MINIMAL CHANGE DISEASE background also known as lipoid nephrosis or nil disease is the most common single form of nephrotic syndrome in children It refers to a histopathologic lesion in the glomerulus that almost always is associated with nephrotic syndrome. It typically is a disease of childhood, but it also can occur in adults.
MINIMAL CHANGE DISEASE PATHOPHYSIOLOGY It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows.
MINIMAL CHANGE DISEASE PATHOPHYSIOLOGY Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells.
MINIMAL CHANGE DISEASE PATHOPHYSIOLOGY Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy. this marker could be used in the future to help determine appropriate therapy
MINIMAL CHANGE DISEASE PATHOPHYSIOLOGY Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. An animal study by Lai suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria.
MINIMAL CHANGE DISEASE PATHOPHYSIOLOGY In patients who develop acute renal failure, endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the nonacute renal failure group. The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria. Although a multitude of studies have been published, the mechanism by which T cells increase glomerular permeability has remained unproven .
MINIMAL CHANGE DISEASE COMPLICATIONS Hypovolemic shock is perhaps the most serious complication of MCD. Hypovolemic shock typically occurs during the edema-forming phase of relapse and may be precipitated by diarrhea, sepsis, drainage of ascitic fluid, or the use of diuretics. Hypertension, somewhat paradoxically, also may occur in approximately 9-14% of children. Hypertension occurs in approximately 30% of adults, with a greater incidence in older patients (>60 y).
MINIMAL CHANGE DISEASE COMPLICATIONS Thromboembolic events are serious complications of nephrotic syndrome. Peripheral thrombosis may result in gangrene, and deep venous thrombosis in the legs or pelvic veins may be a source of pulmonary emboli. Bacterial infections, especially peritonitis, occur with greater frequency, partly because of the loss of immunoglobulin G (IgG) and complement factors B and D in the urine. In fact, the largest reduction in mortality in these patients follows the introduction of antibiotics rather than any specific therapy.
MINIMAL CHANGE DISEASE SUSCEPTIBILITY Race = Asians may be at increased risk. Sex = It is found twice as frequently in boys than in girls; The frequency is the same between the sexes in adults. Age = The incidence peaks in children aged 2 years, with approximately 80% being younger than 6 years at the time of diagnosis; In adults, the mean age of onset is 40 years.
MINIMAL CHANGE DISEASE CLINICAL SIGNS Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, or the use of certain drugs or malignancies. Facial edema is noted first. Malaise and easy fatigability can occur. Weight gain often is an additional feature. The patient also may present with the following: Hypovolemia, Hypertension, Thromboembolism, Infection
MINIMAL CHANGE DISEASE PHYSICAL SIGNS The blood pressure usually is normal in children but may be elevated in adults. (In addition, the plasma creatinine in adults is often slightly elevated at presentation.) Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual edema with horizontal lines (called Muehrcke lines ) also may occur. Hernias may be found, and the elasticity of the ears may be decreased.
MINIMAL CHANGE DISEASE PHYSICAL SIGNS Heavy proteinuria over an extended period of time leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure. Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the first indication of an underlying nephrotic syndrome. Children may have growth failure .
MINIMAL CHANGE DISEASE DIFFERENTIAL DIAGNOSES <ul><li>Other Problems to Be Considered </li></ul><ul><li>C1q nephropathy </li></ul><ul><li>Focal segmental glomerulosclerosis </li></ul><ul><li>Immunoglobulin M (IgM) nephropathy </li></ul><ul><li>Membranous nephropathy </li></ul><ul><li>Other variables </li></ul>
MINIMAL CHANGE DISEASE LABORATORY STUDIES Urine analysis is benign, but profound proteinuria and oval fat bodies may be observed. A random albumin-to-creatinine concentration ratio is in excess of 5. Urine specific gravity is high because of proteinuria. A 24-hour urine measurement is obtained for protein and creatinine clearance. Hypoalbuminemia is an important marker of nephrotic syndrome. The level at which edema occurs varies, but it tends to be lower in children than in adults. Nephrotic syndrome in children is defined by a serum albumin of less than 2.5 g / dL.
MINIMAL CHANGE DISEASE LABORATORY STUDIES Hyperlipidemia also is a feature of a nephrotic state Serologic workup (including antinuclear antibodies, complements, and cryoglobulins) is normal. Hyponatremia often is observed, which is, in part, a spurious finding secondary to the hyperlipidemic state. This condition also occurs from water retention caused by hypovolemia and antidiuretic hormone release. Elevated hemoglobin and hematocrit are consequences of plasma volume contraction.
MINIMAL CHANGE DISEASE HISTOLOGICAL FINDINGS Electron microscopy: Retraction of the epithelial foot processes is observed consistently in patients with MCD. This is, at times, erroneously described as foot-process fusion and results from disordered epithelial cell structure with withdrawal of the dendritic process. This finding is not unique to MCD, and the diagnosis is one of exclusion of other diseases based on lack of other processes on light microscopy, immunohistology, or electron microscopy
MINIMAL CHANGE DISEASE TREATMENT Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases. If patients are steroid-resistant or they relapse frequently, a trial of immunosuppressants is given ( cyclophosphamide and chlorambucil ) These drugs expose the patient to a wide range of serious adverse effects that include life-threatening infections, gonadal dysfunction, bone marrow dysfunction, and, in the case of chlorambucil, increased risk of leukemia. Mycophenolate mofetil (MMF) has been shown in limited studies to be beneficial to patients who are steroid-dependent or with frequent remissions
MINIMAL CHANGE DISEASE TREATMENT Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers , alone or in combination should be used with a goal of reducing the proteinuria Hypovolemia: purified plasma protein fraction isotonic sodium chloride solution albumin infusion (not appropriate) Edema dietary sodium restriction use of diuretics
MINIMAL CHANGE DISEASE TREATMENT Thrombotic episodes Mobilization meticulous attention to venipuncture intravenous infusion sites heparinization Infections administration of penicillin prophylaxis corticosteroids increase the problem of infection.
MINIMAL CHANGE DISEASE TREATMENT Diuretics These agents control volume overload. Furosemide (Lasix)= Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle Corticosteroids For remission of proteinuria. Antineoplastic agents For remission of nephrotic syndrome.
MINIMAL CHANGE DISEASE TREATMENT Diuretics These agents control volume overload. Furosemide (Lasix)= Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle Corticosteroids For remission of proteinuria. Antineoplastic agents For remission of nephrotic syndrome. Cyclophosphamide (Cytoxan, Neosar) = Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.
MINIMAL CHANGE DISEASE TREATMENT Immunosuppressant agents For remission of nephrotic syndrome. Cyclosporine A (Sandimmune, Neoral) = Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes. Chlorambucil (Leukeran) = To induce remission of proteinuria. Interferes with DNA replication and RNA transcription.
MINIMAL CHANGE DISEASE TREATMENT Immunomodulators To induce remission of nephrotic syndrome. Levamisole (Ergamisol) = Stimulates formation of antibodies and enhances T-cell responses. Acts as a biochemical modulator of fluorouracil Mycophenolate mofetil (CellCept)= Inhibitor of de novo purine pathway with preferential inhibitory effects on T and B lymphocyte proliferation, has been used to treat steroid-dependent nephrotic syndrome.
The histologic section of an H&E stained glomerulus in hows the characteristic light microscopic finding, i.e., no abnormality. Sometimes there may be a little bit of mesangial hypercellularity in a few segments. Otherwise, any scarring, any infiltration of leukocytes, any necrosis, or any other substantial structural changes in glomeruli rule out a diagnosis of minimal change glomerulopathy.
a representative immunofluorescence micrograph of the immunohistology of minimal change glomerulopathy, i.e., background staining. There are occasional specimens that will have small amounts of exclusively mesangial immunoglobulin (especially IgM) or complement accumulation that can still be designated minimal change glomerulopathy.
The three hallmarks of Minimal Change Disease: diffuse loss of podocyte foot processes, vacuolation, and the appearance of microvilli.