Department of Physiology: Renal & Urinary System Physiology-Offline information

Urine Concentration and Juxtamedullary Nephrons: Only the juxtamedullary nephrons have loops of Henle that descend deep into the medulla, but enough of them exist to maintain a high concentration of solutes in the interstitial fluid of the medulla. Not all of the nephrons need to have loops of Henle that descend into the medulla to concentrate urine effectively. The cortical nephrons function as the juxtamedullary nephrons do, but their loops of Henle are not as efficient at concentrating urine. However, because the filtrate from the cortical nephrons passes through the collecting ducts, water can diffuse out of the collecting ducts into the interstitial fluid. Thus, the filtrate becomes concentrated. Animals that concentrate urine more effectively than humans have a greater percentage of nephrons descending into the kidney medulla. For example, in desert mammals, many nephrons descend into the medulla, and the renal pyramids are longer than those in humans and most other mammals.

Diabetic nephropathy a disease of the kidneys associated with diabetes mellitus, and it is the principal is cause of chronic renal failure. This condition damages renal glomeruli and ultimately destroys functional nephrons through progressive scar tissue formation, mediated in part by an inflammatory response. The damaged glomeruli no longer filter the blood effectively, allowing proteins to pass through the filtration membrane and be excreted in the urine. The presence of protein in the urine of people who have type 2 diabetes strongly suggests significant diabetic nephropathy, which can lead to end-stage renal failure. About 1 in 14 Americans over age 30 have some degree of type 2 diabetes mellitus, and most hemodialysis patients have type 2 diabetes mellitus. The development of diabetic nephropathy is complex. Although the mechanism is not completely understood, the level of angiotensin II is elevated in diabetes mellitus. This causes exaggerated efferent arteriole vasoconstriction and consequently increased glomerular capillary pressure. The increased glomerular capillary pressure dam ages the glomerular basement membrane, causing it to thicken and become more permeable. The glomerular basement membrane is also dam aged by the production of glycoproteins called advanced glycosylation end products (AGEs). AGEs are produced when glucose forms irreversible cross-links with kidney and plasma proteins. The AGEs stimulate the secretion of growth factors from glomerular cells, which promote glomerular basement membrane thickening. Because the glomerular basement membrane in patients with diabetes mellitus is more permeable than normal, plasma proteins cross the filtration membrane and enter the urine. The initial amount of protein entering the urine is small, a condition called microalbuminuria. However, as the number of functional nephrons in the kidney decreases, microalbuminuria eventually progresses to overt proteinuria, the secretion of more than 300 mg albumin/day. By the time overt proteinuria has developed, which may take 10–15 years, the number of functional nephrons has decreased to less than 10% of normal, and the kidneys are no longer able to excrete adequate amounts of waste products. This condition is called end-stage renal disease (ESRD). In ESRD, renal failure has worsened to the point that kidney function is less than 10% of normal. Unless ESRD is treated by hemodialysis or kidney transplantation, the patient dies. The use of angiotensin-converting enzyme (ACE) inhibitors slows or, in some cases, even halts the progression of proteinuria and end stage renal disease. ACE inhibitors prevent the formation of angiotensin II; consequently, arterial blood pressure and glomerular capillary pressure remain within their normal ranges. When ACE inhibitors are used in combination with drugs called angiotensin receptor blockers (ARBs), which prevent angiotensin II molecules from binding to their receptors, proteinuria decreases up to 45%. People with type 2 diabetes who maintain their blood glucose within normal levels have a much lower incidence of diabetic nephropathy and ESRD.

Polycystic Kidney Disease: Polycystic kidney disease (after diabetes mellitus and high blood pressure). Approximately 90% of patients inherit the condition as an autosomal dominant is the third leading cause of renal failure trait. Consequently, if one parent carries an allele for this disorder, each child has a 50% chance of also having the disorder (see chapter 29). The gene for this condition is located on chromosome 16 and codes for a protein that may regulate cell-to-cell interactions. In people affected by polycystic kidney disease, the kidneys are enlarged and often contain large, fluid-filled cysts varying in size from a few millimeters to centimeters. The cysts increase in number and enlarge as the person ages. Development of the cysts results from abnormal cell-to-cell interactions and causes excess proliferation of the epithelial cells that make up the kidney nephrons and collecting ducts. Polycystic kidney disease is often detected using ultrasound techniques. The condition is usually diagnosed when patients are between 30 and 50 years of age. Approximately 50% of patients require hemodialysis (see Systems Pathology) by 70 years of age.

Describe the effects of aging on the kidneys. Aging causes the kidneys to gradually decrease in size, beginning as early as age 20, becoming obvious by age 50, and continuing until death. The decrease in kidney size appears to be related to changes in the blood vessels of the kidney. The amount of blood flowing through the kidneys gradually decreases. Starting at age 20, there appears to be an approximately 10% decrease every 10 years. Small arteries, including the afferent and efferent arterioles, become irregular and twisted. Functional glomeruli are destroyed. By age 80, 40% of the glomeruli are not functioning. About 30% of the glomeruli that stop functioning no longer have a lumen through which blood flows. Other glomeruli thicken and assume a structure similar to that of arterioles. Some nephrons and collecting ducts become thicker, shorter, and more irregular in structure. The capacity to secrete and absorb declines, and whole nephrons stop functioning. The kidney’s ability to concentrate urine gradually declines. Eventually, changes in the kidney increase the risk for dehydration because of the kidney’s reduced ability to produce concentrated urine. The ability to eliminate uric acid, urea, creatinine, and toxins from the blood also decreases.

Diabetes insipidus is a disease associated with the inadequate secretion or action of ADH. When the secretion of ADH is adequate, but a genetic defect in the ADH receptors or the aquaporin channels renders the kidneys incapable of responding to ADH, the condition is called nephrogenetic diabetes insipidus. Without proper ADH secretion or action, the collecting ducts are not very permeable to water, and so a large volume (5 to 10 L per day) of dilute urine is produced. The dehydration that results causes intense thirst, but a person with this condition has difficulty drinking enough to compensate for the large volumes of water lost in the urine.

Hemodialysis is used when a person is suffering from severe acute or chronic kidney failure. T e procedure substitutes for the excretory functions of the kidney. Hemodialysis is based on blood ﬂow through tubes composed of a selectively permeable membrane. Blood is usually taken from an artery, passed through tubes of the dialysis machine, and then returned to a vein. On the outside of the dialysis tubes is a fluid, called dialysis fluid, which contains the same concentration of solutes as normal plasma, except for the metabolic waste products. As a consequence, the metabolic wastes diffuse from the blood to the dialysis fluid. The dialysis membrane has pores that are too small to allow plasma proteins to pass through them, and because the dialyis fluid contains the same beneficial solutes as the plasma, the net movement of these substances is zero. Peritoneal dialysis is sometimes used to treat kidney failure. The principles by which peritoneal dialysis works are the same as for hemodialysis, but the dialysis ﬂuid ﬂows through a tube inserted into the peritoneal cavity. The visceral and parietal peritonea act as the dialysis membrane. Waste products diff use from the blood vessels beneath the peritoneum, across the peritoneum, and into the dialysis ﬂuid.

Kidney transplants are sometimes performed on people who have severe renal failure. Often, the donor has suffered an accidental death and had granted permission to have his or her kidneys used for transplantation. The major cause of kidney transplant failure is rejection by the recipient’s immune system. Physicians therefore attempt to match the immune characteristics of the donor and recipient to reduce the tendency for rejection. Even with careful matching, recipients have to take medication for the rest of their lives to suppress their immune reactions. In most cases, the transplanted kidney functions well, and the tendency of the recipient’s immune system to reject the transplanted kidney can be controlled. Neuromuscular irritability results from the toxic effect of metabolic wastes on the central nervous system and ionic imbalances, such as elevated blood K+ levels. Involuntary jerking and twitching may occur as neuromuscular irritability develops. Physicians therefore attempt to match the immune characteristics of the donor and recipient to reduce the tendency for rejection. Even with careful matching, recipients have to take medication for the rest of their lives to suppress their immune reactions. In most cases, the transplanted kidney functions well, and the tendency of the recipient’s immune system to reject the transplanted kidney can be controlled.

Chronic kidney failure

Charles B., a forty-three-year-old muscular construction worker, had been feeling unusually tired for several weeks, with occasional dizziness and difficulty sleeping. More recently he had noticed a burning pain in his lower back, just below his rib cage, and his urine had darkened. In addition, his feet, ankles, and face were swollen. His wife suggested that he consult their family physician about these symptoms. The physician found that Charles had elevated biood pressure (hypertension) and that the regions of his kidneys were sensitive to pressure. A urinalysis revealed excess protein (proteinuria) and blood (hematuria), Blood tests indicated elevated blood urea nitrogen (BUN), elevated serum creatinine, and decreased serum protein (hypoproteinemia) concentrations. The physician told Charles that he probably had chronic glomerulonephritis, an inflammation of the capillaries within the glomeruli of the renal nephrons, and that this was an untreatable progressive degenerative disease. Microscopic examination of a sample of kidney tissue (biopsy) later confirmed the diagnosis. In spite of medical treatment and careful attention to his diet, Charles's condition deteriorated rapidly. When it appeared that most of his kidney function had been lost (end-stage renal disease, or ESRD). He was offered artificial kidney treatments (hemodialysis). To prepare Charles for hemodialysis, a vascular surgeon created a fistula in his left forearm by surgically connecting an artery to a vein. The greater pressure of the blood in the artery that now flowed directly into the vein swelled the vein, making it more accessible. During hemodialysis treatment, a hollow needle was inserted into the vein of the fistula near its arterial connection. This allowed the blood to flow, with the aid of a blood pump, through a tube leading to the blood compartment of a dialysis machine. Within this compartment, the blood passed over a selectively permeable membrane. On the opposite side of the membrane was a dialysate solution with a controlled composition. Negative pressure on the dialysate side of the membrane, created by a vacuum pump, increased the movement of fluid through the membrane. At the same time, waste and excess electrolytes diffused from the blood through the membrane and entered the dialysate solution. The blood was then returned through a tube to the vein of the fistula. In order to maintain favorable blood concentrations of waste, electrolytes, and water, Charles had to undergo hemodialysis three times per week, with each treatment lasting three to four hours. During the treatments, he was given an anticoagulant to prevent blood clotting, an antibiotic drug to control infections, and an antihypertensive drug to reduce his blood pressure. Charles was advised to carefully control his intake of water, sodium, potassium, proteins, and total calories between treatments. He was also asked to consider another option for the treatment of ESRD— a kidney transplant—which could free him from the time-consuming dependence on hemodialysis. In a transplant, a kidney from a living donor or a cadaver, whose tissues are antigenically similar (histocompatible) to those of the recipient, is placed in the depression on the medial surface of the right or left ilium (iliac fossa). The renal artery and vein of the donor kidney are connected to the recipient's iliac artery and vein, respectively. and the kidney's ureter is attached to the dome of the recipient's urinary bladder. The patient must then remain on immunosuppressant drugs to prevent rejection of the transplant.

Nephritis: Is an inflammation of the kidney, Glomerulonephritis is an inflammation of the glomeruli, and it may be acute or chronic and can lead to renal failure. Acute glomerulonephritis (AGN) usually results from an abnormal immune reaction that develops one to three weeks following bacterial infection by beta-hemolytic Streptococcus. As a rule, the infection occurs in some other part of the body and does not affect the kidneys directly. Instead, bacterial antigens trigger an immune reaction. Antibodies against these antigens form insoluble immune complexes that travel in the bloodstream to the kidneys. The antigen-antibody complexes are deposited in and block the glomerular capillaries, which become further obstructed as the inflammatory response sends many white blood cells to the region Those capillaries remaining open may become abnormally permeable, sending plasma proteins and red blood cells into the urine. Most glomerulonephritis patients eventually regain normal kidney function. However, in severe cases, renal functions may fail completely. Without treatment, the person is likely to die within a week or so. Chronic glomerulonephritis is a progressive disease in which increasing numbers of nephrons are slowly damaged until finally the kidneys are unable to function. This condition is usually associated with certain diseases other than streptococcal infections, and it also involves formation of antigen-antibody complexes that precipitate and accumulate in the glomeruli. The resulting inflammation is prolonged, and it is accompanied by fibrous tissue replacing glomerular membranes. As this happens, the functions of the nephrons are permanently lost, and eventually the kidneys fail.

The nephrotic syndrome: Is a set of symptoms that often appears in patients with renal diseases. It involves considerable loss of plasma proteins into the urine (proteinuria), resulting in widespread edema, and increased susceptibility to infections. Plasma proteins are lost into the urine because of increased permeability of the glomerular membranes, which accompanies renal disorders such as glomerulonephritis. As a consequence of a decreasing plasma protein concentration (hypoproteinemia), the plasma colloid osmotic pressure falls, increasing net filtration pressure in capillaries throughout the body. This may lead to widespread, severe edema as a large volume of fluid accumulates in the interstitial spaces within the tissues and in body spaces such as the abdominal cavity, pleural cavity, pericardial cavity, and joint cavities. Also, as edema develops, blood volume decreases and blood pressure drops. These changes may activate the renin-angiotensin system, leading to the release of aldosterone from the adrenal cortex, which, in turn, stimulates the kidneys to conserve sodium ions and water. This action reduces the urine output and may aggravate the edema. The nephrotic syndrome sometimes appears in young children who have lipoid nephrosis. The cause of this condition is unknown, but it alters the epithelial cells of the glomeruli so that the glomerular membranes enlarge and distort, allowing proteins through.

Kidney stones, which are usually composed of calcium oxalate, calcium phosphate, uric acid, or magnesium phosphate, sometimes form in the renal pelvis. If such a stone passes into a ureter, it may produce severe pain, beginning in the region of the kidney and radiating into the abdomen, pelvis, and lower limbs. Nausea and vomiting may also occur. About 60% of kidney stones pass spontaneously; the others must be removed. In the past, such removal required surgery or instruments that could be passed through the tubes of the urinary tract to capture or crush the stones. Today, shock waves applied from outside the body are used to fragment kidney stones. This procedure, Called extracorporeal shock-wave lithotripsy (ESWL), focuses high-energy shock waves through water (either in a tub or in a water-filled sack placed against the patient). The shock waves break the stones into fragments small enough to be eliminated with the urine.

NOTES: The corticopapillary osmotic gradient is created by juxtaglomerular nephrons, which represent a relatively small proportion of total nephron number (30%). The remaining 70% are superficial and have short loops, which limits the maximal degree to which urine can be concentrated. Desert rodents such as the Australian hopping mouse (Genus Notomys; Figure) can produce 10,000 mOsm/kg urine. Their kidneys contain a much higher proportion of juxtaglomerular nephrons compared with superficial nephrons, and concentrating ability is increased accordingly. This remarkable ability to conserve fluid means that hopping mice are able to subsist on water extracted from their food (e.g., roots, leaves, and berries) and never need to drink, which has clear survival advantages in an arid environment.

Clinical Correlate: In nephrogenic diabetes insipidus (DI), ADH receptors are not functioning and it is not possible to increase reabsorption at the collecting duct. The patient loses free water and develops hypernatremia. Treatment is reduction of extracellular volume with a thiazide diuretic. This increases peritubular oncotic pressure, in turn increasing water reabsorption in the proximal tubule. The elevated water reabsorption, along with sodium loss in the urine (action of thiazide diuretics), corrects the hypernatremia.

Clinical Correlate: A 25-year-old man spends a week in the desert. Due to severe dehydration, his volume status is depleted → high angiotensin II → vasoconstriction of the efferent arterioles → an increase in GFR and decrease in RPF (renal plasma ﬂow) → an increase in FF (filtration fraction) → more plasma filtered in the glomeruli → higher albumin concentration (hence higher oncotic pressure) in the glomerular capillaries → higher oncotic pressure in the peritubular capillaries → an increase in peritubular reabsorption. Therefore, an increase in the FF → an increase is reabsorption at the proximal tubules. A dehydrated patient needs to increase reabsorption of ﬂuid at the proximal tubules to preserve volume. Angiotensin II helps preserve GRF and volume in a volume-depleted state.

Clinical Correlate: What would happen if you gave Non-steroidal anti-inflammatory drugs (NSAIDs) to the 75-year-old man who is hemorrhaging? During a stress state the increase in sympathetic tone causes vasoconstriction of the afferent arterioles. The same stimuli activate a local production of prostaglandins. Prostaglandins lead to vasodilation of the afferent arterioles, thus modulating the vasoconstriction. Unopposed, the vasoconstriction from the sympathetic nervous system and angiotensin II can lead to a profound reduction in RPF and GFR, which in turn, could cause renal failure. NSAIDs inhibit synthesis of prostaglandins and interfere with these protective effects

Administration of ACE (angiotensin converting enzyme) inhibitors and Angiotensin II receptor blockers (ARBs): ACE inhibitors and ARBs are used for diabetic nephropathy because they lead to a reduction in glomerular capillary pressure and reduce damage and fibrosis of the glomeruli (which will delay the need for hemodialysis). They treat hyper-filtration. In most cases, there is a small and transient drop in GFR. Inhibition of angiotensin II leads to vasodilation of the efferent arteriole, which leads to decreased glomerular capillary pressure and decreased GFR. It also leads to increased RPF because of the decrease in resistance to ﬂow. The pressure downstream from the efferent arteriole (peritubular capillary pressure) increases because there is a decreased resistance at the efferent arteriole. Use the following guidelines for using ACE inhibitors and ARBs: l Give ACE inhibitors to patients with nephrotic syndrome and stable chronic renal failure. l Avoid ACE inhibitors and ARBs in patients with severely compromised GFR (risk of hyperkalemia) and with acute renal failure. l ACE inhibitors and ARBs may cause a type IV RTA because they block aldosterone (leading to hyperkalemia); in this case they must both be held. If ACE inhibitors cause hyperkalemia, so will ARBs. l Switch from ACE inhibitor to ARB in cases with ACE-inhibitor cough, not for hyperkalemia. l ACE inhibitors and ARBs are contraindicated in bilateral renal artery stenosis, where both kidneys have such low perfusion that GFR is highly dependent on constriction of EA. When the effect of angiotensin II is removed, the result is a significant drop in GFR and acute renal failure.

Clinical Correlate: A 55-year-old woman with a history of end-stage renal failure presents with confusion after missing a dialysis session. Her potassium is elevated. While waiting for the nurse to set up the dialysis, the patient is treated with an injection of bicarbonate and insulin with dextrose Giving bicarbonate gives the patient an alkalosis. This causes protons to leave the intracellular space down its concentration gradient. To maintain electroneutrality, potassium shifts into cells. This decreases the extracellular potassium concentration. Insulin activates the sodium/potassium ATPase and that increases the shift of potassium into the cell also.

THINK ABOUT THIS: Creatinine is formed from creatine phosphate, which is stored in the muscle and is normally excreted by the kidneys. It is produced constantly and is directly related to muscle mass. Serum creatinine and GFR are inversely related. A rise in serum creatinine suggests renal disease, because the kidneys are unable to excrete it. If creatinine rises by 50% in the blood, then GFR has gone down by 50%—in other words, 50% decrease in kidney function. When the GFR is decreased, the glomerulus is not filtering as it should because it is sick. Therefore, you see a rise in the serum creatinine. GRF cannot be measured directly. It has to be calculated. GFR is an estimate of renal function and is calculated by a formula using urine and plasma creatinine (don’t worry; the physician will do the calculating). Since urine creatinine is needed to figure GFR, how do we get this value? A creatinine clearance value from the 24-hour urine specimen is used. Creatinine clearance is the amount of creatinine excreted from the kidneys in 24 hours. This is one reason to obtain a 24-hour urine specimen. Creatinine clearance is used to determine the rate of glomerular filtration. There is no way to determine exactly what the GFR is, but creatinine clearance is used to help determine an estimate of GFR. Specifically, the creatinine clearance measures the amount of blood that is cleared of creatinine in 1 minute. This value is plugged into a formula to determine GFR.