Hemolytic Uremic Syndrome (Clinical)

Overview

Definition

Hemolytic uremic syndrome Hemolytic uremic syndrome A syndrome that is associated with microvascular diseases of the kidney, such as renal cortical necrosis. It is characterized by hemolytic anemia; thrombocytopenia; and acute renal failure. Hypocoagulable Conditions ( HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome) is a disease of the 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: Histology (microangiopathy) that causes the formation of blood clots, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types caused by the destruction of RBC in these clotted 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: Histology ( hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia), acute kidney injury Acute Kidney Injury 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, and low platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology ( thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia).

Epidemiology^[1–4]

• Majority of cases seen in children < 5 years of age
• 2–3 cases per 100,000 children in the United States
• Major cause of acute kidney injury Acute Kidney Injury 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 in children (> 6 months to 5 years of age)
• Previously classified as:
  • Typical HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome:
    • Most commonly seen in the summer and in rural populations
    • 90% of cases are associated with diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea caused by Shiga toxin Shiga toxin A class of toxins that inhibit protein synthesis by blocking the interaction of ribosomal RNA; with peptide elongation factors. They include shiga toxin which is produced by Shigella dysenteriae and a variety of shiga-like toxins that are produced by pathologic strains of Escherichia coli such as Escherichia coli o157. Diarrheagenic E. coli–producing Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli (STEC). 
  • Atypical HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome: nondiarrheal
• Research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest has shown that aside from 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, genetic mutations Genetic Mutations Carcinogenesis and different triggering factors lead to HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome (see Etiology).

Etiology

Etiology is classified as acquired (infectious versus noninfectious) or hereditary.^[2,5,6,13]

• Acquired HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome:
  • Infectious
    • Shiga toxin Shiga toxin A class of toxins that inhibit protein synthesis by blocking the interaction of ribosomal RNA; with peptide elongation factors. They include shiga toxin which is produced by Shigella dysenteriae and a variety of shiga-like toxins that are produced by pathologic strains of Escherichia coli such as Escherichia coli o157. Diarrheagenic E. coli–producing E. coli (STEC): most common in children < 5 years of age
    • Shigella Shigella Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. Shigella spp.
    • 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
    • HIV HIV Anti-HIV Drugs
  • Autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques to complement factors
  • Drug toxicity Toxicity Dosage Calculation:
    • Drugs associated with malignancy Malignancy Hemothorax or organ transplant recipients ( 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 and tacrolimus Tacrolimus A macrolide isolated from the culture broth of a strain of streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. Immunosuppressants)
    • Drugs of abuse ( cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics)
  • Other:
    • 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
    • Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome
• Hereditary HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome:
  • Complement gene Gene 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. Basic Terms of Genetics mutations (involving complement 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 C3 and CD46 and complement factors H, B, and I)
  • Inborn errors of metabolism ( cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 C metabolism)

Pathophysiology

The pathophysiology for HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome secondary to Shiga-like toxin Shiga-Like Toxin Hemolytic Uremic Syndrome has been well described.^[7] 

1. Infection, most commonly from E. coli bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, is contracted by ingestion or consumption of undercooked beef or unpasteurized milk.
2. Bacterial toxins are absorbed by the gut and enter the systemic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment.
3. Bind BIND Hyperbilirubinemia of the Newborn to endothelial cells causing direct endothelial injury via:
   • Nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs (NO) production
   • Secretion Secretion Coagulation Studies of interleukin-1 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins (IL-1) and 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))
   • Macrophage activation Macrophage activation The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (maf) and the macrophage migration-inhibitory factor (mmif), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. IL-12 Receptor Deficiency
4. Cause 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 and localized thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus in 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: Histology and arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology:
   • Glomeruli vessels are especially affected → decreased glomerular filtration rate Glomerular filtration rate 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 ( 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)
   • Decreased renal blood flow Renal blood flow The amount of the renal blood flow that is going to the functional renal tissue, i.e., parts of the kidney that are involved in production of urine. Glomerular Filtration → increased renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation
5. Erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology are mechanically injured when going through the thrombotic microvasculature: causes microangiopathic hemolytic anemia Microangiopathic Hemolytic Anemia Hemolytic Uremic Syndrome

Other forms of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome:

• Varied pathological mechanisms
• All have endothelial damage in common.
• Lead to thrombus production and hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia

Clinical Presentation

History^[2,8,9]

• Typical HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome: prodromal illness with abdominal pain Abdominal Pain Acute Abdomen, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and bloody diarrhea Bloody diarrhea Diarrhea
• Pneumococcal HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome is preceded by:
  • Severe pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (usually with effusion) or 
  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis or
  • Less commonly, sinus or ear 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
• Other historical clues may include:
  • Concurrent known HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome outbreak/family member with concurrent HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome
  • Family member with history of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome (may be suggestive of a genetic cause)
  • Previous episode of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome (may be suggestive of a complement-mediated cause)

Physical examination^[2,8,9]

Symptoms usually occur 5–7 days after diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea and may include:

• Acute-onset lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia or irritability
• Pallor
• 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:
  • Oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation, volume overload, or dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
• Progression to neurologic symptoms:
  • Altered mental status Altered Mental Status Sepsis in Children
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Other organ involvement:
  • Cardiac: signs of fluid overload
  • 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: hepatomegaly

Diagnosis

Clinical diagnosis^[2,8,11,13]

Diagnosis per both US and UK criteria is clinical, based on the classic triad of:

1. Microangiopathic hemolytic anemia Microangiopathic Hemolytic Anemia Hemolytic Uremic Syndrome:
   • Normocytic anemia Normocytic Anemia Anemia: Overview and Types with hemoglobin level < 8 g/dL
   • Negative direct Coombs test Negative Direct Coombs Test Hemolytic Uremic Syndrome
   • ↓ Haptoglobin, ↑ reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count, ↑ lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma), ↑ indirect bilirubin Indirect Bilirubin Liver Function Tests
   • Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types → schistocytes Schistocytes Hemolytic Uremic Syndrome and helmet cells Helmet Cells Hemolytic Uremic Syndrome
2. Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia:
   • Platelet count < 140,000/mm³ (usually around 40,000/mm³)
3. Acute kidney injury Acute Kidney Injury 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:
   • Elevated serum creatinine and blood urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle (BUN)
   • May manifest as hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, or oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation

Additional tests^{[13,15,18,19]}

• Serum electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests, amylase Amylase A group of amylolytic enzymes that cleave starch, glycogen, and related alpha-1, 4-glucans. Digestion and Absorption, lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion:
  • In severe renal injury, acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis with hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia can occur.
  • ↑ Transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids levels can be seen.
  • Pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis and transient 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 can develop from pancreatic involvement.
• Prothrombin time Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis (PT), partial thromboplastin time Partial thromboplastin time The time required for the appearance of fibrin strands following the mixing of plasma with phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides). It is a test of the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (fibrinogen, prothrombin, factors V and X) of blood coagulation. Hemostasis (PTT)
• Stool culture and polymerase chain reaction Polymerase chain reaction Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) (detecting Shiga toxin Shiga toxin A class of toxins that inhibit protein synthesis by blocking the interaction of ribosomal RNA; with peptide elongation factors. They include shiga toxin which is produced by Shigella dysenteriae and a variety of shiga-like toxins that are produced by pathologic strains of Escherichia coli such as Escherichia coli o157. Diarrheagenic E. coli):
  • In children presenting with bloody diarrhea Bloody diarrhea Diarrhea
  • Best done early in the presentation
• If atypical HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome is suspected:
  • C3 and C4
  • Factor H and I concentration
  • Autoantibody screen
  • Genetic analysis
• Other tests depend on the presentation (e.g., chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification MRI if CNS abnormalities are present)

Renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis^[3,8,11,19]

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is not required for the diagnosis of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome, but when performed for disambiguation, 3 patterns are usually seen:

• Glomerular thrombotic microangiopathy:
  • 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: Histology appear thicker and have a double “contour” due to an increase in thickness of the subendothelial Subendothelial Membranoproliferative Glomerulonephritis layer.
  • Glomeruli appear large and blocked with microclots 
• Patchy cortical necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Arterial thrombotic microangiopathy:
  • Primarily seen in non-STEC HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome
  • Affects arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology, causing luminal wall necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and clotting

Diagnostic approach to a patient with thrombotic microangiopathy^[11]

Thrombotic microangiopathy (TMA) is seen in multiple disease processes aside from HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome. Among these, thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura ( TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura) is a medical emergency requiring urgent plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura. Because of this consideration, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship presenting with TMA should be evaluated as described below to determine the risk for TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura and the necessity for treatment.

• Includes patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
  • Clinical symptoms (neurologic, renal, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).) suggestive of TMA with or without evidence of organ damage
  • Peripheral smear confirming microangiopathic hemolytic anemia Microangiopathic Hemolytic Anemia Hemolytic Uremic Syndrome (will show large platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology due to a strong 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 response and fragments of red blood cells Red blood cells Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology).
• In these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship, rule out underlying conditions that can present with TMA:
  • Malignancy Malignancy Hemothorax
  • Disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation
  • Preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders/ HELLP syndrome HELLP syndrome A severe form of preeclampsia with Hemolysis (with: LDH > 600 IU/L, ↑ Bilirubin, Schistocytes on blood smear, Anemia), ↑ Liver enzymes (with AST and/or AST > 2 times upper limit of normal), ↓ Platelet count, and thrombocytopenia (< 100,000). Hypertensive Pregnancy Disorders
  • Organ transplant
  • Rheumatic disease
• Important to note that:
  • Kidney injury is a prominent feature of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome (but 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 in TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura).
  • Unlike HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome, immune TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura is characterized by severe ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 Type 1 Spinal Muscular Atrophy motif member 13) deficiency.
• Approach those who present with TMA by applying the PLASMIC score:
  • Platelets, combined hemoLysis 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, absence of Active cancer, no Stem cell or solid organ transplant, M CV CV Vasculitides, INR, Creatinine
  • 1 point given for each of the findings below:
    • Platelet count < 30,000/µL
    • Hemolysis (defined by reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count > 2.5%, undetectable haptoglobin, or indirect bilirubin Indirect Bilirubin Liver Function Tests > 2 mg/dL)
    • No active cancer
    • No solid organ or stem cell transplant
    • MCV < 90 fL
    • INR < 1.5
    • Creatinine < 2.0 mg/dL
  • Interpret PLASMIC score PLASMIC score The PLASMIC score predicts the probability of TTP in the presence of schistocytes on blood smear. Thrombotic Thrombocytopenic Purpura:
    • 6–7 points: high likelihood of TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
    • 5 points: intermediate likelihood of TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
    • 0–4 points: low likelihood of TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
• Next steps:
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a PLASMIC score PLASMIC score The PLASMIC score predicts the probability of TTP in the presence of schistocytes on blood smear. Thrombotic Thrombocytopenic Purpura of ≥ 6 should be treated empirically for TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura with therapeutic plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura.
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a score of 5:
    • Send for ADAMTS13 activity testing. 
    • Obtain expert consultation and consider plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura if no other etiology is identified.
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a score of ≤ 4 should be risk-stratified (based on clinical suspicion).
    • Consider alternative conditions.
    • ADAMTS13 activity testing is done if no other etiology is identified.

Management

Practice guidelines may vary depending on location. The following information is based on US, European, and UK literature and guidelines.

Management of HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome is primarily through supportive care.^{[2,12,13,15‒17,19]}

• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: RBC transfusions when indicated (hemoglobin < 6 or 7 g/dL)
• Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia: platelet transfusions only for significant clinical bleeding
• Acute kidney injury Acute Kidney Injury 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:
  • IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
  • Electrolyte management
  • Discontinuation of any nephrotoxic drugs
  • 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 if severe:
    • Uremia Uremia A clinical syndrome associated with the retention of renal waste products or uremic toxins in the blood. It is usually the result of renal insufficiency. Most uremic toxins are end products of protein or nitrogen catabolism, such as urea or creatinine. Severe uremia can lead to multiple organ dysfunctions with a constellation of symptoms. Acute Kidney Injury present
    • Severe fluid overload refractory to medical therapy
    • Severe acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis and electrolyte refractory to medical therapy
    • Azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury (BUN ≥ 80 mg/dL)
    • Nutritional support needed for a child with anuria Anuria Absence of urine formation. It is usually associated with complete bilateral ureteral (ureter) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present. Acute Kidney Injury
• 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 ( calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers ( nifedipine Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) or nicardipine Nicardipine A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers))):
  • Angiotensin-converting enzyme (ACE) inhibitors generally are not used during the acute phase Acute phase Short Bowel Syndrome (due to decreased renal perfusion).
  • ACE inhibitors ACE inhibitors Truncus Arteriosus are used when long-term renal effects are noted after the acute phase Acute phase Short Bowel Syndrome has passed.
• Nutrition: caloric intake according to needs
• Eculizumab:^[13–16,19]
  • Monoclonal antibody (binding C5) that blocks 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
  • Approved for atypical HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome or complement-mediated HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome
  • May be beneficial for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship presenting with severe neurologic involvement (e.g., coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures)
  • Meningococcal prophylaxis Prophylaxis Cephalosporins is needed (due to increased risk of infection with encapsulated Encapsulated Klebsiella organisms with eculizumab use).
• Plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura:
  • Uncertain benefits for STEC HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome
  • Used for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with suspected TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura while awaiting genetic tests or with confirmed TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
• Monitoring after the acute illness has passed:
  • Blood pressure
  • Renal function
  • 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

Note that antibiotic treatment during bloody diarrheal illnesses caused by Shiga toxin-producing bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology is associated with an increased risk of developing HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome.

Prognosis

• Early diagnosis and treatment have a favorable outcome: mortality Mortality All deaths reported in a given population. Measures of Health Status: < 5%^[1,3,4,10]
• Most recover renal function completely; however:
  • 30% are left with some degree of renal insufficiency.
  • 5% are left dependent on 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.
• When HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome is not associated with diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, the 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 is more severe:
  • Pneumococci-related HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome:
    • Oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia last longer.
    • Higher mortality Mortality All deaths reported in a given population. Measures of Health Status
    • Up to 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship require 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.

Differential Diagnosis

• Disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation ( DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation): associated with children with serious illnesses, such as septic shock Septic shock Sepsis associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status. Sepsis and Septic Shock. Unlike HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome, DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation presents with abnormal coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies, including prolonged prothrombin time Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis (PT) and partial thromboplastin time Partial thromboplastin time The time required for the appearance of fibrin strands following the mixing of plasma with phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides). It is a test of the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (fibrinogen, prothrombin, factors V and X) of blood coagulation. Hemostasis (PTT), decreased fibrinogen Fibrinogen Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides a and b, the proteolytic action of other enzymes yields different fibrinogen degradation products. Hemostasis, and increased D-dimer D-dimer Deep Vein Thrombosis.
• Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura ( TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura): occurs due to inhibition or deficiency of ADAMTS13, which causes decreased degradation of von Willebrand factor von Willebrand factor A high-molecular-weight plasma protein, produced by endothelial cells and megakaryocytes, that is part of the factor VIII/von Willebrand factor complex. The von Willebrand factor has receptors for collagen, platelets, and ristocetin activity as well as the immunologically distinct antigenic determinants. It functions in adhesion of platelets to collagen and hemostatic plug formation. The prolonged bleeding time in von Willebrand diseases is due to the deficiency of this factor. Hemostasis (VWF) multimers, and increased 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 and thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus. Laboratory analysis shows schistocytes Schistocytes Hemolytic Uremic Syndrome, increased lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma), and normal coagulation parameters. Symptoms include a classic pentad of neurologic and renal symptoms, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and microangiopathic hemolytic anemia Microangiopathic Hemolytic Anemia Hemolytic Uremic Syndrome. 
• Systemic 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: Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with systemic 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 would not have a prodrome Prodrome Symptoms that appear 24–48 hours prior to migraine onset. Migraine Headache of diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea associated with illness. They would also likely have systemic symptoms, such as arthralgias and/or rash Rash Rocky Mountain Spotted Fever.