PBSN 529 Pharmacology & Medicinal Chemistry II Fall 2024 Past Paper PDF

PBSN: 529- Pharmacology & Medicinal Chemistry II Fall 2024 Part-II AKI-CKD-ESRD Pharmacology of Diuretics Time: Tues 10:15 AM to 12:30 PM/ Thurs: 2 PM to 4:00 PM 1 ...

PBSN: 529- Pharmacology & Medicinal Chemistry II Fall 2024 Part-II AKI-CKD-ESRD Pharmacology of Diuretics Time: Tues 10:15 AM to 12:30 PM/ Thurs: 2 PM to 4:00 PM 1  Lecture-Specific Objectives * Explain Electrolyte imbalances in the body and its consequences on AKI, CKD & other renal disorders; * List various diuretics used to control renal disturbances; * Critically analyze ADME of all types of diuretics including their MOAs. * Describe how diuretics are used to control various physiological disorders; * Identify medication-related causes of the various types of acute kidney injury * Describe complications associated with acute kidney injury * Explain approach and management of AKI/CKF and other renal disorders; * Describe risk factors and preventive strategies of AKI & CKD;  Frequently Used Terminologies in this field Mix – Match Exercise before January 11, 2024 1. Urgency A. Frequent voiding- Excessive urination (4) 2. Pyuria B. Strong desire to void (1) 3. Proteinuria C. Painful or difficult voiding (12) 4. Polyuria D. Delay, difficulty in initiating voiding (8) 5. Oliguria E. Excessive urination at night (6) 6. Nocturia F. Involuntary loss of urine (7) 7. Incontinence G. Involuntary voiding during sleep (11) 8. Hesitancy H. Increased volume of urine voided (10) 9. Hematuria I. Urine output less than 500 ml/day (5) 10. Frequency J. Urine output ‘zero’ or less than 50 ml/day (13) 11. Euresis K. Red blood cells in the urine (9) 12. Dysuria L. Abnormal amounts of protein in the urine (3) 13. Anuria M. Pus in the urine (2) 14. Azotemia N. Elevation of nitrogenous wastes (14) 15. Uremia O. Clinical syndrome which occurs due to azotemia (15) 16. Sepsis P. The systemic presence of bacteria, toxin etc. (16)  Part-I: Pharmacology of Diuretics MEMORIZE Classes of Diuretics 1. Carbonic anhydrase inhibitors (Acetazolamide, acetazolamide, methazolamide, and dorzolamide) 2. Loop diuretics (Furosemide, Bumetanide, Torsemide, Ethacrynic acid) 3. Thiazide diuretics (Chlorthalidone, Indapamide, Metolazone, Bendroflumethiazide) 4. Loop agents + Thiazides Osmotic diuretics (Mannitol) 5. K+ Sparing diuretics (Amiloride, Triamterene, Eplerenone, Spironolactone) Changes in Urinary electrolyte patterns and body pH in response to diuretic drugs. +, increase; −, decrease; 0, no change; ↓ or ↑= acidosis or alkalosis. Urinary Electrolytes Group Body pH NaCl NaHCO3 K+ Carbonic anhydrase + +++ + ↓ inhibitors V more "t" means stronger effect Loop agents ++++ 0 + ↑ Thiazides ++ + + ↑ Loop agents plus thiazides +++++ + ++ ↑ - action is more pronounced ↓ / combination treatment + K -sparing agents + (+) − ↓ https://accesspharmacy-mhmedical-com.lb-proxy13.touro.edu/content.aspx?sectionid=175217531&bookid=2249&Resultclick=2  1. CARBONIC ANHYDRASE INHIBITORS ACETAZOLAMIDE [Indisulam, Methazolamide, Topiramate, Benzthiazide] * A potent carbonic anhydrase inhibitor used to treat edema from heart failure or medications, certain types of epilepsy, and glaucoma. * Very effectively controls fluid secretion (e.g., some types of glaucoma), in the treatment of certain convulsive disorders (e.g., epilepsy) and in the promotion of diuresis in instances of abnormal fluid retention (e.g., cardiac edema). * CA catalyzes the reversible reaction involving the hydration of CO2 and the dehydration of carbonic acid. * The diuretic effect is due to its action in the kidney on the reversible reaction involving hydration of carbon dioxide & dehydration of carbonic acid. [H2CO3 ⇌ H2O + CO2 /H2CO3 ⇌ HCO3− + H+ ] * The net result is renal loss of HCO3 ion, which carries out sodium, water, and potassium. Alkalinization of the urine and promotion of diuresis are thus affected. * Alteration in ammonia metabolism occurs due to increased reabsorption of ammonia by the renal tubules as a result of urinary alkalinization. > done to counteract metabolic acidosis  MEMORIZE 2. LOOP DIURETICS L (FUROSEMIDE, BUMETANIDE, TORSEMIDE, ETHACRYNIC ACID) ① ② ③ Furosemide (FUR) is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver ① ⑤ = end L stage cirrhosis, renal disease, and hypertension. (MEMORIZE liver disease * MOA: FUR inhibits absorption of sodium and chloride both in PCTs and DCTs but also in the loop of Henle; The action on the DCT is independent of any inhibitory effect on CA and aldosterone. (MEMORIZE -phase z metabolism * FUR is metabolized in kidneys and small % in the liver; Extensively bound to plasma proteins, mainly to albumin; Major metabolites (i) FUR-glucuronide (pharmacologically active), and (ii) saluamine (4-chloro-5- sulfamoylanthranilic acid); 85% cleared by kidneys & >40% unchanged. * The onset of diuresis begins within 1 hr; Then it peaks within the 1st or 2nd hr; Diuretic effect lasts 6 to 8 hours; * The bioavailability of FUR in fasted is ~60-64%; The terminal 1/2-life of furosemide is approx. 2 hrs; * Excretion is greater via IV injection than the tablet or oral solution; * FUR binding to albumin may be reduced in elderly patients & FUR is predominantly excreted unchanged in the urine; Initial diuretic effect declines in aged subjects compared to younger subjects; * The renal clearance of furosemide after IV admin in older healthy males (60 to 70 years of age) is statistically significantly smaller compared to younger healthy males (20 to 35 years of age);  3. THIAZIDES HYDROCHLOROTHIAZIDE (HCTZ) MOA: * They act directly on the kidneys and promote diuresis (excess urine flow) by inhibiting the sodium/chloride cotransporter located in the DCT of a nephron; *Thiazides increase excretion of sodium and chloride in approximately equivalent amounts, which in turn decreases extracellular fluid and plasma volume; reduce BP; * Natriuresis (water loss) causes a secondary loss of potassium and bicarbonate but retain Calcium. * The mechanism of the antihypertensive effect of thiazides is unknown; * The mean plasma half-life of hydrochlorothiazide in fasted individuals has been reported to be approx. 2.5 hours. * Onset of diuresis occurs in 2 hours and the peak effect at about 4 hours; action persists for approx 6-12 hours. * HCTZ is eliminated rapidly by the kidney; At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency (weak diuretic);  4. K+-SPARING AGENTS Amiloride, Triamterene, Eplerenone, Spironolactone MOA: * K+ sparing effect is through inhibition of sodium reabsorption at the DCT, cortical collecting tubule & collecting duct; this decreases the net negative potential of the tubular lumen & reduces both K+ and H+ secretion & their subsequent excretion. Ami is a pyrizine compound used to treat hypertension & congestive heart failure. * Amiloride HCl (antikaliuretic) possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity; [partially additive to the effects of thiazide diuretics] * In the presence of a thiazide or loop diuretic, amiloride decreases the enhanced urinary excretion of magnesium; * Ami is not an aldosterone antagonist; Rather spironolactone, eplerenone are aldosterone antagonists; * Acts within 2 hours after an oral dose; effect on electrolyte excretion reaches a peak between 6 and 10 hrs and lasts about 24 hrs; Peak plasma levels are obtained in 3 - 4 hrs and the plasma half-life varies from 6 to 9 hrs; * AMI is not metabolized by the liver (patients with hepatic dysfunction do not accumulate the drug); Excreted unchanged by the kidneys; accumulation likely in hepatorenal syndrome; * About 50% of a 20 mg dose is excreted in the urine and 40% in the stool within 72 hours; Ami has little effect on GFR or renal blood flow. ## Read more on Amiloride and defn of Hepatorenal syndrome in the textbox below!  MISC OTHERS ON RENAL MGMT Antidiuretic hormone (ADH) and Desmopressin are prototypical ADH agonists. They are peptides and must be given parenterally. Conivaptan and Tolvaptan are ADH antagonists. Demeclocycline was previously used as an antagonist. Lithium also has ADH-antagonist effects but is never used for this purpose. ADH facilitates water reabsorption from the collecting tubule by activation of V2 receptors, which stimulate adenylyl cyclase via Gs. The increased cyclic adenosine monophosphate (cAMP) causes the insertion of additional aquaporin AQP2 water channels into the luminal membrane in this part of the tubule. Conivaptan is an ADH inhibitor at V1a and V2 receptors. Tolvaptan is a more selective V2 blocker with little V1 affinity. Demeclocycline and lithium inhibit the action of ADH at some point distal to the generation of cAMP and presumably interfere with the insertion of water channels into the membrane. 1. Agonists ADH and desmopressin reduce urine volume and increase its concentration. Thus, ADH and desmopressin are useful in pituitary diabetes insipidus (insufficient ADH). They are of no value in the nephrogenic form of the disease (resistance to ADH), but salt restriction, water restriction, thiazides, and loop diuretics may be used. These therapies reduce blood volume, a very strong stimulus to proximal tubular reabsorption. The proximal tubule thus substitutes—in part—for the deficient concentrating function of the collecting tubule in nephrogenic diabetes insipidus. 2. Antagonists ADH antagonists oppose the actions of ADH and other naturally occurring peptides that act on the same V2 receptor. Such peptides are produced by certain tumors (eg, small cell carcinoma of the lung) and can cause significant water retention and dangerous hyponatremia. This syndrome of inappropriate ADH secretion (SIADH syndrome) causes hyponatremia and can be treated with demeclocycline and conivaptan or tolvaptan. Lithium also works but has greater toxicity and is never used for this indication. Conivaptan and tolvaptan are also used off label in some patients with heart failure complicated by hyponatremia. PBSN: 529- Pharmacology & Medicinal Chemistry II Spring 2024 Part-IV Chronic Kidney Disease (CKD) & Its Management Time: Tues 10:15 AM to 12:30 PM/ Thurs: 2 PM to 4:00 PM 12  Lecture-Specific Objectives * Identify the most common causes and risk factors for the progression of chronic kidney disease (CKD). * Define CKD based on structural and functional abnormalities and categorize patients based on CKD KDOQI stages; * Explain the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative classification system to stage a CKD patient’s degree of renal impairment; * Contrast the National Kidney Foundation’s staging system with the Kidney Disease: Improving Global Outcomes guidelines. * List risk factors for CKD and Classify type and recommend treatment options for albuminuria, proteinuria and hematuria; * Calculate ACR, PCR evaluate result, and provide recommendations for treatment; * Identify symptoms by early CKD vs. late CKD stages; * Describe the management of hypertension, hyperglycemia, and nutritional needs for patients with CKD; * Describe interventions that may help to slow the progression of CKD; * Compare and contrast the mechanism of action and side effects of phosphate binders; * Describe the place in therapy of phosphate binders, vitamin D analogs and cinacalcet in the management of CKD-related mineral and bone disorder (CKD-MBD); * Identify current recommendations for proper use and potential side effects of iron therapy and erythropoiesis stimulating agents to treat anemia of CKD;  Chronic Kidney Disease Definition An irreversible decrease in the number of functioning nephrons resulting in progressive and permanent deterioration of renal function. medications > Al I was not halted by ; progression of AKI-CKD Definition and classifications National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) ~ Kidney damage for > 3 months as defined by: *Structural or functional abnormality of the kidneys; * With or without decreased GFR; * Often manifested by either pathologic abnormalities; or markers of kidney damage; * Abnormalities in the composition of blood or urine, or abnormalities in imaging tests; - need to do a complete bloodwork ~ GFR < 60 mL/minute/1.73 m2 for 3 months, with or without kidney damage; Clinical Manifestations OF CKD  Classifying CKD: GENERAL Causes focal segmental glomeriosclerosis Type of Disease Examples of systemic diseases Examples of Primary kidney affecting the kidney disease Glomerular diseases DM, Autoimmune Disease (e.g., SLE), FSGS, Primary Membranous, diabetes infections, neoplasia Minimal Change, Proliferative or mellitus > ex -. UTI (bad bic , sterile) wrine is usually crescentic GNs Tubulointerstitial Infections, Sarcoid, Drugs, Urate, UTIs, Stones, Obstruction diseases myeloma, environmental toxins Vascular Disease Atherosclerosis, HTN, ischemia, ANCA-associated renal limited cholesterol emboli, systemic vasculitis, fibromuscular dysplasia vasculitis, TMAs, scleroderma Cystic & Congenital PKD: Polycystic Kidney disease, Renal dysplasia, medullary cystic Disease Alports syndrome, Fabry’s disease kidney disease FSGS: Focal Segmental Glomerulosclerosis; ANCA: Anti-Neutrophilic Cytoplasmic Autoantibody; TMA: Thrombotic Microangiopathy; Sarcoidosis: Sarcoidosis is an inflammatory disease that affects multiple organs in the body, but mostly the lungs and lymph glands.; IMPORTANT Genetics of CKD – Predisposing Factors- *Diabetes mellitus *Hypertension *CV disease *Family members of patients with ESRD Markers of kidney function found to be 27-33% heritable. Biomarkers are: Serum creatinine, GFR, albumin, proteinuria, BUN Many genes associated with chronic kidney disease: https://ghr.nlm.nih.gov/search?query=chronic+kidney+disease 1. REN-related kidney disease Q. Make sure you 2. Polycystic kidney disease know the causes and gene responsible? 3. Uromodulin-associated kidney disease 4. Medullary cystic kidney disease type 1 ONLY MEMORIZE 5. Kidney stones THESE 6. Fabry disease 7. Dent disease  The stages of CKD Stages are stratified by measuring or calculating GFR, which is the gold standard for the quantitative index of renal function. * There is a gradual, age-related decline in GFR that often is asymptomatic and goes unnoticed; stress on the nephrons accumulates over time, especially in the presence of comorbidities such as hypertension and DM; * The rate at which GFR declines can be a useful predictor of progression to end- stage renal disease (ESRD). GFR, usually expressed as mL/min, represents the volume of plasma ultra-filtrate presented to the nephrons per unit time during the process of urine formation; * Note : Kidneys nate diabetes b/c of hyperglycemia (pressure buildup highest in the glomerulus) Refresh Your Memory- GFR Q. How to calculate NFP? S CONSTANTS  GFR Categories Q. GFR stages and range? > End stage renal disease CESRD) Albumin excretion < rate Protein excretion < rate Albumin to creatinine ratio protein to creatinine < ratio  > cannot tolerate (we CAN tolerate HYPERglycemia Bleeding diathesis means a tendency to bleed or bruise easily; irregular or slow blood clotting! F Related image Related image def. nails become Club shaped (dome) FYI Understanding eGFR > Angiotensin receptor blockers in Angiotens converting enzyme Q. What is eGFR? Q. At what stage do you start ACE/ARB therapy? Anemia: The primary cause of anemia in CKD patients is a decreased production of erythropoietin (EPO); In the kidneys, peritubular cells sense hypoxia and mediate synthesis and release of EPO, a glycoprotein; EPO is a hormone that regulates RBC proliferation and differentiation in bone marrow by stimulating proliferation of erythroid progenitor cells in the bone marrow and promoting the release of reticulocytes (immature RBCs) from the marrow; Transfer in saturation 1 IRON DEFICIENCY - ANEMIA MEDICATIONS Erythrocyte stimulating agents -  L inflammatory marker HEPCIDIN: Additional Mechanisms of Iron deficiency Very common in stage 5 CKD, it happens because of the following: Erythrocytes #1 vole : - oxygen transport - Decreased GI absorption of iron - Excession in liver ~ Inflammation (Hepcidin mediated) ↓ hemachromatosis ~ frequent blood testing ~ blood loss from hemodialysis ~ Increased iron demands from erythropoietin-stimulating agent (ESA) therapy; & Imbalance in Hepcidin synthesis: A hormone produced by the liver that regulates iron, it directly binds to ferroprotein (FPN) (the cellular iron exporter) MEMORIZE ~ High iron = High Hepcidin (to prevent export of iron Hepcidin is decreased or absent in iron deficiency, increased by transfusion-induced from iron stores); iron overload and inflammatory diseases, and in ~ Low iron = Low Hepcidin (to promote export of general shows high correlation with serum iron when needed, ex. Erythropoiesis; ferritin levels. An oral load of 65 mg of iron in ~ Inflammation or infection = high Hepcidin (which healthy volunteers caused > 5-fold increase in means, low iron in the plasma); hepcidin within 1 day; Misc: Decreased RBC life span (from the normal of 120d to approx 60d in individuals with stage 5 CKD): Vitamin B12 deficiency & Folate deficiency are common.  D/C CkD pts. / show anemic conditions Iron supplementation is required by most CKD patients receiving an ESA * This is because there is an increased demand from stimulation of RBC production; * Iron is absorbed after oral administration, then absorbed in the duodenum; L pancreas * Acidic conditions in the - gallbladder stomach keep iron in the - - stomach - reduced ferrous form, 3 areas that open which is the more soluble form; at duodenum * Absorption of iron decreases with increased dose; * Recommended daily dose of iron taken in 2 -3 divided doses; Complications of CKD: Mineral and Bone Disorders (MBD)  Calcium 2 + ca (blood) : mg/dL ca't (cell) : mcg Bone (microgram * 99% of Ca2+ is found in bone, (preserved as minerals - 1 % of calcium is component of Hydroxyapatite; distributed The body throughout (free calcium) > - this carries out calcium-dependent * Dietary Ca2+ is determined by the needs for events (activate bone development and maintenance which proteases nucreases , phospho- etc. ) varies throughout life; , * Ca2+ is important in signal transduction; * Normally, the concentration of Ca2+ in the plasma is constant and is about in 9-10.5 mg/dL; * Concentration regulated by interactions between PTH and various forms of vitamin D, and calcitonin; * Calcium absorption in the intestine involves a Ca2+ binding protein whose synthesis is regulated by calcitriol;  regulate phosphate using salts levels Phosphate Binding Agent Therapy L note : aluminum causes neurotoxicity  CALCIMIMETIC COMPOUNDS (Sinacalcet/ Sensipar; Etelcalcetide (Parsabiv®) Calcimimetics enhance the sensitivity of parathyroid to Ca2+ in the blood: * The goal of the therapy is to decrease PTH, this eventually results in reducing the risk of 2nd hyperparthyrodisim; There are two types of Calcimimetics (Sinacalcet/ Sensipar; Etelcalcetide (Parsabiv®): 1. Type I - agonists, and include various inorganic and organic cations, they are not used clinically; 2. Type II - allosteric activators can activate the receptor indirectly such as Cinacalcet; MOA: 7 a. K. ) a. free calcium (1 % * Enhance the sensitivity of the PTH calcium sensing receptor (CaSR) to the concentration of blood [ionized calcium] --> indirectly activating calcium receptors; Make the CaSR more responsive to calcium; cavities in > can cause mothers during pregnancy ( ?( * Suppress PTH; Prevent renal calcium reabsorption; DO NOT NEED TO MEMORIZE -FOCUS ON PREVIOUS SLIDE How Calcimimetic Agents work? Calcimimetic agents are the newest addition to the armamentarium for treating secondary HPT. The available drug is cinacalcet-HCl (30-, 60-, and 90-mg) tablets. The usual starting dose is 30 mg and is titrated upward depending on the PTH level. The maximum dose is 180 mg, but most patients will respond well to 90 or 120 mg. Two things must be kept in mind about calcimimetic agents: First, the drug is very effective in lowering PTH and is akin to chemical parathyroidectomy, and second, the drug can cause significant hypocalcemia so serum calcium must be monitored. MOA: Calcimimetics stimulate the calcium-sensing receptor, so the parathyroid gland senses a higher ionized calcium, which decreases the secretion of PTH. A high concentration of calcium-sensing receptor is present in parathyroid cell membrane, the kidney, bone, brain, and lungs, and small changes in the extracellular ionized calcium level will activate this receptor. In fact, decreased secretion of PTH by parathyroid cells occurs within seconds of increasing blood ionized calcium. However, the calcium-sensing receptor is also sensitive to magnesium, trivalent elements, and gadolinium. Consequently, stimulation of the calcium-sensing receptor in the kidney increases urinary calcium and magnesium. Interestingly, concomitant treatment with vitamin D sterols often given to hemodialysis patients not only acts to decrease PTH but also helps by ameliorating the hypocalcemic effects of calcimimetic drugs. Currently, cinacalcet hydrochloride is not approved for treating patients with CKD stages 3 and 4.  is Cholester a precursor of many/all hormones - Vitamin D Therapy Vitamin D consists of a group of lipophilic pre-hormones; They are converted in the body to biologically active metabolites that function as hormones: The maintenance of plasma Ca2+ by: (i) Increase Ca2+ absorption in the small intestine; (ii) Decrease Ca2+ renal excretion; (iii) Mobilize Ca2+ from bone Vitamin D; There are two sources of vitamin D:: Dietary ergocalciferol (D2), derived from ergosterol in plants and Cholecalciferol (D3) generated in the skin from 7-dehydrocholesterol by the action of UV irradiation;  ROLE OF PHOSPHATE Indispensable for many cellular functions; a constituent of nucleic acids, ATP, important in phosphorylation; Hyperphosphatemia can cause osteomalacia; * Important in excretion of H+ ions from kidney; PTH increases phosphate excretion; * Calcitriol regulates phosphate deposition in the bone as hydroxyapatite; This is regulated by PTH, which is sensitive to Ca2+ in the plasma; * Whereas FGF-23: Regulates phosphate concentration in plasma. It is a phosphatonin hormone that is elevated in CKD to promote renal phosphate excretion;  modified Bones nothing collagen fibers - are but Structure of Done Image result for hydroxyapatite collagen fibres > func : build the Done (single Fiber (  FGF-23: BONE-DERIVED FIBROBLAST GROWTH FACTOR-23 * FGF-23 binds to FGF receptor (FGF-R) to exert its effects; Regulators: are hyperphosphatemia & oral Pi loading, calcitriol and PTH; * Osteoblasts – site of synthesis and secretion, exhibits endocrine function; Increase in FGF23 activity = < can result in hyponatremia ~ Increase kidney excretion of phosphate and down-regulates sodium reabsorption; * In the kidneys – mediates phosphaturic effect by reducing the expression and activity of sodium- phosphate (Na/Pi) co-transporters in the proximal tubules; it results in direct inhibition of intestinal Pi- absorption; * FGF-23 lowers serum calcitriol [inhibits calcitriol [1,25(OH)2D) production] by decreasing the renal expression of 1-alpha-hydroxylase (CYP27B1), the rate limiting step in calcitriol synthesis and increasing the expression of 24-hyroxylase (CYP24A1) which degrades calcitriol; * As calcitriol itself stimulates FGF-23 by binding to the FGF-23 promoter gene, a regulatory feedback loop b/w FGF-23 and calcitriol exists;  Angiotensin receptor blockers ACEI/ARB decrease angiotensin II effects & vasodilation & drop in BP Angiotensin converting enzyme inhibitor * The combo of an ACE inhibitor or ARB with a diuretic is particularly effective in lowering BP; Why? in * Primarily dilate afferent and efferent arterioles; (located the glomerulus) * Help relieve glomerular pressure; * Protective towards kidneys; > remember : nephrons cannot duplicate * Loop diuretics & thiazide diuretics facilitate the response to other antihypertensive agents in CKD; synergistic effect > * Diuretics interfere with sodium reabsorption, lower ECF volume, and potentiate the antihypertensive effect of the antihypertensive agents; * Loop diuretics act by inhibiting the Na+-K+-2Cl- cotransporter in the thick ascending limb of the loop of Henle; * This decreases tubular sodium reabsorption, thereby increasing sodium excretion, reversing ECF volume expansion, and lowering blood pressure; * Thiazide diuretics act by inhibiting the apical Na+-Cl- cotransport system in the distal tubule. [pril" family ACE inhibitors: benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril ("Artan" family ARBs = Atacand (candesartan); Avapro (irbesartan); Benicar (olmesartan); Cozaar (losartan); Diovan (valsartan); ECF: Extracellular Fluid  Chronic Metabolic Acidosis in CKD * know the difference between carbonic acid a bicarbonate * Increase skeletal muscle breakdown; * Decreased albumin synthesis * Muscle weakness (pain) * Release of Ca++ and PO4 from bone, which can worsen bone health classical alternate lectin * Activation of complement pathway  promote tubulo-interstitial injury > complements : series of proteins found in blood ; work in a cascade manner if they get damage - angry , can any all antigen-antibody complex - attracts complements to destroy them Rx: **HCO3 supplementation may slow progression  Cystatin C (Shows GFR rate) (0.53-0.95 mg/L) * A cystatin 3, a protein encoded by the CST3 gene (13 kDa protein) produced by all nucleated cells; * Freely filtered at glomerulus; * 99% reabsorbed at PCT and catabolized; * Can't be used to measure clearance * Level rises with age & w/inflammation/CRP * An alternative biomarker in early detection of AKI ( in selected populations). * It increases as GFR decreases in AKI & CKD, & it also serves as an alternative to sCr for estimating GFR. * Its not perfect (functionality remains controversial) Indications for renal replacement therapy include the following: Severe metabolic acidosis Hyperkalemia Pericarditis Encephalopathy Intractable volume overload Failure to thrive and malnutrition Peripheral neuropathy Intractable gastrointestinal symptoms In asymptomatic patients, a GFR of 5-9 mL/min/1.73 m², irrespective of the cause of the CKD or the presence or absence of other comorbidities  Distinguishing Acute Kidney Injury From Chronic Kidney Disease Finding Comment Decreased kidney function (estimated glomerular Most reliable evidence of CKD filtration rate [eGFR] < 60 mL/min/1.73 m2) for ≥ 3 mo Renal sonogram showing small kidneys Usually CKD Renal sonogram showing normal or enlarged kidneys May be AKI or some forms of CKD (diabetic nephropathy, acute hypertensive nephrosclerosis, polycystic kidney disease, myeloma, rapidly progressive glomerulonephritis, infiltrative diseases [eg, lymphoma, leukemia, amyloidosis], obstruction) Oliguria, daily increases in serum creatinine and BUN Probably AKI or AKI superimposed on CKD No anemia Probably AKI or CKD due to polycystic kidney disease Severe anemia, hyperphosphatemia, and hypocalcemia Possibly CKD but may be AKI https://www.merckmanuals.com/professional/genitourinary-disorders/chronic-kidney-disease/chronic-kidney- disease?query=chronic%20kidney%20disease  Compensatory Renal Hypertrophy/ Compensatory Renal Cell Proliferation * Upon removal of one kidney, the other enlarges and increases its function. The mechanism for the sensing of this change and the growth is incompletely understood but begins within days. * Compensatory renal hypertrophy (CRH) is the dominant contributor to the growth. In many individuals undergoing nephrectomy for cancer or kidney donation this produces a substantial and helpful increase in renal function. * Two main mechanisms have been proposed: (i) increased activity by the remaining kidney via hypertrophy; (ii) release of a kidney specific factor in response to a unilateral nephrectomy that initiates CRH. * Like regeneration, this phenomenon—known as compensatory hypertrophy—can take place only if some portion of the original structure is left to react to the loss. NETHRONs formed only increasing size NO NEW * Compensatory Renal Cell Proliferation > , When kidney mass goes down, the remaining renal tissue undergoes compensatory growth. This is associated with both an increase in size of the kidney tubules and the glomeruli and an increase in single nephron glomerular filtration rate (SNGFR).  Select all the correct statements from the following: A. Elevated level of hepcidin is observed during Stage 3b of CKD; B. Elevated level of hepcidin is observed during Stage 5 of CKD; C. Hepcidin is decreased or absent in iron deficiency, increased by transfusion-induced iron overload and inflammatory diseases; D. IV preps of iron includes iron dextran and sodium ferric gluconate; E. Epoetin alfa and Darbepoetin alfa are frequently used as ESAs in kidney diseases; F. G4 stage of CKD is considered severely decreased GFR state to levels of 30-44 ml/min/1.73 m2 G. When urine albumin reaches a concentration of >300 mg/g; the patient is considered in severely increased state; H. When GFR rate is ≥ 90 ml/min/1.73 m2 with albumin concentration in the urine 20% and >100 ng/ml B. >20% and >100 mg/ml C. >30% and >100 microgram/ml D. >10% and >100 ng/ml Hepcidin is a hormone produced by the liver that regulates iron. It directly binds to ferroprotein, the cellular iron exporter. Hepcidin is decreased or absent in iron deficiency, increased by transfusion-induced iron overload and inflammatory diseases, and in general shows high correlation with serum ferritin levels. Hepcidin decrease is very common during which of the following diseases? A. CKD- Stage 5 B. T2DM- early stages C. Hypernatremia - early stages D. Hyperkalemia- early stages E. Gestational Diabetes- early pregnancy Q. FGF-23, the bone derived fibroblast growth factor, regulates phosphate concentration in plasma. It is a phosphatonin hormone that is elevated in CKD to promote renal phosphate excretion. Besides hyperphosphatasemia & oral Pi loading, it is influenced by calcitriol and PTH. ✓A. TRUE B. FALSE Conclusions!