Professional Documents
Culture Documents
VAN DEN
Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam,
The Netherlands
INTRODUCTION
Urine is practically devoid of high-molecular mass proteins, which is achieved by the sieving characteristics of
the glomerular filtration barrier and by resorption of proteins in the proximal tubules of the kidney. Many glomerular diseases result in a pathological increase in glomerular permeability to proteins. If proteinuria exceeds
40 mg m2 h1 , hypoalbuminaemia accompanied by
oedema will ensue. The clinical picture of proteinuria,
hypoalbuminaemia and oedema is referred to as
nephrotic syndrome (NS).
The term idiopathic NS is often used to describe
a heterogeneous group of proteinuric glomerulopathies
that occur predominantly in children. Over the last few
years it has become recognized that some forms of
NS formerly assigned as idiopathic NS are caused by
mutations in genes that encode structural components
Key words: allergy, atopy, focal and segmental glomerulosclerosis (FSGS), minimal change nephrotic syndrome (MCNS), nephrotic
syndrome, podocyte.
Abbreviations: FSGS, focal and segmental glomerulosclerosis; GBM, glomerular basement membrane; IFN- , interferon- ;
IL, interleukin; NS, nephrotic syndrome; MCNS, minimal change nephrotic syndrome; PBMC, peripheral blood mononuclear
cells; TNF, tumour necrosis factor.
Correspondence: Dr Jose G. van den Berg (email j.g.vandenberg@amc.uva.nl).
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MCNS
In children, MCNS is the most common form of NS,
accounting for 3580 % of the cases of NS, depending
on ethnicity [49]. In adults, MCNS is the third most
common form of NS, next to membranous nephropathy
and FSGS, accounting for 1525 % of the cases of unexplained adult NS [10]. MCNS is more common in
Hispanics, Asians, Arabs and Caucasians than in African
Americans [9,1114]. Depending on race, the reported
incidence of MCNS varies from 216 per 100 000 children
under 16 years of age [11,1517]. Previous studies report
higher incidences of MCNS than more recent studies do,
probably because the incidence of FSGS has increased
over time while the incidence of MCNS may be
decreasing [9,10,18].
Clinically, MCNS is characterized by highly selective
proteinuria, i.e. mainly albuminuria, which generally
responds well to treatment with corticosteroids. Approx.
90 % of children with MCNS and up to 70 % of adult patients will respond with a complete remission to a course
of corticosteroids [7,19], yet are prone to relapse. Relapses
are most frequent in children. In a follow up study, 95 %
of children with biopsy-proven MCNS relapsed during
17 years follow-up [20]. Lower relapse rates have been
reported, depending on the therapy regimen [21,22]. If
responsive to steroids, the outcome of the disease is
excellent. Long-term studies with a follow-up of up to
20 years have shown that practically none of the children
with steroid-sensitive biopsy-proven MCNS develop
hypertension, loss of renal function or FSGS [20,23,24].
In adults, the outcome is similar [2527]. Therefore
MCNS is often referred to as steroid-sensitive NS.
In frequently relapsing patients and in steroid-dependent patients, prolonged or repeated steroid therapy can
lead to a variety of serious side effects. In these patients,
alternative therapeutic strategies can be used to induce
long-lasting remission. These include other drugs that
modulate the immune system, such as cyclosporine [28
31] and levamisole [3235], and alkylating agents, such as
cyclophosphamide [3638] and chlorambucil [39].
FSGS
FSGS is a non-specific pattern of glomerular injury
that is frequently encountered in human renal biopsies.
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Cross-sections of the glomerular capillary wall in a non-proteinuric patient (A and B) and in a patient with MCNS (C and D) as revealed by electron microscopy. Cell
bodies of podocytes (P) extend into the urinary space, while their foot processes attach to the GBM. In normal individuals, foot processes are arranged in a regular
interdigitating pattern (B) with interconnecting slit diaphragms (small arrows). In nephrotic patients, foot processes are irregularly flattened and show distorted slit
diaphragms (D; arrowhead). US, urinary space; CL, capillary lumen. Magnification, 11 000 (A and C) and 108 000 (B and D).
will discuss the pathogenesis of both MCNS and FSGS
as separate entities.
PODOCYTE INJURY IN NS
NS is associated with dramatic changes in podocyte
architecture, as detected by electron microscopy. These
changes consist of loss or effacement of the podocyte foot
processes (Figures 1C and 1D) and suggest a process of
transdifferentiation. The precise mechanism underlying
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mRNA expression of IL-10 (A) and IL-13 (B) by PBMC from MCNS patients during relapse (n = 15) and in remission (n = 15), and from a control group of patients
with NS primarily caused by endogenous alterations within the glomerular filter (n = 7), as detected by quantitative real-time PCR. Values are expressed relative to
the mRNA levels of the house-keeping gene -actin, in arbitrary units. All patients were free of immunosuppressive drugs for at least 3 weeks. (C) Plasma IL-10 levels
in the same patients, as detected by ELISA. Horizontal lines denote median values. KruskalWallis tests and MannWhitney tests were applied to evaluate differences
between the patient groups.
illustrate the heterogeneity of the patient groups studied;
approximately half of the patients had up-regulation of
the particular cytokine.
adhesion receptor complexes are linked to the submembranous actin cytoskeleton and mediate not only cell
adhesion, but also in inside-out and outside-in signalling.
We and others have shown that, in addition to adhesion
receptors, podocytes constitutively express functional
transmembrane receptor complexes for IL-4, IL-10,
IL-13 [152,153] and TNF- [154]. The IL-4/IL-13
receptor complex is also expressed by endothelial cells,
including glomerular epithelium in vivo [152,155]. The
presence of cytokine receptors at the glomerular capillary
wall is puzzling and raises teleological questions: what is
their significance in normal states and what is their role
in disease?
In immune cells, cytokines function as soluble messengers and binding of cytokines to their cognate
receptors induces a variety of intracellular changes, which
have been studied extensively. These changes include
cytoskeletal rearrangements, as has been shown for IL-4
and IL-13 in B-cells, granulocytes and macrophages
[156160]. Also, in cultured HUVECs (human umbilical
vein endothelial cells), IL-4 and IL-13 regulate cell
morphology, cytoskeleton and proliferation [161]. In
cultured podocytes, we have shown that IL-4 and IL-13
directly alter protein sorting, ion transport and activity of
lysosomal enzymes, such as cathepsin L and heparanase
[152,162]. Others have shown the effects of pro-inflammatory cytokines IL-1 and TNF- on the expression
of nephrin by podocytes [163] and on cytoskeleton
reorganization in podocytes [164].
Thus cytokine receptors render the glomerular capillary wall responsive to immunological signals from the
environment. One may hypothesize that, under physiological circumstances, the levels of circulating cytokines
are low and their effects at the glomerular capillary wall
may be less pronounced, whereas, in disease, elevated
ACKNOWLEDGMENTS
We wish to thank Nike Claessen, Sandrine Florquin and
Jan Aten for invaluable help and support. This work was
supported by grants from the Dutch Kidney Foundation
(No. C98.1720), and from The Netherlands Organization
for Scientific Research (NWO; Grant 920-903-062).
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