PHP 327 Clinical & Therapeutic Sciences Renal Pathophysiology Part 2 2024 PDF

10/19/2024 PHP 327 Clinical and Therapeutic Sciences Renal Pathophysiology: Part 2 Todd Brothers Pharm D, BCCCP, BCPS Clinical Associate Professor...

10/19/2024 PHP 327 Clinical and Therapeutic Sciences Renal Pathophysiology: Part 2 Todd Brothers Pharm D, BCCCP, BCPS Clinical Associate Professor Department of Pharmacy Practice College of Pharmacy University of Rhode Island 1 Lecture Outline Review systemic blood pressure and influence on GFR Hormonal regulation of renal perfusion Types of kidney injury Urine analysis and renal diseases 2 Learning Objectives Discuss the roles of the renin–angiotensin–aldosterone system, atrial natriuretic peptide (ANP), and pressure natriuresis to control intravascular volume balance Describe the components of a urinary dipstick Compare and Contrast the three main classification systems for AKI Evaluate and Apply urine analysis findings to clinical case scenarios 3 1  10/19/2024 Regulation of Kidney Function (Intrinsic and Extrinsic Mechanisms) Mechanisms acting from outside the kidney include: (1) systemic blood pressure; (2) Antidiuretic Hormone (ADH) + Atrial Natriuretic Peptide (ANP); and (3) aldosterone Mechanisms acting from inside the kidney include: (1) Juxtaglomerular apparatus; (2) Renin-Angiotensin-Aldosterone System (RAAS) 4 Systemic Blood Pressure Rate of glomerular filtration is directly related to the hydrostatic blood pressure in glomerular capillaries Any increase in blood pressure results in a corresponding increase in filtration and urine output Since this process ultimately decreases blood volume, the kidneys are a powerful means of controlling long term blood pressure Conversely, drops in blood pressure have the opposite effect This mechanism is important because it illustrates how circulatory and renal systems interact as blood pressure changes affect kidney function and vice versa 5 Hypotension: JxA Responds! A portion of the distal tubule, the macula densa, detects a reduction in fluid flow through the nephron Once detected, cells of the afferent arteriole, the Juxtaglomerular Cells, are stimulated to release the enzyme Renin into blood entering the glomerulus Concept Check: Low BP = Macula densa, JxA response = Renin release 6 2  10/19/2024 7 Renin-Angiotensin System (RAS) 8 Renin-Angiotensin System (RAS) 9 3  10/19/2024 What….would be….really smart? ? 𝑛 𝑛 𝑛 𝑘 𝑛−𝑘 𝑥+𝑎 =෍ 𝑥 𝑎 𝑘 𝑘=0 10 Anti-Hypertensives ACE-Inhibitors (ACE-i) Angiotensin Receptor Blockers (ARB’s) Renin Inhibitor Benazepril Azilsartan Aliskiren Captopril Candesartan Enalapril Eprosartan Fosinopril Irbesartan Lisinopril Losartan Moexipril Olmesartan Perindopril Telmisartan Quinapril Valsartan 11 Hi I’m Wellington 12 4  10/19/2024 1st ACEi = Captopril = 1981 and 1st ARB = Losartan =1995 13 SARS-CoV-2 (COVID-19) + ACE2 ACE2 is the portal of entry for SARS-CoV Affinity of SARS-CoV-2 for ACE2 is 10–20- fold more than that of SARS-CoV; explaining the greater transmissibility of SARS-COV-2 Illustration demonstrating the theoretical benefit of ARB use in COVID-19 ARB directly blocks the Angiotensin receptor from AGII and upregulates ACE2 which degraded Angiotensin II 14 Aldosterone Released from the adrenal cortex (‘hat’ on top of the kidney) Na+ is retained, Cl- and water follow The increase in fluid retention and expansion of volume improve systemic blood pressure Side note: aldosterone release tells the nephrons to secrete excess potassium into the urine as well Steroid (prednisone) use can cause edema 15 5  10/19/2024 Atrial Natriuretic Peptide (ANP) Primarily released from the atria in response to volume expansion, sensed as an increase in atrial stretch ANP has two major actions that contribute to volume regulation: Direct vasodilator that lowers the systemic blood pressure Increases urinary sodium and water excretion 16 Hormonal Regulation of Volume Balance ANP RAAS Release of ANP is enhanced by Renin release stimulated by volume volume expansion (high-salt diet) depletion (low-salt diet) Results in increased sodium excretion Generates angiotensin II + aldosterone = and systemic vasodilatation Na+retention and systemic vasoconstriction Concept Check: ANP and RAAS function as counterbalancing systems 17 When the hormonal control of Na+ excretion fails… 18 6  10/19/2024 Volume Regulatory System ‘Back Up Plan’: Pressure Natriuresis Healthy subjects: a small elevation in blood pressure results in a large increase in the urinary excretion of Na+ and water, no hormone regulation needed Aldosterone Escape Scenario: Healthy subjects given aldosterone + high Na+ diet Initially: volume expansion, mild increase in blood pressure, low potassium (aldosterone) Over a few days: spontaneous natriuresis, lowers plasma volume back to normal Lastly, Na+ intake and excretion remain equal, yet mild hypertension and hypokalemia persist Concept Check: Hyperaldosteronism in young patients may “look” asymptomatic as Na levels and edema may not be present. Since the increase in renal blood flow and release of ANP helps ‘off-set’ the effects of aldosterone 19 Regulation of Kidney Function (Intrinsic and Extrinsic Mechanisms) Mechanisms acting from outside the kidney include: (1) systemic blood pressure; (2) Antidiuretic Hormone (ADH) + Atrial Natriuretic Peptide (ANP); and (3) aldosterone Mechanisms acting from inside the kidney include: (1) Juxtaglomerular apparatus; (2) Renin-Angiotensin-Aldosterone System (RAAS) Backup plan: pressure natriuresis 20 Clinical Application Diuretics: increase NaCl excretion in hypertension and edematous states Initial salt and water loss from the medication will activate counterregulatory systems Hormonal include activation of RAAS and decreased release of ANP Balance viewpoint: natriuretic effect of medication is gradually counteracted by increased anti-natriuretic forces = a new steady state of Na+ intake + output occurs Clinical importance: Maximum natriuretic response to a diuretic will be seen with the first dose New steady state generally achieved within 1 to 2 weeks 21 7  10/19/2024 Urinalysis Reporting 22 How do we know the kidneys are functioning well? 23 Urine Composition ‘Waste’ Overview Urea (from the metabolic deamination of amino acids in the liver) and uric acid (nucleotide derivatives from the metabolism of nucleic acids in the liver) qualify as wastes Any material that occurs in the body in quantities greater than those needed become waste(i.e. excess water, excess salts, excess hydrogen or bicarbonate ions, vitamins, medications) must be excreted Urine composition is constantly changing as different materials occur in excess in the body 24 8  10/19/2024 Kidney Disease Assessment Summary Patients with kidney disease may have a Many patients are asymptomatic variety of clinical presentations Routine examination (ex: annual physical) found to have an elevated serum creatinine concentration or an abnormal urinalysis Symptoms can be directly referable to either: Once kidney disease is discovered: The kidney [itself]: the presence/degree of kidney (ex: gross hematuria, flank pain) dysfunction and rapidity of progression are assessed Extrarenal symptoms: underlying disorder is diagnosed (ex: edema, hypertension, signs of uremia) 25 Functional Classification (3) Major Types of Renal Disease 1) Prerenal - which results from decreased renal perfusion in the setting of undamaged parenchymal tissue 2) Intrinsic- the result of structural damage to the kidney, most commonly the tubule from an ischemic or toxic insult 3) Postrenal - caused by obstruction of urine flow downstream from the kidney 26 Blood flow Blood “in” flow “ in” Structural damage Obstruction Obstruction It’s Plumbing! 27 9  10/19/2024 A midstream ‘clean catch’ specimen is adequate after first cleansing the external genitalia to avoid contamination with local secretions Urine Examination: Analysis should be performed within 30 to 60 Urinalysis Logistics minutes after voiding Fresh urine should be centrifuged at 3,000 rpm/min for 3 to 5 minutes Most of the supernatant should then be poured into a separate tube, and the sediment at the bottom of the tube resuspended by gently flicking the side of the tube The sediment should be poured or transferred with a pipette onto a slide and covered with a cover slip Both the supernatant and the sediment are now ready for detailed analysis Evaluation of the supernatant usually begins with a dipstick that can test for numerous items 28 Supernatant Analysis: Dip Stick Test a. Leukocytes/Nitrites b. Protein c. pH d. Blood e. Specific Gravity f. Ketones g. Glucose 29 Urine Dipstick Values and Inference a. Leukocytes/Leukocyte esterase: high levels suggest infection b. Nitrites: Dietary nitrate is normally excreted in the urine If bacteria are present, urinary nitrate can be partially converted to nitrite. Positive dipstick for nitrite is a screening test for a urinary tract infection c. Blood/Heme: positive, indicative of red cells being present Dipstick can also detect free heme proteins as with hemoglobinuria due to intravascular hemolysis and myoglobinuria due to skeletal muscle breakdown (rhabdomyolysis) Supernatant will be heme positive, but few or no red cells in the urine sediment 30 10  10/19/2024 Urine Dipstick Values and Inference d. Specific Gravity: defined as the weight of the f. Glucose: filtered glucose load is solution compared with the weight of an equal increased to a level that exceeds volume of distilled water; is proportional both to proximal glucose reabsorptive capacity, the number of solute particles present and to the resulting in glucosuria weight of the solute particles present Normal range: 1.002 and 1.030; Above 1.010 can indicate mild dehydration g. Ketones: uncontrolled diabetes mellitus also may have ketoacidosis. Acetoacetic acid + acetone e. pH: urine normally ranges between 5 and 6.5, (β-Hydroxybutyric acid) is the primary depending primarily on dietary intake ketone formed, but not found on a above 7.5 to 8 suggests a urinary tract dipstick infection 31 Urinary Proteins + Kidney Disease h. Protein: h. Glomerular proteinuria: increase in the permeability of the glomerular capillary wall that leads to the abnormal filtration and subsequent excretion of larger, normally nonfiltered proteins, albumin loss = marker of glomerular disease i. Tubular proteinuria: Low-molecular-weight proteins are normally filtered and then largely reabsorbed in the proximal tubule; marker of chronic kidney disease j. Overflow proteinuria: increased production of smaller proteins leads to a rate of filtration that exceeds normal proximal reabsorptive capacity; marker of multiple myeloma and other plasma cell dyscrasias 32 Necessary to accurately classify and Urine Sediment measure urine components: Epithelial cells, non-epithelial cells, casts, salts/crystals, and microorganisms Casts represent precipitated proteins and cells that form within the tubular lumen Clinically important: it identifies the kidney as the source of the cells Casts containing white cells indicates inflammation in the kidney 33 11  10/19/2024 Urinary Na+ Excretion Estimation of the rate of sodium excretion is used in the differential diagnosis of hyponatremia and distinguishing between prerenal disease and acute tubular necrosis as the cause of acute kidney injury Two different methods are used to estimate sodium excretion from a random urine specimen: Measurement of the urine sodium concentration urine sodium concentration is usually below 25 mEq/L with volume depletion and above 40 mEq/L with normovolemia or acute tubular necrosis Calculation of the fractional excretion of sodium (FENa) 34 Fractional Excretion of Sodium (FENa) Calculation of the FENa allows FENa (%) = (Naurine x Crserum) sodium handling to be looked at x 100 (Naserum x Cr urine) directly without the confounding effect of the rate of water reabsorption FENa reflects the percentage of the FENa: < 1% suggests pre-renal (ex: dehydration) filtered sodium load that is excreted Useful when urine volume < 500 mL/day FENa: > 2% suggests intrinsic 35 Clinical Application 25-year-old woman presented to the ED after she noticed some discomfort on urination and reported a 101F temperature. She felt nauseated and noticed pain on her right side. Her physician recorded her history: fever, dysuria (painful urination), urinary frequency, and urinary urgency. He noted tenderness when he pressed on the part of the abdomen overlying the bladder. When he tapped on the right side of her back near her kidney, she winced in pain. A urine specimen for urinalysis was sent for evaluation. Under the microscope the specimen showed large numbers of bacteria and leukocytes, and the leukocytes were clumped together in thread-like masses called casts. The rest of the sample was sent to a microbiology lab for culture What is the likely diagnosis? How did you determine this? 36 12  10/19/2024 Synopsis Glomerular filtration is directly related to the hydrostatic blood pressure in glomerular capillaries; therefore diseases that affect blood pressure and vascular expansion/contraction directly influences GFR Intravascular volume and content is balanced by a complex renal hormonal and pressure natriuretic system; understanding the counter-regulatory influences are key to determining the etiology of the renal injury Urine analysis by dipstick and microscopy identifies numerous renal diseases; interpretation of these values aids in their diagnoses Calculation and utilization of FENa scores can be helpful to determine the classification of the renal failure (pre-renal, intrinsic, or post-renal) 37 13