Basic Renal Function - Part 1 Notes 2024 PDF

WSUSOM Medical Physiology Rossi-Renal Physiology Page 1 of 16 Kidney Anatomy, Basic Functions and Processes Kidney Anatomy, Basic Functions and Processes Learning Objectives - 1. Incidence and prevalence and cost of kidney disease 2. Anatomic term...

WSUSOM Medical Physiology Rossi-Renal Physiology Page 1 of 16 Kidney Anatomy, Basic Functions and Processes Kidney Anatomy, Basic Functions and Processes Learning Objectives - 1. Incidence and prevalence and cost of kidney disease 2. Anatomic terminology A. Distinguish between cortex and medulla B. Identify the arterial and venous blood supply of the kidney C. Describe the nephron as the functioning component of the kidney and all its components 3. Renal function and processes A. Define renal blood flow, renal plasma flow and glomerular filtration and the typical values for these functions B. Identify factors that lead to variations in these parameters C. Define and characterize glomerular filtration, tubular reabsorption and tubular secretion 4. Urinary flow rate and urinary excretory rate A. Quantitate overall urinary flow rate and urinary excretory rate by using standard algebraic equations B. Understand the concept of filtered load and be able to quantify it C. Exercise comparisons between filtered load and excretory rate thereby being able to deduce the net tubular effect on a given solute 5. Glomerular filtration barrier A. Identify the components that comprise the glomerular capillary filtration barrier and their relationship to each other B. Recognize the properties of a given solute that contribute to its filtration (or not) at the glomerular capillary 6. Basic renal processes: filtration, secretion and reabsorption A. Define the processes whereby the kidney processes solutes B. Quantitate the excretory rate of a solute as a function of the plasma concentration of that solute. C. Understand the three prototypes of solute handling by the kidney a. filtered only b. filtered and reabsorbed c. filtered and secreted ‘ WSUSOM Medical Physiology Rossi-Renal Physiology Page 2 of 16 Kidney Anatomy, Basic Functions and Processes Incident & prevalent patient counts (USRDS) Incident Count Prevalent Count Incident cases = number of NEW patients Prevalent cases = total number of patients These and the following slides were obtained from USRDS – United States Renal Data System and can be accessed at http://www.usrds.org/ This is a comprehensive view of everything you were afraid to ask about chronic kidney disease (CKD) or end stage kidney disease (ESRD) including transplant. As of 2019, there were 809,103 individuals with ESRD (or 2,302 per 1 million population). Data comes from USRDS based in Ann Arbor, MI and started with a $25,000 grant from the National Kidney Foundation of Michigan many years ago. Now it is the source for information on medico-socio-economic issues involving kidney disease. The analysis provided here is the most recent data from 2021 and includes data up to 2019. Prevalence of ESRD, by primary diagnosis Note that the majority of ESRD occurs due to diabetes and hypertension! Learning to prevent diabetes mellitus (type II which is associated with obesity and inactivity) and understanding and treating it as well as controlling blood pressure is of crucial importance in the prevention of kidney disease and ESRD. Incident counts & adjusted rates of ESRD, by race and biologic sex ESRD (end stage renal disease) Note that the total NUMBER of total white patients with ESRD is higher than other races/ethnicities and continues to rise (not shown) HOWEVER when adjusted per population but the number of individuals who identify as African American/black is disproportionately affected (left graph; ~2.7x greater). The decline in incidence in the WSUSOM Medical Physiology Rossi-Renal Physiology Page 3 of 16 Kidney Anatomy, Basic Functions and Processes Native American population occurred after programs were instituted to treat type 2 diabetes mellitus aggressively. IT CAN BE DONE! Men are also much more likely to have ESRD than women (right graph). The graphs highlight only some of the health disparities that occur in the U.S. It should be noted that the differences are not inherent in race itself but socioeconomic, political, and environmental disparities. Survival on hemodialysis Five year survival from the initiation of hemodialysis is ~ 42% Note the initial downtrend in the first 6 months after ESRD and dialysis is initiated. Peritoneal survival rates are very similar (approximately 10 months longer survival vs hemodialysis). ESRD patients that received a deceased donor transplant had a survival of 83% and living donor transplant 93%. Note, however, to be on the transplant list requires that the individual have fewer comorbidities. Total Medicare ESRD expenditures per person per year, by modality Total Medicare expenditures for chronic kidney disease = $87 billion. Total Medicare expenditures for ESRD in the USA = $51 billion (more than the gross domestic product of many countries! The above costs do not account for private insurance coverage of some expenditures. Cost per patient year Hemodialysis ~ $93K Peritoneal dialysis ~ $77K Transplant ~ $37K Preserving kidney health is important. So learning about normal kidney function is where it all begins! WSUSOM Medical Physiology Rossi-Renal Physiology Page 4 of 16 Kidney Anatomy, Basic Functions and Processes The Kidney Nephron: structural and functional unit of the kidney Each kidney has » 1 million nephrons Blood vessels: renal artery ® interlobar arteries ® arcuate arteries ® interlobular arteries ® terminal arteries ® afferent arteriole ® glomerulus ® efferent arteriole ® peritubular capillaries including the vasa recta ® venules ® renal vein Cortex: contains glomeruli and tubular structures and corresponding blood vessels Medulla: contains only tubular structures, vasa recta Here is how the kidney TISSUE looks! Nephron is the structural and functional unit of the kidney and is comprised of both tubular and vascular components. Vascular: afferent arteriole, glomerulus, efferent arteriole and peritubular capillaries (including vasa recta) Tubular: proximal tubule ® descending limb of Henle ® thin and thick ascending limbs of Henle ® distal convoluted tubule ® collecting tubules and duct Each normal kidney consists of 1 million nephrons, or 2 million total nephrons/2 kidneys. WSUSOM Medical Physiology Rossi-Renal Physiology Page 5 of 16 Kidney Anatomy, Basic Functions and Processes Renal Function: Average Values Renal blood flow (RBF) 20% of cardiac output » 1000 mL/min Renal plasma flow (RPF) since blood = 40% cells, 60% plasma » 600 mL/min Glomerular filtration rate (GFR) » 20% of RPF filtered across the capillaries into tubules = 125 mL/min Variations for age and sex The values given above for RBF, RPF, and GFR are averages for a healthy, lean, young adult (» 25 yr) male. Variations exist with age and sex (e.g., average GFR for healthy lean female of same age » 110 mL/min). GFR is lower in children and declines with age. Cockroft and Gault developed a formula that takes these variations into account. This formula gives the estimated GFR (vs actually measured in later lectures). Pcr is the plasma creatinine concentration (more about this later). Pharmacologists use this equation primarily. #1) est GFR » (140 - age [in years]) * lean body weight [in kg] x (0.85 if female) 72 * PCr The MDRD formula (#2) for estimating GFR results in a 20% higher value for African Americans of the same age and sex. This calculation is the one that appears on lab reports in all hospitals at least until this year. #2 ) est GFR (ml/min/1.73m2) = 186 x (Pcr)-1.154 x (age)-0.203x (0.742 if female) x (1.21 if African Am) The accuracy and appropriateness of this formula has been revisited over the last couple of years. Several task forces agreed that the MDRD formula is racially biased. No data exist to suggest that African Americans have a 20% higher GFR than other races. This calculation may exclude black individuals from appropriate listing for renal transplant, use of medications, etc. Nonetheless, be aware that when you enter the clinics or read older literature (pre 2021), that historic data on patients will have been based on MDRD and comparisons to previous values will need to take this into consideration. The 2021 CKD-EPI Creatinine eGFR equation (#3) eliminates race from the equation. It is the formula now recommended (but not yet established in all laboratory reports). α -1.200 age #3) eGFR = 142 x [min(Scr/κ,1)] x [max(Pcr/κ,1)] x 0.9938 x 1.012 [if female] Where Pcr = plasma creatinine; k = 0.7 (females) and 0.9 (males); a = -0.241 (female) and -0.302 (male); min(Pcr/k) indicates the minimum of either Pcr/k or 1; max (Pcr/k) indicates the maximum of either Pcr/k or 1. WSUSOM Medical Physiology Rossi-Renal Physiology Page 6 of 16 Kidney Anatomy, Basic Functions and Processes The formulae are not valid in children, pregnancy, amputees, and those not in the sample. You will NOT be asked to calculate these formulas in the exam. But you will be expected to interpret what the formulas tell you and when/if they are valid in given circumstances with respect to the impact of age, sex, lean body wt, etc. on GFR. You will see and use the results of these formulas again in your clinical years. Do NOT memorize these formulae. They are to be used as reference this year. DO note that the GFR is inversely proportional to the plasma creatinine. Also, that for the SAME plasma creatinine the GFR is lower in females vs males (sex is a biological variable) and lower with increasing age. For the purposes of “simplicity” we will assume all nephrons are alike. That is NOT true and should be in the back of your mind. There are subtle differences, but the principles of function are alike. For example, the juxtamedullary nephrons (JM) have longer loops of Henle than the superficial ones. The JM nephrons also have higher glomerular filtration rates (GFR; discussed in lecture 2) and contribute more to the ability to concentrate the urine (lecture 6). This will have implications for predilection for disease processes by some nephrons. (You will find that much of what you learn now is refined later and it may seem your professors (me) have lied to you. We are only trying to make things simpler…believe it or not. Sometimes, our efforts actually make things more muddy…. ASK if it does not make sense.) Three renal processes are involved in urine formation: #1 = filtration #2 = reabsorption #3 = secretion Urinary Excretion = filtration - reabsorption + secretion Each nephron functions individually, but we can discuss the whole kidney functionally as one giant nephron. WSUSOM Medical Physiology Rossi-Renal Physiology Page 7 of 16 Kidney Anatomy, Basic Functions and Processes Renal Processes Glomerular Filtration: P = plasma nonselective (sort of …will see nuances in a bit) ISF = interstitial fluid filtrate composition identical to ISF TF = tubular fluid Tubular reabsorption selective active (can be primary or secondary) passive (may be facilitated) from TF ® thru cell/paracellular path ® ISF ® P Tubular secretion selective active or passive from P ® ISF ® thru cell/paracellular path ® TF Glomerular filtration is a nonselective process. Glomerular filtrate is identical in composition to ISF (i.e., little or no protein in NORMAL conditions and Gibbs-Donnan applies). Final urine is VERY different from ISF due to transport processes (reabsorption and secretion). Reabsorption is a selective process of a filtered substance in tubular fluid (TF) across (or between) the tubular cells into the interstitial fluid (ISF) and then diffuse from the ISF into plasma (P) in the peritubular capillaries. Reabsorption may be active or passive. Facilitated transport is passive (does not require ATP) but still utilizes a carrier. Secretion is a selective and active (primary or secondary) or passive (facilitated) transport process of a substance from the plasma to ISF across tubular cells into the TF. #1. Glomerular filtration #2. Tubular reabsorption #3. Tubular secretion In most texts “Px” is used denoting “plasma concentration of X”. We will use the term “Ax” to denote arterial plasma concentration to stress that the formulae require arterial plasma to be technically precise. In the clinical setting plasma from venous blood is often used. WSUSOM Medical Physiology Rossi-Renal Physiology Page 8 of 16 Kidney Anatomy, Basic Functions and Processes Ux * V = (GFR * Ax) - Rx + Sx (This is a VERY IMPORTANT FORMULA!) The term Ux * V is the excretory rate. (This is a VERY IMPORTANT TERM!) amount volume amount volume time time The term GFR * Ax is the filtered load. (This is a VERY IMPORTANT TERM!) volume amount amount time volume time The excretory rate is the amount of “x” excreted into the urine per unit time. E.g., if a person excretes 2L urine a day with a Na concentration (UNa) of 70 mmol/L, then the excretory rate would be Na excretory rate = 2 L/day * 70 mmol/L = 140 mmol/day The filtered load is the amount of “x” filtered by the glomerular capillaries per unit time. For example, if a person filters 125 ml/min (180 L/day) with a plasma Na concentration of 150 mmol/L, then the filtered load of Na would be Filtered load of Na = 180 L/day x 150 mmol/L = 27,000 mmol/day Note that both excretory rate and filtered load are in units of amount/time. Also note that this individual excretes only ~0.5% of the filtered Na load. The rest of the Na is reabsorbed! So knowing the filtered load tells you quite a lot about the amount of work (= oxygen consumption and ATP used) the tubules will need to do to prevent the loss of all the filtered Na into the urine. Rx is the reabsorptive rate of substance “x” and is also an amount/time. Sx is the secretory rate of “x” and is in units of amount/time. IMPORTANT For water: V = GFR - RH2O For solute X: Ux * V = (GFR * Ax) - Rx + Sx Important points 1. This assumes that solute “x” is freely filtered. If “x” is not freely filtered, a correction must be made. Example: 50% of total Ca in plasma is bound to plasma proteins. Proteins are not filtered. Only the “free” unbound Ca is filtered at the glomerulus (see below). 2. Comparing excretion with filtration helps infer conclusions about NET reabsorption and NET secretion. Example: If Ux * V > GFR * Ax that means that the excretory rate > filtered load. Then, one can conclude that net secretion occurred. This does not mean that reabsorption may not have occurred as well, but that the overall balance indicates NET secretion. WSUSOM Medical Physiology Rossi-Renal Physiology Page 9 of 16 Kidney Anatomy, Basic Functions and Processes Less important points 1. Gibbs-Donnan Effect applies: plasma [Na] > glomerular filtrate [Na] plasma [Cl] < glomerular filtrate [Cl] 2. GFR is the volume of plasma (not the volume of plasma H2O) filtered per unit time Both these points are usually ignored, but lead to confusion when you look at figures with numbers in textbooks (Boron) where precise experimental concentrations are used. Note the position of the distal tubule (actually the point where the thick ascending limb of Henle turns into the distal tubule) that comes between the afferent and efferent arterioles forming the juxtaglomerular apparatus. This “microanatomy” will be important in subsequent lectures on tubuloglomerular feedback and later on control of renin secretion. Schematic of the glomerular capillary tuft surrounded by Bowman’s capsule Left: light microscopic view of normal glomerulus Right: low magnification electron micrograph of glomerular mesangium and capillaries. WSUSOM Medical Physiology Rossi-Renal Physiology Page 10 of 16 Kidney Anatomy, Basic Functions and Processes Note the endothelial cell (E) lining the lumen of the capillary, the glomerular basement membrane, and the epithelial cells known as podocytes (P) with foot processes impinging on the glomerular basement membrane. The mesangial cell (M) is located at the central section of the glomerular tuft. Left: electron micrograph with higher magnification of the glomerular capillary loop. The lower section is of even higher magnification and shows the three layers of the filtration barrier: 1. the endothelium with pores 2. the glomerular basement membrane (with three laminae: rara, densa, rara) 3. the podocyte foot processes with slit diaphragms between them Right: scanning EM from the lumen of the capillary onto the endothelium thereby highlighting the pores. The pictures above are three different perspectives of the podocyte. The arrow is the slit diaphragm. WSUSOM Medical Physiology Rossi-Renal Physiology Page 11 of 16 Kidney Anatomy, Basic Functions and Processes Ux * V = (GFR * Ax) - Rx + Sx Determinants of filterability: Size Shape Charge Equation assumes solute X is freely filtered protein binding (e.g., Ca2+) capillary may be less than fully permeable to X in some cases The glomerular filtration barrier is made up of three layers 1. endothelial cells with pores 2. basement membrane 3. foot processes of podocytes with slit diaphragms Charge, size and shape are important factors for filtration (see figure) 1. Positively charged particles are filtered more easily than negatively charged particles of same size and shape. 2. Globular particles of the same size and charge are filtered more easily than elongated particles (e.g, globulins vs albumin) 3. Smaller particles are more easily filtered than larger ones. For substances (ions, drugs, etc.) that are bound to protein, only that component that is free in plasma may be filtered and then only if the substance itself is of the proper size, shape and charge. For example, the seizure medicine diphenylhydantoin is small but is 99% bound to serum albumin. Albumin is not freely filtered…hence only the 1% of diphenylhydantoin that is free in plasma is available to be filtered. Molecular size, Angstroms WSUSOM Medical Physiology Rossi-Renal Physiology Page 12 of 16 Kidney Anatomy, Basic Functions and Processes Podocyte Overview The podocyte foot processes and barrier can be damaged by disease. Effacement of foot processes occurs in many glomerular diseases and is typically associated with protein in the urine. This figure (left) shows the podocyte foot processes with attention to the components of the slit diaphragm. A. The foot processes with the general scheme of the assembly of proteins that make up the slit diaphragm. Note that there are proteins that also anchor the foot processes to the basement membrane. B. Detailed view of the slit diaphragm proteins as they interdigitate from either side. C. EM of two podocyte membranes with the slit diaphragm proteins interdigitating. The filtration barrier is composed of three levels: 1. the size of the pores in the endothelium and 2. the negative charge of the glomerular basement membrane 3. the slit diaphragms between the podocytes are also an integral part of the filtration barrier. (Large proteins, particularly albumin, are NOT found in the urine in normal conditions.) Mutations in nephrin and podocin, proteins that are part of the slit diaphragm complex, result in excretion of proteins in the urine and the development of inherited forms of a condition called nephrotic syndrome…more next year.) WSUSOM Medical Physiology Rossi-Renal Physiology Page 13 of 16 Kidney Anatomy, Basic Functions and Processes Ux * V = (GFR * Ax) - Rx + Sx For as substance, X, that is FREELY filtered Compare excretion rate (Ux*V) with filtered load (GFR * Ax) if Ux*V > GFR * Ax, then NET tubular secretion occurred. if Ux*V < GFR * Ax, then NET tubular reabsorption occurred. NET secretion ¹ ONLY secretion NET reabsorption ¹ ONLY reabsorption Ux * V = (GFR * Ax) - Rx + Sx This is one of those IMPORTANT EQUATIONS! Given a substance X UxV = excretory rate (the rate at which X is excreted in the urine, units mg/min) GFR * Ax = filtered load (rate at which X is filtered, also amount/time) Rx = reabsorptive rate (rate at which X is reabsorbed, amount/time) Sx = secretory rate (rate at which X is secreted, amount/time) A substance may be filtered only OR filtered and reabsorbed OR filtered and secreted OR filtered, reabsorbed AND secreted. Some substances may be metabolized by the kidney as well. The above statements refer only to the NET effect of what goes into the nephron and what finally exits by way of the urine. Curve #1: filtration only; X = inulin Uinulin* V = GFR * Ainulin Curve #2: filtration + secretion; X = PAH UPAH* V = GFR * APAH + SPAH Curve # 3: filtration – reabsorption; X = glucose Uglucose * V = GFR * Aglucose - Rglucose Inulin is a substance that is only filtered (not secreted or reabsorbed, Rx = 0 and Sx = 0. PAH, para-aminohippuric acid, is filtered at the glomerulus and secreted by the proximal tubules (not reabsorbed, Rx = 0). Glucose is filtered at the glomerulus and then reabsorbed by the proximal tubules (but not secreted, Sx = 0). WSUSOM Medical Physiology Rossi-Renal Physiology Page 14 of 16 Kidney Anatomy, Basic Functions and Processes We will use these three substances as examples in the following slides. [If you find the curves in the next section confusing, it may help to read ahead on Tm mechanisms about 47 pages ahead, OR come back to this when we’ve covered tubular reabsorption.] Ux * V = (GFR * Ax) - Rx + Sx Note that the formula takes the form y = mx - b + c where y = UxV, m = GFR, Ax = x, b = Rx and C = Sx. In this case, b and c = 0 Curve #1: X = inulin Uinulin* V = [GFR * Ainulin] Inulin is freely filtered NOT secreted (Sx = 0) NOT reabsorbed (Rx = 0) Slope of INULIN curve = GFR Thus, the SLOPE of the curve for excretion of inulin = the GFR. Slope = GFR = Uin* V Ain Ux * V = (GFR * Ax) - Rx + Sx Curve #3: X = glucose Glucose is filtered and reabsorbed, but not secreted. Uglucose* V = [GFR * Aglucose] -Rglucose Glucose is freely filtered NOT secreted (Sx = 0) reabsorbed As Aglucose ­, filtered glucose­ and Rglucose ­ to a constant maximum Excreted glucose < filtered glucose (in normal individuals, under normal conditions) As plasma [glucose] increases, filtered glucose increases. Also, as plasma [glucose] increases, reabsorption increases to a constant maximum value (determined by the Tm for glucose, concept of Tm will be discussed later). WSUSOM Medical Physiology Rossi-Renal Physiology Page 15 of 16 Kidney Anatomy, Basic Functions and Processes Note that no glucose is excreted initially. At low plasma concentrations of glucose, ALL the filtered glucose is reabsorbed and none appears in the urine. After a certain point (threshold, to be discussed later), the SLOPE of the curve for excretion of glucose also becomes parallel to than that for inulin (GFR). The transport of glucose (and other reabsorbed substances) often depends on more than one transporter. We observe the net effect of all the transporters together when we measure excretory rate, Uglucose* V. Secretion Analogy to enzymes…but not the same since we are taking into account transport by multiple proteins, not just one. Enzymes have a maximal rate of reaction which they reach asymptotically. For a simple reaction, one can envision the following: For the tubules, the excretory rate of a substance such as PAH that is filtered and secreted by the tubules the result is a bit more subtle: It is the sum of the filtered load (a) and the amount of X secreted (b), resulting in total excretion rate of a+b in the figure. Ux * V = (GFR * Ax) - Rx + Sx Curve #2: X = PAH UPAH* V = [GFR * APAH ]+ SPAH PAH, para-aminohippuric acid, is freely filtered secreted NOT reabsorbed (Rx = 0) As APAH ­, filtered PAH ­ and SPAH ­ (to a constant maximum) Excreted PAH > filtered PAH As plasma [PAH] increases, filtered PAH increases. Also, as plasma [PAH] increases, secretion of PAH increases to a constant maximum value (determined by the Tm for PAH discussed later) excreted PAH > filtered PAH Note that the SLOPE of the curve for excretion of PAH is initially steeper (this is due to the excretory rate being due to BOTH secretion and filtration) but that after a point it becomes parallel to than that for inulin (GFR) once the secretory transporters become saturated (see future lectures re: Tm). This is because filtration of a freely filtered substance is not limited by transporters unlike the secretory processes in the tubules. WSUSOM Medical Physiology Rossi-Renal Physiology Page 16 of 16 Kidney Anatomy, Basic Functions and Processes Ux * V = (GFR * Ax) - Rx + Sx