Nephro 2

Kidney
They range in length and weight,
respectively, from approximately
6cm and 24g in a full-term newborn
to 12cm and 150g in an adult.

 The glomerular network of specialized capillaries

serves as the filtering mechanism of the kidney.
The glomerular capillaries are lined by
endothelial cells and have very thin cytoplasm
that contains many holes (fenestrations).
The glomerular basement membrane (GBM)
forms a continuous layer between the endothelial
and mesangial cells on one side and the
epithelial cells on the other.

 The membrane has 3 layers: (1) a central

electron-dense lamina densa; (2) the lamina
rara interna, which lies between the lamina
densa and the endothelial cells; and (3) the
lamina rara externa, which lies between the
lamina densa and the epithelial cells.
The visceral epithelial cells cover the capillary
and project cytoplasmic foot processes, which
attach to the lamina rara externa. Between the
foot processes are spaces or filtration slits.

 The mesangium (mesangial cells and matrix) lies between the

glomerular capillaries on the endothelial cell side of the GBM and
forms the medial part of the capillary wall.
The mesangium may serve as a supporting structure for the
glomerular capillaries and probably has a role in the regulation of
glomerular blood flow, filtration, and the removal of
macromolecules (such as immune complexes) from the
glomerulus.
Bowman's capsule, which surrounds the glomerulus, is composed
of a basement membrane, which is continuous with the basement
membranes of the glomerular capillaries and the proximal tubules,
and the parietal epithelial cells, which are contiguous with the
visceral epithelium

 As the blood passes through the glomerular capillaries, the

plasma is filtered through the glomerular capillary walls.
The ultrafiltrate, which is cell free, contains all of the
substances in plasma (electrolytes, glucose, phosphate,
urea, creatinine, peptides, low molecular weight proteins)
except proteins having a molecular weight of 68kd (such
as albumin and globulins).
The filtrate is collected in Bowman's space and enters the
tubules, where its composition is modified by tightly
regulated secretion and absorption of solute and fluid, until
it leaves the kidney as urine.

 Glomerular filtration is the net result of opposing forces applied

across the capillary wall.
The force for ultrafiltration (glomerular capillary hydrostatic
pressure) is a result of systemic arterial pressure, modified by the
tone of the afferent and efferent arterioles.
The major force opposing ultrafiltration is glomerular capillary
oncotic pressure, created by the gradient between the high
concentration of plasma proteins within the capillary and the almost
protein-free ultrafiltrate in Bowman's space.
Filtration may be modified by the rate of glomerular plasma flow,
the hydrostatic pressure within Bowman's space, and/or the
permeability of the glomerular capillary wall.

 Although glomerular filtration begins at approximately the

6th wk of fetal life, kidney function is not necessary for
normal intrauterine homeostasis because the placenta
serves as the major fetal excretory organ.
After birth, the glomerular filtration rate (GFR) increases
until renal growth ceases (by age ~18-20 years in most
people).
To compare GFRs of children and adults, the GFR is
standardized to the body surface area (1.73m 2) of an
ideal 70-kg adult. Even after correction for surface area,
the GFR of a child does not approximate adult values until
the 3rd yr of life.

 The GFR is optimally measured by the clearance of inulin, a fructose

polymer having a molecular weight of approximately 5kd.
Because the inulin clearance technique is cumbersome, the GFR is
commonly estimated by the clearance of endogenous creatinine.
Formulas that estimate creatinine clearance accurately in clinical
settings have been useful tools in patient care.
The Schwartz formula is the most widely used pediatric formula and is
based on the serum creatinine, patient height, and an empirical
constant.
Another endogenous marker, cystatin C, a 13.6-kd protease inhibitor
produced by nucleated cells, might prove to be a more reliable marker
than serum creatinine in estimating the GFR because its serum levels
are unaffected by sex, height, muscle mass, bilirubin, or red blood cell
hemolysis.

 The absence of plasma proteins larger than the size of albumin

from the glomerular filtrate confirms the effectiveness of the
glomerular capillary wall as a filtration barrier. Major factors
restricting the filtration of these and other macromolecules include
their size and their ionic charge. Morphologic studies suggest that
the size-selective filtration barrier resides within the GBM.
The endothelial cell, basement membrane, and epithelial cell of the
glomerular capillary wall possess strong negative ionic charges
(heparan sulfate and glycoproteins containing sialic acid).
Proteins in the blood have a relatively low isoelectric point and
carry a net negative charge, and they are repelled by the negatively
charged sites in the glomerular capillary wall, thus restricting
filtration.

Glomerular diseases
Glomerular injury may be a result of genetic,
immunologic, perfusion, or coagulation disorders.
Genetic disorders of the glomerulus result from
mutations in the exons of DNA encoding proteins
located within the glomerulus, interstitium, or tubular
epithelium; mutations in the regulatory genes
controlling DNA transcription; abnormal posttranscriptional modification of RNA transcripts; or
abnormal post-translational modification of proteins.
Immunologic injury to the glomerulus results in
glomerulonephritis, which is a generic term for
several diseases and a histopathologic term signifying
inflammation of the glomerular capillaries.

 Evidence that glomerulonephritis is caused

by immunologic injury includes morphologic
and immunopathologic similarities to
experimental immune-mediated
glomerulonephritis; the demonstration of
immune reactants (immunoglobulin,
complement) in glomeruli; abnormalities in
serum complement; and the finding of
autoantibodies (anti-GBM) in some of these
diseases.

 There appear to be 2 major mechanisms of

immunologic injury: glomerular deposition of
circulating antigen-antibody immune complexes
and interaction of antibody with local antigen in
situ.
In the latter circumstance, the antigen may be a
normal component of the glomerulus (the
noncollagenous domain [NC-1] of type IV collagen,
a putative antigen in human anti-GBM nephritis) or
an antigen that has been deposited in the
glomerulus.

Cellular location of injury during

glomerulonephritis
Mesangial cells are directly exposed to the circulation.
Deposition of immune complexes within these cells is
typically seen in disorders such as immunoglobulin A (IgA)
nephropathy; it results in proliferation and expansion of the
cells leading to hematuria, proteinuria, and renal
impairment.
Epithelial cells, in conjunction with basement membrane,
allow filtration of plasma solutes but retard passage of cells
and plasma proteins. Disease related to these cells is
typified by the presence of subepithelial deposits and
flattening of the foot processes that engage the basement
membrane, resulting in disruption of the filtration barrier
and proteinuria.

 Endothelial cell disease can result from

deposition of immune complex (as occurs in
mesangiocapillary glomerulonephritis),
attachment of antibody to the basement
membrane (Goodpasture disease), or trauma and
activation of coagulation (hemolytic uremic
syndrome). Endothelial cell proliferation and
necrosis are accompanied by leukocyte
accumulation, and rupture of the basement
membrane, crescent formation, and disruption of
glomerular architecture can develop. A nephritic
or rapidly progressive presentation ensues.

 In immune complexmediated diseases, antibody is produced against and

combines with a circulating antigen that is usually unrelated to the kidney.
The immune complexes accumulate in GBMs and activate the complement
system, leading to immune injury.
Acute serum sickness in rabbits is produced by a single intravenous injection
of bovine albumin.
Within 1wk after injection, a rabbit produces antibody against bovine
albumin, and the antigen remains in the blood in high concentration.
As antibody enters the circulation, it forms immune complexes with antigen.
Although the amount of antigen in the circulation exceeds that of antibody
(antigen excess), the complexes formed are small, remain soluble in the
circulation, and are deposited in glomeruli. The processes involved in
glomerular localization are not well understood but include characteristics of
the complex (concentration, charge, size), and/or the glomerulus (mesangial
trapping, negatively charged capillary wall); hydrodynamic forces, and the
influence of various chemical mediators (angiotensin II, prostaglandins).

 With deposition of immune complexes in glomeruli, rabbits

develop an acute proliferative glomerulonephritis.
Immunofluorescence microscopy demonstrates granular
(lumpy-bumpy) deposits containing immunoglobulin and
complement in the glomerular capillary wall.
Electron microscopic studies show these deposits to be on
the epithelial side of the GBM and in the mesangium.
For the next few days, as additional antibody enters the
circulation, the antigen is ultimately removed from the
circulation and the glomerulonephritis subsides.

 An example of in situ antigen-antibody

interaction is anti-GBM antibody
disease, in which antibody reacts with
antigen(s) of the GBM.
Immunopathologic studies reveal linear
deposition of immunoglobulin and
complement along the GBM as in
Goodpasture syndrome and certain types
of rapidly progressive glomerulonephritis.

 The inflammatory reaction that follows immunologic injury results

from activation of 1 or more mediator pathways.
The most important of these is the complement system, which has
2 initiating sequences: the classic pathway, which is activated by
antigen-antibody immune complexes, and the alternative or
properdin pathway, which is activated by polysaccharides and
endotoxin.
These pathways converge at C3; from that point on, the same
sequence leads to lysis of cell membranes.
The major noxious products of complement activation are
produced after activation of C3 and include anaphylatoxin (which
stimulates contractile proteins within vascular walls and increases
vascular permeability) and chemotactic factors (C5a) that recruit
neutrophils and perhaps macrophages to the site of complement
activation, leading to consequent damage to vascular cells and
basement membranes.

 The coagulation system may be activated

directly, after endothelial cell injury that
exposes the thrombogenic subendothelial layer
(thereby initiating the coagulation cascade), or
it may be activated indirectly, after
complement activation. Consequently, fibrin is
deposited within glomerular capillaries or
within Bowman's space as crescents. Activation
of the coagulation cascade can also activate
the kinin system, which produces additional
chemotactic and anaphylatoxin-like factors.

Pathology
Proliferation of glomerular cells occurs in most forms of
glomerulonephritis and may be generalized, involving all
glomeruli, or focal, involving only some glomeruli and
sparing others.
Proliferation commonly involves the endothelial and
mesangial cells and is often associated with an increase in
the mesangial matrix.
Mesangial proliferation can result from deposition of
immune complex within the mesangium. The resultant
increase in cell size and number, and production of
mesangial matrix, can increase glomerular size and narrow
the lumens of glomerular capillaries, leading to renal
insufficiency.

 Crescent formation in Bowman's space (capsule) is a result of

proliferation of parietal epithelial cells. Crescents develop in several forms
of glomerulonephritis (termed rapidly progressive or crescenteric)
and are a characteristic response to deposition of fibrin in Bowman's
space.
Newly formed crescents contain fibrin, the proliferating epithelial cells of
Bowman's space, basement membranelike material produced by these
cells, and macrophages that might have a role in the genesis of
glomerular injury. Over the subsequent days to weeks, the crescent is
invaded by connective tissue and becomes a fibroepithelial crescent. This
process generally results in glomerular obsolescence. Crescent formation
is often associated with glomerular cell death. The necrotic glomerulus has
a characteristic eosinophilic appearance and usually contains nuclear
remnants. Crescent formation is usually associated with generalized
proliferation of the mesangial cells and with either immune complex or
anti-GBM antibody deposition in the glomerular capillary wall.

 Certain forms of acute glomerulonephritis show glomerular

exudation of blood cells, including neutrophils, eosinophils,
basophils, and mononuclear cells. The thickened
appearance of GBM can result from a true increase in the
width of the membrane (as seen in membranous
glomerulopathy), from massive deposition of immune
complexes that have staining characteristics similar to the
membrane (as seen in systemic lupus erythematosus), or
from the interposition of mesangial cells and matrix into
the subendothelial space between the endothelial cells and
the GBM. The last can give the basement membrane a split
appearance, as seen in type I membranoproliferative
glomerulonephritis and other diseases.

 Sclerosis refers to the presence of scar tissue within the

glomerulus. Occasionally, pathologists use this term to refer to
an increase in mesangial matrix.
Tubulointerstitial fibrosis is present in all patients who have
glomerular disease and who develop progressive renal injury.
This fibrosis is initiated by injury to the renal tubules, resulting in
mononuclear cell infiltrates that release soluble factors that
have fibrosis-promoting effects.
Matrix proteins of the renal interstitium begin to accumulate,
leading to eventual destruction of renal tubules and peritubular
capillaries.
The actual transformation of tubular epithelium to mesenchymal
tissue can contribute to progressive tubulointerstitial fibrosis.