GLOMERULAR FILTRATION Glomerular filtration refers to the process of ultrafiltration of plasma from the glomerular capillaries into the

Bowmans capsule. Composition of glomerular filtrate The unique characteristic features of the glomerular filtration membrane determine the composition of glomerular filtrate, in that it is like that of plasma except for absence of proteins (colloids) and cells. Filtration membrane permeability alteration in diseases, however, may alter diffusibility of colloids and cell. As a result filtration of proteins is increased, and albumin appears in the urine in significant amount (albuminuria or proteinuria). Dynamics of glomerular filtration The forces which determine the bulk flow or ultrafiltration of protein-free plasma across the glomerular membrane are the same which determine formation of tissue fluid. The glomerular filtration rate (GFR) will depend upon the balance of the starling forces. According to starling hypothesis the GFR can be expressed as: GFR = K f [(PGC - PBS) = (GC - BS)] where: GFR is the filtration across the glomerular membrane. K f is the filtration coefficient of the glomerular membrane. PGC is glomerular capillary hydrostatic pressure. Its normal value is about 45 mmHg. GC is the glomerular capillary oncotic pressure. Its normal value is 25 mmHg. BS is the Bowmans space oncotic pressure. Its normal value is zero, because glomerular filtrate contains no proteins. Normal glomerular filtration rate The normal glomerular filtration rate (GFR) in an average sized man is about 125 ml/min (range 90-140 ml/min.) The values in women are 10% lower than those in men. Factors affecting glomerular filtration rate 1. Filtration coefficient (K f): - Increased K f raises GFR and decreased K f reduces GFR as K f is the product of permeability and filtration area of the glomerular capillary membrane. 2. Hydrostatic pressure in Bowmans space fluid (PBS):- opposes filtration and therefore GFR is inversely related to it. It is increased in acute obstruction of urinary tract (e.g. a ureteric obstruction by stone. 3. Glomerular capillary hydrostatic pressure ( PGC ):- GFR is mainly dependent on arterial pressure, renal blood flow, afferent arteriolar resistance, and efferent arteriolar resistance. 4. Glomerular capillary oncotic pressure (GC ):- GFR is inversely proportional to GC . In hyperproteinaemia and in haemoconcentration, the GC is raised leading to decrease in GFR. Conversely in hypoproteinaemia and haemodilution the GC is reduced leading to increased GFR. TUBULAR REABSORPTION AND SECRETION Of the 180 L glomerular filtrate formed per day, about 1.5 L (i.e. less than 1 %) per day is excreted as urine. The different segment of the renal tubule viz. proximal tubule, loop of Henle, distal tubule, and collecting duct determine the composition and volume of the urine by process of selective reabsorption of solutes and water and selective secretion of solutes.

Tubular reabsorption denotes the active transport of solutes and passive movement of water from the tubular lumen into peritubular capillaries. In other words, reabsorption is the removal of substances of nutritive value such as glucose, amino acids, electrolytes (Na +, K+, CI -, HCO3 -) and vitamins from the glomerular filtrate. Small proteins and peptide hormones are reabsorbed in the proximal tubules by endocytosis. Tubular secretion refers to the transport of solutes from the peritubular capillaries into the tubular lumen, i.e. it is the addition of a substance to the glomerular filtrate. Active secretion of substances occurs into the tubular fluid with the help of certain non-selective carriers. The carrier which secretes para-aminohippuric (PAH) acid can also secrete uric acid, bile acids, oxalic acid, penicillin, probenecid, cephalothin and furosemide. TRANSPORT ACROSS DIFFERENT SEGMENTS OF RENAL TUBULE TRANSPORT ACROSS PROXIMAL TUBULE The proximal tubule reabsorbs: Approximately 67% of the filtered water. Na+, CI- , K+ and other solutes, and Almost all the glucose and amino acids filtered by the glomerulus. The proximal tubule does not reabsorb inulin, creatinine, sucrose and mannitol. The proximal tubule secretes H+, PAH, urate, penicillin, sulphonamides, and creatinine. Sodium reabsorption The process of sodium reabsorption in proximal tubule is isosmotic, i.e. the reabsorption of sodium and water are exactly proportional. Mechanisms of Na+ reabsorption Na + is reabsorbed by cotransport with H+ or organic solutes ( glucose, amino acids, phosphate and lactate) The Na absorption is a two-step process : Across the basolateral membrane, Na + moves against an electrochemical gradient via Na+ K+ ATPase pump, which pumps Na into the paracellular spaces and lowers the intracellular Na concentration. Across the apical membrane, the sodium moves down an electrochemical gradient as above. The entry of Na+ is mediated by specific antiporter and symporter proteins, and not by diffusion through channels. Water reabsorption Approximately 67% of the filtered water is absorbed in the proximal tubule by osmosis in response to a transtubular osmotic gradient established by the solute reabsorption (i.e. Na+ CI-, Na+ glucose, and so forth). The osmotic water absorption is termed as obligatory water absorption as it cannot be changed according to the needs of the body.

Protein reabsorption
Normally, only a small amount of proteins is filtered by the glomerulus (40mg/L). However, because of high GFR (180 L/day) the total amount of proteins filtered per day is significant (180 L/day x 40 mg/L=7.2 gm/day). Normally, the proteins are completely taken into the cells of proximal tubules by the process of

endocytosis. Once inside the cells, enzymes digest the proteins and peptides into their constituent amino acids which exit across the basolateral membrane and return to the blood in the peritubular capillaries. When the amount of filtered proteins increases (due to disruption of glomerular filtration barrier in Kidney diseases), the reabsorbing mechanisms saturate and the proteins may appear in the urine (proteinuria).

Glucose reabsorption
Glucose is freely filtered into the glomerular filtrate. Filtration load of glucose increases in direct proportion to the plasma glucose concentration (P glucose ). Filtered load of glucose = GFR x P glucose (PG).

Mechanism of tubular reabsorption

All the filtered glucose is completely reabsorbed into the proximal tubule by an active transport mechanism.

Carrier mediated Na+ glucose cotransport. Carrier protein located at the apical membrane in the
proximal tubule reabsorbs glucose from tubular fluid into the blood. . The carrier protein for glucose in early and late proximal tubule is called SGLT-2 and SGLT-1, respectively (SGLT= sodium-dependent glucose transporter).

Facilitated diffusion moves the glucose out of the cell through the basolateral membrane. The carrier
for facilitated diffusion across the basolateral membrane in early and late proximal tubule is called GLUT2 and GLUT-1, respectively (GLUT = glucose transporter).

Characteristics of glucose transport and glucose excretion

Glucose is reabsorbed by a transport maximum process, i.e. there are limited numbers of Na+- glucose carriers. The characteristics of glucose transport and glucose excretion can be elicited from the glucose titration curve.

Glucose titration curve (Fig 9.2-5) depicts that: Filtered load increases with the plasma glucose concentration (PG ). Renal threshold, i.e. the plasma glucose concentration at which glucose first appears in the urine
(glycosuria) is about 180-200 mg% . At plasma levels below renal threshold the reabsorption of glucose is complete (100%).

Transport maximum As shown in Fig. 9.2-5, beyond plasma glucose concentration of 350 mg% (TmG
)the reabsorption rate does not increase, i.e. becomes constant and is independent of PG . Therefore, as the TmG is reached, the urinary excretion rate increases linearly with increase in plasma glucose concentration. Splay refers to the region of the glucose curve between threshold and T mG , i.e. between PG 180mg% and 350 mg%. It represents the excretion of glucose in urine before the TmG is fully achieved. Note that in the region of splay the reabsorption curve is rounded indicating that though the reabsorption rate is increasing with increase in PG , but reabsorption is less than filtration. Similarly, the excretion curve is

also rounded in the region of splay, indicating that though the urinary excretion is increasing with increase in PG , but there is no linear relation.

Causes of splay are:

. Heterogenicity in glomerular size, proximal tubular length, and number of carrier proteins for glucose reabsorption. . Variability in TmG of the nephron.

TRANSPORT ACROSS LOOP OF HENLE

About 20% of filtered Na+ and CI- , 15% of filtered water and cations such as K +, Ca2+ and Mg2+ are reabsorbed in the loop of Henle. Reabsorption occurring in different parts of loop of Henle is: Thin descending limb of loop of Henle Water absorption occurs passively (because of hypertonic interstitial fluid) in this part of loop of Henle. It is accompanied by diffusion of sodium ions from interstitial fluid into tubular lumen. Thick ascending limb of loop of Henle This limb is impermeable to water but is involved in the reabsorption of 20% of filtered Na+ , and CI- and other cations . Note. Thick ascending limb is impermeable to water. Thus, NaCl and other solutes are reabsorbed without water. As a result, tubular fluid Na+ and tubular fluid osmolarity decreased to less than their concentration in plasma. This segment is therefore called the diluting segment. Further, Na+ reabsorbed from this segment is the main driving force behind the counter-current multiplier system which concentrates Na+ and urea in medullary interstitium. TRANSPORT ACROSS DISTAL TUBULES AND COLLECTING DUCT Approximately 7% of the filtered NaCI , and about 8-17% of water is reabsorbed and K+ and H+ are secreted in these segments. Early distal tubule Early distal tubule (initial segment of distal tubule) reabsorbs Na+, CI- and Ca2+, and is impermeable to water. Late distal tubule and collecting duct Late distal tubule and collecting duct have two cell types (principal cells and intercalated cells) which perform both reabsorption and secretory functions: Role of ant diuretic hormone. H2O absorption occurs in response to the effect of antidiuretic hormone (ADH) on the principal cells. ADH increases H2 O channels in the luminal membrane. In the absence of ADH, the principal cells are virtually impermeable to water.