Page 952 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 68 Immunological Renal Diseases 919

other than kidney biopsy to establish a diagnosis of minimal KeY COnCePtS
change nephropathy, although proteinuria exclusively comprising
albumin is characteristic; standard immunological screening tests Focal Segmental Glomerulosclerosis
are usually normal. • Nephrotic syndrome with progressive renal insufficiency
• Glomerular permeability factor in plasma of some cases
Etiology and Pathogenesis • Unpredictable responses to glucocorticoids or cyclophosphamide
The cause of MCD is largely unknown. There is evidence of • Cyclosporine effective, but relapses common upon withdrawal
immune dysregulation, mainly involving cell-mediated immunity, • Moderately high relapse rate in renal allografts
which is supported by the tendency of the disease to manifest
and relapse after viral infections or an allergic reaction, the
association of some cases with Hodgkin lymphoma, and its a poorer response to immunosuppressive drug therapies, and a
characteristically favorable response to immunosuppressive drugs. higher risk of progression to end-stage renal failure. The incidence
Another hypothesis is that a systemic circulating factor of immune of FSGS is clearly increasing as a cause of nephrotic syndrome,
5
origin results in increased glomerular permeability (discussed particularly among black patients.
in the section on “Focal Segmental Glomerulosclerosis”)
The basic lesion of MCD is loss or neutralization of the normal Etiology and Pathogenesis
high density of anionic proteoglycans in the glomerular capillary Diverse etiologies may disrupt the podocyte structure and function
loops. Dissipation of the negative-charge barrier allows anion- leading to the histological expression of FSGS. Genetic mutations
charged albumin to pass freely. Interdigitating foot processes of key podocyte proteins, such as podocin and nephrin play a
normally joined by intercellular bridges, called slit diaphragms, role in a subset of FSGS that occurs in children or young adults.
form a second barrier to the passage of protein into the urinary Circulating permeability factors have been proposed as mediators
space. Characteristically, the podocyte foot processes and slit of podocyte injury in FSGS (i.e., soluble urokinase-type plas-
diaphragms are also disrupted in minimal change nephropathy. minogen activator receptor). In certain situations, it appears
that podocytes have increased surface expression of the trans-
Pathology membrane protein B7-1 (CD80) that stimulates interactions with
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With the use of light microscopy, renal biopsy results are found T cells and leads to foot process effacement. “Secondary” forms
to be essentially normal. Electron microscopy shows the char- of FSGS may result from toxic effects of drugs (i.e., pamidronate),
acteristic pathological lesion, where there is fusion of the foot viral infections (e.g., human immunodeficiency virus [HIV]) or
processes of the epithelial cells (podocytes) diffusely around maladaptive hemodynamic stress (i.e., resulting from obesity or
glomerular capillaries. reduced nephron mass).
Treatment Pathology
MCD is characteristically exquisitely sensitive to glucocorticoids The characteristic renal pathology includes segmental areas of
(remitting within the first few weeks of therapy in >90% of podocyte damage and detachment, irregular foot process fusion,
children). The response rate to glucocorticoids in adults is and collapse of glomerular capillaries associated with marked
somewhat lower and more delayed. A substantial portion of local increase in matrix and collagen accumulation. Segmental
patients with minimal change nephropathy face long-term dif- sclerotic areas typically stain nonspecifically with antisera to
ficulties because of the disease and the therapy: Some are IgM and C3 (but not to IgG or IgA), particularly in areas of
steroid-resistant from the start; others are steroid-dependent for glomerular tuft hyalinosis (representing trapped plasma con-
control of nephrotic syndrome; still others become frequent stituents), but none of these collections should be considered
relapsers and suffer substantial steroid toxicity with repeated to represent classic immune complexes. Various histological
treatments. Controlled trials have shown that alkylating agents subtypes of FSGS have been described on the basis of the type
(i.e., cyclophosphamide) increase response rates and reduce rates and location of lesions. One classification scheme divides FSGS
of relapse. Cyclosporine (CSA) and tacrolimus are alternatives into five variants: tip, perihilar, cellular, collapsing, and not
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to prolonged and repeated courses of steroid therapy, but relapses otherwise specified (NOS) (Fig. 68.4). The collapsing variant
frequently occur with drug withdrawal. Rituximab (a monoclonal of FSGS, which has been associated with viral infections, notably
antibody [mAb] to CD20 on B cells) has been used with variable HIV, tends to follow a particularly aggressive course.
success, particularly in those who are steroid-dependent or
frequent relapsers. Also, rituximab may have “off target” effects Treatment
on the podocyte cytoskeletal structure. 6 Patients with primary FSGS generally have hypoalbuminemia
The risk of progression to end-stage renal failure is extremely and nephrotic range proteinuria, whereas those with secondary
low in true MCD. Renal biopsy sampling errors account for a FSGS typically have subnephrotic proteinuria, a normal or near
mistaken diagnosis of MCD in a proportion of cases that are, normal serum albumin concentration, no peripheral edema, and
in fact, focal segmental glomerulosclerosis (FSGS). It is debated focal rather than diffuse foot process effacement on kidney biopsy.
whether MCD and FSGS represent different manifestations of The possibility of genetic forms of FSGS should be considered
one disease (with MCD potentially progressing to FSGS), or if before beginning immunosuppressive therapy, but steroid
they represent two different diseases. resistance may also serve as a clue to genetic forms of FSGS.
Treatment of genetic and hyperfiltration-induced forms of
FOCAL SEGMENTAL GLOMERULOSCLEROSIS FSGS is focused mostly on renoprotection with angiotensin
antagonists and lipid-lowering agents (statins). The treatment
Patients with FSGS have a higher frequency of microscopic of other forms of primary FSGS is basically similar to that of
hematuria, higher frequency of persistent nephrotic syndrome, MCD and includes immunosuppression with prednisone,