The composition of the ultrafiltrate is: Plasma minus protein

* Examples of Modification of the ultrafiltrate: In the proximal tubule, 100 % of filtered glucose is reabsorbed by a carrier mediated transport mechanism 2° active transport. - In the apical luminal side of the cell we have Na+ - Glucose luminal transporters: SGLT 1&2. * Here, Na+ is transported down its gradient, but glucose is actively transported against its gradient. BUT, if we don ’ t have Na+, No glucose will be absorbed.

Tubular Function GTC Renal threshold for glucose is 180mg/dl. What does this tell you? Renal threshold for glucose is 180mg/dl. What does this tell you?.

Glucose MW is small (180), → freely filtered. - Plasma concentration of glucose is between 70 – 110 mg/dl) -The filtered load of glucose? It's the amount of glucose filtered per minute. Filtered load = Plasma conc. * GFR = 100 mg / dl * 1.25 dl/min. = 125 mg / min Now, if we increase the glucose conc. in plasma - Filtration will increase, (Linear relationship). - Reabsorption will increase until we reach Tmax * Tmax for glucose is 320 mg/dl, or 375 mg/min (filtered load)

This curve is called: Glucose Titration Curve GTC. Until plasma concentration of glucose is 180 mg/dl, we have no excretion 100% of glucose is reabsorbed. At normal or even slightly higher than normal, all G are reabsorbed, meaning that kidney is not a major regulator for G. Since threshold & Tm for Glucose are far above normal plasma G level (G  or  still 100% is reabsorbed).

Threshold : The conc. of glucose in plasma at which glucose starts to appear in urine = (180 mg/dl) venous blood or 200 mg/dl art.bld Theoretically, Threshold & Tmax should match, but practically they do not.

-If we have Glucosuria, it may be: 1. Diabetogenic because of diabetes 2. Nephrogenic the number of glucose carriers in this person is less than normal less threshold any small rise in the plasma glucose conc. (ex: after meals) will induce glucosuria. Nephrogenic Glucosuria is benign, not associated with other renal problems, & will not cause any problem later on…good prognosis….you do not need to mention it. Conclusion: if the patient glucosuria, do a blood glucose level test (e.g FBS), if normal, then it's nephrogenic….just ignore it.

Second, KFT: blood tests to assess kidney function: Urea, Creatinine, Electrolyte. - If creatinine is in it s normal range ( mg/dl), this does not always exclude kidney impairment… you should notice the range is double…actually it depends on muscle mass for example…however, if [plasma creatinine] today is 0.8 mg/dl and after few weeks it increases to 1.4 mg/dl…this indicates decrease in GFR….so previous reading is important if available. * Still, plasma creatinine is the best indicator as KFT. It is more important than urea because urea is subjected to other variables. (Like in cases of dehydration or GI bleeding), it's plasma level increases without kidney damage. * Creatinine also rises due to increase muscle mass (body builders). Elderly have less muscle mass.

Third, Another tests involve urine analysis ; * urine is very informative and easy to deal with. * We can test: 1. Volume of urine (24 h Urine collection) 2. Presence or absence of Glucose, proteins, RBCs, WBC, casts, etc… 3. SG 4. Color 5. pH

Notes: In nephrectomy, other nephrons may compensate partially. We may have congenital one kidney & that's okay if it's functioning well & has no malformations Silent malignant Kidney stone :if present, it might give only a discomfort feeling, different from colic pain. - Renal colicky pain – caused by stones – is benign, bc it alarms the patients always to go to doctor. obstruction by stone might damage the kidney, because it will increase Bowman's capsular hydrostatic pressure & oppose the filtration. This leads to cortical atrophy → permanent kidney damage.

Sodium Homeostasis Sodium is an electrolyte of major importance in the human body. It is necessary for : Sodium is an electrolyte of major importance in the human body. It is necessary for : 1. normal extracellular volume dynamics 2. excitability of certain tissues 3. cotransport and countertransport…glucose, a.a, H + 4. countercurrent mechanism 5. concentration of urine in thick ascending 6. Sodium accounts for a significant portion of plasma osmolarity. The latter can be estimated by multiplying plasma sodium concentration times H + secretion (acid – base balance) and K + secretion occur as countertransport with Na +. Most of the primary active transport in the entire tubular system is to transport Na +

Normal Renal Tubular Na + Reabsorption 0.6 % (150 mEq/d) (16,614 mEq/day) 65 % ( 6390 mEq/d) (617 mEq/d) 2.4% 25,560 mEq/d 25 % (1789 mEq/d) 7 %

Sodium Homeostasis Sodium balance is achieved when intake and output equal each other. Sodium balance is achieved when intake and output equal each other. Sodium intake is about mmol/d in the average American diet. Logically, the daily output would be mmol/d as well. Sodium intake is about mmol/d in the average American diet. Logically, the daily output would be mmol/d as well. The kidney accounts for mmol of this output. Hence, the kidney is a major organ in sodium homeostasis. The kidney accounts for mmol of this output. Hence, the kidney is a major organ in sodium homeostasis.

Na Clearence Sodium clearance can be calculated as follows: Sodium clearance can be calculated as follows: U Na+ = 150mmol/d ÷ 1.5l/d urine per day = 100mmol/l U Na+ = 150mmol/d ÷ 1.5l/d urine per day = 100mmol/l C Na+ = (U Na+ / P Na+ ) * V = (100 / 145) * 1 = 0.69ml/min C Na+ = (U Na+ / P Na+ ) * V = (100 / 145) * 1 = 0.69ml/min Notice that the value is less than 1 ml/min, which indicates that sodium is mostly reabsorbed. Notice that the value is less than 1 ml/min, which indicates that sodium is mostly reabsorbed. Sodium reabsorption is rather extensive. In order to appreciate this, let ’ s do the math. Sodium reabsorption is rather extensive. In order to appreciate this, let ’ s do the math. Amount of sodium filtered per day = 180l/d * 140mM = 25200mEq Amount of sodium filtered per day = 180l/d * 140mM = 25200mEq Amount of sodium excreted by the kidney = 150 mM Amount of sodium excreted by the kidney = 150 mM Percent reabsorbed = / = 99.4% Percent reabsorbed = / = 99.4%

sodium homeostasis Three factors are principally involved in sodium homeostasis: Three factors are principally involved in sodium homeostasis: 1. GFR, 2. Aldosterone, 3. Atrial natriuretic peptide.

Na + & H 2 O reabsorption occurs as the following : Segment Na + % H 2 O% Proximal tubule 65%65% Descend (Henle) -15% Ascending (Henle 25%- Distal tubule 5%10% Collecting duct 4%9%

C Na+ = U Na+ /P Na+ ] x V = 100/140 x 1 = < 1 ml/min Prox desc asc distal coll.duct Flow rate 125 ml/min <1ml/ min

about the curve : about the curve : 1. the decrement in the flow rate (F.R) throughout the kidney tubules. 2. F.R remains relatively constant at the level of the ascending limb of Henle.

There are 2 ways to handle Na+ in the kidney : There are 2 ways to handle Na+ in the kidney : 1) Through filtration or 2) Reabsorption Ex: when Na + intake↑  ↑Na + filtered  reabsorption in distal tubule Na + reabsorption is decreased.  more excretion Ex: when Na + intake↑  ↑Na + filtered  reabsorption in distal tubule Na + reabsorption is decreased.  more excretion

B. Reabsorption in descending limb of Henle (no reabsorption). B. Reabsorption in descending limb of Henle (no reabsorption). C. Reabsorption in the Ascending limb of Henle. C. Reabsorption in the Ascending limb of Henle. reabsorption involves ( Na + -K + -2Cl - ) co- transporter without H 2 O, this is called [single effect]  ↑ osmolarity in the interstitium, osmolarity in the TF. reabsorption involves ( Na + -K + -2Cl - ) co- transporter without H 2 O, this is called [single effect]  ↑ osmolarity in the interstitium, osmolarity in the TF.

Clinical point 1. Furesamide ( Lasix): a potent loop diuretic acts on the thick ascending limb of Henle TAL where it inhibits Na-2Cl-K  ↑ Na+ Excretion. Lasix is used in pulmonary edema & hypertension. Lasix is used in pulmonary edema & hypertension. 2. Thiazide/Chlorothiazide (moderate diuretic) acts on distal convoluted tubule DCT inhibiting Na/Cl reabsorption Those 2 diuretics are called [potassium- wasting diuretics]…they induce hypokalemia Those 2 diuretics are called [potassium- wasting diuretics]…they induce hypokalemia

Reabsorption of Na+ D. Reabsorption in late distal tubules & cortical collecting duct. D. Reabsorption in late distal tubules & cortical collecting duct. Reaborption of Na+ & secretion of K+ occur through the principal cells. Reaborption of Na+ & secretion of K+ occur through the principal cells.

Clinical point 1. Spironolactone (aldactone): works on principal cells by decreasing K+ secretion  aldactone diuretics are called [K + sparing diuretics] or [aldosterone antagonists]. 1. Spironolactone (aldactone): works on principal cells by decreasing K+ secretion  aldactone diuretics are called [K + sparing diuretics] or [aldosterone antagonists]. 2. Osmotic diuretics, (ex: Mannitol) is a glomerular marker & has an osmotic effect i.e. it's not reabsorbed so it drives H 2 O with it, used in brain edema. 2. Osmotic diuretics, (ex: Mannitol) is a glomerular marker & has an osmotic effect i.e. it's not reabsorbed so it drives H 2 O with it, used in brain edema.

Control of Na ++ when Na + intake is increased  increase in GFR through increasing ECV and BP. when Na + intake is increased  increase in GFR through increasing ECV and BP. When ECV increases  π in peritubular capillary decreases due to dilution

Control of Na + How does the body control increase in Na+ intake ? How does the body control increase in Na+ intake ? 1. Altering GFR 2. Altering Reabsorption 1-Altering GFR: 1-Altering GFR: When Na + intake increases  Glomerulotubular feedback does not work for unknown reason  increase Na + Excretion. When Na + intake increases  Glomerulotubular feedback does not work for unknown reason  increase Na + Excretion. increase Na + intake  increase Pa  increase GFR ( Pressure Natriuresis) increase Na + intake  increase Pa  increase GFR ( Pressure Natriuresis)

Control of Na + 2-Altering reabsorption: When Na+ intake increases the RFC is shifted to the left to ensure increase Na+ excretion. This shift means less production of AII…which results in less Na reabsorption and thus increase its excretion. In addition less AII means less aldosterone and less Na reabsorption. When Na+ intake increases the RFC is shifted to the left to ensure increase Na+ excretion. This shift means less production of AII…which results in less Na reabsorption and thus increase its excretion. In addition less AII means less aldosterone and less Na reabsorption. Aldosterone is also autoregulated….means whenever [Na+] in plasma increases, Aldosterone production decreases Aldosterone is also autoregulated….means whenever [Na+] in plasma increases, Aldosterone production decreases ANP (Atrial Natriuretic Peptide) increases due to ANP (Atrial Natriuretic Peptide) increases due to atrial pressure  atrial pressure  1. Afferent Arterial dilatation. 1. Afferent Arterial dilatation. 2. inhibit adrenal cortex  decrease aldosterone production. 2. inhibit adrenal cortex  decrease aldosterone production.

Diuretics They are actually 7 groups each work on a specific cell and with a different mechanism. They are actually 7 groups each work on a specific cell and with a different mechanism. some of these groups are used for specific indications like carbonic anhydrase inhibitors which is used in glaucoma some of these groups are used for specific indications like carbonic anhydrase inhibitors which is used in glaucoma hypokalemia is a serious complication of loop diuretics and thiazide hypokalemia is a serious complication of loop diuretics and thiazide

Diuretics ClassMechanismSite of Action osmotic diureticsMannitol loop diuretics like furosemide, ethacrynic acid and bometanide inhibit Na-K-2Cl cotransport. Most powerful available. They increase *Ca++ and *Mg++ elimination At thick ascending **ThiazideInhibit Na-Cl cotransport.: increase Ca reabsorption increase At distal Acetazolamide (Diamox)C.A inhibitorsProximal..used for glucoma ***SpironolactoneInhibit Na + reabsorptionAt principal cells Na + channel blockers such as Amiloride and triamterene Because they inhibit Na + reabsorption, they also inhibit K + secretion. Therefore, they are also K+ sparing.