a cardiac cause, because volume overload in
children is relatively rare; and the absence of visible hematuria (a presentation that is
relatively common).
Physicians must consider the possibility of acute poststreptococcal glomerulonephritis in
children with symptoms that may be secondary to hypertension or congestive heart failure,
even in the absence of visible hematuria or a history of a preceding streptococcal infection.
Most patients with acute glomerulonephritis exhibit milder symptoms and/or signs
somewhere between the extremes described below.
Asymptomatic versus symptomatic presentation

At one extreme is the asymptomatic child whose disease is discovered only by examination
of the urine. Based on surveillance studies of the siblings and/or household contacts of
children affected with acute poststreptococcal glomerulonephritis (APSGN), at least 50% of
persons with laboratory evidence of nephritis (ie, abnormal urinalysis) appear to have no
symptoms or signs of clinical illness.
At the other extreme is the child who presents with severe disease manifested by oliguria,
edema, hypertension, and azotemia and with proteinuria, hematuria, and urinary casts
(cylindruria).
Typical postinfectious presentation

In those patients whose acute glomerulonephritis is the result of a postinfectious cause (ie,
poststreptococcal acute glomerulonephritis being the most common), a latent period of 7-21
days between onset of the streptococcal infection and development of clinical
glomerulonephritis is characteristic.[45] This latent period, more clearly defined after
pharyngeal infections than after pyoderma, averages approximately 10 days.

Almost characteristic by their absence are arthralgia, arthritis, carditis, hepatic involvement,
and gastrointestinal bleeding. Pallor is common at onset and is not explained entirely by the
presence of anemia.
The median age of presentation in childhood is age 6-8 years, with the condition being
extremely rare prior to age 2 years.[46, 47, 48, 49, 50] In very young children, it is postulated that
APSGN is rare because of the low rate of streptococcal pharyngitis in this age group and an
immature immune response.[49] Males are 2 times more likely to have this condition compared
with females; the reason this difference in sex prevalence is not known.[46, 49, 50] However, the
site of streptococcal infection (pyoderma or pharyngitis) does not influence the sex
difference.
Edema and/or hematuria
Edema and/or gross hematuria represent the most common clinical presentation resulting in
patients seeking medical attention. One or both findings usually appear abruptly and may be
associated with various degrees of malaise, lethargy, anorexia, fever, abdominal pain, and
headache. The classic description of tea- or cola-colored urine occurs in approximately 2560% of patients.
Edema is the most frequent and sometimes the only clinical finding. According to some
investigators, edema is found in approximately 85% of patients. Edema usually appears
abruptly and first involves the periorbital area, but it may be generalized. The degree of
edema widely varies and depends on a number of factors, including the severity of
glomerular involvement, the fluid intake, and the degree of hypoalbuminemia. The triad of
edema, hematuria, and hypertension is classic for APSGN. Three phases of the disease can be
identified: the latent phase, the acute phase, and the recovery phase.
Gross hematuria occurs at onset in 30-50% of children with poststreptococcal acute
glomerulonephritis who require hospitalization. The urine is usually described as being
smoky, cola colored, tea colored, or rusty. The color is usually dependent on the amount of
blood present and the pH of the urine. Observant parents may note oliguria. Clots are
exceedingly rare in persons with acute glomerulonephritis.
Proteinuria
Varying degrees of proteinuria are also typically present, but nephrotic syndrome is rare,
occurring in 2-4% of cases.[46] . Both microscopic proteinuria and mild proteinuria may persist
for several months after the acute presentation.
Hypertension
Hypertension is the third cardinal feature of poststreptococcal acute glomerulonephritis and is
reported in 50-90% of children who are hospitalized with acute glomerulonephritis. The
magnitude of the increase in blood pressure widely varies; however, systolic pressures greater

than 200 mm Hg and diastolic pressures greater than 120 mm Hg are not unusual.
Hypertension usually resolves in 1-2 weeks and rarely requires long-term treatment.[51, 52]
Hypertensive encephalopathy
Hypertensive encephalopathy can be the presenting feature of postinfectious
glomerulonephritis. This condition has been reported in approximately 5% of hospitalized
children and is the most serious early complication of this disease. In these patients,
hypertension is usually severe and is accompanied by signs of central nervous system (CNS)
dysfunction such as headache, vomiting, depressed sensorium, confusion, visual disturbances,
aphasia, memory loss, coma, and convulsions. The mechanism of hypertension is most likely
retention of sodium and water with resulting expansion of the extracellular space.[51]
Hypertensive encephalopathy has been reported in the occasional individual with minimal or
no edema and with minimal urinary abnormalities. Since the urinalysis in such patients
exhibits minimal abnormalities, the underlying cause may not be readily apparent. A high
index of suspicion is required to make an appropriate diagnosis.
Circulatory congestion
Circulatory congestion is apparent in most children admitted to the hospital but is responsible
only rarely for significant early symptoms. Dyspnea, orthopnea, and cough may be present.
Both systolic and diastolic hypertension may be present to a varying degree. Either
bradycardia or tachycardia may be observed.
Pulmonary rales are often audible. At times, the only evidence of congestion is detected on
chest radiograph. A prominent cardiac shadow may be present until the onset of diuresis. In
the patient with an otherwise normal cardiovascular system, cardiac failure is unusual.
Uncommon/atypical presentation suggesting alternative diagnosis

The development of clinical nephritis (ie, hematuria and/or edema) either during or within 25 days after the onset of a respiratory tract infection is atypical and suggests the possibility of
some other form of glomerulonephritis. Subclinical cases may be missed and are sometimes
identified based on knowledge of the affected family or contacts. One report found APSGN
in 20% of asymptomatic family members with the condition.[34, 53] Numerous case reports
describe children who present with extreme manifestations, usually hypertensive
encephalopathy, who do not display the typical urinary findings at presentation.[54] Serial
examination of the urine after presentation may eventually confirm the suspicion of acute
glomerulonephritis.
An insidious onset of edema is more indicative of other forms of renal disease.
An occasional child may have a scarlatiniform rash or evidence of a viral exanthema, but
petechial or purpuric rashes suggest other conditions.

Typical physical findings

The most frequent findings on clinical examination are features of an acute nephritic
syndrome such as edema with mild hypertension, and there may be evidence of healed or
healing impetigo.
Urine dipsticks analysis usually shows blood and mild proteinuria. Hematuria is rarely gross,
and nephrotic-range proteinuria is seen in 5-10% of cases. Red blood cells casts are detected
in urine sediment. Often, patients have oliguria that resolves within a week. Microscopic
hematuria and mild proteinuria may persist for several months after the acute presentation.
In cases complicated by acute kidney injury or hypertensive crises, the physical findings vary
with the severity of the complications seen.

Approach Considerations
As noted earlier, consider the possibility of acute poststreptococcal glomerulonephritis
(ASPGN) in children with symptoms that may be secondary to hypertension or congestive
heart failure, even in the absence of visible hematuria or a history of a preceding
streptococcal infection. A urinalysis is helpful as microscopic hematuria is typically present
in children with APSGN.

Streptococcal antibodies
Recent poststreptococcal infection is most commonly demonstrated by serological markers
for elevated antibodies to extracellular streptococcal antigens. The streptozyme test, which
measures 5 different streptococcal antibodies, is positive in more than 95% of patients with
APSGN due to pharyngitis. However, sensitivity drops to 80% if APSGN follows pyoderma.
The streptococcal antibodies measured include the following:

Antistreptolysin (ASO)

Antihyaluronidase (AHase)

Antistreptokinase (ASKase)

Antinicotinamide-adenine dinucleotidase (anti-NAD)

Anti-DNAse B antibodies

Apart from antistreptokinase (ASKase), all other streptococcal antibodies are commonly
elevated after a pharyngitis, whereas only anti-DNAase B and AHase titers are typically
increased after pyoderma. Thus, if only an ASO titer is used to screen for APSGN after skin
infections, it may be falsely low or negative, and if the patient has received prior antibiotic
treatment for a pharyngitis, this may blunt the rise in ASO titer.

Complement profiles

Theoretically, the complement (or C3) levels should be decreased in all such patients;
however, the duration of low values may be quite brief and, therefore, missed, even when
examined serially. When the serum level is low in individuals with APSGN, a depressed level
for longer than 6-8 weeks is unusual. Thus, if the value remains low after this period of time,
thinking of some other nephritic process, such as membranoproliferative glomerulonephritis
(MPGN), is wise.

Kidney biopsy
Kidney biopsy is generally not recommended in the evaluation of patients with APSGN since
the clinical history is usually highly suggestive and resolution of APSGN typically begins
within 1 week of presentation. However, the performance of a renal biopsy is indicated in
patients whose clinical presentation, laboratory findings, or disease course is atypical. In such
persons, study of the histology by light, immunofluorescent, and electron microscopy may be
diagnostic. Indications for kidney biopsy include the following:

Failure to document a recent streptococcal infection by a rise in ASO or streptozyme

titer

Normocomplementemia

Renal insufficiency, especially if the glomerular filtration rate remains less than 30
mL/min/1.73 m 2 for more than 1 week

Persistently low complement (C3) levels beyond 6-8 weeks, without resolution of
features of acute glomerulonephritis.

Recurrent episodes of hematuria, especially frank hematuria

The typical light microscopy findings are that of diffuse hypercellularity of endothelial and
mesangial cells and infiltration of the glomerular tuft with polymorphonuclear cells.[56] In
more severe cases, epithelial crescents may form during the course of APSGN. In a small
percentage of patients, crescentic involvement may be present in over 50% of glomeruli,
leading to the clinical picture of rapidly progressive glomerulonephritis.[57, 58, 59]
Immunofluorescence performed on biopsy specimens taken during the acute phase of the
illness shows discrete granular deposits of IgG and C3 in a capillary loop and mesangial
distribution[60, 61] However, IgG deposits may be absent in about a third of biopsy samples. The
presence of heavy and sometimes confluent capillary loop deposits with the total absence of
mesangial deposits leads to the starry-sky appearance described in these biopsy reports.
The presence of subepithelial humps on electron microscopy is the hallmark finding in biopsy
specimens from patients with APSGN. These electron-dense deposits may also occur in
subendothelial and intramembranous locations.

Imaging studies
No specific radiologic studies are particularly helpful in either the evaluation or the treatment
of patients with APSGN. Renal ultrasonography generally demonstrates normal to slightly

enlarged kidneys bilaterally with some evidence of increased echogenicity, and chest
radiographs commonly demonstrate central venous congestion in a hilar pattern, the degree of
which parallels the increase in extracellular fluid volume. Occasionally, an enlarged cardiac
shadow is evident.
Approach Considerations

By the time the child with acute poststreptococcal glomerulonephritis (APSGN) presents with
symptoms, the glomerular injury has already occurred, and the healing process has begun.
Thus, influencing the ultimate course of the disease by any specific therapy directed at the
cause of the nephritis is not possible. Conversely, morbidity and early mortality are
influenced considerably by appropriate medical therapy. Even then, treatment is usually
supportive and directed toward the potential complications.
Only a small percentage of patients with acute glomerulonephritis require initial
hospitalization, and most of those are ready for discharge in 2-4 days. As soon as the blood
pressure (BP) is under relatively good control and diuresis has begun, most children can be
discharged and monitored as outpatients.
If indicated at any time during the course of the disease, an experienced nephrologist should
perform renal biopsy percutaneously.
Transfer of responsibility for the patient with acute glomerulonephritis is rarely indicated,
except in those instances in which a consultation with a nephrologist is not easily obtainable
in the local area or by telephone, facsimile, or e-mail.
See Consultations for instances that necessitate consultation with a pediatric nephrologist.
See also Acute Glomerulonephritis and Emergent Management of Acute Glomerulonephritis.
Diet and activity

A low-sodium, low-protein diet should be prescribed during the acute phase, when edema and
hypertension are in evidence; however, prolonged dietary restrictions are not warranted.
Limitation of fluid and salt intake is recommended in the child who has either oliguria or
edema. Curtailment of fluid to amounts consistent with insensible losses helps to minimize
vascular overload and hypertension. In patients with oliguric acute kidney injury, potassium
intake should be restricted to prevent hyperkalemia.
Limited activity is probably indicated during the early phase of the disease, particularly if
hypertension is present. Bedrest may lessen the degree and duration of gross hematuria if
present; however, longer periods of bedrest do not appear to influence the course or long-term
prognosis; therefore, they are generally not recommended.

Consultations

The general pediatrician should be capable of treating patients with mild to moderate acute
glomerulonephritis. Consultation with a pediatric nephrologist is necessary when 1 or more
of the following are present:

Severe hypertension

Severe oliguria

Severe edema

Nephrotic-range proteinuria

Azotemia (moderate to marked)

Recurrent episodes of gross hematuria

Persistently depressed C3 (past 8-10 wk)

For failure of expected resolution of clinical signs, consultation is indicated for the following:

Gross hematuria within the preceding 10-14 days

Microscopic hematuria within 1 year

Edema within 2 weeks

Proteinuria (>50 mg/dL) within 6 months

Azotemia within 1 week

Hypertension within 6 weeks

Long-Term Monitoring
Long-term follow-up for a patient following acute poststreptococcal glomerulonephritis
(APSGN) primarily consists of blood pressure measurements and urine examinations for
protein and blood. In general, examinations are performed at 4- to 6-week intervals for the
first 6 months and at 3- to 6-month intervals thereafter, until both hematuria and proteinuria
have been absent and the blood pressure has been normal for 1 year. Documenting that the
low C3 has returned to normal after 8-10 weeks may be useful.
Follow up at 0-6 weeks as frequently as necessary to determine the following:

Hypertension has been controlled.

Edema has started to resolve.

Gross hematuria has resolved.

Azotemia has resolved.

Follow up at 8-10 weeks after onset to assess the following:

Azotemia has subsided.

Anemia has been corrected.

Hypertension has resolved.

C3 and C4 concentrations have returned to normal.

Follow up at 3, 6, and 9 months after onset to check the following:

Hematuria and proteinuria are subsiding gradually.

Blood pressure is normal.

Follow up at 12 months after onset to evaluate that proteinuria and microscopic hematuria
have disappeared.
Follow up at 2, 5, and 10 years after onset to check the patient's urine, blood pressure, and
serum creatinine level are normal.
Prevention of APSGN

A vaccine targeted against group A streptococci will prevent both invasive disease and
nonsuppurative complications. The current thrust of group A streptococcal vaccine research
has been to target the M protein.[69] A 26-valent vaccine has been developed that targets the
variable region of the M proteins of the most common rheumatogenic cocci. Unfortunately,
no M protein from nephritogenic streptococci were included in the vaccine. In addition, the
most common M protein types in the developing world differ from those of more developed
countries, thus rendering the vaccine less efficacious. The most effective public health
measure in the developing world is to improve hygiene and provide better housing conditions
to avoid overcrowding. This offers the best hope for elimination of epidemic pyoderma and
thus preventing APSGN.

Inpatient Management

General management begins with a decision to admit the child with acute glomerulonephritis
to the hospital or merely have him or her undergo frequent outpatient examinations.
Hospitalization is indicated if the child has significant hypertension or a combination of
oliguria, generalized edema, and elevation of serum creatinine or potassium.

Severe hypertension
Severe hypertension, or that associated with signs of cerebral dysfunction, demands
immediate attention. Debate exists regarding the agent that is most effective in patients with
severe hypertension.
Three drugs are commonly cited as having a high benefit-to-risk ratio: labetalol (0.5-2
mg/kg/h intravenously [IV]), diazoxide, and nitroprusside (0.5-2 mcg/kg/min IV; in patients
with severe hypertension that is refractory to the previous agents). Recently, sodium
nitroprusside has been replaced by the use of nicardipine in the United States and much of
Western Europe (start at 5 mg/h intravenously [IV], increase by 2.5 mg/h every 5-15 min as
needed, maximum dose 15 mg/h). Discontinue if hypotension or tachycardia is present (may
restart at 3-5 mg/h IV). In combination with any of these agents, the simultaneous IV
administration of furosemide at doses of 2 mg/kg may be merited. Diazoxide use for blood
pressure (BP) control is limited because, once administered, no further control of pressure is
possible, unlike labetalol or nitroprusside.
Severe hypertension without encephalopathy can be treated in the manner described above or,
more commonly, by administration of vasodilator drugs, such as hydralazine or nifedipine.
The doses of these drugs can be administered either by injection or by mouth and can be
repeated every 10-20 minutes until a suitable response is obtained. For most children, the
need for more than 2-3 doses is unusual.

Mild-to-moderate hypertension
Mild-to-moderate hypertension does not warrant emergency management and is treated most
effectively with bedrest, fluid restriction, and less-frequent doses of the medications
mentioned above.
The use of loop diuretics, such as furosemide (1-3 mg/kg/d oral [PO], administered 1-2 times
daily), may hasten resolution of the hypertension.
For patients resistant to treatment, either hydralazine or nifedipine is indicated.
Angiotensin-converting enzyme (ACE) inhibitors are effective, although these agents have
the potential to produce hyperkalemia and usually are not first-line drugs in acute
glomerulonephritis.
Edema and circulatory congestion are usually not sufficiently marked to produce more than
minimal discomfort. Restriction of fluids to those amounts needed to replace insensible losses
is the best treatment for edema and circulatory congestion.

Loop diuretics (furosemide) administered PO have been reported to reduce the length of
hospitalization in children who are edematous. If congestion is marked, administer
furosemide parenterally (2 mg/kg).
Phlebotomy, rotating tourniquets, dialysis, or digitalization is rarely necessary.

Anuria or oliguria
Anuria or severe and persistent oliguria may occur in 3-6% of children with acute
glomerulonephritis and may necessitate hospitalization. Fortunately, both of these conditions
are usually transient.
Because they may be ototoxic, avoid large doses of furosemide in children with symptoms of
anuria or severe and persistent oliguria. In addition, osmotic diuretics, such as mannitol, are
contraindicated, as they might increase vascular volume.

Other medical management strategies

A course of penicillin can be administered to avoid contamination of contacts with a
nephritogenic strain of streptococci; however, in most instances, these contacts do not
develop overt acute glomerulonephritis.[38] Such therapy may not influence the course of the
disease in the index patient, but it may alter the response that confers type-specific immunity.
To date, only one report suggests that patients with APSGN who receive antibiotic treatment
have a milder clinical course.[63] Throat cultures of immediate family members might detect
patients who are asymptomatic but infected.
The diagnosis of streptococcal pharyngitis on clinical grounds alone is uncertain, and only
10-20% of the patients who present with sore throat in general clinical practice have a
positive culture for group A streptococci.[64] Several clinical scoring systems have been
developed to increase the accuracy of diagnosis for the prescription of antibiotics. The most
commonly used is that of Centor et al[65] and McIsaac et al.[66] These have a range of 1-4 and
incorporate age as a risk factor. The following is the McIsaac score, showing each criterion
and its corresponding score:

Temperature higher than 38 C and no cough - 1 point

Tender anterior cervical adenopathy - 1 point

Tonsillar swelling or exudates - 1 point

Age between 3 and 14 years - 1 point

Age 15-44 years is assigned no points, and age older than or equal to 44 years garners -1
point. Based on the scoring systems, it is recommended that antibiotic treatment is
administered based on clinical grounds alone when the score is 4, antibiotic treatment is not
recommended (and culture is unnecessary) when the score is 0 or 1, and culture should be
obtained and treatment given only when the result is positive if the score is 2 or 3. Rapid test
for streptococcal antigen detection may be used as a confirmatory test for children with

tonsillar exudate.[67] However, the sensitivity is too low to support use without culture
confirmation of negative results.[68]
In resource-limited settings, the author is of the view that all patients with acute APSGN be
treated as though they have active streptococcal infection. This recommendation is based on
the finding of positive cultures for Streptococcus in patients with APSGN in whom upper
respiratory tract or skin infections are not clinically evident.
Steroid therapy is indicated only in patients with severe crescentic glomerulonephritis or in
those with rapidly progressive glomerulonephritis. Selected patients with Henoch-Schnlein
purpura (HSP) nephritis and membranoproliferative glomerulonephritis (MPGN) also may
benefit from such agents. An experienced nephrologist should make decisions regarding the
indication for such treatment.

Cronic

Background
Nearly all forms of acute glomerulonephritis have a tendency to progress to chronic
glomerulonephritis. The condition is characterized by irreversible and progressive glomerular
and tubulointerstitial fibrosis, ultimately leading to a reduction in the glomerular filtration
rate (GFR) and retention of uremic toxins. If disease progression is not halted with therapy,
the net results are chronic kidney disease (CKD), end-stage renal disease (ESRD), and
cardiovascular disease. Chronic glomerulonephritis is the third leading cause and accounts for
about 10% of all causes of CKD.
The exact cause of CKD in patients with chronic glomerulonephritis may never be known in
some patients. Therefore, it has generally been accepted that the diagnosis of CKD can be
made without knowledge of the specific cause.[1]
The National Kidney Foundation (NKF) defines CKD on the basis of either of the following:

Evidence of kidney damage based on abnormal urinalysis results (eg, proteinuria or

hematuria) or structural abnormalities observed on ultrasound images

A GFR of less than 60 mL/min for 3 or more months

In accordance with this definition, the NKF developed guidelines that classify the progression
of renal disease into five stages, from kidney disease with a preserved GFR to end-stage
kidney failure. This classification includes treatment strategies for each progressive level, as
follows:

Stage 1 This stage is characterized by kidney damage with a normal GFR ( 90

mL/min); the action plan consists of diagnosis and treatment, treatment of comorbid

conditions, slowing of the progressing of kidney disease, and reduction of

cardiovascular disease risks

Stage 2 This stage is characterized by kidney damage with a mild decrease in the
GFR (60-90 mL/min); the action plan is estimation of the progression of kidney
disease

Stage 3 This stage is characterized by a moderately decreased GFR (to 30-59

mL/min); the action plan consists of evaluation and treatment of complications

Stage 4 This stage is characterized by a severe decrease in the GFR (to 15-29
mL/min); the action plan is preparation for renal replacement therapy

Stage 5 This stage is characterized by kidney failure; the action plan is kidney
replacement if the patient is uremic

At the later stages of glomerular injury, the kidney are small and contracted and biopsy
results cannot help distinguish the primary disease. Histology and clues to the etiology are
often derived from other systemic diseases (if present). Considerable cause-specific
variability is observed in the rate at which acute glomerulonephritis progresses to chronic
glomerulonephritis.
The prognosis depends on the type of chronic glomerulonephritis (see Etiology). ESRD and
death are common outcomes unless renal replacement therapy is instituted.

Pathophysiology
Reduction in nephron mass from the initial injury reduces the GFR. This reduction leads to
hypertrophy and hyperfiltration of the remaining nephrons and to the initiation of
intraglomerular hypertension. These changes occur in order to increase the GFR of the
remaining nephrons, thus minimizing the functional consequences of nephron loss. The
changes, however, are ultimately detrimental because they lead to glomerulosclerosis and
further nephron loss.
In early renal disease (stages 1-3), a substantial decline in the GFR may lead to only slight
increases in serum creatinine levels. Azotemia (ie, a rise in blood urea nitrogen [BUN] and
serum creatinine levels) is apparent when the GFR decreases to less than 60-70 mL/min. In
addition to a rise in BUN and creatinine levels, the substantial reduction in the GFR results in
the following:

Decreased production of erythropoietin, thus resulting in anemia

Decreased production of vitamin D, resulting in hypocalcemia, secondary

hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy

Reduction in acid, potassium, salt, and water excretion, resulting in acidosis,

hyperkalemia, hypertension, and edema

Platelet dysfunction, leading to increased bleeding tendencies

Accumulation of toxic waste products (uremic toxins) affects virtually all organ systems.
Azotemia occurring with the signs and symptoms listed above is known as uremia. Uremia
occurs at a GFR of approximately 10 mL/min. Some of these toxins (eg, BUN, creatinine,
phenols, and guanidines) have been identified, but none has been found to be responsible for
all the symptoms.

Etiology
The progression from acute glomerulonephritis to chronic glomerulonephritis is variable,
depending to a considerable extent on the cause of the condition. Whereas complete recovery
of renal function is the rule for patients with poststreptococcal glomerulonephritis, several
other glomerulonephritides, such as immunoglobulin A (IgA) nephropathy, often have a
relatively benign course, and many do not progress to ESRD. Progression patterns may be
summarized as follows:

Rapidly progressive glomerulonephritis or crescentic glomerulonephritis - About 90%

of patients progress to ESRD within weeks or months.

Focal segmental glomerulosclerosis: - About 80% of patients progress to ESRD in 10

years; patients with the collapsing variant (malignant focal segmental
glomerulosclerosis) have a more rapid progression; this form may be idiopathic or
related to HIV infection

Membranous nephropathy About 20-30% of patients with membranous nephropathy

progress to chronic renal failure (CRF) and ESRD in 10 years

Membranoproliferative glomerulonephritis: - About 40% of patients with

membranoproliferative glomerulonephritis progress to CRF and ESRD in 10 years [2]

IgA nephropathy About 10% of patients with IgA nephropathy progress to CRF and
ESRD in 10 years [3]

Poststreptococcal glomerulonephritis - About 1-2% of patients with poststreptococcal

glomerulonephritis progress to CRF and ESRD; older children who present with
crescentic glomerulonephritis are at greatest risk

Lupus nephritis Overall, about 20% of patients with lupus nephritis progress to CRF
and ESRD in 10 years; however, patients with certain histologic variants (eg, class
IV) may have a more rapid decline

Epidemiology
In the United States, chronic glomerulonephritis is the third leading cause of ESRD and
accounts for 10% of patients on dialysis.

In Japan and some Asian countries, chronic glomerulonephritis has accounted for as many as
40% of patients on dialysis; however, subsequent data suggest that in Japan, for instance, the
rate of chronic glomerulonephritis in patients on dialysis is 28%.[4] The cause of this declining
rate is not known. Concurrent with the decline in chronic glomerulonephritis in these
countries is an increase in diabetic nephropathy in up to 40% of patients on dialysis.

Patient Education
Dietary education is paramount in managing patients with CKD. The typical dietary
restriction is 2 g of sodium, 2 g of potassium, and 40-60 g of protein a day. Additional
restrictions may apply for diabetes, hyperlipidemia, and fluid overload.
Patients should be educated regarding the types of ESRD therapy. The specific choices of
ESRD therapy include hemodialysis, peritoneal dialysis, and renal transplantation. For further
information, see Mayo Clinic - Kidney Transplant Information.
Patients opting for hemodialysis should be educated on home hemodialysis (in which patients
are trained to do their dialysis at home) and center hemodialysis (in which patients come to a
center 3 times a week for 3.5- to 4-hour dialysis sessions). They should also be educated on
the types of vascular access. Arteriovenous fistulae should be created when the GFR falls
below 25 mL/min or the serum creatinine level is greater than 4 mg/dL to allow maturation of
the access before the initiation of dialysis.
In the United States and most developed countries, patients on dialysis can travel. In fact,
there are even dialysis cruises. However, patients should inform their social workers to make
the necessary arrangements beforehand to ensure that the destination has the right resources
to continue dialysis.
Sexual dysfunction and loss of libido are common in patients with kidney disease, especially
men. Patients should be instructed to seek medical therapy if they experience these
symptoms.
Renal failure and hypertension worsen during pregnancy in patients with CKD, particularly
when the serum creatinine level exceeds 2 mg/dL, and this leads to decreased fetal viability
and increased maternal morbidity in pregnant women with CKD. Therefore, women with
CKD should consult their doctors before becoming pregnant.[5, 6]

History
The history should begin by focusing on cause-specific symptoms to determine the source of
the chronic kidney disease (CKD) if this is unknown. Recognition of such symptoms
facilitates the planning of further workup and management of the disease (if systemic).
The next step is to look for symptoms related to uremia to determine if renal replacement
therapy is needed. The following symptoms suggest uremia:

Weakness and fatigue

Loss of energy, appetite, and weight

Pruritus

Early morning nausea and vomiting

Change in taste sensation

Reversal in sleep pattern (ie, sleepiness in daytime and wakefulness at night)

Peripheral neuropathy

Seizures

Tremors

The presence of edema and hypertension suggests volume retention. Dyspnea or chest pain
that varies with position suggests fluid overload and pericarditis, respectively. Leg cramps
may suggest hypocalcemia or other electrolyte abnormalities. Weakness, lethargy, and fatigue
may be due to anemia.

Physical Examination
Cause-specific physical examination findings are discussed elsewhere, in articles describing
the specific causes (see Etiology). Uremia-specific physical findings include the following:

Hypertension

Jugular venous distention (if severe volume overload is present)

Pulmonary rales (if pulmonary edema is present)

Pericardial friction rub in pericarditis

Tenderness in the epigastric region or blood in the stool (possible indicators of uremic
gastritis or enteropathy)

Decreased sensation and asterixis (indicators of advanced uremia)

Complications
The presence of the following complications generally indicates a need for urgent dialysis:

Metabolic acidosis

Pulmonary edema

Pericarditis

Uremic encephalopathy

Uremic gastrointestinal bleeding

Uremic neuropathy

Severe anemia and hypocalcemia

Hyperkalemi

Pharmacologic Therapy
Blood pressure management

The target blood pressure for patients with proteinuria in excess of 1 g/day is less than 125/75
mm Hg; for patients with proteinuria of less than 1 g/day, the target pressure is less than
130/80 mm Hg.
Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used and are usually the
first choice for treatment of hypertension in patients with chronic kidney disease (CKD).
ACEIs are renoprotective agents that have additional benefits beyond lowering pressure.
They effectively reduce proteinuria, in part by reducing the efferent arteriolar vascular tone,
thereby decreasing intraglomerular hypertension.
In particular, ACEIs have been shown to be superior to conventional therapy in slowing the
decline of the glomerular filtration rate (GFR) in patients with diabetic and nondiabetic
proteinuric nephropathies. Therefore, ACEIs should be considered for treatment of even
normotensive patients with significant proteinuria.[8]
The role of angiotensin II receptor blockers (ARBs) in renal protection is increasingly being
established, and these medications have been found to retard the progression of CKD in
patients with diabetic or nondiabetic nephropathy, much as ACEIs do.[9]
A combination of ACEI therapy and ARB therapy has been shown to achieve better pressure
control and preservation of renal function than either therapy alone could. Therefore, in
patients without hyperkalemia or an acute rise in serum creatinine levels after the use of
either therapy, combination therapy should be attempted.[10]
However, in patients with vascular disease or diabetes, combination ACEI and ARB therapy
has been associated with increased adverse effects, including hyperkalemia, worsening renal
function, and mortality. As such, combination ACEI and ARB therapy should not be used to
treat hypertension in these groups of patients with CKD.[11]
Diuretics are often required because of decreased free-water clearance, and high doses may
be required to control edema and hypertension when the GFR falls below 25 mL/min.
Diuretics are also useful in counteracting the hyperkalemic potential of ACEIs and ARBs.

However, they should be used with caution when given together with ACEIs or ARBs
because the decline in intraglomerular pressure induced by ACEIs or ARBs may be
exacerbated by the volume depletion induced by diuretics, potentially precipitating ARF.
Beta blockers, calcium channel blockers,[12] central alpha2 agonists (eg, clonidine), alpha1
antagonists, and direct vasodilators (eg, minoxidil and nitrates) may be used to achieve the
target pressure.
Fibrosis inhibition

Because progressive fibrosis is the hallmark of chronic glomerulonephritis, some

investigators have focused on finding inhibitors of fibrosis in an attempt to slow progression.
Of the many compounds that have been considered, pirfenidone, an inhibitor of transforming
growth factor beta and hence of collagen synthesis, has emerged as the best candidate.
Cho et al, in an open-label study involving 21 patients with idiopathic and postadaptive focal
segmental glomerulosclerosis, found that pirfenidone yielded a median 25% improvement in
the rate of decline of the estimated GFR; the drug did not affect proteinuria or blood pressure.
[13]
Among the adverse events attributed to therapy were dyspepsia, sedation, and
photosensitive dermatitis. It is hoped that pirfenidone therapy will prove an effective means
of slowing progressive fibrosis; however, more studies are needed.
Role of antioxidants (bardoxolone)

Cells have the ability to produce antioxidants, anti-inflammatory and detoxifying enzymes
that are useful for cell viability, but this pathway is constantly being inhibited by an enzyme
called KEAP. Inhibition of KEAP may therefore improve the antioxidant activity of cells and
promote cell viability. Bardoxolone, an oleanolic acid derivative, blocks Keap and has been
postulated as a potential mechanism to retard progression of CKD. In one study, patients
receiving bardoxolone had significant increases in the mean ( standard deviation) estimated
GFR, as compared with placebo, at 24 weeks. The improvement persisted at 52 weeks,
suggesting that bardoxolone may have promise for the treatment of CKD, however a phase 3
randomized clinical trial failed to achieve the primary end point and was associated with side
effects and so the study was stopped.[14] It is not likely that Bardoxolone will be used for
renoprotection any time soon.
Role of sodium bicarbonate

Sodium bicarbonate has been shown to reduce tubulointerstitial injury and endothelin
production with substantial benefits in slowing progressive kidney damage. In one study on
patients with advanced kidney failure, the administration of sodium bicarbonate preserved
GFR decline.[14] Even in patients with relatively preserved GFR in stage 2 CKD, the
administration of sodium bicarbonate was shown to preserve kidney function over 5 years.[15]
A study in patients with stage 4 CKD found that 1 year of consuming a diet that included
fruits and vegetables dosed to reduce dietary acid by half had effects comparable to those of
daily oral sodium bicarbonate at 1.0 mEq/kg per day.[16]

Role of direct renin inhibitors

Preliminary studies using aliskiren,[17] a direct renin inhibitor, show reductions in proteinuria
over 6 months, but larger studies did not show benefit.
Management of other problems

Renal osteodystrophy can be managed early by replacing vitamin D and by administering

phosphate binders. Seek and treat nonuremic causes of anemia, such as iron deficiency,
before instituting therapy with erythropoietin.
Treat hyperlipidemia (if present) to reduce overall cardiovascular comorbidity, even though
evidence for lipid lowering in renal protection is lacking.
Renal Replacement Therapy

Discuss options for renal replacement therapy (eg, hemodialysis, peritoneal dialysis, and
renal transplantation).
Arrange permanent vascular access when the GFR falls below 20-25 mL/min, when the
serum creatinine level exceeds 4 mg/dL, or when the rate of increase in the serum creatinine
level indicates the need for dialysis within 1 year. Arteriovenous fistulas are preferred to
arteriovenous grafts because of their long-term high-patency rates and should be placed
whenever possible. Place peritoneal dialysis catheters 2-3 weeks before anticipated dialysis
therapy.
Preemptive transplantation before the initiation of dialysis results in better survival than
transplantation after the initiation of dialysis. Therefore, preemptive transplantation should be
explored from live donors. Patients without live donors can be placed on the deceased donor
wait list when the GFR falls below 20 mL/min to accrue time. Patients who opt for no
treatment when it is indicated should be informed of imminent renal failure in a shorter time.
Expose patients to educational programs for early rehabilitation from dialysis or
transplantation.
Patients with any evidence of kidney disease should be referred to a kidney specialist (ie, a
nephrologist). Early referral of patients with CRF (serum creatinine, 1.5-2 mg/dL) to a
nephrologist is important for managing complications and organizing the transition to renal
replacement therapy. Some evidence indicates that early referral of CRF patients to a
nephrologist improves the short-term outcome. The nephrologist will usually determine the
frequency of visits on the basis of the degree of CKD.
When dialysis is imminent, a surgical consultation should be sought for creation of an
arteriovenous fistula or graft to allow insertion of a peritoneal dialysis catheter. Consultation
with a transplant surgeon is appropriate for evaluation for kidney transplantation.

Diet and Activity

Protein-restricted diets (0.4-0.6 g/kg/day) are controversial but may be beneficial in slowing
the decline in the GFR and reducing hyperphosphatemia (serum phosphate > 5.5 mg/dL) in
patients with serum creatinine levels higher than 4 mg/dL. Monitor these patients for signs of
malnutrition, which may contraindicate protein restriction. Educate patients about how
potassium-rich diets help control hyperkalemia. Many dietary restrictions are no longer
necessary with the initiation of renal replacement therapy.
Encourage patients to increase their activity level as tolerated. Increased activity may aid in
blood pressure control.
In obese patients with mild to moderate CKD, weight loss may help reverse renal
dysfunction, manifesting as reduction in proteinuria and albuminuria.[18, 19]
Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Medications used to treat chronic glomerulonephritis include angiotensin-converting enzyme
(ACE) inhibitors (ACEIs), diuretics, calcium channel blockers, beta-adrenergic blockers, and
alpha-adrenergic agonists.
Laboratory Studies
Urinalysis

The presence of dysmorphic red blood cells (RBCs), albumin, or RBC casts suggests
glomerulonephritis as the cause of renal failure. Waxy or broad casts are observed in all forms
of chronic kidney disease (CKD), including chronic glomerulonephritis. Low urine-specific
gravity indicates loss of tubular concentrating ability, an early finding in persons with CKD.
See Urinalysis.
Urinary protein excretion

Urinary protein excretion can be estimated by calculating the protein-to-creatinine ratio on a

spot morning urine sample. The ratio of urinary protein concentration (in mg/dL) to urinary
creatinine (in mg/dL) reflects 24-hour protein excretion in grams. For instance, if the spot
urine protein value is 300 mg/dL and the creatinine value is 150 mg/dL, the protein-tocreatinine ratio is 2. Thus, in this example, the 24-hour urine protein excretion is 2 g.[7]
The estimated creatinine clearance rate is used to assess and monitor the glomerular filtration
rate (GFR). The 2 formulas available for calculation of the GFR are the Cockcroft-Gault
formula, which estimates creatinine clearance, and the Modification of Diet in Renal Disease
(MDRD) Study formula, which is used to calculate the GFR directly.
The Cockcroft-Gault formula is simple to use but overestimates the GFR by 10-15% because
creatinine is both filtered and secreted. The MDRD formula is much more complex but can

be determined with a smartphone and tablet application available from the National Kidney
Foundation or can be calculated online through the Hypertension, Dialysis, and Clinical
Nephrology Web site.
The estimated creatinine clearance rate is also used to monitor response to therapy and to
initiate an early transition to renal replacement therapy (eg, dialysis access placement and
transplantation evaluation). The degree of proteinuria, especially albuminuria, helps predict
the renal prognosis in patients with chronic glomerulonephritis. Patients with proteinuria
exceeding 1 g/day have an increased risk of progression to end-stage renal failure.
Complete blood count

Anemia is a significant finding in patients with some decline in the GFR. Physicians must be
aware that anemia can occur even in patients with serum creatinine levels lower than 2
mg/dL. Even severe anemia can occur at low serum creatinine levels. Anemia is the result of
marked impairment of erythropoietin production.
Serum chemistry

Serum creatinine and urea nitrogen levels are elevated. Impaired excretion of potassium, free
water, and acid results in hyperkalemia, hyponatremia, and low serum bicarbonate levels,
respectively. Impaired vitamin D-3 production results in hypocalcemia, hyperphosphatemia,
and high levels of parathyroid hormone. Low serum albumin levels may be present if uremia
interferes with nutrition or if the patient is nephrotic. Recently, a high fibroblast growth factor
21 (FGF21) was found to be significantly elevated in patients with CKD and the high levels
of FGF21 may explain the excess overall and cardiovascular mortality in patients with CKD.
These adverse effects of elevated FGF21 are not clearly understood but research is underway
to elucidate its biologic effects.
Other Studies
Renal ultrasonography

Obtain a renal ultrasonogram to determine renal size, to assess for the presence of both
kidneys, and to exclude structural lesions that may be responsible for azotemia. Small
kidneys often indicate an irreversible process.
Kidney biopsy

If the kidney is small, kidney biopsy is usually unnecessary; no specific pattern of disease can
be discerned at this point. A kidney biopsy may be considered in the minority of patients who
exhibit an acute exacerbation of their chronic disease. This may be particularly pertinent to
patients with preserved kidney size and in those with lupus nephritis.
In early stages, the glomeruli may still show some histologic evidence of the primary disease.
In advanced stages, the glomeruli are hyalinized and obsolescent. The tubules are disrupted
and atrophic, and marked interstitial fibrosis and arterial and arteriolar sclerosis occur.