PANCE Blueprint Renal System (5%)

Nephrotic syndrome (ReelDx + Lecture)


Poststreptococcal glomerulonephritis

Patient will present as → a 6-year-old boy who is brought to the emergency department by his mother due to swelling around his eyes and legs. The mother reports that the patient recently recovered from an upper respiratory tract infection. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia and normal complement levels. Urinalysis demonstrates 4+ protein and fatty casts with "maltese cross" sign.

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Nephrotic syndrome is defined as urinary excretion of > 3 g of protein on a 24-hour urine due to a glomerular disorder plus edema and hypoalbuminemia

  • Proteinuria occurs because of changes to capillary endothelial cells, the glomerular basement membrane (GBM), or podocytes, which normally filter serum protein selectively by size and charge.
  • The disorder results in urinary loss of macromolecular proteins, primarily albumin (protein) but also opsonins, immunoglobulins, erythropoietin, transferrin, hormone-binding proteins, and antithrombin III.
Consider nephrotic syndrome in patients, particularly young children, with unexplained edema or ascites.

  • Massive edema + urine 3.5 grams of protein on 24-hour urine
  • Fatty casts with “maltese cross” sign
  • Hypoalbuminemia, hyperlipidemia, and lipiduria
  • Oval fat bodies

The most common primary causes are:

  • Membranous nephropathy: most common in non-diabetic adults associated with malignancies.
    • Caused by immune complex formation in the glomerulus.
  • Minimal change disease: most common cause in kids. Assume minimal change disease if a child with idiopathic nephrotic syndrome improves after treatment with corticosteroids.
    • The cause and pathogenesis of minimal change disease is unclear and it is currently considered idiopathic.
  • Focal segmental glomerulosclerosis: obese patients, heroin, and HIV+ black males.
    • Primary, when no underlying cause is found
    • Secondary, when an underlying cause is identified
      • Toxins and drugs such as heroin and pamidronate
      • Familial forms
      • Secondary to nephron loss and hyperfiltration, such as with chronic pyelonephritis and reflux, morbid obesity, diabetes mellitus

The most common secondary causes are:

  1. Lupus: both nephritic and nephrotic.
  2. Diabetes: common cause of nephrotic syndrome and subsequent renal failure.
  3. Preeclampsia

Diagnosis is suspected in patients with edema and proteinuria on urinalysis and confirmed by random (spot) urine protein and creatinine levels or 24-h measurement of urinary protein. The cause may be suggested by clinical findings (eg, SLE, preeclampsia, cancer); when the cause is unclear, additional (eg, serologic) testing and renal biopsy are indicated.

  • Urine random (spot) protein/creatinine ratio ≥ 3 or significant proteinuria (3 g protein in a 24-h urine collection) is diagnostic (normal excretion is <150 mg/day).
  • Serologic testing and renal biopsy unless the cause is clinically obvious
  • Besides proteinuria, urinalysis may demonstrate casts (hyaline, granular, fatty, waxy,- or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells (oval fat bodies), within casts (fatty casts), or as free globules, suggests a glomerular disorder causing nephrotic syndrome.
  • Serum albumin often is < 2.5 g/dL
  • Total cholesterol and triglyceride levels are typically increased.

Treat the causative disorder and with angiotensin inhibition, Na restriction, and often diuretics and/or statins.

  • Minimal change disease: Prednisone 1 mg/kg (up to 80 mg every day) × 4-8 weeks; gradually taper if a response is noted. ACE-Is may also be used as an adjunct to therapy (to reduce proteinuria), or as sole therapy in mild cases.
    • Frequent relapsers: Prolonged treatment with immunosuppressants chlorambucil, cyclosporine, or cyclophosphamide should be considered.
  • Membranous nephropathy: Depends on the risk of progression to ESRD; judged by the amount of proteinuria and the degree of renal insufficiency. Patients at moderate to high risk should be treated with a combination of glucocorticoids and cytotoxic therapy (cyclophosphamide). Those at low risk can be treated with ACE-Is. Lipid-lowering agents should be used in cases of persistent nephrotic syndrome.
  • Focal segmental glomerulosclerosis: ACE-I should be used for reduction of proteinuria. Immunosuppression with prednisone is the first-line therapy.
    • Steroid-resistant cases may benefit from addition of cyclosporine. Relapses require reinitiation of steroids.

IM_MED_Nephrotic-Syndrome_394_V1.1_ASSETS_ Nephrotic syndrome is a group of symptoms including massive proteinuria defined as a daily loss of 3.5 gm or more of protein, hyperlipidemia, generalized edema, and hypoalbuminemia which results from renal pathology. Nephrotic syndrome is caused by several diseases including membranous glomerulonephritis, minimal change disease, and focal segmental glomerulosclerosis. Nephrotic syndrome is usually initially related to a derangement in the glomerular capillary walls that result in increased permeability to plasma proteins. Loss of protein leads to hypoalbuminemia beyond the compensatory rate of synthesis in the liver, which contributes to generalized edema due to decreased colloid osmotic pressure in the blood. Additionally, nephrotic syndromes are often characterized by immunodeficiency due to loss of immunoglobulins and thrombotic complications due to loss of anticoagulants like antithrombin, protein C and protein S in the urine.

Nephrotic Syndrome Picmonic

_IM_Minimal-Change-Disease_v1.7 Minimal change disease is a relatively benign disorder that is the most common cause of nephrotic syndrome in children. This disease is characterized by diffuse effacement of foot processes called podocytes of visceral epithelial cells. This podocyte effacement is visible with examination by electron microscopy while the glomeruli appear virtually normal by light microscopy. In minimal change disease, the glomerular basement membrane loses its negative charge which makes it unable to repel the negatively charged albumin. Therefore, this form of nephrotic syndrome is characterized by selective loss of albumin with minimal loss of immunoglobulins. This disease is typically triggered by a recent infection or immune stimulus like a prophylactic immunization and has dramatic response to corticosteroid therapy.

Minimal Change Disease Picmonic

_DM_MembranousGlomerulonephritis_v1.7_ Membranous glomerulonephritis, also commonly called membranous nephropathy, is the second most common cause of nephrotic syndrome in adults behind focal segmental glomerulosclerosis. This renal disorder is characterized by diffuse capillary and glomerular basement membrane thickening due to the accumulation of electron dense, immunoglobulin containing deposits along the subepithelial side of the basement membrane. This cause of nephrotic syndrome can manifest independently or in association with other systemic diseases and several other identifiable etiologic agents. The most notable associations include drugs like gold, underlying malignant tumors, particularly solid tumors including carcinomas of the lung and colon and melanoma, systemic illnesses like lupus and infections including chronic hepatitis B and hepatitis C. However, it is important to note that approximately 85% of patients have no associated conditions and the disease is considered to be idiopathic. On light microscopy, the glomeruli typically exhibit uniform, diffuse thickening of the capillaries and glomerular basement membrane. On electron microscopy, the thickening is seen to be caused by irregular dense immune complex deposition between the basement membrane and epithelial cells. The basement membrane between the deposits appear as irregular spikes and over time, the spikes thicken to produce dome-like protrusions over the immune deposits. This is commonly described as having a spike and dome appearance with subepithelial deposits. Immunofluorescence demonstrates a granular pattern.

Membranous Glomerulonephritis Picmonic

_DM_Focal-Segmental-Glomerulsclerosis_v1.9_ (1) Focal segmental glomerulosclerosis (FSGS) is the most common adult cause of nephrotic syndrome. As the name implies, these lesions are characterized by sclerosis of some but not all of the glomeruli, making the inflammation focal as opposed to diffuse. Additionally, the lesions within the glomeruli only affect a section of the capillary making the damage segmental. This disease can occur as primary disease but also occurs in association with other conditions including HIV infection and heroine addiction. Clinically, FSGS typically has a high incidence of microscopic hematuria, reduced GFR, hypertension, nonselective proteinuria, and poor response to corticosteroid therapy. This disease has relatively poor prognosis with many individuals progressing to chronic kidney disease and more than half of the patients developing end stage kidney disease in 10 years. On light microscopy, the glomeruli that are affected demonstrate segmental sclerosis and hyalinosis while the unaffected glomeruli appear relatively normal. Electron microscopy demonstrates focal damage of visceral epithelial cells while immunofluorescence staining is usually negative.

Focal Segmental Glomerulosclerosis Picmonic

Type_I_II_membranoproliferate_revised2_ Membranoproliferative glomerulonephritis (MPGN) is a type of nephritic-nephrotic kidney disorder characterized by alterations in the glomerular basement membrane, proliferation of glomerular cells, and leukocyte infiltration. MPGN accounts for approximately 10 to 20% of cases of nephrotic syndrome in both children and young adults and is divided into two major categories on the basis of distinct immunofluorescent and pathologic differences called type I and type II MPGN. In type I MPGN, there is evidence of immune complex deposition in the glomerulus with activation of both the classical and alternative complement pathways. In many cases, the antigens involved in MPGN are thought to be derived from infectious agents such as hepatitis C and hepatitis B viruses. By light microscopy, both types of MPGN demonstrate enlarged hypercellular glomerular caused by proliferation of cells in the mesangium. Electron microscopy shows a glomerular basement membrane that is thickened and the glomerular capillary wall often shows a tram-track appearance caused by duplication, commonly called splitting, of the basement membrane by ingrowth of the mesangium. Specifically, type I MPGN is characterized by the presence of discrete subendothelial immune complexes. Immunofluorescence demonstrates a granular pattern of C3 deposition. Type II MPGN, also called dense deposit disease, has abnormalities that suggest activation of the alternative pathway. More than 70% of patients have a circulating antibody called C3 nephritic factor, which is an autoantibody that binds to the C3 convertase in the alternative pathway. C3 nephritic factor binding causes stabilization of the convertase, protecting it from enzymatic degradation and therefore favors persistent C3 activation and hypocomplementemia. It is called dense deposit disease due to deposition of dense material of unknown composition in the glomerular basement membrane.

Membranoproliferative Glomerulonephritis Picmonic

Question 1
A patient presents with edema, which is most noticeable in the hands and face. Laboratory findings include proteinuria, hypoalbuminemia, and hyperlipidemia. The most likely diagnosis is
congestive heart failure
Dependent edema is the most typical finding with CHF. Laboratory findings do not generally include proteinuria or hypoalbuminemia.
end-stage liver disease
Symptoms of end-stage liver disease usually include increased abdominal girth indicating ascites. Hypoalbuminemia can occur as a result of malnutrition or concurrently with nephrotic syndrome.
nephrotic syndrome
Malnutrition is marked by physical wasting, not edema. Hypoalbuminemia may be seen, but hyperlipidemia is not typical.
Question 1 Explanation: 
Proteinuria, hyperlipidemia, and hypoalbuminemia are consistent with nephrotic syndrome.
Question 2
A 54 year-old woman with history of lupus comes to the office with increasing significant peripheral edema over the past four days. Laboratory findings include marked proteinuria, hypoalbuminemia and hyperlipidemia. Which of the following diagnostic studies is the best for determining the cause of the proteinuria?
Renal ultrasound
Renal ultrasound may identify hydronephrosis from a stone or other source of obstruction.
Renal biopsy
Cystoscopy can be used in the evaluation of hematuria to assess for bladder or urethral neoplasm, benign prostatic hyperplasia, and radiation or chemical cystitis.
Computed tomography scan
CT scanning may identify neoplasms of the kidney or ureter as well as benign conditions such as urolithiasis.
Question 2 Explanation: 
Renal biopsy is performed in adults with new onset of nephrotic syndrome to determine the cause of the proteinuria and to guide management decisions.
Question 3
Of the following, which is more commonly recognized as a secondary cause of nephrotic syndrome?
Sjögren syndrome
Cushing disease
Hemolytic anemia
Question 3 Explanation: 
Nephrotic syndrome can be primary (a disease specific to the kidneys) or secondary (a renal manifestation of a systemic general illness). In all cases, injury to glomeruli is an essential feature. Kidney diseases that affect tubules and interstitium, such as interstitial nephritis, do not cause nephrotic syndrome. Primary causes of nephrotic syndrome include the following, in approximate order of frequency:
  • Minimal-change nephropathy
  • Focal glomerulosclerosis
  • Membranous nephropathy
  • Hereditary nephropathies
Secondary causes include the following, again in order of approximate frequency:
  • Diabetes mellitus
  • Lupus erythematosus
  • Viral infections (eg, hepatitis B, hepatitis C, HIV)
  • Amyloidosis and paraproteinemias
  • Preeclampsia Alloantibodies from enzyme replacement therapy
Question 4
Which of the following statements is accurate regarding the presentation of nephrotic syndrome?
Hematuria is among the most common presenting symptoms in adults with nephrotic syndrome
The first sign of nephrotic syndrome in children is usually swelling of the face
The presence of deep venous thrombosis or pulmonary embolism suggests a diagnosis other than nephrotic syndrome
Weight loss and hypotension are frequently present in adults with nephrotic syndrome
Question 4 Explanation: 
The first sign of nephrotic syndrome in children is usually swelling of the face; this is followed by swelling of the entire body. Adults can present with dependent edema. Foamy urine may be a presenting feature. A thrombotic complication, such as deep venous thrombosis of the calf veins or even a pulmonary embolus, may be the first clue to nephrotic syndrome. Additional historical features can be related to the cause of nephrotic syndrome. Thus, the recent start of a nonsteroidal anti-inflammatory drug (NSAID) suggests such drugs as the cause, and a greater-than-10-year history of diabetes with symptomatic neuropathy indicates diabetic nephropathy. Edema is the salient feature of nephrotic syndrome and initially develops around the eyes and legs. With time, the edema becomes generalized and may be associated with an increase in weight, the development of ascites, or pleural effusions. Hematuria and hypertension manifest in a minority of patients; this condition is sometimes referred to as "nephritic-nephrotic." Additional features on examination vary according to cause and as a result of whether renal function impairment is present. Thus, in the case of longstanding diabetes, the patient may have diabetic retinopathy, which correlates closely with diabetic nephropathy. If the kidney function is reduced, the patient may have hypertension, anemia, or both.
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