MINIMAL CHANGE
DISEASE
Minimal change disease (MCD, also
known as nil disease and lipoid nephrosis) is the leading cause of nephrotic
syndrome in children, accounting for 90% of cases in this population, and a
major cause of nephrotic syndrome in adults. In addition to its predilection
for children, MCD also occurs more frequently in Asians and Caucasians than in
African-Americans.
The name of this disease refers to
the seemingly normal appearance of glomeruli when visualized using light
microscopy. On electron microscopy, however, diffuse foot process effacement
can be seen, which is the basis for the proteinuria.
The vast majority (>85%) of MCD cases are primary, idiopathic phenomena. In the remaining
cases, MCD occurs secondary to a systemic insult, such as drugs (e.g., NSAIDs,
lithium), neoplasms (especially hematologic malignancies), infections (e.g.,
tuberculosis, syphilis), and allergies to common irritants (i.e., poison ivy,
ragweed, poison oak, bee stings, certain foods).
PATHOPHYSIOLOGY
The precise mechanism of MCD is not
known. One theory speculates that dysfunctional T-cells produce a cytokine
called the glomerular permeability factor, which injures podocytes (visceral
epithelial cells) and leads to foot process effacement. Loss of the slit
diaphragm architecture, which constitutes the normal barrier to protein
filtration, leads to proteinuria. B cells may also play a role, either by
producing the glomerular permeability factor or, alternatively, by secreting an
antibody that targets a glomerular antigen.
The immune-mediated hypothesis is
supported by the efficacy of immunomodulatory treatments, as well as the fact
that MCD may occur secondary to allergens, infections, and cancers of the
immune system. In cases of idiopathic MCD, it is not clear what would trigger
this abnormal immune response. Some have postulated that viral or bacterial
infections may be responsible, although at present there is no evidence for
this claim. Despite the damage to podocytes, the remainder of the glomerulus
remains normal. Thus renal function remains intact or is only slightly impaired.
PRESENTATION AND DIAGNOSIS
The most common presentation of MCD
is the sudden onset of nephrotic syndrome (see Plate 4-7). Thus patients
typically have substantial edema and the laboratory findings of nephrotic-range
proteinuria, hypoalbuminemia, and hyperlipidemia. In MCD, the proteinuria tends
to be more profound than with other causes of nephrotic syndrome (e.g., > 10 to 15 g/day). Serum markers of renal function, such as creatinine
concentration, are typically normal or only slightly elevated. In a subset of
adults, however, acute kidney injury may occur, possibly because of ischemic acute
tubular necrosis resulting from massive loss of intravascular volume. For
unclear reasons, adults are also more likely than children to have hypertension
and hematuria.
Because patients with MCD tend to
have very severe proteinuria, clinicians must be alert for the presence of
related complications. As in all cases of nephrotic syndrome, patients are at
risk for systemic thromboses. In addition, infection may occur because of
multiple factors, including urinary losses of immunoglobulins, alternative complement
factor B, and hemolytic factor D. If there is significant edema, the risk of
cellulitis increases.
The gold standard for diagnosis of
MCD is renal biopsy. In children, however, MCD accounts for such an
overwhelming majority of nephrotic syndromes that it is often diagnosed on a
presumptive basis, with renal biopsy not performed unless empiric treatment
fails. In adults, the differential diagnosis for nephrotic syndrome is very
broad, and thus in the absence of a clear underlying cause (such as
long-standing diabetes mellitus), renal biopsy is essential for optimization of
management.
On light microscopy, the glomeruli
generally appear normal. Immunofluorescence is usually unremarkable, although
occasional mesangial IgM or complement deposits may be seen. Further
examination with electron microscopy, however, reveals diffuse foot process
effacement. This finding is not pathognomonic for MCD, however, unless seen in
the presence of normal light microscopy findings in an adequate sample size
(typically at least 15 glomeruli).
It is important but sometimes
challenging to distinguish MCD from FSGS. In some cases, patients diagnosed
with MCD fail to respond to treatment and, on repeat biopsy, are found to have
FSGS. It is not clear if these cases indicate missampled FSGS in the original
biopsy, or a progression of MCD to FSGS due to prolonged periods of heavy
proteinuria. Indeed, the relationship between these two entities is poorly
understood and controversial; some experts believe that the two entities are on
two ends of a continuum.
Once the diagnosis of MCD is
established, patients should be screened for the major causes of secondary MCD.
If all of these tests are negative or normal, the MCD can be ruled idiopathic.
TREATMENT
The primary, idiopathic form of MCD
is very responsive to steroids. Up to 95% of patients achieve complete
remission, defined as proteinuria declining to levels below 300 mg/day with
stable renal function. Among children, half respond within 2 weeks of
treatment, and nearly all of the others respond within 8 weeks. Among adults,
half respond within 4 weeks of treatment, but the rest may require several
months of additional corticosteroids. For as long as the nephrotic syndrome
persists, all patients should adopt a low-salt diet, and diuretics should be
used as needed for edema control. ACE inhibitors and statins are generally not
required in steroid-responsive patients because their disease is short in
duration.
Secondary forms of MCD should be
treated by focusing on removal or mitigation of the inciting insult, such as
discontinuation of a certain drug or treatment of an underlying malignancy.
PROGNOSIS
Patients who experience total
remission have a very good long-term prognosis. In contrast, patients with
disease that is unresponsive to treatment may experience progressive scarring
of glomeruli, with an associated decline in renal function that ultimately
leads to end-stage disease.
More than half of adult MCD
patients will have a relapse during their lifetime, and up to one in
four will become a frequent relapses, experiencing more than
three episodes per year. In general, children and adults who go into remission
quickly sometimes within the first week of treatment are
less likely to have subsequent relapses. Because long-term use of
steroids has numerous adverse effects, patients with relapsing disease are
often prescribed alternative immunomodulatory therapies, such as calcineurin
inhibitors, mycophenolate mofetil, and cyclophosphamide.
