Renal Function Anatomy & Structure Exam Notes PDF

Manautou -- Renal Function Anatomy & Structure Key Kidney Function - Maintain a constant volume and composition of body fluids by varying the excretion of solutes and water, even in the face of changes in dietary intake or endogenous production rate. - This function is essential to unde...

Manautou -- Renal Function Anatomy & Structure Key Kidney Function - Maintain a constant volume and composition of body fluids by varying the excretion of solutes and water, even in the face of changes in dietary intake or endogenous production rate. - This function is essential to understand, as it directly impacts drug dosing, metabolism, and elimination. Role of the Kidney - Major function of kidney is to maintain homeostasis for a number of solutes and water - Acute kidney Injury -- can be caused by medications - Inflammatory response can retain organ and create systemic damage - Chronic kidney disease - ie. diabetes can lead to CKD - Fluid retention → debris - Affect other organs (HF) →→ - Homeostasis: Relevant Substances - Electrolytes: sodium, potassium, chloride - Water (osmolality) - Acid-base balance: bicarbonate (extracellular fluid volume buffering effect) - Minerals: calcium, phosphorus, magnesium - Waste material: urea (protein), creatinine (muscle -- biomarker for indications regarding kidneys), uric acid (nucleic acids) Principles of Water, Na+ Balance - Steady-state balance is maintained by matching excretion with intake - Under steady state conditions for renal excretion is determined by fluid intake - The extracellular fluid (ECF) and intracellular fluid (ICF) are in osmotic equilibrium - Osmolarity tends to stay constant - Changing sodium will not change sodium ECF concentration, but will change volume of ECF Additional Concepts of Balance -- mostly FYI!! - Neutral balance: is the state where dietary intake plus endogenous production equals excretion rate of the kidney. Under neutral balance, total body contents of the substance remains stable - Positive balance: intake plus endogenous production is greater than renal excretion rate, leading to increased total body content (can lead to fluid retention, higher blood pressure, and potentially edema). - Negative balance: intake plus endogenous production is less than renal excretion rate, leading to decreased total body content (can lead to decreased total body content of sodium and water, resulting in dehydration and low blood pressure). Approximately 2/3 of total body water is intracellular fluid and one third is extracellular fluid - 60% is basically water → intra and extracellular fluid - Major cation of extracellular fluid is Na+ - Plasma and interstitial fluid - Major cation of intracellular fluid is K+ - Osmotic pressure gradients determine movement between ECF and ICF(e.g., Na+ , K+ ) - Dictated by movement of Na/K across the compartments Kidneys - Paired organ -- posterior part of abdominal wall - Capsule -- provides cushioning - Protection - Adrenal Glands - Capsule and fat covered by renal fascia? Capsule surrounds each kidney which is then embedded in fat to provide protection - Kidneys are embedded in fat layer to prevent bruising - Marathon runners have low fat and it can impact the kidney fat - “Floating kidneys” → lose cushion and bruise kidneys Kidney Anatomy - Layers - Capsule ➔ Cortex ➔ Medulla (darker in color) - Hilum - Entry and exit - Renal Hilum : area in which vessels get into kidneys (arteries, veins, and components of lymphatic system, and nerve fibers) - Passage of Urine - Pyramid ➔ Papilla ➔ Calyx ➔ Pelvis ➔ Ureter ➔ Bladder - Pyramid : cone shaped region with lines - Lines in the diagram are basically due to straight segment of nephrons (characteristic of this structure) - Papilla: Apex of pyramid - Calyx: minor and major ⇒ Cop (?) like structure? - Nephron is the functional unit of the kidneys - Kidney contains 1.2 million nephrons - Subunits of nephron include glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule - 2 types (juxtaposition or arrangement of nephrons): - Cortical nephrons (85%) -- most abundant - Sitting high in cortex of kidney - Juxtamedullary nephrons (15%) - Start in the cortex and deeper into the medulla Kidney Anatomy -- continued - Nephron - Juxtapositioning - Blood supply Note the close positioning of the distal convoluted tubule next to the glomerulus; important for sodium and other cations homeostasis. Renal Corpuscle (Glomerulus + Bowman’s capsule) - Corpuscle - Glomerulus: tufts of capillaries that look into the bowman's capsule - Bowman’s capsule - Bowman’ s space - Filtration function: - Three layers - Pores - Podocytes Afferent arteriole: brings blood into the glomerulus - Where is the blood? - glomerular capillaries - Where is the filtrate? - Bowman’s space Structure of the Filtration Membrane - Inner epithelium is the endothelium that lines the glomerular capillaries. This is a fenestrated endothelium that penetrates through the endothelial cells. - Fenestrations allow certain substances of a particle size and charge to go through the pores for filtration process - The next layer is the glomerular basement membrane (GBM), the basement membrane at the junction of the two epithelia. - At interface → basement membrane (junction of two epithelial - endo and epi) - Outermost portion of capillary - Outer epithelium contains podocytes, cells with elaborate interdigitating processes known as foot processes – filtration slits that filter macromolecules. - SOME selectivity Juxtaglomerular Apparatus (JGA) Role in controlling renal blood flow, glomerular filtration, renin-angiotensin aldosterone system (RAAS) - Cells: - Juxtaglomerular cells: renin-producing granular cells - Macula densa: distal tubule cells in contact with afferent and efferent arterioles  Juxtaglomerular Apparatus (JGA) - Afferent arteriole brings blood in - Efferent arteriole brings blood out - In blood vessels (granular renin-producing cells) ⇒ PRODUCE RENIN - Macular dena cells → interaction between cells is critical for controlling urine concentration and blood flood in response to sudden changes - REMEMBER: juxtaglomerular function is secrete renin in response to sudden changes in renal pressure or blood flow. ⇒ also produces erythropoietin - Main function is to secrete renin in response to decreases renal blood pressure or blood flow; also produces EPO (erythropoietin) Histology of the Nephron - Proximal tubule - Cells are cuboidal cells -- rich in microvilli - Important for cells bc they are doing alot of transport processes (Absorption and secretion) - Microvilli increase SA for transport processes - Distal tubule - Loop of Henle: - Thin: squamous cells - Thick: cuboidal cells - Collecting duct - Principal cells: tall epithelial cells - Intercalated cells: epithelial cells with microvilli and mitochondria Location of Tubular Cells in the Nephron ⇒ Summary: Nephron Function - Importance of Na+ reabsorption - Na+ balance - Water balance - Reabsorption of other solutes - Sites of action of diuretics ⇒ Inhibition of Na+ reabsorption - Transport is critical and it is regulated Renal Blood Flow Blood Flow ⇒ FYI (primarily) - Renal artery – 20-25% of cardiac output - Interlobar artery – Arcuate arteries - Interlobular arteries - Glomerular capillaries - Vasa recta -- flow is opposite - Along Loop of Henle - Blood to medulla - Permeable to water & solutes - Countercurrent exchange - Renal veins Factors Influencing Blood Flow --fyi? Constriction Dilation - Angiotensin II and renin - Glucocorticoids - Endothelin - Nitric oxide - Sympathetic nerve innervation - Prostaglandins - Atrial natriuretic peptide - Adenosine - Kinins - Dopamine Kidney Functions - Regulatory - Regulate body osmolality and volume and blood pressure - Balance electrolytes and minerals - Regulate acid-base balance - Excretory - Excrete waste, drugs, and metabolites - Endocrine - Produce renin, erythropoietin, 1,25-dihydroxyvitamin D3 Blood Pressure Regulation - Kidney: critical organ for maintaining normal blood pressure: - homeostasis of sodium and water, maintaining normal extracellular fluid volume - control of the renin – angiotensin- aldosterone axis - production of vasodilatory substances - OTHER FUNCTIONS - Catabolism of small peptide hormones, such as insulin. With decreased nephron mass, there is decreased insulin catabolism, resulting in longer circulating insulin half-life. - Kidneys can produce some glucose via gluconeogenesis during fasting. - Much lower than the capacity of the liver - Kidney is responsible for elimination of many medications and their metabolites. - Therefore, alterations in kidney function can change drug plasma concentrations. Glomerular Filtration - Glomerular filtration rate (GFR) is the volume of filtrate formed per minute by kidneys. - GFR and pressure relationship: – - Constriction of afferent arteriole reduces blood flow to the nephron and glomerular pressure. This decreases GFR and body fluids are conserved. - This is an auto-regulatory feedback mechanisms intrinsic to the kidney that counteracts blood pressure changes and maintains a steady GFR - Glomerular and tubular events must work at unison to achieve normal kidney function determined by glomerular filtration rate (GFR) - GFR: best index of overall kidney function - Other kidney functions correlate with GFR: - e.g., filtration of waste products, fluid balance, nutrient reabsorption. Urine Formation - Blood flows into afferent arteriole No glucose should be in the urine!!! - Filters into glomerulus - There is a threshold -- surpassing - Drains into Bowman’ s capsule (filtrate) capacity for transporters - Proceeds through proximal convoluted tubule - Passes along the loop of Henle - Continues into distal convoluted tubule - Urine drains into renal pelvis - Urine goes to ureter - Urine stored in bladder - Urethra 1. Glomerular Filtration 2, Reabsorption - Ultrafiltration based on size and - From lumen of tubule to blood molecular charge - Active transport - Pressure in glomerulus increases due to - Solute reabsorption drives water narrowing of capillaries reabsorption - Needed to maintain filtration 3. Secretion - Bigger glomerulus to smaller size - From blood to tubule lumen → hydrostatic pressures pushes - Active transport fluid out of vessel into bowman's space - Forces plasma to leave capillary and enter Bowman’s capsule - Filtrate is protein free 🚀 - Proteins = Houston we have a problem Excretion = Filtration – Reabsorption + Secretion know. Steps in Urine Formation This is s schematic representation of the steps presented in the previous slide - Hydrostatic pressure = important!!!!!! - Transport mechanisms throughout nephron buy bulk of work is done through the proximal convoluted tubule. Mechanism of Kidney Function - Glomerular level: - Massive quantities of plasma ultrafiltrate are formed at the glomerulus (180 L per day) - Maintained by dramatic blood flow to kidneys: ~20% of total cardiac output - Tubular level: - Greater than 99% of glomerular filtrate must be reabsorbed Selective reabsorption and secretion determines urinary excretion rates Factors Affecting GFR - Glomerular capillary hydrostatic pressure - Change in renal blood flow - Change in renal capsule hydrostatic pressure - Oncotic pressure (plasma albumin content) - Albumin critical for maintaining molecules within vessels - Water cant stay in blood vessels because of lack of albumin -- ascites ! - Glomerular capillary permeability - Filtration surface area that is functional - Physicochemical characteristics of macromolecules (e.g., size, shape, and charge) CAN LOSE NEPHRONS (kidney damage) ⇒ Composition of Filtrate -- “Ultrafiltrate of Plasma” - Devoid of cellular elements (endothelium) - Essentially protein free (podocytes & glomerular basement membrane - GBM) - < 10 kDa (freely filtered) ⇒ water, electrolytes, small peptides * - > 10 but < 60 kDa (variably filtered – charge matters!) - > 60 - 70 kDa (not filtered) *substances of less than 10 Kda in size are fully filtered Segment-Specific Functions - Glomerulus - Filtration of plasma - Proximal Tubule - Reabsorption of electrolytes, glucose, amino acids, urea, water - Secretion of foreign substances - Loop of Henle - Concentration of urine - Descending loop: water reabsorption - Ascending loop: Sodium reabsorbed (active transport), no water reabsorption - Distal Tubule - Reabsorption of water (in some cases) and electrolytes – - Secretion of electrolytes, urea, some drugs - Collecting Duct - Reabsorption of water - Reabsorption or secretion of electrolytes Urine Composition - Electrolytes/Solutes: - Sodium, potassium, ammonia, calcium, magnesium, chloride, phosphate, urea, creatinine, drugs - Urine pH ranges from 4.6 to 8.0 but is typically acidic - Should not be there: - Glucose, amino acids, proteins, blood, ketones, leukocytes, bilirubin - As learned in endocrine, glucose should not be in urine! Proximal Convoluted Tubule - Reabsorption: - 65% of filtered Na+ /K+ /Ca2+ and Mg2+ - 85% of NaHCO3 - 100% of glucose and amino acids - Water reabsorbed passively - Mechanisms of Reabsorption - Specific Transport: NaHCO3 , NaCl, glucose, amino acids, organic solutes - Paracellular: K+ - Functions: - Reabsorption of Na+ (majority), Cl- , HCO3 - , K+ , water - Secretion of H+ - Tubular fluid is isosmotic relative to plasma - Key players: - Na+ /H+ exchanger - Carbonic anhydrase - Na+ /K+ ATPase - Cl- /base exchanger Proximal Tubule Reabsorption Secretion Albumin Choline Salicylates Ascorbate Creatinine Thiamine Fructose Histamine Urate Galactose p-aminohippurate Bile salts Glutamate Penicillin Cimetidine Glucose Probenecid Oxalates Phosphate Diuretics Dopamine Sulfate Atropine Quinine Procainamide Thin Limbs of Henle - Descending Limb - Reabsorption of water leading to concentrated tubular fluid (hyperosmotic) - Permeable to water - Impermeable to solutes - Ascending Limb - Reabsorption of Na+ , Cl- - Impermeable to water - Permeable to solutes - Secretion of urea Thick Ascending Limb - Function: - Reabsorb Na+ , Cl- , Ca2+ , Mg2+, K+ from lumen - Tubular fluid is hypo-osmotic relative to plasma - Dilution of urine (impermeable to water) - Key Players: -- fyi - Na+ /K+ /2Cl- cotransporter (NKCC2) - Na+ /K+ ATPase Distal Tubule - Function: - Contain macula densa - Reabsorb Na+ , Ca2+ , Cl- - Water reabsorbed in the distal segment of distal tubule -- aquaporin water channel? - Secretion of H+ - Key Players: - Na+ /Cl- cotransporter (NCC) - Na+ /K+ ATPase - Calcium channel and Na+ /Ca2+ exchanger  Collecting Tubules Function 1: Solute Transport Function 2: Water reabsorption - Reabsorbs NaCl (2-5% of what is - Final urine concentration determined filtered); Key Players: - Aquaporin-2 (AQP2); Vasopressin Receptor - Secrete K+ Regulation: - Final urine concentration determined - Antidiuretic hormone zADH) controls insertion of Cell types: water channels (AQP2 -- water pore) into apical - Principal Cells: membrane by G protein-coupled and cAMP process - Na+ , K+ and water transport - Under regulation of vasopressin receptor → - Intercalated Cells: through cAMP process causes incorporation - H+ secretion and reabsorption of onto apical side and causes: (below) - INCREASE ADH, INCREASE HCO3 - AQP2= INCREASE H2O Regulation: ⇒ Aldosterone permeability (reabsorption from - Tries to correct sodium changes lumen), more concentrated urine Regulation of Water & Sodium Angiotensin II: Generated from precursors by renin - INCREASE water and sodium reabsorption in proximal tubule Aldosterone: Produced in adrenal cortex and released in response to angiotensin II - INCREASE sodium reabsorption in thick ascending limb - INCREASE water and sodium reabsorption in distal tubule and collecting duct Antidiuretic Produced in posterior pituitary, also called vasopressin hormone (ADH): - INCREASE water reabsorption in distal tubule and collecting duct Atrial natriuretic Produced in atrial myocytes and brain peptide (ANP): - DECREASE sodium and water reabsorption Dopamine: - DECREASE water and sodium reabsorption in proximal tubule Sympathetic nerves: - INCREASE water reabsorption in proximal tubule, distal tubule and collecting duct Countercurrent Mechanism - Fluids (blood and filtrate) flow in opposite directions through parallel tubes to produce concentrated urine - Loop of Henle (filtrate) - Vasa recta (blood) - The term "countercurrent" highlights the opposing directions of flows. - As the fluid moves through the Loop of Henle, sodium and other solutes are actively transported out, creating a concentration gradient that increases from cortex to medulla. - CONCENTRATION GRADIENT - Water moves out of the Loop of Henle and into the surrounding tissue, allowing the body to reabsorb water and produce concentrated urine. - Loops of Henle multiply the concentration gradient, and the vasa recta acts as a countercurrent exchanger to maintain the gradient. - The countercurrent mechanism maintains the medullary hyperosmolarity essential for water reabsorption from the tubular fluid and production of concentrated urine - NUMBER ON BAR ON THE LEFT (concentration of interstitial fluid) - Environment in deep in the medulla is hyper osmotic VINO -- Diuretics 1) Osmotics Currently in use today are classified by their chemical - Mannitol class (thiazides), site of action (loop diuretics), mechanism - Sorbitol - Isosorbide of action (carbonic anhydrase inhibitors and osmotics) or (2) Carbonic Anhydrase Inhibitors effect on urine contents (potassium sparing diuretics). - Acetazolamide - Metazolamide - Ethoxzolamide - Dichlorphenamide (3) Thiazides and Thiazide-like - Chlorothiazide - Benzthiazide - Quinethazone - Indapamide (4) Loop or High-ceiling - Furosemide - Bumetanide - Ethacrynic Acid - Torsemide (5) K+-sparing: a. Mineralocorticoid Receptor Antagonists - Spironolactone - Canrenone - Eplerenone b. Antagonists of Na+ channels - Triamterene - Amiloride - Diuretics are chemicals that increase the rate of urine formation: - Increase excretion of electrolytes (Na+ , Cl- ) and water - Do not affect protein, vitamins, glucose, etc. reabsorption - Treatment of edematous conditions (congestive heart failure, nephrotic syndrome, chronic liver disease, etc.) - Wide range of clinical conditions including hypertension (hypercalcemia, diabetes, glaucoma, etc.) - Kidney (lumina of the nephrons, ~1 million): - Maintain homeostasis of electrolytes and water - Excrete water-soluble end products of metabolism NEPHRON Key points for diuretics - Diuretics increase rate of urine flow, also increase excretion of Na+ and an accompanying anion (Cl- ) - NaCl is the major determinant of extracellular fluid volume - Most diuretics directed at reducing extracellular fluid volume by decreasing total body NaCl content - After consistent diuretic use, kidney readjusts Na+ excretion using diuretic braking Classification of Diuretics - Classified by - Chemical class (thiazides) - Mechanism of action (carbonic anhydrase inhibitors and osmotics) - Site of action (loop diuretics) - Effects on urine contents (potassium-sparing diuretics) - Vary in efficacy and site of action within nephron - Potency is the amount of diuretic required to produce a specific diuretic response - Efficacy is measured as ability of the diuretic to increase the excretion of sodium ions filtered at the glomerulus - Efficacy is determined in part by the site of action SUMMARY OF DIURETICS Osmotics - Are not frequently used in clinic currently -> can expand extracellular fluid volume - Exception: prophylaxis of acute renal failure or severe bleeding -> maintain urine flow  - Also occasionally used to reduce acute intraocular or intracranial pressure Increase intraluminal osmotic pressure, causing H2O to pass from the body into the tubule, increase volume of urine and the excretion of H2O and almost all electrolytes - (note sites of action on the scheme) Carbonic Anhydrase Inhibitors - Carbonic anhydrase (CA) catalyzes the formation of carbonic acid from CO2 and H2O (makes urine acidic) - Sulfanilamide renders urine alkaline because of inhibition of carbonic anhydrase - Inhibiting CA decreases bicarbonate (HCO3) reabsorption - Shuts down the symporter - Decreases activity of the antiporter (fewer H+ ions) - Must inhibit 99% of CA to observe diuretic effect and then, only affects 2-5% of filtered load of Na+ - Na+, bicarbonate and water excreted (diuretic effect) SO2-NH2 (sulfonamide group) is essential for activity, substitutions at this site completely block the effects of the drug in inhibiting carbonic anhydrase Thiazides - R6 = H has very little diuretic activity, whereas compounds with Cl, Br, or CF3 are very active – an electron withdrawing group is necessary - Substitution of a lipophilic group at position 3 increases the potency and increases the duration of action - Saturation of the double bond (N4-C3) produces active diuretics - An alkyl substitution at the 2 position decreases the polarity and increases the duration of action; although these compounds have carbonic anhydrase activity, there is no correlation of this activity with their saluretic (excretion of Na+ and Cl- ions) activity - Replacement of the sulfonamide group at 7 by CH3SO2 or H gives compounds with almost no activity Thiazide-like Drugs Loop or High-ceiling - Pharmacological rather than chemical similarities - The greatest peak diuresis – name “high ceiling” - Site of action – ascending limb of the loop of Henle (some activity on proximal or distal tubules) - Efficacy explained by: - Approximately 25% of filtered Na+ load is reabsorbed by AL - Nephron segments past AL do not possess great reabsorptive capacity - Lumenal Na+/K+/Clsymporter inhibitors - Fast onset (~ 30 min) - Short duration (about 6 hours) Inhibiting the luminal Na+/K+/2Cl- symporter - Symporter captures free energy in the Na+ electrochemical gradient and uses it to force the “uphill” transport of K+ and Cl Potassium-Sparing: Mineralocorticoid Receptor Antagonists  - - Ligand binding domain of mineralocorticoid receptor (green) bound to aldosterone (magenta) Potassium-Sparing: Mineralocorticoid Receptor Antagonist - Aldosterone promotes salt and water retention - Substance that antagonizes the effects of aldosterone could be a good diuretic - Spironolactone - Competitive antagonist to mineralocorticoid receptor - Prevents reabsorption of Na+, Cland water - Late DCT and CD - Metabolized to active metabolite, canrenone and canrenoic acid anion - Eplerenone - Similar mechanism of action as spironolactone - Primarily used for cardiovascular applications Other Potassium-Sparing: Antagonists of Na+ channels The epithelial sodium channel (ENaC, also: amiloride-sensitive sodium channel) - 2,4-diamino-6,7-dimethylpyridine a potent diuretic ⇒ Triamterene - Interferes with process of cationic exchange by blocking luminal sodium channels - Blocks the reabsorption of sodium and the excretion of potassium - Does not antagonize aldosterone - Useful in combination with a thiazide or loop diuretic - Amiloride - Structurally related to triamterene - Same mechanism of action as triamterene - Side effect of all potassium-sparing diuretics: hyperkalemia Adams -- Introduction to Chronic Kidney Disease (CKD) Demographics - 1 in 7 adults in the US are estimated to have CKD - More common as patients age: - 65 years or older (34%) than in 45-64 years (12%) or 18-44 years ( 6%) - More common in - non hispanic Black adults (20%) than non hispanic asian adults *(14%), hispanic adults (14%) or non-hispanic White adults (12%) Background Chronic Kidney Disease: - Defined by “abnormalities of kidney structure or function, present for a minimum of 3 months, with implications for health” (KDIGO 2024) - Progressive worsening of kidney disease - It is classified using: - eGFR function (G1 - G5) - Albuminuria (A1-A3) eGFR and Albuminuria - eGFR: - Estimated glomerular filtration rate - It tells how well the kidney is filtering waste products - Calculated using blood creatinine - Albuminuria: - Albumin in the urine - Healthy kidneys stops the albumin from being filtered out the kidney, however with CKD and kidney damage, the albumin may be let into the urine - Some symptoms: foamy urine, frequent urination, or puffiness around the eyes or swelling of the feet, ankles, belly area or face - Urine albumin-creatinine ratio (uACR): - Used to assess for albuminuria - Greater than 30 mg/g is a sign of CKD → FYI! Risk Factors: - Hypertension - Diabetes → damage to nephrons → decreased filtration - Cardiovascular disease - Prior AKI/AKD → damages to kidneys and increase CKD chances CLASSIFICATIONS Take home: as EGfr and albuminuria worsens so does CKD Can progress to renal failure Complications More prevalent as patients ages in nearly every stage of the CKD - Examples: - Kidney failure - Cardiovascular disease (heart disease and/or stroke) - Hypertension - Metabolic acidosis - Electrolyte abnormality: hyperkalemia, hyponatremia, and volume overload - Gout Management of Complications - Blood pressure control - Glycemic control - Lipid management - Weight management - Smoking cessation Guidelines - KDIGO CKD: Kidney Disease: Improving Global Outcomes - NKF KDOQI: National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nephroprotective Agents → SLOW/DELAY progression of worsening kidney disease - ACE Inhibitors - ARBs - Finerenone - SGLT2 Inhibitors - GLP-1 Receptor Agonists ACE Inhibitors & ARBs - ACE inhibitors and ARBs both work by lowering the effects of angiotensin II (AT2 - AT2 is a hormone made by your body that helps modulate blood pressure - → NO MOA asked ACE INHIBITORS ARBs - Benazepril (Lotensin) - Losartan (Cozaar) - Ramipril (Altace) - Irbesartan (Avapro) - Lisinopril (Prinivil, Zestril) - Valsartan (Diovan) - Enalapril (Vasotec) - Olmesartan (Benicar) How are ACE Inhibitors and ARBs nephroprotective? Inhibition of Angiotensin II causes vasodilation of efferent arterioles (E → exit kidney, A→ to kidney) - Reduce intraglomerular pressure by preferentially dilating the efferent arteriole - Decrease glomerular permeability to proteins and lower proteinuria - Decrease systemic blood pressure, reducing stress on the kidneys - Improve renal blood flow - RELAX PRESSURE ON KIDNEY Afferent and Efferent Arterioles - NSAIDs cause vasoconstriction of the afferent arterioles - Via inhibition of prostaglandin production - *NSAIDS are nephroTOXIC - ACEs and ARBs cause vasodilation of the efferent arterioles - Via inhibition of angiotensin II - Together? ⇒ predispose CKD patients to kidney injury GUIDELINE RECOMMENDATIONS KDIGO (2024) ⇒ if patients have CKd and elevated albumin ( uACR >30) ⇒ ACE OR ARB! - For people with CKD and severely increased albuminuria without diabetes - For people with CKD and moderately increased albuminuria without diabetes - Urine albumin-creatinine ratio uACR > 30 - For people with CKD and moderately-to-severely increased albuminuria with diabetes Clinical Use of ACEi/ARBs - ACEs & ARBs are nephroprotective - ACEs & ARBs are also cardioprotective and are used to treat hypertension and heart failure - ACEi or ARBs are up-titrated to maximum tolerated dose - Use should be accompanied by dietary salt intake restriction - Combinations are NOT recommended - ACEi may cause bradykinin accumulation, notable for side effects like cough and angioedema Monitoring: - May cause hyperkalemia, monitor serum potassium - May cause an initial bump in serum creatinine - monitor renal function (SCr, GFR) Contraindications: - In renal artery stenosis - Concurrent use with NSAIDs - NSAIDs causing afferent arterial vasoconstriction Finerenone A nonsteroidal mineralocorticoid receptor antagonist (MRA) - Works similar to spironolactone (same bucket of meds) - FDA approved in July 2021 to treat CKD associated with Type II Diabetes - finerenone (Kerendia) - spironolactone (Aldactone) - eplerenone (Inspra) Other members of the aldosterosterone receptor antagonists - EXISTS !!! → SEE BELOW How is finerenone nephroprotective? - Blocks the over activation of mineralocorticoid receptors - Decreases inflammation and fibrosis in the kidneys - A reduction in albuminuria - FIDELIO-DKD, FIGARO-DKD trials - Reduced cardiovascular risk in people with CKD and T2D - A reduction in kidney failure outcomes Clinical Use of Finerenone Finerenone is specifically indicated for chronic kidney disease associated with T2D - The only nonsteroidal MRA and provides greater selectivity in the mineralocorticoid receptor and no activity at the steroid receptor - Lower incidence of hyperkalemia - Lower incidence of gynecomastia Recommended for patients with - eGFR > 25 mL/min/1.73 m2 - Normal serum potassium levels (< 5.0 mEq/L) - Albuminuria Contraindications - Use with strong CYP3A4 inhibitors/inducers - Grapefruit or grapefruit juice - Patients with adrenal insufficiency GUIDELINE RECOMMENDATION KDIGO (2024) - For adults with T2D, and eGFR > 25 mL/min per 1.73 m2, normal serum potassium concentrations, and albuminuria (> 30 mg/g (>3 mg/mmol)) despite maximum tolerated dose of RAS inhibitor - ALL DATA IS PT ON ACE/ARB and Finereone !! NOT A MONOTHERAPY! SGLT2 Inhibitors → Sodium-glucose cotransporter-2 Inhibitors (SGLT2i) Inhibit the reabsorption of sodium and glucose from the proximal tubules - Canagliflozin (Invokana®) - Dapagliflozin (Farxiga®) - Empagliflozin (Jardiance®) - Ertugliflozin (Steglatro®) Pearls Indications: CHF, CKD, T2DM Side effects: Increased urination and thirst Contraindications: - Avoid SGLT2i use in patients with a history of UTI requiring hospitalization or bladder/urinary devices - This includes patients who are unable to maintain their own personal hygiene - Should be discontinued in pregnant patients **Renal dose adjust based on eGFR*** How are SGLT2is nephroprotective? - Decrease sodium and glucose reabsorption - ↓ Intravascular volume - ↓ Blood pressure - Increases sodium to distal nephron and macula densa - Normalizes tubuloglomerular feedback - Decrease intraglomerular pressure - Decrease glomerular hyperfiltration FOCUS ON POPULATION AND OUTCOMES SECTION - SGLT2s were ADDED onto ACe/ARBS - Pts had TYPE 2 DIABETES - Reduced kidney failure - Patients w CKD and Diabetes → USE SGLT2s GUIDELINE RECOMMENDATIONS KDIGO (2024) - Treat patients with type 2 diabetes, CKD AND an eGFR > 20mL/min/1.73m2 with an SGLT2i - Treat adults with CKD with an SGLT2i for eGFR > 20mL/min/1.73m2 with urine ACR > 200mg/g OR heart failure, irrespective of level of albuminuria - DAPA-HF, DELIVER, EMPEROR-Reduced, EMPEROR-Preserved ADA (2024) - For people with type 2 diabetes and CKD, use of an SGLT2 inhibitor is recommended to reduce CKD progression and cardiovascular events in individuals with eGFR ≥20 mL/min/1.73 m2 and urinary albumin ranging from normal to 200 mg/g creatinine - ACR = albumin-to-creatinine ratio GLP-1 Receptor Agonists -- Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs) GLP-1s increase insulin release and suppress glucagon release - ↑ Glucose uptake in muscle and peripheral tissue - ↓ Hepatic glucose production GLP-1 Receptor Antagonists - Semaglutide (Ozempic®, Wegovy®, Rybelsus®) - Liraglutide (Saxenda®, Victoza®) - Dulaglutide (Trulicity®) Pearls Indications: T2DM and weight loss Side effects: Constipation, diarrhea, loss of appetite, stomach pain, nausea, vomiting - Slows stomach emptying Contraindications: - Avoid use in patients with a history of pancreatitis Dulaglutide, liraglutide and semaglutide (SQ) are preferred in patients with ASCVD to improve CV outcomes How are GLP-1s nephroprotective? - ↓ Glomerular hyperfiltration - ↑ Diuresis and natriuresis - ↓ Blood pressure - Suppresses overactivation of RAAS GLP-1s with proven renal benefits Liraglutide -- Trials: LEADER, SCALE, LIRA-RENAL - Renal endpoint: Composite of macroalbuminuria, doubling of SCr, eGFR