Loop of Henle

Renal Handling of Urea

July 22, 2017 Laboratory Medicine, Nephrology, Physiology and Pathophysiology, Urology No comments , , , , , , ,

Renal Handling of Urate

Urate, an anion that is the base form of uric acid, provides a fascinating example of the renal handling of organic anions that is particularly important for clinical medicine and is illustrative of renal pathology. An increase in the plasma concentration of urate can cause gout and is thought to be involved in some forms of heart disease and renal disease; therefore, its removal from the blood is important. However, instead of excreting all the urate it can, the kidneys actually reabsorb most of the filtered urate. Urate is freely filterable. Almost all the filtered rate is reabsorbed early in the proximal tubule, primarily via antiporters (URAT1) that exchange urate for another organic anion. Further on the proximal tubule urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. Because the total rate of reabsorption is normally much greater than the rate of secretion, only a small fraction of the filtered load is excreted.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimulated, thereby increasing urate excretion.

Given these mechanisms of renal urate handling, the reader should be able to deduce the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: 1) decreased filtration of urate secondary to decreased GFR, 2) excessive reabsorption of urate, and 3) diminished secretion of urate.

Urate, and some other organic solutes, although more membrane permeable in the neutral form, are less soluble in aqueous solution and tend to precipitate. The combination of excess plasma urate and low urinary pH, which converts urate to the neutral uric acid, often leads to the formation of uric acid kidney stones.

Renal Handling of Urea

Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also an important component for the regulation of water excretion. Urea differs from all the other organic solutes in several significant ways. 1) There are no membrane transport mechanisms in the proximal tubule; instead, it easily permeates the tight junctions of the proximal tubule where it is reabsorbed paracellularly. 2) Tubular elements beyond the proximal tubule express urea transporters and handle urea in a complex, regulated manner.

Urea is derived from proteins, which form much of the functional and structural substance of body tissues. Proteins are also a source of metabolic fuel. Dietary protein is first digested into its constituent amino acids. These are then used as building blocks for tissue protein, converted to fat or oxidized immediately. During fasting, the body breaks down proteins into amino acids that are used as fuel, in essence consuming itself. The metabolism of amino acids yields a nitrogen moiety (ammonium) and a carbohydrate moiety. The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product. Ammonium per se is rather toxic to most tissues and the liver immediately converts most ammonium to urea and a smaller, but crucial amount to glutamine. While normal levels of urea are not toxic, the large amounts produced on a daily basis, particularly on a high protein diet, represent a large osmotic load that must be excreted. Whether a person is well fed or fasting, urea production proceeds continuously and constitutes about half of the usual solute content of urine.

The normal level of urea in the blood is quite variable, reflecting variations in both protein intake and renal handling of urea. Over days to weeks, renal urea excretion must match hepatic production; otherwise plasma levels would increase into the pathological range producing a condition called uremia. On a short-term basis (hours to days), urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level.

The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed passively in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted.

pH Dependence of Passive Reabsorption or Secretion

Many of the organic solutes handled by the kidney are weak acids or bases and exist in both, neutral and ionized forms. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. Neutral solutes are more permeable than ionized solutes. As water is reabsorbed from the tubule, any substance remaining in the tubule becomes progressively more concentrated. And the luminal pH may change substantially during flow through the tubules. Therefore, both the progressive concentration of organic solutes and change in pH strongly influence the degree to which they are reabsorbed by passive diffusion through regions of tubule beyond the proximal tubule.

At low pH weak acids are predominantly neutral, while at high pH they dissociate into an anion and a proton. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, acidification converts much of the acid to the neutral form and therefore, increases its permeability. This favors diffusion out of the lumen (reabsorption). Highly acidic urine tends to increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just opposite. At low pH they are protonated cations. As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted.

Histology of Renal Tubules and Capillaries

October 8, 2015 Nephrology, Physiology and Pathophysiology No comments , , , , , ,

Renal Tubule

The renal tubule begins at and leads out of Bowman’s capsule on the side opposite the vascular pole (the tubule pole, compare the Arctic pole and Antarctic pole of Earth). The tubule has a number of segments divided into subdivisions. Throughout its length the tubule is made up of a single layer of epithelial cells resting on basement membrane and connected by tight junctions that physically link the cells together.

Renal tubule segments include proximal convoluted tubule, proximal straight tubule, descending thin limb of the loop of Henle, the ascending thin limb of the loop of Henle (only long loop nephrons), ascending thick limb of the loop of Henle, distal convoluted tubule, connecting tubule, and collecting duct.

The proximal tubule is the first segment. It drains Bowman’s capsule and consists of a coiled segment – the proximal convoluted tubule – followed by a shorter straight segment – the proximal straight tubule. The coiled segment is entirely within the cortex, whereas the straight segment descends a short way into the outer medulla. Most of the length and functions of the proximal tubule are in the cortex. The next segment is the descending thin limb of the loop of Henle. The descending thin limbs of all nephrons begin at the same level, at the point where they connect to straight portions of proximal tubules in the outer medullaThis marks the border between the outer and inner stripes of the outer medulla.

In contrast, the descending thin limbs of different nephrons penetrate down to varying depths in the medulla. At their ending they abruptly reverse at a hairpin turn and become an ascending portion of the loop of Henle parallel to the descending portion. In long loops, the ones that have penetrated deep into the inner medulla, the epithelium of the first portion of the ascending limb remains thin, although different functionally from that of the descending limb. This segment is called the ascending thin limb of Henle’s loop, or simple the ascending thin limb. Further up the ascending portion the epithelium thickens, and this next segment is called the thick ascending limb. In short loops, there is no ascending think portion, and the thick ascending portion begins right at the hairpin loop.

All thick ascending limbs begin at the same level, which marks the border between the inner and outer medulla. Therefore, the thick ascending limbs begin at a slight deeper level in the medulla than do thin descending limbs. Each thick ascending limb rises back into the cortex right back to the very same Bowman’s capsule from which the tubule originated. Here it passes directly between the afferent and efferent arterioles at the vascular pole of Bowman’s capsule. The cell in the thick ascending limb closest to Bowman’s capsule (between the afferent and efferent arterioles) are specialized cells known as the macula densa. The macula densa marks the end of the thick ascending limb and the beginning of the distal convoluted tubule. This is followed by the connecting tubule, which leads to the cortical collecting duct, the first portion of which is called the initial collecting tubule. Connecting tubules from several nephrons merge to form a given cortical collecting duct.

All the cortical collecting ducts then run downward to enter the medulla and become outer medullary collecting ducts, and continue to become inner medullary collecting ducts. These merge to form larger ducts, the last portions of which are called papillary collecting ducts, each of which empties into a calyx of the renal pelvis. Each renal calyx is continuous with the ureter. The tubular fluid, now properly called urine, is not altered after it enters a calyx. Up to the distal convoluted tubule, the epithelial cells forming the wall of a nephrons in any given segment are homogeneous and distinct for that segment. For example, the thick ascending limb contains only thick ascending limb cells. However, beginning in the second half of the distal convoluted tubule the epithelium contains 2 intermingled cell types. The first constitutes the majority of cells in a particular segment and are usually called principal cells. Thus, there a segment-specific principal cells in the distal convoluted tubule, connecting tubule, and collecting ducts. Interspersed among the segment-specific cells in these regions are cells of a second type, called intercalated cells, that is, they are intercalated between the principal cells. The last portion of the medullary collecting duct contains neither principal cells nor intercalated cells but is composed entirely of a distinct cell type called the inner medullary collecting-duct cells.

Renal VesselsScreen Shot 2015-10-04 at 4.06.11 PM

Blood enters each kidney at the hilum via a renal artery. After several divisions into smaller arteries blood reaches arcuate arteries that course across the tops of the pyramids between the medulla and cortex. From these, cortical radial arteries project upward toward the kidney surface and give off a series of afferent arterioles (AAs), each of which leads to a glomerulus within Bowman’s capsule. These arteries and glomeruli are found only in the cortex, never in the medulla. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles, the efferent arterioles (EAs). The vast majority of the EAs soon subdivide into a second set of capillaries called peritubular capillaries. These capillaries are profusely distributed throughout the cortex intermingled with the tubular segments. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney. EAs of glomeruli situated just above the corticomedullary border (juxtamedullary glomeruli) do not brach into peritubular capillaries the way most EAs do. Instead these arterioles descend downward into the outer medullar. Once in the medulla they divide many times to form buddies of parallel vessels called vasa recta. These bundles of vasa recta penetrate deep into the medulla.

Vasa recta on the outside of the vascular bundles “peel off” and give rise to interbundle networks of capillaries that surround Henle’s loops and the collecting ducts in the outer medullaOnly the center-most vasa recta supply capillaries in the inner medulla; thus, little blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex.