Nephrotic Syndrome

Overview

Definition

Nephrotic syndrome is characterized by heavy proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children (> 3.5 g/day), low serum albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests (< 3 g/dL), and peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema.

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in children: 2–7 cases per 100,000 population
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in adults: approximately 3 cases per 100,000 population; varies depending on the underlying cause (e.g., diabetes Diabetes 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)

Primary etiologies (“immune podocytopathies”)

• 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 (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 Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure: APOL1, MYH9)

Secondary etiologies

• Metabolic causes:
  • Diabetes Diabetes 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 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 Microscopic polyangiitis A primary systemic vasculitis of small- and some medium-sized vessels. It is characterized by a tropism for kidneys and lungs, positive association with anti-neutrophil cytoplasmic antibodies (ANCA), and a paucity of immunoglobulin deposits in vessel walls. Vasculitides
  • Serum sickness Serum sickness Immune complex disease caused by the administration of foreign serum or serum proteins and characterized by fever, lymphadenopathy, arthralgia, and urticaria. When they are complexed to protein carriers, some drugs can also cause serum sickness when they act as haptens inducing antibody responses. Type III Hypersensitivity Reaction
  • Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis
  • 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 Cryoglobulinemia A condition characterized by the presence of abnormal quantities of cryoglobulins in the blood. Upon cold exposure, these abnormal proteins precipitate into the microvasculature leading to restricted blood flow in the exposed areas. Rapidly Progressive Glomerulonephritis
    • IgA-associated vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
    • 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 Idiopathic Dermatomyositis: 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
• Drug-related:
  • Heroin
  • Interferon alfa Interferon Alfa Antivirals for Hepatitis C
  • Lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly
  • NSAIDs NSAIDS Primary vs Secondary Headaches
  • Pamidronate Pamidronate An aminobisphosphonate that inhibits bone resorption and is used for the treatment of osteolytic lesions, bone pain, and severe hypercalcemia associated with malignancies. Bisphosphonates
• 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • 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. Plasmodium/Malaria
  • Schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis due to S. haematobium S. haematobium A species of trematode blood flukes of the family schistosomatidae which occurs at different stages in development in veins of the pulmonary and hepatic system and finally the bladder lumen. This parasite causes urinary schistosomiasis. Schistosoma/Schistosomiasis
  • EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
  • 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 HIV Anti-HIV Drugs
• 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 Congenital Chorioretinitis nephrotic syndromes

Pathophysiology

The major target of injury in diseases that cause primary nephrotic syndrome is the podocyte Podocyte Highly differentiated epithelial cells of the visceral layer of bowman capsule of the kidney. They are composed of a cell body with major cell surface extensions and secondary fingerlike extensions called pedicels. They enwrap the kidney glomerulus capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the kidney. Nephritic Syndrome. Increased filtration across the glomerular capillary wall results in proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children.

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

• Glomerular barrier Glomerular barrier A specialized barrier in the kidney, consisting of the fenestrated capillary endothelium; glomerular basement membrane; and glomerular epithelium (podocytes). The barrier prevents the filtration of plasma proteins. Glomerular Filtration: filtration structure of the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy that surrounds the glomerular capillaries Glomerular capillaries Kidneys: Anatomy and includes the following 3 layers:
  • Capillary endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology: walls of the capillary vessels
  • Glomerular basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) (GBM): formed by the capillary endothelial and podocyte Podocyte Highly differentiated epithelial cells of the visceral layer of bowman capsule of the kidney. They are composed of a cell body with major cell surface extensions and secondary fingerlike extensions called pedicels. They enwrap the kidney glomerulus capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the kidney. Nephritic Syndrome 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: Histology (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: Anatomy processes
    • 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: Anatomy processes interdigitate and form a network that covers the glomerular capillaries Glomerular capillaries Kidneys: Anatomy.
    • Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 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: Anatomy 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: Anatomy.
    • 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: Anatomy allows selective filtration by size and charge. 
• Podocytes in the 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: Histology are the main cell type affected in nephrotic syndrome.
• 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 primarily involves the capillary endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology and GBM.

Pathophysiology

• Podocyte Podocyte Highly differentiated epithelial cells of the visceral layer of bowman capsule of the kidney. They are composed of a cell body with major cell surface extensions and secondary fingerlike extensions called pedicels. They enwrap the kidney glomerulus capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the kidney. Nephritic Syndrome 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: Anatomy proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (e.g., congenital Congenital Chorioretinitis nephrotic syndrome)
  • Response to hyperfiltration Hyperfiltration Chronic Kidney Disease/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 Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis in the urine:
  • Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests → hypoalbuminemia Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children
  • Clotting factors → predisposition to thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus
  • Loss of other proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis ( transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism, vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies–binding protein) usually does not cause significant clinical effects.
• 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:
  • Low serum albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests → low plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products oncotic pressure Oncotic Pressure Edema → fluid shifts from plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products volume to interstitial space → low effective circulating volume Effective circulating volume Renal Sodium and Water Regulation ( ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition) → stimulates RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones → Na⁺ retention → water retention
  • Na⁺ and water retention + sympathetic stimulation + reduced natriuretic peptide release  → pitting edema Pitting edema Edema caused by excess fluid without excess colloid. Leaves “pits” due to fluid displacement when pressure is applied to the area Edema
  • Decreased oncotic pressure Oncotic Pressure Edema → hepatic lipoprotein synthesis Synthesis Polymerase Chain Reaction (PCR) → hyperlipidemia

Clinical Presentations

Primary etiologies are more likely to present with the classic findings of nephrotic syndrome ( proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, 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 Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children), while secondary causes are more likely to present with nephrotic-range proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children only. Diagnosis is made by the clinical history and presentation, degree of proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings.

Common to all etiologies

• Classic clinical presentation of nephrotic syndrome:
  • > 3.5 g/day proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Urine microscopy may show signs of lipiduria:
    • “Oval fat bodies” or fatty casts Fatty Casts Minimal Change Disease on light microscopy
    • “ Maltese cross Maltese Cross Babesia/Babesiosis” on polarized light microscopy
  • Peripheral/ periorbital Periorbital Orbital and Preseptal Cellulitis 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 Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children
  • Hyperlipidemia
  • Serum creatinine is often normal.
• Diagnosis:
  • Secondary etiologies are less likely to present with peripheral/ periorbital Periorbital Orbital and Preseptal Cellulitis 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 Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children, and hyperlipidemia.
  • Nephrotic range proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children (> 3.5 g/day) can be seen without a diagnosis of true nephrotic syndrome; this distinction is clinically important.
  • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children alone is not treated with immunosuppression.

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

• Presentation:
  • Abrupt onset more often than other nephrotic diseases
  • Can have some nephritic features also (microscopic hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma)
  • 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 Idiopathic Dermatomyositis
  • Secondary:
    • Drugs: NSAIDs NSAIDS Primary vs Secondary Headaches (most common secondary cause), certain antibiotics
    • Malignancy Malignancy Hemothorax: leukemia, lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum, thymoma Thymoma A neoplasm originating from thymic tissue, usually benign, and frequently encapsulated. Although it is occasionally invasive, metastases are extremely rare. It consists of any type of thymic epithelial cell as well as lymphocytes that are usually abundant. Malignant lymphomas that involve the thymus, e.g., lymphosarcoma, Hodgkin’s disease (previously termed granulomatous thymoma), should not be regarded as thymoma. Primary Lymphatic Organs
• Diagnosis:
  • Usual clinical findings and labs
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is not always needed, as 90% of cases respond to steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors within 4 weeks.
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 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: Anatomy process effacement
• Management:
  • High-dose steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors with a long taper over several months
  • Many do not need ACEi ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors or statin (unlike other nephrotic diseases).

Membranous nephropathy

• Presentation:
  • Primary: classic nephrotic syndrome
    • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Hypoalbuminemia Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children
    • 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
  • Secondary:
    • Slow onset of nephrotic-range proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Less likely to have classic symptoms of nephrotic syndrome 
• Etiologies:
  • Primary autoimmune process (70% of cases):
    • IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis attacks the M-type phospholipase A2 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (PLA2R). 
    • Immune complex formation → complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus → podocyte Podocyte Highly differentiated epithelial cells of the visceral layer of bowman capsule of the kidney. They are composed of a cell body with major cell surface extensions and secondary fingerlike extensions called pedicels. They enwrap the kidney glomerulus capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the kidney. Nephritic Syndrome injury
    • Serum anti-PLA2R can be measured for diagnosis; biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma may not be needed.
  • Secondary (30% of cases):
    • Infection ( 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, 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 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)
    • Malignancy Malignancy Hemothorax (lung, breast, GI) in approximately 10% 
    • Drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches, gold, penicillamine Penicillamine 3-mercapto-d-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in wilson’s disease. Wilson Disease, tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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 Hypoalbuminemia A condition in which albumin level in blood (serum albumin) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (albuminuria). Nephrotic Syndrome in Children) 
  • Labs:
    • High-grade proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children: urine protein-to-creatinine ratio Protein-to-creatinine ratio Chronic Kidney Disease > 2
    • Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children: no hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
    • GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests: well preserved
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings:
    • Light microscopy: spike-and-dome pattern on silver stain Silver stain The use of silver, usually silver nitrate, as a reagent for producing contrast or coloration in tissue specimens. Legionella/Legionellosis
    • Immunofluorescence: IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis, 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 Subepithelial Membranoproliferative Glomerulonephritis 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: Anatomy process effacement
• Management:
  • All cases:
    • ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication 
    • Loop diuretic
    • Dietary Na⁺ restriction
    • Statin for hyperlipidemia (if not improved with disease treatment)
  • High-risk individuals:
    • Treat with immunosuppression
    • Cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants or cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants + prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants
    • Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants (monoclonal antibody to CD20)
    • Treatment can be monitored by following anti-PLA2R titers.
• Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • Approximately 66% will have at least partial spontaneous remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches (< 2 g/day proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children) at 5 years.
  • Good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas overall if responds to immunosuppressive therapy
  • Relapse Relapse Relapsing Fever may occur.
  • Progression to ESRD is possible; consider for transplantation.

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 Idiopathic Dermatomyositis): presents with classic nephrotic syndrome 
  • Secondary: often presents with non–nephrotic-range proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children due to:
    • Decreased nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast in solitary kidney
    • Recurrent kidney injury due to reflux nephropathy Reflux nephropathy Vesicoureteral Reflux or 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
    • 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 HIV Anti-HIV Drugs
    • Drugs: pamidronate Pamidronate An aminobisphosphonate that inhibits bone resorption and is used for the treatment of osteolytic lesions, bone pain, and severe hypercalcemia associated with malignancies. Bisphosphonates, interferon, heroin
  • Genetic causes: may present at any age
• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings of FSGS should prompt an evaluation to determine the underlying cause:
  • Light microscopy: segmental sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
  • 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: Anatomy process effacement localized to regions of segmental sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
• Management:
  • Primary:
    • General measures ( ACEi ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors, statin, loop diuretic, low-Na⁺ diet)
    • High-dose steroid with a long taper
    • Steroid-dependent with relapses → cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants
    • Steroid-resistant → cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants + prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants or mycophenolate Mycophenolate Immunosuppressants mofetil
    • Resistant to all therapies suggests misdiagnosed genetic FSGS → transplantation
  • Secondary and genetic:
    • General measures ( ACEi ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors, statin, loop diuretic, low-Na⁺ diet)
    • Treat underlying disease
    • Stop offending drug, if identified
    • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery 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 Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • Primary: will progress to ESRD if not treated
  • Secondary: stable renal function or spontaneous remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches is possible
  • “Collapsing FSGS”: Rapid progression to ESRD is common.
    • Specific histologic variant that carries the worst prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • More severe injury on biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma → treatment is often ineffective
    • Associated with HIV HIV Anti-HIV Drugs

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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children.

Diabetic nephropathy Diabetic nephropathy Kidney injuries associated with diabetes mellitus and affecting kidney glomerulus; arterioles; kidney tubules; and the interstitium. Clinical signs include persistent proteinuria, from microalbuminuria progressing to albuminuria of greater than 300 mg/24 h, leading to reduced glomerular filtration rate and end-stage renal disease. Chronic Diabetic Complications:

• Most common cause of nephrotic-range proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
• 20%–30% of all individuals with diabetes Diabetes 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 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). Peritoneal Dialysis and Hemodialysis)
• Presentation: progresses from microalbuminuria to nephrotic proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children over many years
• Diagnosis is based on kidney biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 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 ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors
  • Additional renal-protective medications:
    • Sodium-glucose cotransporter 2 (SGLT2) inhibitors
    • Nonsteroidal selective mineralocorticoid receptor antagonists Mineralocorticoid receptor antagonists Drugs that bind to and block the activation of mineralocorticoid receptors by mineralocorticoids such as aldosterone. Potassium-sparing Diuretics ( MRAs MRAs Drugs that bind to and block the activation of mineralocorticoid receptors by mineralocorticoids such as aldosterone. Potassium-sparing Diuretics)
  • 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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
• 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 Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings:
  • Light microscopy: “tram-track” (double contouring) of basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN)
  • Immunofluorescence: varies depending on etiology
  • Electron microscopy: subendothelial Subendothelial Membranoproliferative Glomerulonephritis deposits
• Treatment: steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors + mycophenolate Mycophenolate Immunosuppressants mofetil
• Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas varies with the cause:
  • Idiopathic Idiopathic Dermatomyositis: approximately 30% progress to ESRD within 10–15 years
  • Infectious/autoimmune: good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas 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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children (> 3.5 g/day) 
• Diagnosis:
  • SPEP with immunofixation (IFE)
  • UPEP
• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings:
  • Light microscopy: apple-green birefringence on polarized microscopy with Congo red stain
  • Electron microscopy: amyloid fibrils
• Treatment:
  • ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication 
  • Loop diuretic
  • Dietary Na⁺ restriction
  • Statin for hyperlipidemia
• Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas: 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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Helps reduce the progressive loss of glomerular function
• ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication or angiotensin-receptor blockers ( ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication):
  • Decrease proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children 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 Lisinopril One of the angiotensin-converting enzyme inhibitors (ACE inhibitors), orally active, that has been used in the treatment of hypertension and congestive heart failure. Renin-Angiotensin-Aldosterone System Inhibitors ( ACEi ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors)
    • Losartan Losartan An antagonist of angiotensin type 1 receptor with antihypertensive activity due to the reduced pressor effect of angiotensin II. Hypertension Drugs (ARB)
• SGLT2 inhibitors SGLT2 inhibitors Non-insulinotropic Diabetes Drugs:
  • Decrease proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • May benefit individuals with 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 and proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children (even without a diagnosis of diabetes Diabetes 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)
• Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication:
  • Reduce hypervolemia Hypervolemia Renal Sodium and Water Regulation 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 Hypovolemia Sepsis in Children if serum albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests is very low
  • Examples of drugs used:
    • Furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics
    • Bumetanide Bumetanide A sulfamyl diuretic. Loop Diuretics
    • Torsemide Torsemide A pyridine and sulfonamide derivative that acts as a sodium-potassium chloride symporter inhibitor. It is used for the treatment of edema associated with congestive heart failure; chronic renal insufficiency; and liver diseases. It is also used for the management of hypertension. Loop Diuretics
• Statin ( HMG-CoA reductase HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism inhibitor) for hyperlipidemia:
  • May not be needed if improved with disease treatment
  • Examples of drugs used:
    • Atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins
    • Simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins

Complications

• Thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus:
  • Up to 40% prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency 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 Antithrombin Endogenous factors and drugs that directly inhibit the action of thrombin, usually by blocking its enzymatic activity. They are distinguished from indirect thrombin inhibitors, such as heparin, which act by enhancing the inhibitory effects of antithrombins. Anticoagulants III ( anticoagulation Anticoagulation Pulmonary Hypertension Drugs 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 Hemoconcentration Neonatal Polycythemia → platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis → thrombus formation 
  • Risk factors:
    • > 10 g/day proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Very low serum albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests (< 2 g/dL)
    • Secondary membranous nephropathy (most common association)
  • High-risk individuals may benefit from prophylactic anticoagulation Anticoagulation Pulmonary Hypertension Drugs.
• Hyperlipidemia:
  • Low oncotic pressure Oncotic Pressure Edema from albuminuria Albuminuria The presence of albumin in the urine, an indicator of kidney diseases. Kidney Function Tests → 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 HMG-CoA reductase Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield mevalonic acid. Cholesterol Metabolism 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • 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: Types and Functions in the urine
    • Treatment with immunosuppressive medications
  • Vaccinations are important for prevention.

Differential Diagnosis

• 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: broad category of glomerular diseases, characterized by glomerular hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, 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 IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions nephropathy may overlap with nephrotic syndrome. Diagnosis is suggested by hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, mild-to-moderate proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, and certain serologies (e.g., ANCA ANCA Group of systemic vasculitis with a strong association with anca. The disorders are characterized by necrotizing inflammation of small and medium size vessels, with little or no immune-complex deposits in vessel walls. Rapidly Progressive Glomerulonephritis); kidney biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is necessary in most cases. Management varies as widely as the clinical presentations, from watchful waiting in mild cases to immunosuppression and plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome in aggressive disease.
• Lupus nephritis Lupus nephritis Glomerulonephritis associated with autoimmune disease systemic lupus erythematosus. Lupus nephritis is histologically classified into 6 classes: class I – normal glomeruli, class II – pure mesangial alterations, class III – focal segmental glomerulonephritis, class IV – diffuse glomerulonephritis, class V – diffuse membranous glomerulonephritis, and class VI – advanced sclerosing glomerulonephritis (the world health organization classification 1982). Diffuse Proliferative Glomerulonephritis: 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 Hematuria Presence of blood in the urine. Renal Cell Carcinoma but may overlap with nephrotic syndrome. Diagnosis is made by low complement level, positive ANA/double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure (dsDNA) testing, and kidney biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 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: malignant condition of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells (activated B lymphocytes B lymphocytes Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions) due to light-chain deposition primarily seen in the elderly. Excessive secretion Secretion Coagulation Studies 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: Types and Functions results in proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children and associated kidney damage; tissue deposition of amyloid fibrils also causes end-organ damage. Diagnosis is established by plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques and bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. 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 Anasarca Hookworm Infections: Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (HF), 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: Anatomy 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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children. 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 HF. Treatment is with diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication and addresses the underlying causes.