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Pre-Renal Acute Kidney Injury Pathogenesis

Pre-Renal Acute Kidney Injury Pathogenesis

Hyponatremia- Physiology

Hyponatremia: Physiology Authors: Mannat Dhillon Reviewers: Andrea Kuczynski Kevin McLaughlin* * MD at time of publication Abnormal Renal H2O Handling (hypo-osmolar serum) AKI/CKD Heart failure ↓ renal blood flow ↓ glomerular filtration GFR < 25 mL/min, ↓ urine dilution ↑ H2O retention Note: • Plasma [Na+] is regulated by water intake/excretion, not by changes in [Na+]. • Artifactual hyponatremia can be differentiated by a normal or hyperosmolar serum. Appropriate ADH secretion ↓ EABV Hypovolemia: losses via GI, renal, skin, 3rd spacing, bleeding Hypervolemia: heart failure, cirrhosis ↑ Na+/H2O absorption at PCT ↓ EABV, ↑ H2O retention Urine [Na+] < 20 mmol/L Hereditary: tubular disorders (Bartter, Gitlemann syndromes). Thiazide diuretics Inappropriate: SIADH, hypothyroidism, AI Normal EABV Anti-diuresis Primary polydipsia, eating disorder ↑ H2O or ↓ solute intake ↓ Osmoles Impaired desalination Block NCC ↑ H2O retention ↑ Na+/K+ excretion Hyponatremia Serum [Na+] < 135 mmol/L Urine osmolality > 100 mmol/L Urine osmolality < 100 mmol/L Cerebral edema, ↑ intracranial pressure, vasoconstriction If hypovolemic: ↓ JVP, ↓ blood pressure Lethargy, altered mental status Abbreviations: AKI: Acute Kidney Injury CKD: Chronic Kidney Disease GFR: Glomerular Filtration Rate H2O: Water PCT: Proximal Convoluted Tubule EABV: Effective Arterial Blood Volume NCC: Na+/Cl- Co-Transporter SIADH: Syndrome of Inappropriate ADH Secretion AI: Adrenal Insufficiency Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 11, 2019 on www.thecalgaryguide.com

chronic-myeloid-leukemia

Chronic Myeloid Leukemia (CML): Pathogenesis and Clinical Presentation Translocation of a Chr 9 segment onto Chr 22, creating a Philadelphia chromosome (Chr 22) containing the BCR-ABL1 fusion gene Mutations from ionizing radiation Other genetic abnormalities Authors: Yan Yu Katie Lin Reviewers: Jennifer Au Crystal Liu Danielle Chang Lynn Savoie* *Indicates faculty member at time of initial publication These genetic abnormalities accumulate in the earliest cell of the blood cell differentiation sequence: the pluripotent hematopoietic stem cell Hematopoietic stem cell division in the bone marrow becomes unregulated 1. Chronic Stage (85% of clinical presentation): Hematopoietic stem cell division/differentiation in the bone marrow results in ↑ production of multiple blood cell lines (detectable on CBC, but patients are usually asymptomatic at this stage) Acquired ↑ genetic abnormalities 2. Accelerated Stage More and more immature precursor cells (”blasts”) divide and accumulate in bone marrow (where 10-19% of blood cells are “blasts”.) Blasts start to spill over into the peripheral blood Acquired ↑ genetic abnormalities 3. Blast crisis (transformation into AML/ALL) Neoplastic blast cells have filled up the bone marrow (where >20% of blood cells are blasts). More blasts spill out into the peripheral blood. Multifactorial causes, most Weight loss, malaise, fever/ with unclear mechanisms Neoplastic division of platelet precursor cells Neoplastic division of WBC precursor cells, especially neutrophil precursors Dividing “blasts” limit the space and resources available for RBC synthesis chills, night sweats Thrombocytosis Leukocytosis: · Neutrophilia, basophilia, & eosinophilia · “Left shift”: ↑ neutrophil & band production · Disorderly WBC differential: i.e. “myelocyte bulge” Trapping of WBC’s in the spleen enlarges the spleen Splenomegaly: · Left upper quadrant pain · Early satiety (large spleen compresses the stomach) · Associated hepatomegaly (if spleen is overfilled & WBCs spill over into liver) Anemia ↓ oxygenation of blood means blood is less red & body tries to compensate Pallor Dyspnea Tachycardia High turnover of these cancerous cells → excess cell lysis Release of intracellular contents (uric acid, K+, LDH) into plasma · Hyperkalemia · High (LDH) Hyperuricemia Gout Acute Kidney Injury Expanding marrow pushing on bone Bone marrow expands into sternum Bone pain Sternal tenderness Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 15, 2019 on www.thecalgaryguide.com

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia (ALL): Pathogenesis and Clinical Presentation Authors: Yan Yu, Katie Lin Reviewers: Crystal Liu, Kara Hawker, Jennifer Au, Lynn Savoie* * MD at time of initial publication Note: ALL is much rarer than AML and is usually seen in children Accumulation of genetic abnormalities in immature lymphoid precursor cells (B/T cell precursors) Neoplastic lymphoid precursor cells (“blasts”) divide and accumulate in bone marrow Abundance of blasts displaces other blood precursors from marrow, inhibiting their development/differentiati on After neoplastic blasts fill up bone marrow, they spill out into blood High turnover of these cancerous cells Multifactorial causes, most with unclear mechanisms Expanding marrow pushing on bone Pancytopenia on CBC 20% of marrow is blasts (on bone marrow aspirate and/or biopsy) Neoplastic blasts continue to divide and accumulate in lymph nodes and spleen (can occur, but not that common) Blasts detected as white blood cells on CBC High rate of cell lysis Weight loss, malaise, fever/chills, night sweats Bone pain (worse than that felt in AML, especially in children) ↓ in neutrophils ↓ in RBCs ↓ in platelets, reduced blood clotting ability Lymphadenopathy Splenomegaly May cause leukocytosis, despite pancytopenia Release of intracellular contents (uric acid, K+, LDH) into plasma Greater chances of infection Anemia Fatigue, shortness of breath, pallor Easy bruising and petechiae on skin Hyperuricemia Hyperkalemia High [LDH] Tumor lysis syndrome Acute kidney injury Gout Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published May 5, 2019 on www.thecalgaryguide.com

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS): Pathogenesis and clinical findings

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS): Pathogenesis and clinical findings Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome Shiga toxin from E. coli 0157:H7 infection Acquired ADAMTS13 auto-antibodies Pregnancy/Post-partum Unclear mechanism Failure to cleave large vWF multimers Accumulation of large vWF multimers (Usually broken down by ADAMTS13) Platelet aggregation and formation of platelet thrombi Widespread microthrombi occluding blood vessels causing tissue damage/necrosis Congenital ADAMTS13 mutation Triggering event ADAMTS13 deficiency Drug dependent antibodies target platelets Direct tissue toxicity (unclear mechanism) ADAMTS 13 Inhibition Widespread hemolysis Shut down of complement regulatory genes Uninhibited membrane attack complex formation Drugs (Quinine, Chemotherapy) Abbreviations: • vWF – von Willebrand Factor • ADAMTS13 (vWF cleaving protein) – A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13. Formation of fibrin strands Microangiopathic Hemolytic Anemia (schistocytosis) Cellular damage due to fibrin deposit (intravascular, non- autoimmune hemolysis) ↑ serum indirect bilirubin ↑ serum lactate dehydrogenase ↓ serum haptoglobin Authors: Sean Spence Nicole Burma Reviewers: Tristan Jones Yan Yu Man-Chiu Poon* Lynn Savoie* * MD at time of publication Uncontrolled platelet activation and consumption Thrombocytopenia Reduced clotting ability Purpura Central Nervous System (CNS) Confusion, severe headache, focal neurological findings Heart Patchy necrosis of myocardium Arrhythmia, Sudden Cardiac Death Kidney Glomerular damage à↓ GFR + protein leakage into urine Proteinuria, Acute Kidney Injury (AKI) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 1, 2019 on www.thecalgaryguide.com

Tumour-Lysis-Syndrome

Tumour Lysis Syndrome High sensitivity to treatment Highly proliferative malignancy with ↑cell-turnover Large tumour mass Author: Joshua Yu Reviewers: Hannah Yaphe Davis Maclean Tejeswin Sharma Yan Yu* *Peter Duggan *ManChiu Poon *Lynn Savoie *Juliya Hemmett * MD at time of publication High serum phosphate High serum Advanced uric acid Age Volume depletion Pre-existing renal disease Patient risk factors Initiation of cancer treatment Massive tumour cell lysis and release of cellular contents into circulation overwhelms homeostatic mechanisms Tumour properties (hematologic malignancies most common) Though rare, aggressive tumours can spontaneously lyse without treatment Intracellular potassium released into bloodstream Intracellular phosphate released Hyperphosphatemia ↑ serum phosphate Intracellular lactate dehydrogenase (LDH) released ↑ serum LDH Intracellular nucleic acids released Nucleic acids metabolized to uric acid Hyperuricemia ↑ serum uric acid Hyperkalemia ↑ serum potassium (see Hyperkalemia: clinical findings) Uric acid (a crystallizing substance) ↑ precipitation of calcium phosphate ↑ filtration of poorly soluble uric acid into acidic environment of renal tubules Serum phosphate binds serum calcium, forming solid calcium phosphate precipitate crystals High levels of calcium phosphate ↑ uric acid precipitation Uric acid precipitates as crystals and deposits in kidney tubules and collecting ducts Tubular injury and/or intraluminal obstruction Endothelial dysfunction in renal vasculature Renal inflammation, vasoconstriction, and impaired renal vascular autoregulation Decreased renal filtration Acute Kidney Injury (see Acute Kidney Injury Overview) Crystal deposition in the heart Depletion of soluble calcium Hypocalcemia Calcium phosphate crystals deposit in kidneys Main mechanism of Acute Kidney Injury Cardiac Arrythmias ↓ serum calcium (see Hypocalcemia: clinical findings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 25, 2020 on www.thecalgaryguide.com

Membranous Nephropathy

Authors: Jessica Krahn Membranous Nephropathy: Pathogenesis and clinical findings Reviewers: Brooke Fallis, Yan Yu*, Juliya Hemmet* * MD at time of publication Primary (Idiopathic) Membranous Nephropathy Secondary Membranous Nephropathy Drugs, infections, auto-immune diseases, and malignancies make antigens Blood tests for Anti- PLA2R antibodies are positive in ~70% of cases Autoantibodies are made to antigens expressed near or on podocyte surfaces or planted in the glomerular capillary wall (ie. PLA2R; THSD7A; NELL-1) IgG antibodies filter through the glomerulus Autoimmune: (e.g. Systemic Lupus Erythematous, thyroiditis) Drugs: (e.g. NSAIDs, gold, penicillamine, captopril) Malignancies: (ie. Prostate, Colon) Infections: (e.g. Hepatitis B, Syphilis) Circulating antigens filter through the glomerulus and between the GBM and podocytes Antibodies & antigens form immunocomplexes, which lodge Immunofluorescence shows diffuse “granular” between the glomerular basement membrane & podocytes deposits of immunocomplexes throughout GBM Basement membrane is formed between and around immunocomplex deposits Immunocomplexes activate complement and the assembly of the Membrane attack complex (MAC) MAC creates holes in podocyte plasma membranes Stimulates the release/activation of proteases and oxidases from glomerular podocytes and mesangial cells GBM appears thick on light microscopy “Spike and dome” pattern appears with silver stain Podocyte effacement Damage to negatively charged foot processes damages the charge barrier of the glomerulus that repels negatively charged molecules Increased filtration of large negatively charged molecules, especially albumin Induces ↑ hepatic lipoprotein synthesis and ↓ lipoprotein catabolism Hyperlipidemia (↑ serum LDL, VLDL, and triglycerides) ↑ lipid filtration through glomerulus Lipiduria (fatty casts) *Hypo-albuminemia ↓ oncotic pressure in capillaries Fluid leaks into interstitial space ↑ Filtration of Proteins C and S and antithrombin Hypercoagulable state Thrombosis *Edema (especially *Proteinuria ↑ Filtration of immunoglobulins Immunosuppression Infections ↑ Filtration of Plasminogen Plasminogen converted to plasmin in the cortical collecting duct via urokinase- type plasminogen activator Plasmin activates the epithelial sodium channel ↓ intravascular volume Hypotension Pre-Renal Acute Kidney Injury Underfill edema (see slide) peri-orbital, scrotal, labial, and extremities) Overfill edema (see slide) ↑ Na+ and water reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Minimal Change Disease

Minimal Change Disease: Pathogenesis and clinical findings Authors: Jessica Krahn Reviewers: Timothy Fu Brooke Fallis Yan Yu* Juliya Hemmet* * MD at time of publication Damage induced by cytokines, not immunocomplexes Lack of abnormal immunocomplexes (antibody-antigen complexes) present in serum Immunofluorescence test negative Idiopathic/Primary Minimal Change Disease No identifiable extraglomerular disease process causes this condition Secondary Minimal Change Disease Infections, NSAIDS, neoplasms via unclear mechanisms Minimal change to glomerulus seen on light microscopy Podocyte effacement seen on electron microscopy Abnormal T Cell activation and release of cytokines (sometimes called permeability factors) that are toxic to podocytes Podocyte foot processes efface (become flattened) or fuse together Damage to negatively charged foot processes damages the charge barrier of the glomerulus that repels negatively charged molecules ↑ filtration of larger negatively charged molecules, such as low-molecular weight proteins like albumin, from the blood into the renal tubular filtrate Induces ↑ hepatic lipoprotein synthesis and ↓ lipoprotein catabolism Hyperlipidemia (↑ serum LDL, VLDL, and triglycerides) ↑ lipid filtration through glomerulus Lipiduria (fatty casts) Hypo-albuminemia ↓ oncotic pressure in capillaries Fluid leaks into interstitial space ↑ Filtration of Proteins C and S and antithrombin Hypercoagulable state Proteinuria ↑ Filtration of immunoglobulins Immunosuppression Infections ↑ Filtration of Plasminogen Plasminogen converted to plasmin in the cortical collecting duct via urokinase- type plasminogen activator Plasmin activates the epithelial sodium channel ↓ intravascular volume Hypotension Pre-Renal Acute Kidney Injury Underfill edema (see slide) Thrombosis Edema (especially peri- orbital, scrotal, labial, and extremities) Overfill edema (see slide) ↑ Na+ and water reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 30, 2021 on www.thecalgaryguide.com

ACE inhibitors

Angiotensin Converting Enzyme (ACE) inhibitors: Mechanism of Action and Clinical Findings Angiotensin Converting Enzyme (ACE) Inhibitors Inhibits the conversion of angiotensin I to angiotensin IIà↓ serum angiotensin II levels Inhibits breakdown of bradykinin ↓ Activation of zona glomerulosa region of the adrenal cortex ↓ Aldosterone secretion from the adrenal cortex ↓ Expression of basolateral Na+/K+ pump and ↓ insertion of luminal Na+ channels in principal cells of the cortical collecting duct in kidney ↓ K+ secretion into urine ↑ Serum K+ concentration Hyperkalemia ↓ Activation of Na+/H+ exchanger in proximal convoluted tubule (PCT) of the kidney ↓ Na+ absorption into PCT and ↓ H+ excretion into lumen ↓ Na+ absorption into the blood ↓ Renal H2O reabsorption via osmosis ↓ Activation of paraventricular nuclei located in the hypothalamus ↓ Secretion of anti- diuretic hormone (ADH) into the capillaries of the posterior pituitary gland ↓ Aquaporin channel insertion at cortical collecting duct in kidney ↓ Renal H2O reabsorption à↑ serum bradykinin levels Vasodilation of efferent arteriole in kidneys ↓ Hydrostatic pressure within the glomerular capillaries ↑ Activation of cyclooxygenase-2 pathway ↑ Prostaglandin production ↓ Activation of angiotensin II type 1 receptors on surface of arteriolar smooth muscle ↓ Activity of G protein-coupled receptor intracellular secondary messenger cascade ↓ Systemic arteriolar vasoconstriction ↓ Total peripheral resistance (resistance to blood flow by systemic vasculature) ↓ Blood Pressure ↓ total blood flow perfusing kidneys Renal hypoxia ↑ Systemic arteriolar vasodilation ↓ Total peripheral resistance ↓ Blood Pressure ↓ Concentration of protein travelling through tubules for excretion ↓ Fraction of H2O filtered from glomerular capillaries into bowman’s capsule (start of the renal tubule) ↓ Filtration of blood contents through glomerular membranes Sensitization of airway vagal afferent receptors Stimulation of the cough center located in the medulla oblongata Cough ↓ Protein in urine High K+ levels surrounding the heart muscle cellsàchronic depolarization of the cardiomyocyte cell membrane àalters cardiomyocyte conduction (complex mechanisms) Cardiac Arrythmias (see relevant slide on Hyperkalemia: Clinical Findings) ↓ Effective arterial blood volume Authors: Nicole Brockman Reviewers: Emily Wildman, Austin Laing Adam Bass*, Yan Yu* * MD at time of publication Renal tubules have relatively less water compared with the peritubular capillaries ↓ H2O reabsorption from the renal tubule back into the blood ↑ Serum creatinine, ↓ estimated glomerular filtration rate Renal nephron injury and dysfunction Acute Kidney Injury (rise in creatinine >26.5umol/L in <7 days) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 10, 2022 on www.thecalgaryguide.com

NSAIDs and the Kidney mechanism of action and side effects

NSAIDs and the Kidney: Mechanism of Action and Side Effects Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* *MD at time of publication Concurrent use of angiotensin- converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) AECi and ARBs act to ↓ renin- angiotensin-aldosterone system (RAAS) activation Reduced angiotensin (AT) 2 activity at its receptors on efferent arteriole of the nephron Net vasodilation of efferent arterioles ↓ in glomerular pressure ↓ blood perfusing kidney tissueà↑ hypoxemia & renal ischemia Pre-existing ↓effective arterial blood volume (EABV) from dehydration, GI loss, diuretics, CKD, CHF, cirrhosis, etc. Decreased EABV triggers endogenous renal autoregulation, resulting in norepinephrine (NE) mediated vasoconstriction of afferent arteriole of the nephron Net ↓ in renal blood flow and ↓ in glomerular pressure ↓ volume of blood filtered by the glomeruli per unit time Non-steroidal anti-inflammatory drugs (NSAIDs) Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation) ↓ Renal prostaglandin (PG) synthesis: local hormones involved in renal homeostasis NSAID induced nephrotoxicity: associated with chronic usage independent of dosage (see Calgary Guide slide on NSAIDs and the Kidney: NSAID induced nephrotoxicity) ↓ intrarenal PG reduces inhibitory effects of PG over ADH in cortical colleting duct (CCD) of the kidneyà↓ antagonism on ADH activity ↑ ADH activity causes insertion of more aquaporins (water channels) in the collecting duct of renal tubules Net ↑ in volume of water reabsorbed into the blood ↓ vasodilatory effect of PG at the afferent arteriole of the nephron ↓ Glomerular filtration rate (GFR) ↓ PG signalling results in ↓ renin secretion at juxtaglomerular apparatus Low renin levelsà↓ conversion of angiotensinogen into its AT1 form and, by extension, ACE mediated conversion of AT1 to AT2 ↓ ACE 2 signalling leads to ↓ levels of aldosterone in the serum ↓ Na+ and K+ channel insertion on apical surface and ↓ Na/K ATPase activity on basolateral surface of principal cells ↓ K+ excretion into urine, and ↓ Na+ reabsorption back into the blood, at the late DCT and collecting duct of the kidney Pre-renal Acute Kidney Injury (AKI): kidney injury due to renal hypoperfusion Prolonged and/or severe ischemia causes cell death and aggregation of tubular epithelial cells of the kidney with subsequent inability to reabsorb luminal Na+ Renal dehydration predisposes precipitation of uromodulin protein Renal tubules mold uromodulin into cylindrical structures known as “casts”. Casts that contain only uromodulin protein are known as “hyaline casts” Hyaline cast seen on urinalysis Hypoperfusion of the kidney activates the renin- angiotensin- aldosterone system (RAAS) ↑ amount of sodium (Na) reabsorbed from the filtrate (less Na excreted) Fractional excretion of Na <1% Papillary necrosis: ureteral passage of sloughed ischemic tissue causing ureteral obstruction Acute tubular necrosis: a type of kidney injury causing damage to the tubules Hypertension Post-renal AKI: a type of kidney injury due to obstruction of the urinary tract Distal distal obstruction of the urinary tract causes fluid to accumulate within the kidneysàenlarging the kidneys Renal Ultrasound shows hydronephrosis (enlarged kidneys) Damaged tubule epithelial cells slough into the tubular lumen Epithelial cell breakdown in the tubular lumen releases uromodulin & other proteins, which aggregate into “casts” (cylindrical imprints of the renal tubule). The varied protein content of these casts result in them having a coarse, granular appearance Damaged tubular epithelial cells are unable to properly reabsorb sodium ↓ amount of sodium (Na) reabsorbed from filtrate into the blood (more Na excreted) Fractional excretion of Na >2% True excess of free water relative to Na+ in the blood Excess free water ↑ venous hydrostatic pressure (see Calgary Guide slide on edema for full mechanisms) Pitting Edema Hyperkalemia Hyponatremia Coarse granular casts seen on urinalysis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 29, 2022 on www.thecalgaryguide.com

clostridium-difficile-infection-pathogenesis-and-clinical-findings

Clostridium difficile (C. diff) Infection Authors: Ryan Brenneis, Sravya Kakumanu Reviewers: Yoyo Chan, Sean Doherty, Vina Fan, Ben Campbell, Dr. Steve Vaughan*, Dr. Sylvain Coderre* * MD at time of publication Community exposure Infected close contacts Nosocomial exposure (most common) Poor hand hygiene and sanitization of surfaces and medical equipment Nosocomial risk factors Any antibiotic use (Especially clindamycin, fluoroquinolones, penicillins, cephalosporins) ↑ Antibiotic resistant strains Presence of pre-disposing risk factors (Note: do not need to be present for infection) Recent GI surgery Chemotherapy that has antimicrobial and immunosuppressive effects Usage of medications that reduce stomach acid (↑ pH) ↑ C. diff spores on surfaces and personnel Contact exposure Environmental exposure to C. diff carriers Inoculation of GI tract Disruption of normal gut microbiome allowing C. diff overgrowth Comorbidities (>65 years old, cirrhosis, inflammatory bowel disease, enteral feeding, obesity) via fecal-oral route Clostridium difficile Infection of GI Tract Spores unaffected by antibiotics germinate post-antibiotic treatment Infection recurrence Pseudomembranous colitis on endoscopy (colonic ulcerations potentially seen with severe infection) Hypotension Acute kidney injury Release of C. diff toxin A and B inactivates Rho and Ras GTPases in colonic epithelial cells (colonocytes) (Rho and Ras GTPases control cytoskeletal dynamics and gene expression) Cytoskeletal disorganization and arrest of RNA synthesis causes necrosis of colonocytes and triggers host immune response Neutrophil chemotaxis and activation ↑ Inflammation of colon Disruption of tight junctions between colonocytes Release of fluid into intestinal lumen and inability of colon to reabsorb it Toxic megacolon Bowel perforation Bloody stool (<10% of patients) Abdominal cramps Large bowel dilation from muscle paralysis Inflammation and destruction of underlying smooth muscle Breakdown of colonocyte cell membranes Inflammation of visceral peritoneum Volume depletion Watery diarrhea: ↑ frequency, small volume Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 30, 2019, updated May 16, 2022 on www.thecalgaryguide.com

hyperkalemia-↓-renal-excretion-pathophysiology

Hyperkalemia (↓ Renal Excretion): Pathophysiology Non-steroidal anti- inflammatory drugs (NSAIDs) Inhibition of prostaglandins which promote renin secretion (see NSAIDs and the Kidney: Mechanism of Action and Side Effects slide) Diabetic Nephropathy Acute (AIN)and chronic (CIN) interstitial nephritis Immune-mediated damage of the kidney tubule and interstitium Damage to distal tubule leads to aldosterone resistance at principal cell Aldosterone cannot ↑ EnaC insertion on principal cell of CCD Epithelial sodium channel (ENaC) blockers Acute kidney injury and chronic kidney disease ↓ Effective arterial blood volume (volume of blood effectively perfusing tissue) ↓ Oxygen perfusion to renal tissue causing renal ischemia Autonomic neuropathy ↓ sympathetic drive to produce renin Chronic juxtaglomerular cell damage ↓ synthesis of renin Blockage of ENaC on the principal cells of the CCD Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) Angiotensin II is either not formed (ACEi), or blocked at its receptor (ARBs) Angiotensin II cannot stimulate the release of aldosterone from the adrenal cortex Adrenal Insufficiency Adrenal gland cannot produce sufficient amounts of aldosterone ↓ Renin secretion by the afferent arteriole prevents RAAS activation ↓ Aldosterone release from adrenal cortex ↓ ENaC (Na+ reabsorption channel) expression on principal cells of the cortical collecting duct (CCD) Damage to kidney causes renal impairment and ↓ glomerular filtration rate ↓ Glomerular filtrate production means ↓ tubular flow rate ↓ Na+ delivery to the distal tubule ↓ Na+ reabsorption by ENaCs at the principal cell in CCD ↓ Na+ and water reabsorption by ENaCs in CCD ↓ Effective arterial blood volume (EABV) Activates renin-angiotensin-aldosterone system (RAAS) leads to ↑ renin secretion in the afferent arteriole (see Physiology of the renin-angiotensin-aldosterone system (RAAS) slide) ↑ Na+ and water loss in tubular lumen ↑ Positive charge in tubular lumen ↓ Electronegativity gradient in tubular lumen of CCD ↓ K+ excretion by the principal cell in the CCD as there is less of a electronegative gradient ↑ Accumulation of K+ in blood Hyperkalemia Serum [K+] > 5.1 mmol/L See Hyperkalemia: Clinical Findings slide In the case of diabetic nephropathy and NSAIDS ↓ EABV does not stimulate RAAS and therefore aldosterone production ↓ Renin ↓ Aldosterone ↑ Renin secretion activates an ↑ in aldosterone production but aldosterone action at the principal cell is blocked because of ENaCs or resistance in AIN and CIN ↑ Renin ↑ Aldosterone In the case of ACEi, ARBs, or adrenal insufficiency ↑ renin secretion does not lead to ↑ aldosterone ↑ Renin ↓ Aldosterone Note: as described in the above flow chart, measuring serum renin and aldosterone levels can be used to help diagnose the cause of hyperkalemia. Authors: Mannat Dhillon, Joshua Low, Emily Wildman, Huneza Nadeem Reviewers: Andrea Kuczynski, Marissa (Ran) Zhang, Adam Bass*, Kevin McLaughlin* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 2, 2022 on www.thecalgaryguide.com

hypovolemic-shock

Hypovolemic Shock: Pathogenesis, Complications, and Clinical Findings Authors: Dean Percy Miranda Schmidt Reviewers: Yan Yu Tristan Jones Frank Spence* Ben Campbell Ayaaz Sachedina* * MD at time of publication Progressive ↓ in level of consciousness Pulseless Electrical Activity Acute Kidney Injury ↑ Reabsorption of salt and water in the kidney Oliguria (↓ urine output) Inflammation (pancreatitis, cirrhosis, post-operative, etc.) Inflammatory mediators ­ vessel permeability and fluid leaks out Trauma Ruptured vessels leak fluid into potential spaces Hemorrhagic losses (GI bleed, postpartum hemorrhage, etc.) ↓ Intravascular volume ↓ Venous return to the heart ↓ Cardiac output (blood pumped from the heart) Hypovolemic Shock ↓ Oxygen delivery to tissues due to low blood volume Insufficient organ perfusion Non-Hemorrhagic losses (dehydration, GI losses, skin losses / burns, renal losses, etc.) ‘Third Spacing’ of fluid (fluid located outside the intravascular or intracellular space; large collections can occur in the pelvis, thorax, GI tract, long bones of children, intra-abdominally, retroperitoneally) P = Q x R; less ‘flow’ in the vessels (Q), with vessels not constricting enough to maintain resistance (R)à pressure (P) will drop ↓ Blood Pressure Caution: young, healthy individuals can maintain blood pressure during circulatory collapse with ­ cardiac output and ­ vasoconstriction; do not use blood pressure as an indicator of shock severity in children Carotid sinus baroreceptors sense low blood pressure ↓ Carotid sinus inhibition of sympathetic nervous system Release of sympathetic catecholamines (epinephrine and ↓ Pressure in venous circulation Brain Heart Kidneys ↓ Blood in the right internal jugular vein ↓ Oxygen delivery to the brain ↓ Myocardial contractility (from lactic acidosis) ↓ Blood flow to kidneys ↓ Jugular Venous Pressure Catecholamines bind to beta-1 receptors in the sinoatrial node of the heart Beta-1 receptor activation causes ↑ heart rate Tachycardia norepinephrine) Catecholamines bind to and stimulate alpha-1 receptors in peripheral vessels Vasoconstriction of peripheral vessels ↓ Blood flow to peripheral tissue Catecholamines bind to and stimulate beta receptors in sweat glands Diaphoresis (sweating) In all body tissues Inadequate oxygen delivery ↓ ATP production ↑ Anaerobic metabolism ↓ Body temperature Impaired neurological functioning Renal ischemia Activation of the renin-angiotensin aldosterone system ↓ Glomerular filtration rate ↓ Clearance of lactic acid by the kidney ↑ Lactic acid production ↓ Rate of activity of clotting enzymes Lactic Acidosis Unknown mechanism Coagulopathy Hypothermia Trauma Triad of Death ↑ Capillary Cold, mottled refill time extremities Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 24, 2013, updated December 4, 2022 on www.thecalgaryguide.com

Post-Renal Acute Kidney Injury AKI

Post-Renal Acute Kidney Injury (AKI): Pathogenesis and clinical findings Blood clot or cellular debris Foreign body Neurogenic bladder Obstruction intrinsic to urine excretion system Nephrolithiasis (kidney stones) Anatomical defect(s) Intra- abdominal adhesions Retroperitoneal fibrosis (scar-like tissue) Benign or malignant masses Prostate cancer Benign prostatic hyperplasia ↓ Urine flow across point of obstruction Obstruction extrinsic to urine excretion system Urine buildup distends urine collecting system (hydronephrosis) Compression of renal vasculature due to mass effect ↑ Volume/pressure proximal to obstruction ↑ Intratubular pressure ↓ Pressure gradient between glomerular afferent arteriole and Bowman’s space Casts occlude tubules ↓ Filtration of plasma into nephrons ↓ Glomerular Filtration Rate (GFR) Obstruction is relieved ↓ Intratubular pressure Rapid GFR ↑ Rapid diuresis of fluid and electrolytes Dilated pelvicalyceal system on ultrasound ↓ Urine output ↓ Venous drainage and arterial supply Local ischemia and inflammation of kidney Impaired resorption, excretion, and fine tuning by tubules Acute Tubular Necrosis (ATN) with granular casts ↓ Urine output ↓ Clearance of free water and solutes ↑ Intravascular volume ↑ Serum creatinine ↓ Medullary solute concentration, ischemia, ↓ response of collecting ducts to antidiuretic hormone Lasts > 24hrs Post-obstructive diuresis causes hypovolemia and electrolyte derangements Authors: David Campbell, Matthew Hobart Reviewers: Raafi Ali, Luiza Radu Huneza Nadeem, Marissa Zhang, Julian Midgley* * MD at time of publication Resolves < 24hrs in euvolemia Physiologic post- obstructive diuresis ↑ Na+ and Cl- delivery to distal convoluted tubule is sensed by macula densa Secretion of adenosine by macula densa Adenosine constricts afferent arterioles ↓ GFR ↓ Renal clearance of drugs and waste products ↑ Venous hydrostatic pressure ↑ Volume in arterial system overwhelms pressure regulation mechanisms Hypertension Fluid extravasation from veins and capillaries Generalized Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com

Malignant Hyperthermia

Malignant Hyperthermia: Pathogenesis & clinical findings Authors: Haotian Wang, Jen Guo Reviewers: Julena Foglia, Priyanka Grewal, Luiza Radu Kevin Gregg* * MD at time of publication Depolarizing muscle relaxant (e.g., succinylcholine) & volatile anesthetic (e.g., sevoflurane, desflurane, isoflurane, halothane, NOT nitrous oxide) Autosomal dominant mutation in ryanodine receptor (RyR1; RyR1 transports calcium out of the sarcoplasmic reticulum during muscle depolarization) LowerthresholdforactivationofRyR1 state Prolonged opening of RyR1 ↑ Ca2+ in myocyte cytoplasm Capacity of the reuptake protein to carry Ca2+ is overwhelmed Sustained muscle contraction à hypermetabolic state Malignant Hyperthermia Vigorous exercise & heat (rare) Rare life-threatening clinical syndrome that occurs in genetically susceptible patients upon exposure to a triggering agent Skeletal muscle rigidity (i.e., masseter muscle spasm) Sustained muscle contraction Myocytes (muscle cells) deplete available ATP Hypermetabolic state ↑ O2 consumption ↑ Heart rate to meet O2 demand ↑ CO2 production Unexplained ↑ end tidal CO2 (early sign) ↑ Temperature Hyperthermia (late sign) ↓ O2 supply ↑ Anaerobic metabolism ↑ Lactic acid production Metabolic acidosis Cell death Leakage of muscle contents into circulation ↑ Serum creatinine kinase Development of rhabdomyolysis (rapid breakdown of muscle tissue) Myoglobinuria (presence of excess myoglobin in urine) Acute kidney injury** Hyperkalemia Electrolyte imbalances (i.e., hyperkalemia) Abnormal myocyte contraction Cardiac dysfunction Dysrhythmias Cardiovascular collapse Release of thromboplastin (converts prothrombinàthrombin) & other prothrombotic substances (promotes clot formation) Imbalance between thrombotic & antithrombotic pathway ↑ Clot formation from activation of the extrinsic & common pathways Disseminated intravascular coagulation** Tachypnea (in absence of prominent mechanical ventilation) Tachycardia (early sign) Cardiovascular collapse Vital organ failure Coma **See corresponding Calgary Guide slide(s) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 25, 2015; updated Oct 2, 2024 on www.thecalgaryguide.com