Recurrent hematuria

Presentation with gross hematuria is common within 1-2 days after the
onset of an apparent viral upper respiratory tract infection in
immunoglobulin A (IgA) nephropathy, and typically resolves within 5 days.
This relatively short period contrasts to a latency period of 7-21 days
occurring between the onset of a streptococcal pharyngitis or
impetiginous skin infection and the development of poststreptococcal
acute glomerulonephritis.
Gross hematuria in these circumstances can last as long as 4-6wk. Gross
hematuria can also be seen in children with glomerular basement
membrane (GBM) disorders such as hereditary nephritis (Alport syndrome
[AS]) and thin GBM disease.
These glomerular diseases can also manifest as microscopic hematuria
and/or proteinuria without gross hematuria.

Immunoglobulin A Nephropathy
(Berger Nephropathy)
IgA nephropathy is the most common chronic glomerular
disease.
It is characterized by a predominance of IgA
immunoglobulin within mesangial glomerular deposits in
the absence of systemic disease (e.g., symptomatic
systemic lupus erythematosus or Henoch-Schonlein
purpura).
Diagnosis requires renal biopsy, which is performed when
clinical features warrant confirmation of the diagnosis or
characterization of the histologic severity, which might
affect therapeutic decisions.

Pathology and Pathologic

Diagnosis
Focal and segmental mesangial proliferation
and increased mesangial matrix are seen in the
glomerulus.
Renal histology demonstrates mesangial
proliferation that may be associated with
epithelial cell crescent formation and sclerosis.
IgA deposits in the mesangium are often
accompanied by C3 complement

 IgA nephropathy is an immune complex disease that appears

to be caused by abnormalities in the IgA immune system.
The abnormalities identified in the IgA immunoglobulin system
have also been observed in patients with Henoch-Schonlein
purpura and lends support to the hypothesis that these two
diseases are part of the same disease spectrum.
Familial clustering of IgA nephropathy cases suggests the
importance of genetic factors.
Genome-wide linkage analysis suggests the linkage of IgA
nephropathy to 6q22-23 in multiplex IgA nephropathy kindreds.

Clinical and Laboratory Manifestations

IgA nephropathy is seen more often in males
A majority of children with IgA nephropathy
in the USA and Europe present with gross
hematuria, whereas microscopic hematuria
and/or proteinuria is a more common
presentation in Japan. Other types of
presentation include acute nephritic
syndrome, nephrotic syndrome, or a
combined nephritic-nephrotic picture.

 Gross hematuria often occurs within 1-2 days of onset of an upper

respiratory or gastrointestinal infection, in contrast to the longer
latency period observed in acute postinfectious glomerulonephritis,
and may be associated with loin pain.
Proteinuria is often <1000mg/24hr in patients with asymptomatic
microscopic hematuria.
Mild to moderate hypertension is most often seen in patients with
nephritic or nephrotic syndrome but is rarely severe enough to
result in hypertensive emergencies.
Normal serum levels of C3 in IgA nephropathy help to distinguish
this disorder from poststreptococcal glomerulonephritis.
Serum IgA levels have no diagnostic value because they are
elevated in only 15% of pediatric patients.

Prognosis and Treatment

Although IgA nephropathy does not lead to significant kidney
damage in most children, progressive disease develops in
20-30% of patients 15-20yr after disease onset.
Poor prognostic indicators at presentation or follow-up
include persistent hypertension, diminished renal function,
and heavy or prolonged proteinuria.
A more-severe prognosis is correlated with histologic
evidence of diffuse mesangial proliferation, extensive
glomerular crescents, glomerulosclerosis, and diffuse
tubulointerstitial changes, including inflammation and
fibrosis.

 The primary treatment of IgA nephropathy is appropriate blood

pressure control. Fish oil, which contains anti-inflammatory omega-3
polyunsaturated fatty acids, decreases the rate of disease progression
in adults.
Immunosuppressive therapy with corticosteroids or more intensive
multidrug regimens may be beneficial in some patients.
Angiotensin-converting enzyme inhibitors and angiotensin II receptor
antagonists are effective in reducing proteinuria and retarding the rate
of disease progression when used as single agents or in combination.
Tonsillectomy has been used as treatment for IgA nephropathy in many
countries including Japan, but demonstration of its efficacy will require
prospective controlled trials.
Patients with IgA nephropathy may undergo successful kidney
transplantation. Although recurrent disease is frequent, allograft loss
caused by IgA nephropathy occurs in only 15-30% of patients.

Alport Syndrome
AS, hereditary nephritis, is a genetically heterogeneous disease
caused by mutations in the genes coding for type IV collagen, a
major component of basement membranes.
These genetic alterations are associated with marked variability
in clinical presentation, natural history, and histologic
abnormalities.

Genetics
Approximately 85% of patients have X-linked disease caused by a
mutation in the COL4A5 gene encoding the 5 chain of type IV
collagen. Patients with a subtype of X-linked AS and diffuse
leiomyomatosis demonstrate a contiguous mutation within the
COL4A5 and COL4A6 genes that encodes the 5 and 6 chains,
respectively, of type IV collagen.

Pathology
Kidney biopsy specimens during the 1st decade of life might
show few changes on light microscopy.
Later, the glomeruli can develop mesangial proliferation and
capillary wall thickening, leading to progressive glomerular
sclerosis.
Tubular atrophy, interstitial inflammation and fibrosis, and lipidcontaining tubular or interstitial cells, called foam cells,
develop as the disease progresses.
electron microscopy reveals diffuse thickening, thinning,
splitting, and layering of the glomerular and tubular basement
membranes

Clinical Manifestations
All patients with AS have asymptomatic microscopic
hematuria, which may be intermittent in girls and younger
boys.
Single or recurrent episodes of gross hematuria commonly
occurring 1-2 days after an upper respiratory infection are seen
in approximately 50% of patients.
Proteinuria is often seen in boys but may be absent, mild, or
intermittent in girls.
Progressive proteinuria, often exceeding 1g/24hr, is common
by the 2nd decade of life and can be severe enough to cause
nephrotic syndrome.

 Bilateral sensorineural hearing loss

anterior lenticonus (extrusion of the central
portion of the lens into the anterior chamber),
macular flecks, and corneal erosions.
Leiomyomatosis of the esophagus,
tracheobronchial tree, and female genitals in
association with platelet abnormalities is rare.

Diagnosis
The presence of anterior lenticonus is pathognomonic.
AS is highly likely in the patient who has hematuria and
at least 2 of the following characteristic clinical
features: macular flecks, recurrent corneal erosions,
GBM thickening and thinning, or sensorineural
deafness.
Absence of epidermal basement membrane staining for
the 5 chain of type IV collagen in male hemizygotes
and discontinuous epidermal basement membrane
staining in female heterozygotes is pathognomonic for
X-linked AS and can preclude diagnostic renal biopsy.

Treatment
No specific therapy is available to treat AS, although
angiotensin-converting enzyme inhibitors can slow the rate of
progression.
Careful management of renal failure complications such as
hypertension, anemia, and electrolyte imbalance is critical.
Patients with ESRD are treated with dialysis and kidney
transplantation.
Approximately 5% of kidney transplant recipients develop antiGBM nephritis, which occurs primarily in males with X-linked AS
who develop ESRD before age 30yr.

Thin Basement Membrane

Disease
Thin basement membrane disease (TBMD) is defined by the presence of
persistent microscopic hematuria and isolated thinning of the glomerular
basement membrane (GBM) (and occasionally tubular basement
membranes) on electron microscopy.
Microscopic hematuria is often initially observed during childhood and
may be intermittent.
Episodic gross hematuria can also be present, particularly after a
respiratory illness.
Isolated hematuria in multiple family members without renal dysfunction
is referred to as benign familial hematuria.
Although most of these patients will not undergo renal biopsy, it is often
presumed that the underlying pathology is TBMD.

 TBMD may be sporadic or transmitted

as an autosomal dominant trait.
Heterozygous mutations in the COL4A3
and COL4A4 genes, which encode the
3 and 4 chains of type IV collagen
present in the GBM, result in TBMD.
Homozygous mutations in these same
genes result in autosomal recessive
Alport syndrome.