References for Chapter 10We did not mention many references in our discussion today but our listeners may enjoy some of the references below. Effects of pH on Potassium: New Explanations for Old Observations - PMC although the focus of this article is on potassium, this elegant review by Aronson and Giebisch reviews intracellular shifts as it relates to pH and K+.Josh swooned for Figure 10-1 is this right? Which figure was it? which shows the relationship between [H+] and pH. You can find this figure in the original reference from Halperin ML and others, Figure 1 here. Factors That Control the Effect of pH on Glycolysis in Leukocytes Here’s Leticia Rolon’s favorite Henderson-Hasselbalch calculator website: ​​Henderson-Hasselbalch Calculator | Buffer Solutions [hint! for this site, use the bicarbonate (or “total CO2”) for A- and PCO2 for the HA] There’s also a cooking tab for converting units! Fundamentals of Arterial Blood Gas Interpretation - PMC this review published posthumously from the late but beloved Jerry Yee and his group at Henry Ford Hospital, explores the details and underpinnings of our understandings of arterial blood gas interpretation (and this also addresses how our colleagues in clinical chemistry measure total CO2 - which JC referenced- but JC said “machine” and our colleagues prefer the word “instrument.”)Amy went deep on bicarbonate in respiratory acidosis. Here are her refs:Sodium bicarbonate therapy for acute respiratory acidosisSodium Bicarbonate in Respiratory AcidosisBicarbonate therapy in severe metabolic acidosisEffect of Intravenous Sodium Bicarbonate on Ventilation, Gas Exchange, and Acid-Base Balance in Patients with Chronic Pulmonary InsufficiencyBicarbonate Therapy in Severe Metabolic Acidosis | American Society of Nephrology this review article from Sabatini and Kurtzman addresses the issues regarding bicarbonate therapy including theoretical intracellular acidosis. Bicarbonate in DKA? Don’t do it: Bicarbonate in diabetic ketoacidosis - a systematic review Here’s a review  from Bushinsky and Krieger on the effect acidosis on bone https://www.sciencedirect.com/science/article/abs/pii/S0085253822002174Here is the primary resource that Anna used in here investigation of meat replacements Nutritional Composition of Novel Plant-Based Meat Alternatives and Traditional Animal-Based MeatsWe enjoyed this paper that Dr. Rose references from the Journal of Clinical Investigation 1955 in which investigators infused HCl into nephrectomized dogs and observed changes in extracellular ions. https://www.jci.org/articles/view/103073/pdWe wondered about the amino acids/protein in some available meat alternatives they are explored in this article in the journal Amino Acids: Protein content and amino acid composition of commercially available plant-based protein isolates - PMC and you may enjoy this exploration of the nutritional value of these foods: Full article: Examination of the nutritional composition of alternative beef burgers available in the United StatesOutlineChapter 10: Acid-Base Physiology - H concentration regulated tightly - Normal H+ is 40 nm/L - This one millionth the concentration of Na and K - It needs to be this dilute because H+ fucks shit up - Especially proteins - Cool foot note H+ actually exists as H3O+ - Under normal conditions the H+ concentration varies little from normal due to three steps - Chemical buffering by extracellular and intracellular bufffers - Control of partial pressure of CO2 by alterations of alveolar ventilation - Control of plasma bicarbonate by changes in renal H+ excretion - Acid and bases - Use definition by Bronsted - Acid can donate protons - Base can accept protons - There are two classes of acids** - Carbonic acid H2CO3 - Each day 15000 mmol of CO2 are generated - CO2 not acid but combines with water to form carbonic acid H2CO3 - CO2 cleared by the lungs - Noncarbonic acid - Formed from metabolism of protein. Sulfur containing AA generate H2SO4. Only 50-100 mEq of acid produced from these sources. - Cleared by the kidneys - Law of Mass Action - Velocity of reaction proportional to the product of the concentrations of the reactants - Goes through mass action formula for water - Concludes that water has H of 155 nanoM/L, more than the 40 in plasma - Says you can do the same mass experiment for every acid in the body - Can do it also for bases but he is not going to. - Acids and Bases can be strong or weak - Strong acids completely dissociate - Weak acids not so much - H2PO4 is only 80% dissociated - Weak acids are the principle buffers in the body - Then he goes through how H is measured in the blood and it becomes clear why pH is a logical way to measure. - Then there is a lot of math - HH equation - Derives it - Then uses it to look at phos. Very interesting application - Buffers - Goes tot he phosphate well again. Amazing math describing how powerful buffers can be - Big picture the closer the pKa is to the starting pH the better buffer, i.e. it can absorb lots of OH or H without appreciably changing pH - HCO3 CO2 system - H2CO3 to H + HCO3 has a PKA of 2.72 but then lots of Math and the bicarb buffer system has a pKa of 6.1 - But the real power of the bicarb buffer is that it is not a sealed system. The ability to ventilate and keep CO2 constant increases the buffering efficiency by 11 fold and the ability to lower the CO2 below normal increases 18 fold. - Isohydric principle - There is only one hydrogen ion concentration and since that is a critical part of the buffer equation, all buffer eq are linked and you can understand all of them by understanding one of them. So we just can look at bicarb and understand the totality of acid base. - Bicarb is the most important buffer because - High concentration in plasma - Ability for CO2 to ventilate - Other buffers include - Bone - Bone is more than just inorganic reaction - Live bone releases more calcium in response to an acid load than dead bone - More effect with metabolic acidosis than respiratory acidosis - Hgb - Phosphate - Protein

References for Chapter 9One of the few papers that Rose wrote as a single author explores electrolyte free water clearance. This seminal paper explores the issue in greater detail than the book. A New approach to disturbances in the plasma sodium concentrationWondering about the volume of sweat? Josh taught us that the volume of “transepidermal volume loss” is not affected by humidity https://www.jidonline.org/article/S0022-202X(15)48145-X/pdf but is greatly affected by temperature: Skin temperature and transepidermal water lossRegarding normal sweat physiology, there is a nice review (with figures!) titled Physiological mechanisms determining sweat composition which describes all the important cells and channels which make up sweat glands. And an important follow on paper titled Higher Bioelectric Potentials due to Decreased Chloride Absorption in the Sweat Glands of Patients with Cystic Fibrosis describing specifically the sweat characteristics of patients with cystic fibrosis.Melanie was enchanted by work from RA McCance who did early experiments to induce sodium deficiency using very low sodium diets and a homemade sauna-like tent. His musings are fascinating.  Lancet 1936 Experimental human salt deficiency MEDICAL PROBLEMS IN MINERAL METABOLISMAge-related decline in urine concentration may not be universal: Comparative study from the US and two small-scale societies from Jeff Sands (of urea transport fame!)In this initial report, after continually water loading 21 volunteers, the younger group (mean age 31) had a urine osmolality of 52 mOsm/kg compared to in the older group (mean age 84). Influence of age, renal disease, hypertension, diuretics, and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. In a later report older subjects (mean age 72) vs younger controls (mean age 26) drank 20 ml/kg over 40 minutes. The younger group excreted more of the water in the first 2 hours and had a lower mean urine osmolality 86 vs 112 mOsm/kg compared to the older participants. Age-associated Alterations in Thirst and Arginine Vasopressin in Response to a Water or Sodium Load Howard Furst suggests the urine to plasma electrolyte ratio as a simpler strategy to consider the free water clearance: https://nephrology.edublogs.org/files/2014/03/Water-Restriction-in-Hyponatremia1-1eb8n40.pdf  or via pubmed: The urine/plasma electrolyte ratio: a predictive guide to water restrictionRapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following TolvaptanInfoSnack picture of pre and post tolvaptan

References for chapter 8Robert Schrier proposed a unifying hypothesis to explain the sodium retention seen in edematous states like cirrhosis and heart failure, coining the term effective arterial blood volume (EABV). An open access review in JASN 2007 can be found here:  https://jasn.asnjournals.org/content/18/7/2028#ref-3  John P PetersASN Annual Award: https://www.asn-online.org/about/awards/award.aspx?awh_key=0ea83199-f86d-4506-9507-d7e4ce688cb4Short article discussing contributions of Dr. Peters by mentees Dr. Franklin Epstein and Dr. Donald Seldin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588700/ and https://pubmed.ncbi.nlm.nih.gov/12097739/Epstein FH et al. Studies of the antidiuresis of quiet standing: the importance of changes in plasma volume and glomerular filtration. JCI 1950. In this classic report, investigators studied their own sodium excretion supine, standing and with a variety of maneuvers (saline or albumin infusion)  and  showed that urinary sodium excretion is limited in the upright position compared to supine position. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436228/pdf/jcinvest00414-0077.pdfAn interesting review of early concepts on hypertension feature notes on John J Hay and Paul Dudley White. The former was known to say, “The greatest danger to a man with high blood pressure lies in its discovery because then some fool is certain to try and reduce it!” and the latter has been quoted as saying that hypertension might be compensatory but apparently, these quotes are out of context. To find out what they really said, check out:  Elias MF and Goodell AL. Setting the record straight for two heroes in hypertension John J Hay and Paul Dudley White. J Clin Hypertens 2019 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.13650 VA Cooperative Trial was an important study to establish the hypertension should, in fact, be treated The VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980 This study was stopped after only 18 months because of an excess of deaths in the untreated group who had a mean diastolic BP of 115 mmHg. For a long time, only the diastolic BP was felt to be important until the Systolic Hypertension in Elderly Patients (“SHEP study”) clarified that treatment of isolated systolic hypertension is also importantPrevention of Stroke by Antihypertensive Drug Treatment in Older Persons With Isolated Systolic HypertensionWe continued to try to grapple with the work of Jens Titze on sodium which turns many of our assumptions about sodium upside down. His team studied astronauts on a long term high sodium diet and found an unexpected weekly (circaseptan) rhythm seemingly related inversely to aldosterone and directly with cortisol. His work also probes our notion of body sodium content. For a great first hand read, check out Dr TItze’s review in Kidney International 2014 which he aptly dubs, “Spooky Sodium Balence.” https://www.sciencedirect.com/science/article/pii/S0085253815562807Epstein M. The cardiovascular and renal effects of head-out of water Immersion in Man. Circulation Research 1976 Cardiovascular and renal effects of head-out water immersion in man: application of the model in the assessment of volume homeosSpace flight is an exaggeration of the water immersion experiments. Astronauts on either a low or normal sodium diet had a reset of natriuetic peptides. A Salty Tale: Study Examines Sodium Regulation in Space and Natriuretic Peptide Resetting in Astronauts | CirculationBaroreceptors feature mechanically activated ion channels called PIEZO1 and PIEZO2. Zeng W, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102061/We also relearned an unfortunate truth: lots of folks pee in pools. De Laat et al. Water Res. 2011.  Concentration levels of urea in swimming pool water and reactivity of chlorine with urea At the American College of Cardiology meeting in April, investigators shared the news that the combination of an ARB with new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) was not superior to ACE inhibitors at reduction of heart failure following acute MI. Here’s the press release for the PARADISE-MI trial. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial InfarctionA series of elegant experiments by Alicia McDonald’s team to characterize pressure natriuresis. In these studies, they induce hypertension by constriction of the superior mesenteric artery, the celiac artery and the infrarenal aorta (essentially increasing afterload without directly altering the blood flow to the kidney).  With this maneuver, the blood pressure of the experimental animal rises, urinary sodium excretion increases and then they demonstrate a shift in the Na-H ATPase from the apical membrane to intracellular vesicles in the proximal tubule and a shift in NCC from the luminal membrane to the intracellular vesicles in the distal tubules. Yang L et. al Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal 2002 https://journals.physiology.org/doi/full/10.1152/ajprenal.00298.2001?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.orgLee DH Riquier ADM, Yang LE, Leong PK, Maunsbach and McDonough AA. Acute hypertension provokes acute trafficking of distal tubule NaCl (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009 Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles This review in KI reports is also worth a read McDonough AA. Maintaining Balance under pressure-hypertension and the proximal tubule. 2015 ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Chapter 7ReferencesSands JM, Blount MA and Klein JD. Regulation of Renal Urea Transport by Vasopressin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116377/In this invited piece, Sands and colleagues explain that although urea is permeable across membranes, this is slow, thus urea transporters in the kidney, under control of vasopressin, are needed to facilitate transport and create the medullary gradient. Text book using 20% of extracellular compartment being in the intravascular compartment. https://courses.lumenlearning.com/ap2/chapter/body-fluids-and-fluid-compartments-no-content/ another one: https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/25%3A_Body_Fluids_and_Acid-Base_Balance/25.2%3A_Body_Fluids/25.2B%3A_Fluid_Compartments The chapter I wrote where I went through the math in figure 7-3. It was a major revelation to me: https://docs.google.com/document/d/17BM1xihvlztuQlU8GVNhEDoPLzr6GounHYZAtVUkLvw/edit?usp=sharing Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality https://journals.lww.com/ccejournal/fulltext/2020/12000/association_between_icu_acquired_hypernatremia_and.26.aspx Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients https://pubmed.ncbi.nlm.nih.gov/30948456/ Edelman IS, Leibman J, O’Meara MP and Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. JCI 1958. This classic paper calculates the total body exchangeable sodium and potassium and establishes the relationship between these. Understanding this painstacking work helps understand the effect of supplementing potassium in the setting of hyponatremia. https://dm5migu4zj3pb.cloudfront.net/manuscripts/103000/103712/cache/103712.1-20201218131357-covered-e0fd13ba177f913fd3156f593ead4cfd.pdfEdelman is the Root of Almost All Good in Nephrology https://www.renalfellow.org/2014/11/20/edelman-is-root-of-almost-all-good-in/ Jens Titze and his team published a pair of articles that shocked those interested in salt and water in JCI in 2017. High Salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation https://www.jci.org/articles/view/88532Increased salt consumption induces body water conservation and decreases fluid intake https://www.jci.org/articles/view/88530in this exciting exploration of the basic assumptions that we hold true regarding salt and water (and staring Russian cosmonauts and an incredible controlled simulation of salt and water intake), Titze shows that high sodium intake does not simply drive water consumption (as we usually teach) but instead leads to a complex hormonal and metabolic response (even with diurnal variation!) and results in body water conservation and decreased water consumption. And accompanying editorial from Mark Zeidel: salt and water, not so simple. https://www.jci.org/articles/view/94004In addition, Titze and others have done interesting work on sodium deposition in tissues where it may also be a source for systemic inflammation.https://pubmed.ncbi.nlm.nih.gov/28154199/Jens Titze talking about salt, water, thirsting a TEDx talk. https://www.youtube.com/watch?v=jQQPBmnIuCY A discussion/debate of the overfill vs. underfill theory of edema in the nephrotic syndrome (hint- overfill theory triumphs) would be incomplete without a reference to congenital analbuminemia. This reference from Frontiers in Genetics explores the diagnosis, phenotype and molecular genetics and reveal that patients tend to have only mild edema but severe hyperlipidemia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478806/The finding that proteinuria can directly lead to sodium retention based on a study when puromycin aminoglycoside induced proteinuria of one kidney lead to sodium retention by that kidney which was localized to the distal nephron. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436841/?page=9Plasmin may be the culprit at the level of the epithelial sodium channel based on Tom Kleyman’s work: https://jasn.asnjournals.org/content/20/2/233Amiloride may help! (stay tuned for amiloride in a future episode) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016639/An old favorite of JC’s from the Kidney International feature which debates the cause of edema in the nephrotic syndrome.https://www.sciencedirect.com/science/article/pii/S0085253815583075Under protest, we hobbled through a discussion of the Gibbs Donnan affect even encouraged by one of Amy’s fellows based on this article from QJM: https://academic.oup.com/qjmed/article/101/10/827/1520972 suggesting that our understanding of the role of hyponatremia in fractures might be all wrong- it could be related to hypoalbuminemia.

Chapter 6 part 2. ReferencesJosh touts the PARADIGM-HF Trial Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure | NEJM which found this combination was superior to an ARB alone Joel mentions an early atrial natriuretic peptide trial by Julie Lewis et al. Atrial natriuretic factor in oliguric acute renal failure - American Journal of Kidney Diseases and here’s a metanalysis that put this option to bed: Atrial Natriuretic Peptide for Management of Acute Kidney Injury: A Systematic Review and Meta-analysisSnack attack? Check out “Snack induced ANP” Snack-Induced Release of Atrial Natriuretic Factor | NEJMWant more natriuretic peptides than we discussed? Check out this review! Cardiac natriuretic peptides | Nature Reviews Cardiology or this fantastic review: Here’s an excellent review of ANP effect on the kidney: ANP-induced signaling cascade and its implications in renal pathophysiologyCerebral salt wasting and elevated brain natriuretic peptide levels after traumatic brain injury: 2 case reportsJoel mentions the study which probed CRIC cohort regarding NSAIDs. Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study - American Journal of Kidney Diseases and you may like the discussion on NephJC: ​​No Pain for the Kidneys from NSAIDs — NephJCThe KDIGO guidelines can be found here CKD-Mineral and Bone Disorder (CKD-MBD) – KDIGO Regulation and Effects of FGF23 in Chronic Kidney DiseaseElegant work on the calcium sensing receptor by Martin Pollak https://doi.org/10.1016/0092-8674(93)90617-YeClaudin 14, PTH, and calcium absorption in the loop of Henle: Parathyroid hormone controls paracellular Ca 2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14Carboxymaltose induced hypophosphatemia by increasing FGF-23. Randomized trial of intravenous iron-induced hypophosphatemiaCurrent "corrected" calcium concept challenged. | The BMJThe Dialysis Encephalopathy Syndrome — Possible Aluminum Intoxication | NEJMNephMadness covered Aluminum binders in 2016.Roger mentioned the use of ferric citrate as a phosphate binder Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis | American Society of NephrologyJoel reminded us of the misadventures in efforts to normalize hemoglobin, first in hemodialysis patients The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin | NEJMLater, in patients with CKD, normalization was also not shown to be better: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease | NEJM , Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia | NEJMA quick shout out for roxadustat and the Nephmadness Anemia region! Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis | NEJM, #NephMadness 2021: Anemia Region – AJKD BlogIn this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.  This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews®  (and here’s a family with central diabetes insipidus  https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report:    ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion  Influence of ADH on renal potassium handling: A micropuncture and microperfusion study   A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock,  1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (<130 mEq/L) were excluded from the study.Excellent review! Vasopressin and the Regulation of Aquaporin-2This report looks at the PET scan in individuals who are thirsty.  Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousnessHere’s a little discussion of Dr. Grant Liddle. In addition to his eponymous syndrome, he coined the term “ectopic” and developed the dexamethasone suppression test. Grant Liddle (1921–1989) : The EndocrinologistThis is the sad case of licorice gluttony in NEJM which led to hypokalemia and a cardiac arrest. Case 30-2020: A 54-Year-Old Man with Sudden Cardiac ArrestIn this review of the principal and intercalated cells, check out Figure 8 which has an excellent figure of the aldosterone paradox. https://cjasn.asnjournals.org/content/clinjasn/early/2015/01/30/CJN.08880914.full.pdf?with-ds=yes%3Fversioned%3DtrueRemarkably, licorice has been used in dialysis patients to lower potassium in patients in this short term trial. Glycyr-rhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patientsAnimal studies on pregnant rats demonstrating the reset osmostat as predicted by Roger. Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION

Chapter 6 part 1In this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.  This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews®  (and here’s a family with central diabetes insipidus  https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report:    ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion  Influence of ADH on renal potassium handling: A micropuncture and microperfusion study   A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock,  1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (<130 mEq/L) were excluded from the study.Excellent review! Vasopressin and the Regulation of Aquaporin-2This report looks at the PET scan in individuals who are thirsty.  Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousnessHere’s a little discussion of Dr. Grant Liddle. In addition to his eponymous syndrome, he coined the term “ectopic” and developed the dexamethasone suppression test. Grant Liddle (1921–1989) : The EndocrinologistThis is the sad case of licorice gluttony in NEJM which led to hypokalemia and a cardiac arrest. Case 30-2020: A 54-Year-Old Man with Sudden Cardiac ArrestIn this review of the principal and intercalated cells, check out Figure 8 which has an excellent figure of the aldosterone paradox. https://cjasn.asnjournals.org/content/clinjasn/early/2015/01/30/CJN.08880914.full.pdf?with-ds=yes%3Fversioned%3DtrueRemarkably, licorice has been used in dialysis patients to lower potassium in patients in this short term trial. Glycyr-rhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patientsAnimal studies on pregnant rats demonstrating the reset osmostat as predicted by Roger. Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION

References for Chapter 5--the Distal NephronRoger pointed out the fact that the distal nephron can achieve very low urinary sodium as evidenced by observations in people from the Yanomamo tribe Blood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population in this report, 84% of the participants had urinary sodium < 1mmol/24 hours. Information about the Yanomamo Tribe. It looks like they’re starting to make chocolate, now! YanomamiThe Yanomami are great observers of natureThe Amazon's Yanomami utterly abandoned by Brazilian authorities: ReportYanomami Amazon reserve invaded by 20,000 miners; Bolsonaro fails to actI believe this is the original study looking at urine sodium and blood pressure in the Yanomamo Indians, but the INTERSALT trial linked above I believe had more robust urine dataThis study mentions the average lipid profile for men and women along with BMI. I didn’t mention in the “Voice of God” overview, but there is some interest looking at the Yanomamo and rate of cancer as it relates to the correlation with intracellular potassium to sodium ratiosJosh referred back to his notes and realized that the tightest junctions are in the TOAD not FROG bladders Physiology and Function of the Tight JunctionAn excellent review from McCormick and Ellison on the Distal convoluted tubule in Comprehensive Physiology.We flirt with the disorder of Gordon’s syndrome: Familial Hyperkalemic Hypertension | American Society of Nephrology and its alter ego, Gitelman syndrome: Gitelman Syndrome | HypertensionJC spoke about this beautiful report on how calcineurin inhibitors lead to hyperkalemia (and mimic Gordon’s syndrome). The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertensionThis superb review of the DCT includes all the highlights of Rose’s chapter 5 with a modern lens including “braking” from DCT hypertrophy Distal Convoluted Tubule | American Society of NephrologyEchos of the lessons learned in the DCT can be seen in this review: Diuretic Treatment in Heart Failure | NEJMAnna reminds us of the ALL HAT trial which showed that chlorthalidone was superior to the lisinopril and amlodipine groups (and the alpha blocker dropped out earlier) ​​Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs DiureticNice review of drug induced Hyperuricemia with a deep dive into the mechanisms of diuretic induced Hyperuricemia. Drug-induced hyperuricaemia and goutPlus, despite the concerns that thiazides are weaker than loop diuretics and may not work in CKD, this report suggests that it can still be of use. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot studyIf you love diuretics, you will love this classic paper from Craig Brater on diuretics Diuretic Therapy | NEJM which also includes the t1/2 of various diuretics and points out that chlorthalidone’s half life is 24-55 hours so eliminated after 4-10 days. The hypercalcemia seen in some patients who take thiazides may be the unmasking of primary hyperparathyroidism Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two DecadesAs we discussed the relative importance of DCT vs Proximal tubule for the hypercalcemia seen with thiazides, Amy reminded us of about the TRPV5 knockout mice: JCI - Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 JC mentioned the defect in TRPM6 that can cause severe hypomagnesemia:  Novel TRPM6 Mutations in 21 Families with Primary Hypomagnesemia and Secondary HypocalcemiaWe enjoyed talking about Liddle syndrome Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndromeWe wondered about the role of pendrin which was discovered after this book was published. Here’s a nice review: The role of pendrin in renal physiology and also a potential therapeutic target for pendrin: Pendrin—A New Target for Diuretic Therapy? | American Society of NephrologyBradykinen Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting ductMore Bradykinen Chronic Overexpression of Bradykinin in Kidney Causes Polyuria and Cardiac HypertrophyWe ended on a high note when we considered the urothelium of the American black bear. These magnificent creatures have aquaporins 1 &3 that allow them to reabsorb their own urine during hibernation. The urothelium of a hibernator: the American black bear

Show notes with a full set of references are available here: http://www.rosebook.club/episodes/2021/6/22/chapter-fourAlso, please fill out our listener survey: https://forms.gle/DVdcJikKZkzY56mXA

Chapter Three: How the proximal tubule is like Elizabeth Warren and other truths my friends from Boston taught me References for Chapter 3: Faisy C, Meziani F, PLanquette B et al. Effect of Acetazolamide vs. Placebo on Duration of Invasive Mechanical Ventilation among patients with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA 2016 https://pubmed.ncbi.nlm.nih.gov/26836730/This randomized controlled double blinded multi-center study of acetazolamide to shorten the duration of mechanical ventilation (known as DIABLO) there was no statistically significant difference (though it may have been underpowered to do so).Salazar H, Swanson J, Mozo K, White AC, Cabda MM Acute Mountain sickness impact among travelers to Cusco, Peru J Travel Med 2012 https://pubmed.ncbi.nlm.nih.gov/22776382/ Investigators found that altitude sickness is common and alters travel plans for 1 in 5 travelers but was prescribed infrequently.Buzas GM and Supuran CT. Journal of enzyme inhibition and medicinal chemistry 2015 https://www.tandfonline.com/doi/full/10.3109/14756366.2015.1051042This review describes the use of acetazolamide to treat peptic ulcers and how it was later learned that H. pylori have carbonic anhydrase NORDIC idiopathic intracranial Hypertension Study Writing Committee. The effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA 2014 https://pubmed.ncbi.nlm.nih.gov/24756514/In this multi-centered trial, acetazolamide and low sodium weight reduction diet improved mild visual loss more than diet alone. Mullens W et al. Rationale and design of the ADVOR (acetazolamide in decompensated heart failure with volume overload trial) Eur J Heart Failure 2018 https://pubmed.ncbi.nlm.nih.gov/30238574/This reference explains the rationale for this ongoing trial.Gordon CE, Vantzelfde S and Francis JM. Acetazolamide in Lithium-induced nephrogenic diabetes insipidus NEJM 2016 https://www.nejm.org/doi/full/10.1056/NEJMc1609483A case report of efficacy of acetazolamide in a patient with severe polyuria.Zehnder D et al. Expression of 25-hydroxyvitamin D-1alpha hydroxylase in the human kidney. JASN 1999 This report explores the activity in the enzyme in nephron segments and suggests that the distal nephron may play an important part in the formation of 1,25 vitamin D https://jasn.asnjournals.org/content/10/12/2465 Outline: Chapter 3    - This is chapter three, kind of the first real chapter of the book- Proximal Tubule- Reabsorbs 55-60% of the filtrate    - Active sodium resorption        - 65% of the sodium        - 55% of the chloride        - 90% of HCO3        - 100% glucose and amino acids    - Passive water resorption    - Water resorption is isosmotic    - Secretion of        - Hydrogen        - Organic anions        - Organic cations    - Anatomy        - S1, S2, S3 can be differentiated by peptidases         - S1 more sodium resorption and hydrogen secretion, high capacity        - S2 more organic ion secretion    - Cell model        - Basolateral membrane            - Na-K-ATPase powers all the resorption         - Luminal membrane        - 100 liters a day crosses the proximal tubule cells            - Microvilli to increase surface area            - Microvilli has brush border which has carrier proteins as well as carbonic anhydrase            - Water permeable, so sodium resorption leads to water resorption            - Aquaporin-1 (sounds like this transporter is unique to the proximal tubule and RBC)            - HCO3 is reabsorbed early, along with Na, resulting in increased chloride concentration which passively reabsorbed via paracellular route.            - Tight junction has only one strand (on freeze fracture) as opposed to 8 in distal nephron        - The Na-K-ATPase            - Lower activity than in the LOH and distal nephron            - Maintained intracellular Na at effective concentration of 30 mmol/L            - Interior of the cell is negative due to 3 sodium out and 2 K in, then K leaks back out.                - 3 Na out for 2 K in                - An ATP sensitive K outflow channel on the basolateral membrane                    - Increased ATP slows potassium eflux                    - The idea is if Na-K slows, ATP will accumulate and this will slow K leaving, because there is less potassium entering.            - K channel is ATP sensitive, ATP antagonizes K leak.            - Highly favorable ELECTROCHEMICAL gradient for sodium to flow into the cell through the luminal membrane            - Must be via a channel or carrier                - Cotransporters                    - Amino acids                    - Phosphate                    - Glucose                - Called secondary active transport                - Countertransporters                    - Only example is H excretion            - Basolateral membrane                - Na-3HCO3 transporter                    - Powered by the negative charge in the cell- Chloride resorption    - Formate chloride exchanger        - Formate combines with hydrogen in the lumen, becomes neutral formic acid, and is reabsorbed where the higher pH causes it to dissociate and recycle again.        - Dependent on continued H+ secretion        - Chloride moves across basolateral membrane thanks to Cl and KCl transporters, taking advantage of negative intracellular charge- Passive mechanisms of proximal tubule transport    - Accounts for one third of fluid resorption    - Mechanism        - Early proximal tubule resorts most of the bicarb and less of the chloride        - Tubular fluid gets a high chloride concentration        - Chloride flows through the tight junction down its concentration gradient            - Sodium and water follow passively behind            - Water moves osmotically into intercellular space from tubular fluid even though the osmolalities are equal since chloride is an ineffective osmole, so tonicity is not the same. ******    - Argues that bicarb is primarily important solute for passive resorbtion        - Acetazolamide blocks Na and chloride resorption        - Similar thing happens with metabolic acidosis where less bicarb is available to drive passive resorbtion of Na and Cl    - Summary        - Other than Na-K-ATPase Na-H antiporter main determinant of proximal Na and water resorption            - 1. Direct bicarb resorption            - Preferential bicarb resorbtion proximally drives passive chloride resorption            - Drives active the formate exchanger for chloride resorption- Neurohormonal influence    - AT2 drives a lot of Na resorption, primarily in S1 segment        - Does not have a net effect on H-CO3 movement    - Dopamine antagonizes sodium resorption        - Blocks both Na-K-ATPase and        - Na H antiporter- Capillary uptake    - Starlings. Again        - Low hydraulic pressure due to glomerular arteriole        - High plasma on oncotic pressure from loss of the filtrate        - The two together promote resorption        - There maybe movement from interstitial back into tubular fluid (back diffusion) conflicting data- Glomerular tubular balance    - The fractional tubular reabsorption remains constant despite changes in GFR (tubular load)    - It is essential the GFR is matched by resorption    - The rise in capillary osmotic pressure with increased GFR via increased filtration fraction is one mechanism of GT balance    - Glomerular tubular balance os one of three mechanisms that prevents fluid delivery from exceeding the resorptive capacity of the tubules         - GT balance        - TG feedback        - Autoregulation    - GT balance can be altered if patients are volume overloaded or depleted    - Closes this section with a story of a kid born without a brush border    - Primacy of sodium in proximal tubule activity        - Discusses bicarb resorbtion            - There is no Tm for Bicarb as long as volume overload is prevented, in rats can rise over 60!            - If you give NaHCO3 you get volume overload and the Tm I about 60        - Glucose            - S1 and S2 have high capacity, low affinity glucose resorption            - S3 has high affinity 2 Na fo every glucose             - Tm glucose is 375 mg/min                - For a GFR of 125t that comes out to 300mg/dL                - 125 ml/min * 3mg/ml (300 mg/dL) = 375 mg/min                - Functionally this is 200 mg/dL due to splay        - Urea            - Only 50-60 of filtered urea is excreted        - Calcium Loop and distal tubule        - Phosphate - 3Na-Phosphate high affinity transporters late in proximal tubule - three types of Na-Phos transporters, type 2 are the most important - regulated by PTH and plasma phosphate - PTH suppresses Phos resorption -Metabolic acidosis also reduces phosphate resorption (good to have phosphate in the tubule to soak up H+ - Decreased tubular pH converts HPO42- to H2PO4- which has lower affinity for phosphate binding site        - Mg Loop and distal tubule        - Uric Acid Why do I love acetazolamide?-   I love the proximal tubule-   Many uses-   Often forgottenMOA-   Inhibit carbonic anhydraseMain effects-   Renal: less bicarb reabsorption (ie less H secretion) à more distal Na/bicarb delivery à hypokalemic metabolic acidosis-   Brain: reduce CSF production, reduce ICP/IOP, aqueous humor-   Pulm: COPDNotes-   Tolerance develops in 2-3 days-   Sulfonamide derivative-   Highly protein bound, eliminated by kidneys Source: Buzas and upuran, JEIMC, 2016S Data:1968 - High altitudeHigh altitude usually results in respiratory alkalosisAcetazolamide – lessens symptoms of altitude sickness (insomnia, headache) which occur because of periodic breathing/apnea1979- NEJM study took 9 mountaineers asleep at 5360 meters à improvement in sleep, improved SaO2 from 72 to 78.7 mmHg, reduce periodic breathing, increased alveolar ventilation (pCO2 change from 37 mmHg to 30.8mm Hg)1950s - Seizures/migrainesCAI reduces pH (more H intracellularly), K movement extracellularly à hyperpolarization and increase in seizure thresholdWeak CAI (Topamax, zonisamide) but not though to be important mechanism of antiseizure effect (topamax enhances inhibitory effect of GABA, block voltage dependent Na and Ca channels)Pulmonary/COPDThought to help with the metabolic alkalosis and as a respiratory stimulant to increase RR, TV, reduce ventilator timeIn 2001 Cochrane review – no difference in clinical outcomes, but did reduce pH and bicarb minimallyDIABLO study (RCT) on ventilated COPD patients – no difference in median duration of mechanical ventilation despite correction of metabolic alkalosisHigh altitude erythropoiesis (Monge disease)First described in 1925 via Dr. Carlos Monge Medrano (Peruvian doctor), seen in people living > 2500-3000 meters (more common in South America than other high altitude areas)Usually chronic altitude sickness with HgB > 21 g/dL + chronic hypoxemia, pHTNAcetazolamide – reduces polycythemia because induces a met acidosis à increases ventilation and arterial PPO2 and SaO2 à blunts erythropoiesis and reduces HCT and improves pulmonary vascular resistanceGI ulcersWhen H2 and PPI available, less useHistory: 1932 – observed alkaline tide, presumed existence of gastric CA (demonstrated in 1939)Acetazolamide was used to inhibit acid secretion in 1960s, ulcer symptoms, with reversible metabolic acidosis, BUT lots of SE (electrolyte losses, used Na/K/Mg salts to help, renal colic, headache, fatigue, etc)Later found H. Pylori encodes for two different CasHelps to acclimatize to acidic environmentBasically, the Ca changes CO2 into H+ and HCO3They also have a urease which produces NH3The NH3 binds with H+, leaving an alkaline environment for them to live inInhibition of CA with acetazolamide is lethal for pathogen in vitro1940sFound there was CA in pancreasThought acetazolamide to reduce volume of secretions from NGT (output from exocrine pancreas) Source: Human Anatomy at Colby Blog Diuretic resistanceIf develop hyperchloremic metabolic alkalosis, short course of acetazolamide + spironolactone (b/c need distal Na blockage) à can helpMay help with urine alkalization (ie uric acid stone) but increases risk of calcium phosphate stonesADVOR trial acetazolamide in HF exacerbation in Belgiumuse may help to prevent new episode, lower total diuretic doseCSF reduction (pseudotumor cerebri)Reduces CSF by as much as 48% when > 99.5% of CA in choroid plexus is inhibitedNORDIC trial (acetazolamide v. placebo) – improvement in visual symptoms especially if advanced papilledema, and reduced opening pressure)Side note also used off label to help with increased ICP and CSF leaks, as alternative to VP shunts, repeat LPs, etc Source: Eftekari et al, Fluid Barriers CNS, 2019.

The exciting conclusion to Chapter Two: Renal Circulation and Glomerular Filtration Rate - Determinants of GFR    - First step in making urine is separation of an ultrafiltrate    - Governed by starling forces        - Balance of hydraulic and osmotic forces        - GFR = LpS (P gc – P us - Osmotic Pressure Cap p)            - Normal GFR 95 in women, 120 in men            - Cap Hydrolic pressure remains constant             - glom cap Oncotic progressively rises                 - Due to filtration of protein free fluid (protein concentration rises in the capillary)            - Filtration gradient begins at 13 mmHg and falls to zero after filtration of 20% or RPF!            - GFR is capped at 20% of RPF called filtration equilibrium            - So GFR is dependent on RPF, unless you can change glomerular hydraulic pressure        - Glomerular hydraulic pressure is controlled by balance of twin arteriole (afferent and efferent)            - Constriction of afferent arteriole reduces RPF, GFR, and glom pressure            - Dilation of afferent arteriole increases RPF, GFR, and glom pressure            - Constriction of the efferent arteriole increases Glom pressure, increasing GFR        - Besides glom hydrostatic pressure the other starlings forces are rarely relevant to changes in GFR Letty says: referred to this NEJM review article later JC thought she was referring to something else -see #2- and then Roger referred to this again)Normotensive Acute Renal Failure from Gary Abuelo in NEJM 2007. https://www.nejm.org/doi/10.1056/NEJMra064398 (note in this article, Dr. Abuelo acknowledges the newer terminology of the time, AKI rather than ARF but chooses not to embrace it). In figure 2, he highlights the classic examples of how autoregulation can be affected. In the table, additional examples are provided but all within the framework of alterations related to autoregulation and the interplay between the two resistance vessels. - Regulation of GFR    - Autoregulation        - The ability to keep glomerular pressure constant over wide range of systemic arterial pressure        - When pressure < 70 autoregulation fails and GFR will fall with decreases in systemic pressure        - When pressure falls below 40-50 GFR ceases        - At least some of this autoregulation is mediated with Ang2. Giving ACEi markedly disrupts autoregulation        - Nitric oxide, not important    - TGF         - Chloride in macula densa            - Blocked by furosemide            - Group affect of nephrons         - Ang 2 sensitizes        - Adenosine mediates        - Function of TGF            - 90% of filtrate is reabsobed in PT and LOH                - 10% is reabsobed dismally                - Need to control the amount of fluid delivered distally to prevent overwhelming the resorptive capacity of the distal nephron                - Talks about acute renal success without naming it (but did reference it)                - Mentions glucosuria blunts TGF. Hmmm...    - Neurohormonal influences         - Volume changes in ang2, sympathetic NS        - Role of PGE        - Interesting discussion of change of the nephrons perfumed with volume depletion, shifting of blood from outer coretex to inner medullary cortical gloms with their long loops        - Dopamine and ANP both increased with volume up            - Dopamine causes vasodilation of afferent and efferent arteriole            - ANP causes afferent vasodilation and efferent vasodilation constriction, increasing GFR without affecting RPF    - Glomerular hemodynamics and renal failure        - Decreased glomerular mass results in hyperfiltration of remaining gloms        - Mediated through afferent vasodilation JC talks about this classic study in critical care: High vs. Low blood pressure target in Septic Shock. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1312173In this multi-center open label trial of 776 patients randomized to either a MAP of 65-70 or 80-85 with the primary endpoint of mortality. There was no difference in mortality at 28 days between the two groups (but a small difference in AKI in the patients who had chronic HTN- in the higher BP target, there was a decrease in need for RRT; there was also a higher incidence of afib in the high target group overall).          - Results in compensation and stable GFR in short term, long term maladaptive        - Reason for ACEi- Clinical Evaluation of Renal Circulation    - Concept of clearance and measurement of GFR        - GFR as an index of functioning renal mass            - Had a patient today s/p nephrotomy, 72 years old, Cr0.9! Melanie referred to this article in Circulation which demonstrates that SGLT2 inhibitors do decrease single nephron GFR (in mice) and that this is related to a decrease in the afferent arteriole diameter and then they show that this is related to a local increase in adenosine.  Kidokoro K, Cherney DZI et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging  Circulation 140 (4) 2019https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.037418         - Fall in GFR earlier and only sign of renal disease        - Serial monitoring is used to assess severity and follow the course of disease        - GFR is useful for dosing drugs        - How to measure GFR             - Consider fructose polysaccharide inulin (love the parenthetical, not insulin)                 - Inulin filtered = inulin excreted                    - Filtered inulin = plasma inulin concentration x GFR                    - Inulin excreted = urine concentration x urine volume                    - Use Alber a to get GFR = [Urine]insulin x urine volume  / [plasma]inulin        - GFR = inulin clearance                    - There is not an available assay for inulin            - Creatinine clearance                - Freely filtered                - Not reanbsorbed                - Not metabolized                - Small amount excreted                    - CrCl exceeds GFR by 10-20% Roger says the SGLT2 inhibitor story is about the afferent arteriole and he thought it reminded him of the MDRD study and the concept that the lower protein intake would be protective and delay the progression of CKD. The concept was that low protein diets would decrease glomerular pressure by decreasing the intake of amino acids that lead to arteriolar vasodilation and increased GFR. Klaur S, Levey AS et al. The effects of Dietary Protein Restirciton and blood-pressure control on the progression of chronic renal disease. NEJM 1994 330:877-884. https://www.nejm.org/doi/full/10.1056/nejm199403313301301                     - Compensated for by noncreatinine chromogens (acetone proteins, as Orbi acid, pyruvate) that over estimate Cr by 10-20%                 - Cr Cl = [Urine]cr x urine volume / [Plasma]cr                - Two major limitations                    - Incomplete collections                        - 20-25 mg/kg in adult men                        - 15-20 mg/kg in adult women The term “Acute renal success” comes from Thurau K and Boylan JW. Acute renal success. The unexpected logic of oliguria in acute renal failure. Am J Med 1976  61(3): 3038-15.                          - Falls by 50% from age 50 to 90 to 10 mg/kg                    - Increased tubular secretion with decreased kidney function                         - GFR of 40-80 cr secretion may account for as much as 35% of creatinine excretion                        - In some cases CrCl can exceed GFR by a factor of 2                        - Give cimetidine 1200 mg!                - It is important to appreciate however that exact knowledge of GFR is not required. More important to know if GFR is changing                - Why is radio labeling the solution DTPA and iothalamate?                - Talks about the reality of progressive disease despite stable GFR and CrCl            - On to plasma Cr and GFR If you think placing dialysis lines is too easy, here is a wonderful review of micropuncture technique in the kidneys by Volker Vallon.Micropuncturing the Nephron. Pflugers Arch 2009 458(1): 189-201. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954491/                 - Creatinine excretion = creatinine production (and this is constant)                    - Creatinine excretion = [Cr] x GFR = constant                    - If GFR falls in half, creatinine excretion will fall in half, while creatinine production remains the same, so creatinine will rise and rise until [Cr] x GFR = creatinine production and then it will level off.                - Changes in creatinine load                    - High protein diet can increase it                    - Vegetarian diet can decrease it JC brought up studies on fenoldopam, of which there are many. This is one such study in patients undergoing cardiac surgery. JAMA 2014 Bove T et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial https://pubmed.ncbi.nlm.nih.gov/25265449/                     - Cooked meat can increase Cr by 1 mg/dL                - Talks about need for steady state to assess GFR                - Talks about the curvilinear relationship                - Then he talks Cockcroft Gault The one, the only: The Cockcroft Gault: Prediction of creatinine clearance from serum creatinine. Nephron 16: 31–41, 1976 https://pubmed.ncbi.nlm.nih.gov/1244564/                 - Cirrhosis masks kidney insufficiency, low meat intake, low BUN production                - Can someone explain what we are supposed to take from figure 2-12                - Stable Cr does not mean stable kidney disease Roger describes the study design for the seminal paper on the use of ACE inhibitors to slow the decline in renal function in diabetic kidney disease (then called diabetic nephropathy) and the decision to use the doubling of the serum creatinine as an endpoint.  Lewis EJ The effect of Angiotensin-converting-enzyme inhibition on diabetic nephropathy NEJM 1993 https://www.nejm.org/doi/full/10.1056/NEJM199311113292004                     - Ketoacidosis can raise the Cr 0.5 to 2.0mg/dL    - On to BUN        - Destination of amino acids produces ammonia        - We detoxify ammonia by converting to urea            - Increased with increased protein load            - Increased catabolism Melanie mentioned an old study on ingestion of expired blood: Cohen TD. Induced azotemia in humans following massive protein and blood ingestion and the mechanism of azotemia in gastrointestinal hemorrhage. AM J Med Sci 1956 https://pubmed.ncbi.nlm.nih.gov/13302213/             - Tetracycline causes decreased anabolism            - Trauma            - Steroids        - Urea excretion is variable and tied to hydration and FF    - Renal plasma flow and PAH