Continuing Education Activity

Minimal change disease (MCD) is one of the most common causes of idiopathic nephrotic syndrome in children. In the past, MCD was given the labels "nil disease" or "lipoid nephrosis."In adults, MCD closely resembles. Focal Segmental Glomerulosclerosis (FSGS) under light microscopy. However, electron microscopy demonstrates abnormalities in podocyte or glomerular epithelial cells in both MCD and focal segmental glomerulosclerosis (FSGS).

Objectives:

• Identify the etiology of minimal change disease.
• Describe the evaluation of minimal change disease.
• Overview the management options available for minimal change disease.

Introduction

Minimal change disease (MCD) is one of the most common causes of idiopathic nephrotic syndrome in children. It accounts for 70% to 90% of children that present with nephrotic syndrome who are older than one year old as opposed to 10-15% of adults who present with nephrotic syndrome.[1] Minimal change disease is distinctive for proteinuria that results in edema and intravascular volume depletion, with a good response to steroids. Minimal Change Disease has been labeled “minimal change lesion,” “nil disease,” and “lipoid nephrosis (a description of lipid droplets in urine seen on light microscopy).[2] Minimal change disease has a particularly good prognosis in pediatric patients.

Etiology

Mostly minimal change disease is idiopathic (primary) but can occur secondary to exposure to other agents:

• Infections: Tuberculosis, syphilis, mycoplasma, ehrlichiosis, hepatitis C virus
• Neoplasms: Hematologic malignancies, including leukemia, Hodgkin and non-Hodgkin lymphoma
• Allergy: Bee and medusa stings, cat fur, fungi, poison ivy, ragweed pollen, house dust
• Drugs: NSAIDs, lithium, antibiotics (ampicillin, cephalosporins), immunizations, and gamma interferon
• Other glomerular diseases: Associated with IgA nephropathy, SLE, type 1 DM, and HIV

Epidemiology

Minimal change disease has an incidence of 2 to 7 new cases per 100,000 children. The exact prevalence is unknown; however, it is estimated to be about 10 to 50 cases per 100,000 children. A male predominance (2 to 1) is noted during childhood, which disappears during the adolescent years. Minimal change disease is not common in adults, and the exact incidence is not known.[2]

Pathophysiology

Minimal change disease presents with a nephrotic syndrome characterized by an increased renal membrane permeability and loss of protein (primarily albumin) due to damage to the glomerular filtration barrier (GFB). The GFB is composed of fenestrated endothelium (inner layer), the glomerular basement membrane (middle layer), and an outer epithelial layer composed of podocytes. Podocytes are epithelial cells with large cell bodies and long foot processes that run parallel along the outside of glomerular capillaries. The space between foot processes is interspersed by cell-to-cell junctions called slit diaphragms.[3] 

Glomerular filtration is both size-specific and charge-specific. The actin cytoskeleton of podocytes provides support to the GBM and regulates flow across the basement membrane depending on hydrostatic pressures, molecular size, and molecular charge.[3] The apical and luminal membrane of the slit diaphragms and podocytes are coated with a sialoglycoprotein (podocalyxin) which contributes to repels negatively charged molecules such as albumin. The two outer layers of the glomerular basement membrane are composed of heparin sulfate proteoglycans that are also negatively charged and contribute to the charge selectivity of the barrier.[4] Disruption of this barrier leads to the proteinuria seen in nephrotic syndrome.

The pathogenesis of MCD is not exactly known, but it is thought to be multifactorial. Several studies have focused on the integrity and biology of podocytes. Because the actin cytoskeleton of podocytes maintains the integrity of the podocytes by supporting the cell body and foot processes, regulation of flow across the basement membrane is controlled by a series of interactions. As a result, multiple theories have been proposed to explain the cause of proteinuria in MCD. Some of the proposed theories published include T cell dysfunction/dysregulation that leads to cytokine release and upregulation of proteins, such as CD80 and C-mip that affects the integrity of podocytes, systemic circulating factors that disrupt podocyte function, and B- cell activation (suspected due to the efficacy of anti- CD-20 monoclonal antibodies, such as rituximab).[5][6][7]

Histopathology

Light microscopy of renal biopsy specimens from patients with MCD shows minimal to no change; however, electron microscopy reveals the effacement of podocyte foot processes. To add to the conundrum, immunofluorescent staining of biopsy specimens is negative, and no immune complexes are evident.

History and Physical

An accurate history and a thorough physical exam must be performed on each patient who presents with edema and proteinuria. Proteinuria and edema may be presenting symptoms of other conditions such as diabetes mellitus, adverse medication effects, or systemic lupus erythematous. It is also important to consider the patient’s age, family history, and recent illnesses.

Patients with MCD commonly present with periorbital, scrotum, labia, and/or lower extremity edema. On exam, patients may demonstrate anasarca, pericardial or pleural effusion, ascites, and abdominal pain. An affected individual is an intravascularly volume depleted and maybe oliguric, which can lead to acute kidney injury, a finding most frequently noted in adults. Children often present with severe infections (sepsis, pneumonia, and peritonitis) due to the depletion of immunoglobulin.[8] Minimal change disease in adults presents with hematuria, acute kidney injury, and hypertension.

Evaluation

Glomerulonephritis is associated with many diagnoses that are differentiated by histopathology or clinical presentation.[9] To establish the etiology of glomerulonephritis, one must determine whether the patient presents with nephritic or nephrotic syndrome. Nephritic syndrome is associated with hematuria,  proteinuria, and hypertension. Nephrotic syndrome is associated with heavy proteinuria, hypoalbuminemia, peripheral edema, hyperlipidemia, and thrombotic disease. The fluid status in patients with nephrotic syndrome alternates between hypovolemia and hypervolemia. Hypovolemic patients may be referred to as "underfilled" due to the loss of albumin through proteinuria. Hypoalbuminemia leads to decreased oncotic pressure and fluid sequestration in the interstitial space.[10] Hypoalbuminemia and low oncotic pressure induce reflexes through the juxtaglomerular apparatus to compensate for intravascular fluid losses by increasing sodium absorption and water retention. Patients with MCD are commonly hypovolemic (underfilled).

Hypervolemia (overfill) associated with nephrotic syndrome is due to tubular dysregulation, which increases sodium absorption and water retention. In these patients, hypoalbuminemia and decreased oncotic pressure are not the cause of edema.  Therefore, it is important to understand each patient's volume status before initiating therapy that addresses edema.  

In children, MCD is the most common cause of idiopathic nephrotic syndrome. Minimal change disease is the third most common cause of idiopathic nephrotic syndrome in adults after focal segmental glomerular sclerosis and membranous nephropathy. An early kidney biopsy is crucial to making the diagnosis of MCD in adults.[1]

In children, MCD is primarily a clinical diagnosis, and biopsy is only required in the presence of atypical clinical features:

• Age of onset before 1 or after12 years old
• Gross hematuria
• Low serum C3
• Marked Hypertension
• Elevated creatinine
• Renal failure without hypovolemia
• Positive history or serology for secondary causes
• Steroid resistance[2]

A successful response to steroids might be anticipated in children how to present with typical clinical findings of MCD and are:

• Age 1-12 years old
• Normotensive
• Normal Renal Function
• +/- Microscopic hematuria

Basic labs:

• Urinalysis/ Urine microscopy: Dipstick will show 3+/4+ proteinuria. A urine dipstick and urinalysis (UA) are often the initial tests obtained to screen for MCD. In MCD, the urine typically looks frothy secondary to proteinuria, and the microscopy shows oval fat bodies and fatty casts. Dysmorphic RBCs, acanthocytes, abnormal casts, and proteinuria are findings suggestive of glomerular injury not frequently seen in MCD.[9] Keep in mind that a urine dipstick has its limitations. The dipstick cannot identify the extent or type of proteinuria as it primarily detects albumin and does not detect low molecular weight proteins.[11] False-positive test results are noted in the presence of mucus, blood, pus, alkalinity, or concentration.[12] A 24-hour urine collection is required to quantitate urinary protein.
• Urine collection: A spot protein/creatinine ratio greater than 200 mg/mmol in children and protein/creatinine ratio>300-350mg/mmol in adults is consistent with nephrotic syndrome, as is a 24-hour urine collection that reveals a total protein greater than 3 to 3.5 g/24hour in adults. A report of measuring protein output as gms/m2/hr accounts for differences in body mass. A measurement of 40mg/m2/hour or greater (1gm/m2/24hour) is indicative of proteinuria consistent with nephrotic syndrome in children. Microscopic hematuria is present in 10% to 30% of adults.[13]
• Complete metabolic panel (CMP): CMP demonstrates a low total protein, low albumin (frequently <2.5 g/dl), and low total calcium (ionized calcium binds to albumin, and albumin is low).
• Complete blood count (CBC): CBC will show hemoconcentration and thrombocytosis. This is seen due to the intravascular volume contraction from fluid sequestration into the interstitial space.
• Total cholesterol and triglyceride levels: These are increased due to an increase in hepatic lipoprotein synthesis as a result of low oncotic pressures.[3]

Labs to rule out secondary causes:

• Antinuclear antibodies
• Hepatitis B and C serologic tests
• Serologic test for syphilis (e.g., rapid plasma reagin)
• HIV antibody test
• Complement levels (CH50, C3, C4)

Treatment / Management

The initial cornerstone treatment for minimal change disease is steroids. Children frequently achieve remission with steroids within 4 weeks vs. adults who achieve remission in two months or more [2]. The incidence of relapse is high in children and adults.

Children

Initial prednisone therapy is 60 mg/m^2(or 2 mg/kg) administered daily for 4-6 weeks (maximum dose, 60 mg/day), or 40 mg/m2/(or 1.5 mg/kg) on alternate days for 2-5 months taper. Reduce the dose by 5 mg/m2 to 10 mg/m2 each week for another four weeks, then stop, with a minimum duration of 12 weeks [14].

Adults

Initial prednisone treatment is 1mg/kg per day or 2 mg/kg/kg every other day (max 80mg/day or 120 mg every other day) for 4-16 weeks. Taper slowly over a course of 6 months after remission[13].

Patients Who Relapse Demonstrate the following

• Steroid resistance is noted as the persistence of proteinuria in children after 4 weeks of prednisone and after 16 weeks for adults.
• Frequent relapses occur, which are defined as two or more relapses in the first six months of presentation or four or more relapses within any 12 months
• Steroid dependency is defined as relapses that occur during the tapering phase of steroid therapy or less than two weeks after discontinuing steroids
• Relapse nephrosis - > 2+ proteinuria on 3 consecutive days

• Prednisolone should be restarted if there is a relapse: 2 mg/kg daily (maximum 60 mg) until in remission for 3 days, then 1.5 mg/kg alternate days for 4 weeks, then stop or taper the dose over 4-8 weeks.

For frequent relapses/ steroid-dependent (steroid-sparing agents)

• Cyclophosphamide: the dose of 2 mg/kg/ day for 8 to 12 weeks (should be started after reaching remission with the steroid)- potential gonadal toxicity, alopecia, bone marrow suppression.
• Cyclosporine: At a dose of 4 to 5 mg/kg/day, usually for 1-2 years. Levels should be monitored after 1 to 2 weeks. Aim for a trough of 70 to 150. Can cause nephrotoxicity, hirsutism, hypertension, and gingival hyperplasia.

If intolerant to the above-mentioned drugs, can give:

• Mycophenolate mofetil (MMF): Doses of 500 to 1000 mg two times a day for 1 to 2 years. Should be monitored for leukopenia.[14]
• Rituximab (chimeric monoclonal antibody): 375 mg/weekly for 1 to 4 doses.[15] Side effects such as fulminant myocarditis, pulmonary fibrosis, fatal Pneumocystis jirovecii infections, ulcerative colitis, and allergic reactions.[2]

Differential Diagnosis

The differential diagnosis includes:

• Cardiac: Heart failure
• Hepatic: Liver failure, hepatocellular cirrhosis
• Digestive: Protein-losing enteropathy, malnutrition
• Renal: acute Glomerulonephritis, renal failure
• Immune: Angioedema, anaphylaxis
• Lymphatic: Primary/secondary lymphedema, congenital lymphedema

These diagnoses present with edema secondary to decreased intravascular oncotic pressure.

Prognosis

Minimal change disease has very good prognosis for all ages if there is a response to corticosteroid therapy. The primary morbidity is related to the adverse effects of the medications.[2]

Complications

These complications are mainly secondary to the extensive proteinuria that is seen with this disease. 

Children and adults with MCD are at risk for developing complications such as:

• Hypovolemia
• Infections (pneumonia, peritonitis, sepsis): Secondary to the loss of immunoglobulins (IgG) and complement factors via the urine. Also, there is decreased opsonization of capsulated organisms. 
• Venous thromboembolism: due to a decrease in antithrombin III, protein S, plasminogen, and increase in prothrombotic factors.[11]
• Hyperlipidemia
• Acute kidney injury: From the intravascular volume depletion.

Deterrence and Patient Education

Patients with acute and active disease should have low sodium in their diet and should also be encouraged to restrict their fluid intake.

Enhancing Healthcare Team Outcomes

Minimal change disease is frequently encountered as the most common cause of nephrotic syndrome in children, and it is the third most common cause of nephrotic syndrome in adults. An interdisciplinary team including a nephrologist, pharmacist, primary care, and nurse is essential for detection, diagnosis, and optimizing therapy. In children, MCD presents with distinct clinical features. However, in adults, the clinical features may vary. It is important to recognize these clinical and lab findings associated with MCD to tailor and optimize therapy in MCD subgroups.