Nephrotic Syndrome

Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. In contrast, the nephritic syndromes present with hematuria, variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables loss of renal function, and hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. The primary etiologies of nephrotic syndrome are minimal change disease Minimal change disease Minimal change disease (MCD), also known as lipoid nephrosis, is the most common cause of nephrotic syndrome in children. The designation "minimal change" comes from the very little changes noticed in kidney biopsies under light microscopy. Hallmark clinical findings include edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Minimal Change Disease, membranous nephropathy, and focal segmental glomerulosclerosis. The clinical presentation of nephrotic syndrome includes proteinuria (> 3.5 g/day), hypoalbuminemia (< 3 g/dL), and peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. Other frequently observed clinical findings are hyperlipidemia and thrombotic disease. Diagnosis is suggested by the clinical findings, and kidney biopsy is necessary in most cases. Management varies with the etiology and usually involves glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids or other immunosuppressant drugs.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Nephrotic syndrome is characterized by heavy proteinuria (> 3.5 g/day), low serum albumin (< 3 g/dL), and peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema.

Epidemiology

  • Incidence in children: 2–7 cases per 100,000 population
  • Incidence in adults: approximately 3 cases per 100,000 population; varies depending on the underlying cause (e.g., diabetes)

Primary etiologies (“immune podocytopathies”)

  • Minimal change disease (MCD): 
    • Most common cause of nephrotic syndrome in children (approximately 90%)
    • Approximately 10%–15% of nephrotic syndrome in adults
  • Membranous nephropathy:
    • 2nd most common primary cause of the nephrotic syndrome
    • Found on approximately ⅓ of biopsies for nephrotic syndrome
    • Most common in Caucasian men > 40 years of age
  • Focal segmental glomerulosclerosis (FSGS):
    • Most common cause of primary nephrotic syndrome in adults (approximately 35%)
    • 2nd most common cause of nephrotic syndrome in children Nephrotic Syndrome in Children Nephrotic syndrome is a renal disorder caused by conditions that increase the permeability of the glomerular filtration barriers. Nephrotic syndrome affects all age groups but has a higher pediatric prevalence. This disorder can be due to both primary (renal) and secondary (systemic) causes. Nephrotic Syndrome in Children
    • More common in individuals of African descent (related genes: APOL1, MYH9)

Secondary etiologies

  • Metabolic causes:
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
  • Immunologic causes:
    • Microscopic polyangiitis
    • Serum sickness
    • Sjögren syndrome
    • Overlap with nephritic syndrome Nephritic syndrome Nephritic syndrome is a broad category of glomerular diseases characterized by glomerular hematuria, variable loss of renal function, and hypertension. These features are in contrast to those of nephrotic syndrome, which includes glomerular diseases characterized by severe proteinuria, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephritic Syndrome:
      • Cryoglobulinemia
      • IgA-associated vasculitis
      • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
  • Idiopathic: sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
  • Neoplastic:
    • Leukemia
    • Lymphomas
    • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Drug-related:
    • Heroin
    • Interferon alfa
    • Lithium
    • NSAIDs
    • Pamidronate
  • Infectious causes:
    • Leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy
    • Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis
    • Helminthic infections
    • Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria
    • Schistosomiasis Schistosomiasis Schistosomiasis is an infection caused by Schistosoma, a trematode. Schistosomiasis occurs in developing countries with poor sanitation. Freshwater snails are the intermediate host and are transmitted to humans through skin contact with contaminated fresh water. The clinical presentation occurs as a result of the host's immune response to antigens from the eggs. Schistosoma/Schistosomiasis due to S. haematobium
    • EBV
    • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C
    • HIV
  • Genetic syndromes:
    • Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease
    • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
    • Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome (although more commonly nephritic presentation)
    • Rare congenital nephrotic syndromes

Pathophysiology

The major target of injury in diseases that cause primary nephrotic syndrome is the podocyte. Increased filtration across the glomerular capillary wall results in proteinuria.

Nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys anatomy and physiology

  • Glomerular barrier: filtration structure of the nephron that surrounds the glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries and includes the following 3 layers:
    • Capillary endothelium: walls of the capillary vessels
    • Glomerular basement membrane (GBM): formed by the capillary endothelial and podocyte basal laminas
    • Epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium (podocytes): attached to the GBM with multiple foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot processes
      • Foot processes interdigitate and form a network that covers the glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries.
      • Proteins from the adjacent foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot processes further interdigitate and form the slit diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm.
      • The slit diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm allows selective filtration by size and charge. 
  • Podocytes in the epithelium are the main cell type affected in nephrotic syndrome.
  • Nephritic syndrome primarily involves the capillary endothelium and GBM.
Glomerular barrier

Diagram of the glomerular barrier:
A: Fenestrated endothelium of the glomerular capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries
B: Basal membrane
C: Epithelial layer demonstrating podocyte foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot processes and structural proteins creating the slit diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm

Image by Lecturio.

Pathophysiology

  • Podocyte malfunction is due to:
    • Immune complex–mediated injury (e.g., membranous nephropathy and FSGS)
    • Genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of slit diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm proteins (e.g., congenital nephrotic syndrome)
    • Response to hyperfiltration/glomerular capillary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Results in loss of various proteins in the urine:
    • Albumin → hypoalbuminemia
    • Clotting factors → predisposition to thromboembolism
    • Loss of other proteins (transferrin, vitamin D–binding protein) usually does not cause significant clinical effects.
  • Edema:
    • Low serum albumin → low plasma oncotic pressure → fluid shifts from plasma volume to interstitial space → low effective circulating volume (ECV) → stimulates RAAS → Na+ retention → water retention
    • Na+ and water retention + sympathetic stimulation + reduced natriuretic peptide release  → pitting edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Decreased oncotic pressure → hepatic lipoprotein synthesis → hyperlipidemia

Clinical Presentations

Primary etiologies are more likely to present with the classic findings of nephrotic syndrome (proteinuria, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, hypoalbuminemia), while secondary causes are more likely to present with nephrotic-range proteinuria only. Diagnosis is made by the clinical history and presentation, degree of proteinuria, and biopsy findings.

Common to all etiologies

  • Classic clinical presentation of nephrotic syndrome:
    • > 3.5 g/day proteinuria
    • Urine microscopy may show signs of lipiduria:
      • “Oval fat bodies” or fatty casts on light microscopy
      • “Maltese cross” on polarized light microscopy
    • Peripheral/periorbital edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema 
    • Hypoalbuminemia
    • Hyperlipidemia
    • Serum creatinine is often normal.
  • Diagnosis:
    • Secondary etiologies are less likely to present with peripheral/periorbital edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, hypoalbuminemia, and hyperlipidemia.
    • Nephrotic range proteinuria (> 3.5 g/day) can be seen without a diagnosis of true nephrotic syndrome; this distinction is clinically important.
    • Proteinuria alone is not treated with immunosuppression.
Oval fat bodies on urine microscopy

Oval fat bodies on urine microscopy

Image: “Unidentified structures in urine” by Ed Uthman. License: CC BY 2.0

Minimal change disease

  • Presentation:
    • Abrupt onset more often than other nephrotic diseases
    • Can have some nephritic features also (microscopic hematuria)
    • Can present with AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
    • Rarely causes end-stage renal disease (ESRD)
  • Etiologies:
    • Primary: idiopathic
    • Secondary:
      • Drugs: NSAIDs (most common secondary cause), certain antibiotics
      • Malignancy: leukemia, lymphoma, thymoma
  • Diagnosis:
    • Usual clinical findings and labs
    • Biopsy is not always needed, as 90% of cases respond to steroids within 4 weeks.
    • Biopsy findings:
      • Light microscopy: basically normal (minimal change)
      • Immunofluorescence: negative
      • Electron microscopy: diffuse foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot process effacement
  • Management:
    • High-dose steroids with a long taper over several months
    • Many do not need ACEi or statin (unlike other nephrotic diseases).
Electron microscopy of a glomerulus seen in a patient with minimal change disease

Electron microscopy showing glomerular capillary loops with findings of minimal change disease Minimal change disease Minimal change disease (MCD), also known as lipoid nephrosis, is the most common cause of nephrotic syndrome in children. The designation "minimal change" comes from the very little changes noticed in kidney biopsies under light microscopy. Hallmark clinical findings include edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Minimal Change Disease:
Podocytes with extensive, diffuse foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot process effacement (white arrows) and microvillous transformation
No electron-dense deposits
Normal thickness of glomerular basement membrane.

Image: “Pembrolizumab-associated minimal change disease Minimal change disease Minimal change disease (MCD), also known as lipoid nephrosis, is the most common cause of nephrotic syndrome in children. The designation "minimal change" comes from the very little changes noticed in kidney biopsies under light microscopy. Hallmark clinical findings include edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Minimal Change Disease in a patient with malignant pleural mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma” by BMC Cancer. License: CC BY 4.0

Membranous nephropathy

  • Presentation:
    • Primary: classic nephrotic syndrome 
      • Proteinuria
      • Hypoalbuminemia
      • Edema
    • Secondary:
      • Slow onset of nephrotic-range proteinuria
      • Less likely to have classic symptoms of nephrotic syndrome 
  • Etiologies:
    • Primary autoimmune process (70% of cases):
      • IgG attacks the M-type phospholipase A2 receptor (PLA2R). 
      • Immune complex formation → complement activation → podocyte injury
      • Serum anti-PLA2R can be measured for diagnosis; biopsy may not be needed.
    • Secondary (30% of cases):
      • Infection (hepatitis B, hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus, syphilis)
      • Malignancy (lung, breast, GI) in approximately 10% 
      • Drugs (NSAIDs, gold, penicillamine, tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)) inhibitors)
      • Autoimmune (lupus in young women)
  • Diagnosis:
    • Clinical features of nephrotic syndrome ( edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, hypoalbuminemia) 
    • Labs:
      • High-grade proteinuria: urine protein-to-creatinine ratio > 2
      • Urinalysis: no hematuria
      • GFR: well preserved
    • Biopsy findings:
      • Light microscopy: spike-and-dome pattern on silver stain
      • Immunofluorescence: IgG, variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables C3
      • Electron microscopy: subepithelial deposits and diffuse foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot process effacement
  • Management:
    • All cases:
      • ACEis 
      • Loop diuretic
      • Dietary Na+ restriction
      • Statin for hyperlipidemia (if not improved with disease treatment)
    • High-risk individuals:
      • Treat with immunosuppression
      • Cyclophosphamide or cyclosporine + prednisone
      • Rituximab (monoclonal antibody to CD20)
      • Treatment can be monitored by following anti-PLA2R titers.
  • Prognosis:
    • Approximately 66% will have at least partial spontaneous remission (< 2 g/day proteinuria) at 5 years.
    • Good prognosis overall if responds to immunosuppressive therapy
    • Relapse may occur.
    • Progression to ESRD is possible; consider for transplantation.
Individual with both membranous nephropathy and diabetic nephropathy

Individual with both membranous nephropathy and diabetic nephropathy:
A: Deposits of IgG in the basement membrane appear as a diffuse granular pattern as shown on immunofluorescence (×200).
B: Light microscopy shows membranous glomerulonephritis with thickened and prominent capillary loops. Numerous granular dense deposits were located in subepithelial areas (periodic acid–Schiff (PAS) stain, ×200).
C: Electron micrograph of thickened glomerular basement membrane (GBM) with numerous granular, dense deposits located in subepithelial areas (×5000).

Image: “A case with membranous nephropathy (MN) and diabetic nephropathy (DN)” by Zhuo L., et al. License: CC BY 2.0

Focal segmental glomerulosclerosis (FSGS)

  • Focal segmental glomerulosclerosis is a histologic lesion commonly found in individuals with nephrotic syndrome rather than a specific disease entity.
  • Etiologies: 
    • Primary (idiopathic): presents with classic nephrotic syndrome 
    • Secondary: often presents with non–nephrotic-range proteinuria due to:
      • Decreased nephron mass in solitary kidney
      • Recurrent kidney injury due to reflux nephropathy or sickle cell disease
      • Progressive CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease from any etiology
      • Most important viral cause: HIV
      • Drugs: pamidronate, interferon, heroin
    • Genetic causes: may present at any age
  • Biopsy findings of FSGS should prompt an evaluation to determine the underlying cause:
    • Light microscopy: segmental sclerosis
    • Immunofluorescence: nonspecific
    • Electron microscopy: foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot process effacement localized to regions of segmental sclerosis
  • Management:
    • Primary:
      • General measures (ACEi, statin, loop diuretic, low-Na+ diet)
      • High-dose steroid with a long taper
      • Steroid-dependent with relapses → cyclophosphamide
      • Steroid-resistant → cyclosporine + prednisone or mycophenolate mofetil
      • Resistant to all therapies suggests misdiagnosed genetic FSGS → transplantation
    • Secondary and genetic: 
      • General measures (ACEi, statin, loop diuretic, low-Na+ diet)
      • Treat underlying disease
      • Stop offending drug, if identified
      • Weight loss for obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
  • Prognosis:
    • Primary: will progress to ESRD if not treated
    • Secondary: stable renal function or spontaneous remission is possible
    • “Collapsing FSGS”: Rapid progression to ESRD is common.
      • Specific histologic variant that carries the worst prognosis
      • More severe injury on biopsy → treatment is often ineffective
      • Associated with HIV

Specific secondary causes of nephrotic syndrome

The following etiologies are less likely to present with classic nephrotic syndrome, but may still be found on kidney biopsies done for nephrotic-range proteinuria.

Diabetic nephropathy:

  • Most common cause of nephrotic-range proteinuria
  • 20%–30% of all individuals with diabetes will develop some stage of CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease.
  • Most common overall cause of ESRD (approximately 55% of all individuals new to dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis)
  • Presentation: progresses from microalbuminuria to nephrotic proteinuria over many years
  • Diagnosis is based on kidney biopsy if the presentation is not classic: 
    • Characteristically shows Kimmelstiel-Wilson nodules
    • Can coexist with other nephrotic diseases (such as MCD, membranous nephropathy, and FSGS)
  • Treatment:
    • Strict glycemic control and ACEi
    • Possible transplantation

Membranoproliferative glomerulonephritis Membranoproliferative Glomerulonephritis Membranoproliferative glomerulonephritis (MPGN) is also known as mesangiocapillary glomerulonephritis. Membranoproliferative glomerulonephritis is a pattern of glomerular injury characterized by mesangial hypercellularity, endocapillary proliferation, and thickening of the glomerular basement membrane (double contour formation). Membranoproliferative Glomerulonephritis ( MPGN MPGN Membranoproliferative glomerulonephritis (MPGN) is also known as mesangiocapillary glomerulonephritis. Membranoproliferative glomerulonephritis is a pattern of glomerular injury characterized by mesangial hypercellularity, endocapillary proliferation, and thickening of the glomerular basement membrane (double contour formation). Membranoproliferative Glomerulonephritis):

  • Nephritic disease that can overlap with nephrotic-range proteinuria
  • Associated with chronic hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus, autoimmune disease, and dysproteinemias
  • Biopsy findings:
    • Light microscopy: “tram-track” (double contouring) of basement membrane
    • Immunofluorescence: varies depending on etiology
    • Electron microscopy: subendothelial deposits
  • Treatment: steroids + mycophenolate mofetil
  • Prognosis varies with the cause:
    • Idiopathic: approximately 30% progress to ESRD within 10–15 years
    • Infectious/autoimmune: good prognosis if diagnosed/treated early

Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis:

  • Relatively rare cause of nephrotic syndrome
  • Presents with nephrotic-range proteinuria (> 3.5 g/day) 
  • Diagnosis:
    • SPEP with immunofixation (IFE)
    • UPEP
  • Biopsy findings:
    • Light microscopy: apple-green birefringence on polarized microscopy with Congo red stain
    • Electron microscopy: amyloid fibrils
  • Treatment: 
    • ACEis 
    • Loop diuretic
    • Dietary Na+ restriction
    • Statin for hyperlipidemia
  • Prognosis: high risk of progression to ESRD

Management

All etiologies of nephrotic syndrome share similar treatment measures; secondary etiologies also need to have the underlying causes addressed. 

Treatment

  • Dietary Na+ restriction: 2 g/day
  • Strict blood pressure control: 
    • Goal < 130/80 mm Hg
    • Helps reduce proteinuria
    • Helps reduce the progressive loss of glomerular function
  • ACEis or angiotensin-receptor blockers (ARBs):
    • Decrease proteinuria by reducing glomerular capillary pressure
    • Treat systemic hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Examples of drugs used:
      • Lisinopril (ACEi)
      • Losartan (ARB)
  • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics:
    • Reduce hypervolemia and decrease edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • May cause hypovolemia if serum albumin is very low
    • Examples of drugs used: 
      • Furosemide
      • Bumetanide
      • Torsemide
  • Statin (HMG-CoA reductase inhibitor) for hyperlipidemia: 
    • May not be needed if improved with disease treatment
    • Examples of drugs used:
      • Atorvastatin
      • Simvastatin

Complications

  • Thromboembolism:
    • Up to 40% prevalence in individuals with nephrotic syndrome
    • Can be arterial or venous
    • Caused by a hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state:
      • Antithrombin III (anticoagulation factor) lost in the urine 
      • Increased hepatic production of proclotting factors
      • Exacerbated by volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration or diuretic use
      • Hemoconcentration → platelet aggregation → thrombus formation 
    • Risk factors:
      • > 10 g/day proteinuria
      • Very low serum albumin (< 2 g/dL)
      • Secondary membranous nephropathy (most common association)
    • High-risk individuals may benefit from prophylactic anticoagulation.
  • Hyperlipidemia:
    • Low oncotic pressure from albuminuria → increased hepatic lipoprotein production
    • Excessive serum lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids are lost in the urine (i.e., lipiduria).
    • May resolve with successful treatment of the nephrotic syndrome or may require treatment with HMG-CoA reductase inhibitors ( statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins)
  • Infection:
    • Particularly increased risk of Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus and Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae infections
    • Increased risk is due to:
      • Loss of immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins in the urine
      • Treatment with immunosuppressive medications
    • Vaccinations are important for prevention.

Differential Diagnosis

  • Nephritic syndrome: broad category of glomerular diseases, characterized by glomerular hematuria, variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables loss of renal function, and hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. Primary glomerular diseases such as IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy may overlap with nephrotic syndrome. Diagnosis is suggested by hematuria, mild-to-moderate proteinuria, and certain serologies (e.g., ANCA); kidney biopsy is necessary in most cases. Management varies as widely as the clinical presentations, from watchful waiting in mild cases to immunosuppression and plasmapheresis in aggressive disease.
  • Lupus nephritis: presentation is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and is usually nephritic with hematuria but may overlap with nephrotic syndrome. Diagnosis is made by low complement level, positive ANA/double-stranded DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure (dsDNA) testing, and kidney biopsy showing characteristic “wire loops” involving variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables percentages of the glomeruli classified by severity.
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: malignant condition of plasma cells (activated B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells) due to light-chain deposition primarily seen in the elderly. Excessive secretion of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins results in proteinuria and associated kidney damage; tissue deposition of amyloid fibrils also causes end-organ damage. Diagnosis is established by plasma electrophoresis and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy. Treatment is supportive and also with specific chemotherapies.
  • Other causes of severe edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema/anasarca: Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure ( CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure), hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism, or severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease ( cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis) may present with significant edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, but these can be distinguished from the nephrotic syndrome by the presence (or absence) of severe proteinuria. Individuals with nephrotic syndrome can often lie flat comfortably without dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, in contrast to those with CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure. Treatment is with diuretics and addresses the underlying causes.

References

  1. Beck, L. H., Jr., Salant, D. J. (2020). Membranous nephropathy: clinical manifestations, pathology, and diagnosis. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/membranous-nephropathy-clinical-manifestations-pathology-and-diagnosis
  2. Fervenza, F. C., Sethi, S. (2020). Focal segmental glomerulosclerosis: epidemiology, classification, clinical features, and diagnosis. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/focal-segmental-glomerulosclerosis-epidemiology-classification-clinical-features-and-diagnosis
  3. Hill, N. R., et al. (2016). Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One 11(7). https://doi.org/10.1371/journal.pone.0158765
  4. Kelepouris, E., Rovin, B. H. (2019). Overview of heavy proteinuria and the nephrotic syndrome. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/overview-of-heavy-proteinuria-and-the-nephrotic-syndrome
  5. Leung, N., Appel, G. B. (2019). Renal amyloidosis. UpToDate. Retrieved October 24, 2021, from  https://www.uptodate.com/contents/renal-amyloidosis
  6. Meyrier, A., Radhakrishnan, J. (2020). Acute kidney injury in minimal change disease and other forms of nephrotic syndrome. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/acute-kidney-injury-aki-in-minimal-change-disease-and-other-forms-of-nephrotic-syndrome
  7. Radhakrishnan, J. (2021). Hypercoagulability in nephrotic syndrome. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/hypercoagulability-in-nephrotic-syndrome
  8. Niaudet, P. (2020). Etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children. UpToDate. Retrieved October 25, 2021, from https://www.uptodate.com/contents/etiology-clinical-manifestations-and-diagnosis-of-nephrotic-syndrome-in-children

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