Zoltanʼs Kidney FailureRenal Gross Anatomy and Microstructure1. What are the names of the two back muscles which the kidney sit anteriorly to? 12. Where are the three constrictions of the ureter and therefore the sites where kidney stones are most likely to build up?23. Which ribs are the kidneyʼs protected by posteriorly?34. Roughly how many lobes does a single kidney contain?45. Where exactly is the renal papilla?56. Which parts of the nephron are situated in the cortex? 67. Which parts of the nephron are situated in the medulla?78. What constitutes the main component of the glomerular ﬁlter?89. What is the name of the key protein necessary for the function of the glomerular ﬁlter? 910.What exactly is it that creates the 15-20% pressure differential across the renal corpuscle?1011. What is the function of mesangial cells in the glomerular capillaries? 1112. What proportion of the ﬂuid ﬁltered (180/L per day) is ﬁltered in the PCT?121 Psoas major and quadratus lumborym2 Hilum of the kidney (renal pelvis), where the ureter crosses the pelvic brim, as the ureter enters bladder3 11th & 12th ribs4 10-18 lobes5 At the apex of a renal pyramid, where the collecting duct empties to6 Proximal and distal convoluted tubules and renal corpuscles (glomerular apparatus)7 Loop of Henle and the collecting duct (these require a very highly concentrated environment)8The common basal lamina between the podocytes and the fenestrated endothelium of the glomerularcapillaries9 Nephrin10The afferent arteriole is larger in diameter than the efferent arteriole. Angiotensin II constricts the efferentarteriole, making the pressure differential greater and increasing GFR.11Maintenance of the glomerular basement membrane, phagocytosis of debris, contraction in response toangiotensin II to regulate blood ﬂow through glomerular capillaries.12 Around 2/3, PCT has a prominent brush border of microvilli for reabsorbtion
13. Other than the presence of microvilli on the wall of the PCT, what other mechanism is there to ensure signiﬁcant water reabsorbtion at this stage of the nephron? 1314. How does the solute concentration of the medulla compare to that of the blood? 1415. What are the differences between the ascending and descending limbs of the Loop of Henle?1516. What is the main function of the DCT and which hormone in particular regulates this?1617. What is the nature of the reabsorbtion from the collecting duct? 1718. What are the respective functions of:(i) Macula Densa cells18(ii)Juxtaglomerular cells19Functions of the Kidney, Filtration and Clearance1. What is erythropoietin?202. In terms of whether the substance is reabsorbed, secreted or ﬁltered, what properties would you need in a substance used to calculate glomerular ﬁltration rate? 213. What substances are ﬁltered but completely reabsorbed under normal circumstances? 224. What is the approximate width of the ﬁltration slit diaphragm in the corpuscle? 2313 NaCl is pumped into the interstitum which creates an osmotic gradient meaning a lot of water and nearlyall the glucose and amino acids are recovered in the PCT14 Compared to blood, the medulla is highly hypertonic, meaning it has a higher concentration of ions/solute15The descending limb is freely permeable to H20, meaning a lot of H20 moves out into the highlyhypertonic environment in the medulla. By contrast the ascending limb is impermeable to water but activelypumps out ions contributing to the hypertonic ion concentration in the medulla.16 DCT is responsible for reabsorbing many of the remaining ions in the ﬁltrate, controlled by aldosterone17Similar to the descending LOH, the collecting duct is permeable to water and runs through the hypertonicenvironment in the medulla, so water diffuses out.18Macula Densa cells contain chemoreceptors which stimulate juxtaglomerular cells to secrete renin inresponse to low Na+ in the DCT19 Juxtaglomerular cells contain pressure receptors which secrete renin in response to low pressure in theafferent arteriole20A hormone produced by cortical (cortex) cells in response to hypoxia (low oxygen) which stimulates redcell formation in bone marrow21 Something which is ﬁltered but neither secreted nor reabsorbed (e.g. Inulin, creatinine)22 HCO3- (via the buffering process) and Glucose23 25-65nm
5. Which of the following processes are active (ATP using) and which are passive: reabsorbtion, secretion, ﬁltration? 246. What would happen to GFR if you were to constrict the afferent arteriole?257. Describe tubuloglomerular feedback268. What is the effect of adenosine on the kidney and related hormones?279. What is clearance?2810. What substance can be used to determine renal blood ﬂow (i.e. blood ﬂow through theglomerulus)? 29Solute and Water Transport 11. ADH stimulates reabsorbtion in which part of the kidney nephron tubule?302. Out of the DCT, PCT, descending limb and ascending limb, which are impermeable to H20313. Which area of the nephron contains urea transporters?324. Urea is secreted (passively) into which area of the nephron tubule? 3324Filtration is passive whilst secretion and reabsorbtion are active in many cases, though the majority occursby diffusion based on the osmotic gradient25It would decrease because less blood would reach the glomerulus but also the pressure gradient with theother side would even so less would be ﬁltered. This is the opposite effect to efferent constriction withaldosterone, which preferentially increases GFR.26Chemoreceptors in the macula densa detecting high or low Na+ in the distal tubule and adjusting GFRaccordingly by constricting the afferent arteriole to decrease GFR or relaxing it to increase GFR.27 Adenosine is released if there is a high level of ions in the DCT constricts the afferent arteriole to decreaseGFR (opposite to angiotensin), it also inhibits release of renin (RAS)28The amount of substance in plasma vs. urine (i.e. how much is excreted) (urine concentration x urinevolume) divided by plasma concentration (ml/min)29 PAH, which is 100% secreted and excreted in low concentrations after a single pass through the nephron30 The late DCT and collecting duct, without ADH these are impermeable to H2031The PCT and descending LOH are permeable to water, the DCT and ascending LOH are permeable toions but impermeable to H20. The thick descending LOH is permeable to water (which goes out) and ions(which go in, from hypertonic medulla). The collecting duct and DCT become permeable to water in thepresence of vasopressin/ADH (anti diuretic hormone)32 The collecting duct, pumped out into the interstitum to increase medullary osmotic gradient33 The ascending LOH
5. Which parts of the nephron tubule actively reabsorb NaCl?346. What is ʻrenal thresholdʼ and what is the renal threshold for glucose? 357. What is osmotic diuresis?368. What are the 3 main causes of proteinuria? 37Solute and Water Transport 2 (Distal Mechanisms)1. A fall in pressure in which part of the kidney circulation would stimulate the release of renin? 382. List the ion transporters found in the tubular cells of the thick ascending loop of Henle 393. Which channel is inhibited by loop diuretics like furosemide? 404. What substance is transported out of the tubular cell on the same pump as Na+ and what is transported in on the same pump as Na+ going out?415. Which channel is inhibited by thiazide diuretics?426. Which pump is inhibited by amiloride, explain why amiloride is a K+ sparing diuretic?4334 The thick ascending LOH and DCT, there is some passive reabsorbtion of NaCl in the thin ascending LOHbecause up until this point the LOH has been impermeable to ions. Most water reabsorbtion occurs passivelyin the PCT, the active transport in later regions is subject to control mechanisms.35 Transport proteins in the tubular epithelium have a limited capacity (transport maximum), so if the ﬁltrateconcentration of a substance rises beyond a certain level, no more can be reabsorbed. The renal thresholdfor glucose is around 11mmMol/L, after which glucose appears in the urine.36 Where the ion concentration of tubular ﬂuid is raised sufﬁciently (by exceeding renal threshold for thesethings) that it alters the osmolarity of tubular ﬂuid enough for it to mean that more of the other ions arereabsorbed than would be otherwise because of the shift in gradient.37Glomerular proteinuria - pore size larger due to disease/damage, Tubular proteinuria - PCT reabsorbtionmechanism damaged/diseased, Overload proteinuria - plasma contains high concentrations of low molecularweight proteins which are able to pass through the glomerular ﬁlter because of various conditions.38The afferent arteriole, Angiotensin preferentially constricts the efferent arteriole to compensate for a fall inpressure in the afferent, increasing GFR.39Na+, K+ and 2Cl- going into the tubular cells from the lumen. 2K+/3Na+ ATPase transport potassium inand sodium out of the tubular cell into the interstitum. Na+ and HCO3- symporters go out of the tubularlumen,40 Na+/K+/Cl- Ion channels going from the lumen into the tubular cells in the thick ascending loop of Henle41 HCO3- is transported out, K+ is transported in42 Na+/Cl- co transporter going out of the lumen into the tubular cell43Amiloride inhibits the Na+ channels in the late distal tubule and collecting duct. The K+/Na+ ATPaseexchanger therefore draws less K+ into the cell/lumen because there is less Na+ to draw out.
7. Why could excessive levels of aldosterone lead to hypokalaemia?448. What is the effect of parathyroid hormone (PTH)?459. What effect does increased H+ (pH) have on K+ levels?4610.Whereabouts in the nephron is K+ secreted4711.What is the main electrochemical driving force for K+ secretion?4812.What channel does amiloride inhibit?4913.Which hormone is the main regulator for K+ in the nephron? 5014.What is the effect of vitamin D on the kidneys? 51Regulation of Osmolarity, Sodium & Water1. Which 3 main mechanisms control blood volume?522. What effect would drinking 1.5L of isotonic saline have on blood osmolarity? 533. What would happen after a large dietary salt intake?544. Where is vasopressin synthesised and where is it stored? 5544 Aldosterone increases activity of Na+ reabsorbing pumps and also stimulates ROMK (K+ secreter), moreNa+ in the cell means greater activity of the Na+/K+ exchanger so more K+ is drawn in from the interstitium45 Reduced reabsorbtion of Ca2+, Mg2+ and PO42- in the PCT46H+ binds to negatively charged proteins/ions countering negative charge, so K+ moves out of the cell intothe interstitium47 In the late distal tubule and collecting duct48 Negative potential in the lumen as a result of Na+ having been pumped out by this stage draws K+ in49Amiloride is a K+ sparing diuretic which inhibits EnaC Na+ channels. Less Na+ is reabsorbed into the celland therefore less K+ is transported in because the K+/Na+ antiporter is less active.50Aldosterone, because it acts on ROMK and ENaC. Increased plasma K+ stimulates the release ofaldosterone which increases K+ excretion.51 Vitamin D plays a key role in Ca2+ and phosphate reabsorbtion.52 Renin-Angiotensin-Aldosterone, Atrial Naturetic Peptide, Pressure Naturesis53None or very little, because osmolarity is driven by Na+ concentration not blood volume, though drinking1.5L of any liquid containing H20 would increase blood volume54 Increased sodium in blood, increased osmolarity of blood, draws water in from tissues, gives sensation ofthirst (via hypothalamus) as osmoreceptors.55 Synthesised in hypothalamus and then stored in vesicles in the pituitary gland
5. By what chemical mechanism does ADH stimulate water reabsorbtion from tubule? 566. Why can the maximum osmolarity of urine only reach a maximum of 1400mOsm?577. What happens to urine volume and osmolarity in diabetes encephalitis?588. What percentage blood volume loss would stimulate ADH release? 599. Describe the series of factors involved in controlling an increase in blood volume 6010.What are the 3 main direct effects of angiotensin 2?6111.Where is aldosterone produced? 6212.What are the direct effects of aldosterone on the nephron tubule?6313.What effects does increased arterial blood pressure (within 120-190mmHg (systolic) range)have on (i) renal blood ﬂow, (ii) volume of urine excreted, (iii) glomerular ﬁltration rate? 6414.What does naturesis mean? 65Diuretics1. What two conditions relating to CVD are diuretics used to treat? 6656ADH binds to basolateral V2 receptors, cAMP 2nd messenger sent into cell which stimulates aquaporin 2to increase Na+ reabsorbtion through apical membrane channels, H20 follows57because this is the osmolarity of the medulla, if the urine had a higher osmolarity than 1400mOsm, ﬂuidwould be drawn back into the medulla58Failure in aquaporin 2 or other ADH mechanism dramatically reduces reabsorbtion of Na+ and water inglomerular ﬁltrate, urine would be come dilute and be a very high volume (up to 25L per day)59 Around 20-30% reduction in blood volume, such as a severe bleed (see Gusʼ Rugby Injury)60 Increase in blood volume causes increase in CVP/EDP, release of atrial naturetic peptide (ANP). Increasein blood volume detected by arterial baroreceptors, decrease SNS activity and therefore TPR and BP.61 Vasoconstriction, stimulates ADH release, causes the sensation of thirst62 In the zona glomerulosa of the adrenal cortex in the adrenal gland63Increases expression of the Na+ pump, ENaC (Sodium out of lumen) and ROMK (Potassium into lumen)channels in distal convoluted tubule and collecting duct. Enhances K+ secretion and Na+ reabsorbtion.64(i) slightly raised but little effect because auto-regulated, (ii) increases, mechanism assumed to belocalised release of prostaglandins in kidney (iii)increases slightly but again auto-regulated65 Excretion of both water and sodium together66Hypertension (thiaside type diuretics) and Oedematous conditions including heart failure, renal diseaseand hepatic disease (loop diuretics, K+ sparing diuretics)
2. What percentage of plasma (or cardiac output) is ﬁltered as blood passes through the glomerulus? 673. What volume does this roughly equate to?684. What is reabsorbed in the proximal convoluted tubule? 695. What are secreted (pumped out) of the capillaries into the proximal convoluted tubule? 706. ADH primarily affects reabsorbtion of what in which part of the kidney? 717. Which part of the kidney nephron do loop diuretics affect?728. Which part of the kidney nephron do thiazide type diuretics affect?739. Which part of the kidney nephron do K+ sparing diuretics affect?7410.Why do K+ sparing diuretics not risk causing hypokalaemia whereas thiazide and loop diuretics do?7511.What rare side effects can occur in the ear with loop diuretics? 7612.How do thiazide type diuretics reduce blood pressure other than by reducing blood volume? 7713.What are the functions of ENaC and ROMK channels in the collecting duct? 7867 20%68 125ml/min or 180L/day69 HCO3-, glucose and amino acids, 2/3 of water and salts70H+ protons, weak acids and bases (this is important because most diuretics are weak acids and bases, sowhat is not ﬁltered in the glomerulus is secreted into the tubule)71 Reabsorbtion of water and Na+ in the collecting duct72Loop of Henle - they are the most powerful type of diuretic because this is an area of signiﬁcant sodiumreabsorbtion compared to the collecting tubule and distal tubule, which reabsorb a smaller amount73 Smaller fraction of sodium reabsorbtion in distal tubule (less powerful than loop diuretics)74 Collecting duct - weakest diuretics because at this point there is relatively little Na+ reabsorbtion to affect75 Thiazide and loop diuretics block Na+/Cl- symporter (so less ions overall reabsorbed). More ions in theﬁltrate however means greater loss of K+ in the collecting duct. K+ sparing diuretics such as Spironolactoneare used in conjunction with other diuretics and inhibit aldosterone release, so less Na+ reaches collectingduct and therefore K+ loss is not as pronounced.76 Tinnitus, ringing or dizziness, because the same co-transporters affect ﬂuid balance in the inner ear77 By decreasing total peripheral resistance via an unknown mechanism78 ENac channels pump sodium into the cell from the lumen, ROMK pump K+ out of the cell into the lumen,this creates a gradient between the cell and the interstitum which means the Na+/K+ symporter can dropreabsorbed Na+ into the interstitum and excrete K+ into the cell and the lumen
14.How does aldosterone affect K+ and Na+ secretion and reabsorbtion? 7915.What do type A intercalated cells in the collecting duct do?8016.What is the mechanism for the K+ sparing diuretic spironolactone? 8117.What is the mechanism for the K+ sparing diuretics amiloride and triamterene? 8218.What is the mechanism of osmotic diuretics? 83Regulation of Acid Base Status1. Roughly how much H+ is produced per day from metabolism in the body? 842. Deﬁne a ʻbufferʼ and give an example of a chemical used as a physiological buffer?853. What is the range for blood pH outside of which counts as alkalosis or acidosis? 864. What is the most important buffer pair in the body and what key enzyme is used on one half of the reaction? 875. What is normal plasma H+ concentration886. What is normal (buffered) urine pH? 8979Raised plasma potassium is a stimulus for aldosterone release, aldosterone causes increased Na+reabsorbtion and therefore increased K+ secretion in the collecting duct because of the sodium-potassiumsymporters80Operate a K+/H+ exchanger in the collecting duct, so more K+ in the ﬁltrate means more H+ is lost fromthe interstitum to the urine. In the case of high usage of K+ sparing diuretics this may lead to alkalosis.81Aldosterone antagonist (competitive inhibitor), therefore onset of action is slow (days)82Block ENac (exchange) channels in the collecting duct and thus block both Na+ reabsorbtion and K+secretion83Osmotic diuretics are given intravenously and stay in blood (do not act in tissues), but create higherosmolarity in the blood itself and therefore the renal ﬁltrate. Higher osmolarity blood also draws ﬂuid out ofbody tissues into the blood. So both GFR and blood volume increase temporarily, followed by a decrease inblood volume as it is excreted.84Around 60mmol H+ per day is produced by normal metabolism (e.g. NAD+ --> NADH + H+), most of this isexcreted by the lungs but some is excreted by the kidneys85A buffer is a weak acid or base which can accept or donate H+ to make overall pH a certain level. Acommon buffer in the body is HCO3-.86 Blood pH range is 7.35-7.4587 CO2 + H20 <--(carbonic anhydrase enzyme)--> H2CO3 (carbonic acid) <---> HCO3- (bicarbonate) + H+88 40nm (nanomolar)89 Urine is normally pH5-7 even after buffering with HCO3-
7. What are the main urinary buffers other than those mentioned in question 4? 908. Where and how does H+ enter the kidney tubule?919. Name the enzyme which catalyses the breakdown of carbonic acid to H20 and CO2?9210. Including answers to (8) and (9). Describe the process whereby HCO3- acts as a buffer in the PCT?9311. What effect does angiotensin II have on the reabsorbtion of HCO3- and secretion of H? 9412. What is the effect of NH3 on buffering in the lumen? 9513. What happens to tubular NH4+ in the Loop of Henle?9614. Where do the majority of H+ ions get pumped into the lumen? 9715. What do the following indicate about acid-base homeostasis in the kidney?(i) a high concentration of plasma potassium9890 Phosphate (controlled by Parathyroid hormone) and Ammonium91 H+ is pumped into the ﬁltrate (secreted) and then becomes ʻtrappedʼ in the medulla92 Carbonic anhydrase93 H+ are actively pumped into the tubular lumen. HCO3- is ﬁltered in the glomerulus and is therefore foundin the ﬁltrate in the PCT lumen. H+ and HCO3- react with each other in the lumen to form carbonic acid(H2CO3-). The enzyme carbonic anhydrase then catalyses the breakdown of carbonic acid into H20 andCO2. CO2 and H20 then diffuses out of the lumen back into the tubular epithelium. The environment in theepithelium is less acidic than in the lumen, so the CO2 dissociated into H+ and HCO3-. The net effect is thati) HCO3- is reabsorbed from the ﬁltrate and ii) the pH in both the lumen and the epithelium is prevented fromgetting too high or two low (because if it did, the rate of reaction would shift to one side to compensate forthe pH change).94Angiotensin II increases the activity of the channel (symporter) by which Na+ and HCO3- are reabsorbedand increases the activity of the channel which pumps H+ into the lumen. This means the rate of thebuffering reaction increases (more H+ goes in, more HCO3- is able to come out).95NH3 is able to diffuse into the lumen from the epithelium. In the lumen, NH3 becomes NH4 when itcouples with H+ protons. NH4 cannot get out of the lumen and are excreted (urine smells of ammonia)96NH4+ which is the product of buffering H+ further up the tubule, is reabsorbed via the same ion channelswhich absorb K+, 2Cl- and Na+. NH4+ then dissociates into NH3 and H+ in the tubular cell. H+ is thensecreted again whilst some of the NH3 is reabsorbed into the interstitial ﬂuid, making it more alkaline.97More H+ ions are secreted into the lumen by pumps in type A intercalated cells in the late distal tubulethan anywhere else in the tubule. These are then buffered (taken on) by HPO42- or by NH3 and excreted inthe urine.98 A high plasma potassium can be a result of a large amount of H+ going into the tubule in acidosis(because H+ is transported into the tubule by K+/H+ antiporter (exchanger) so more K+ ends up in theinterstitum and so in the blood. A large amount of H+ going into the tubule might be a result of increasedmetabolic production of CO2, because CO2 turns into H+ and HCO3-
(ii)a high concentration of NH4+ in the urine 99(iii)a low concentration of of plasma potassium10016. What happens to acid/base levels during hypokalemia and hyperkalaemia? 10117. When the liver breaks down amino acids, it ends up with excess NH4+ and HCO3-, what are the two pathways for excretion of these substances? 10218. What is the difference between respiratory acidosis/alkalosis and metabolic alkalosis? 10319. Why could blood pH be normal even in situations of alkalosis and acidosis? 10420. What is meant by the ʻanion gapʼ?10599High NH4+ in the urine could be the result of a large amount of H+ being pumped into the tubule (seeabove), where NH3 has diffused into the tubule as a buffer, bound to H+ and made NH4+.100Low plasma K+ could be the result of alkalosis (low plasma pH), because there are not enough H+ toexchange for K+ out of the lumen101 Hypokalemia gives rise to hypokalaemic alkalosis and hyperkalemia to hyperkalaemic acidosis102HCO3- reacts with NH4+ to produce urea. Glutamate reacts with NH4+ and goes to the kidney asglutamine103Respiratory acidosis is caused by excess CO2 buildup from inadequate ventilation and alkalosis from alow CO2 level as a result of hyperventilation. Metabolic acidosis is the result of excess acids produced byloss of bicarbonate in the gut, lactate production etc. Metabolic alkalosis can be a result of loss of acidthrough vomiting.104 Because of the anion gap and ion compensation105The difference between the sum of measured cations and the sum of measured anions (because theycompensate for high or low levels of each other). There is a ʻgapʼ because not all charged substances canbe measured. The result tells you what kind of acidosis or alkalosis there is. It can also be normal in acidoticor alkalotic situations because of the ions compensating for each other.