Chapter 8 Renal Clearance

Oxygen is used regularly and relatively quickly with very little storage (myoglobin) and no recycling, making the input of air with $O_2$ a regular requirement. Life is not sustainable for prolonged periods without the input of air with $O_2$ over the time scale of a few minutes in most individuals. At nearly the same rate, and at times at a slightly higher rate than oxygen utilization carbon dioxide is produced as a waste product of mitochondrial respiration. Input and output of air allows for both the input of oxygen, and the output of carbon dioxide.

When discussing mass balance of nutrients, which includes the consideration of diet and nutrition since it is about the input of nutrients, it is common to break nutrients into two main classifications. Macronutrients are larger molecules that can be utilized for energy purposes. They have an energetic (caloric) value in addition to other physiological roles they fulfill. Macronutrients include carbohydrate, fat and protein. Micronutrients are small molecules and in some cases simply elements or minerals. They do not have an energetic value but are essential to many physiological processes. For muscle physiology it has already become clear that $N{a}^{+}$, $K^{+}$ and $C{a}^{2+}$ are essential micronutrients.

Background: Semantics of Stuff

The same stuff - such as glucose, calcium, sodium and potassium - can be referred to using different words based on context. Glucose is a macronutrient, but once ingested and absorbed and present in the blood or cells it tends to be referred to as substrate. Micronutrients are dietary inputs. They can referred to as electrolytes when considering the role they have in determining the osmolarity of a solution (e.g., $N{a}^{+}$). They are considered ions considering the role they have in membrane potentials (e.g., $K^{+}$). They are considered signaling molecules (or just molecules) when considering the role they play in activation (e.g., $C{a}^{2+}$).

Macronutrients are routinely utilized for energy and structural health of cells, tissues and molecules such as hormones and neurotransmitters. They are also stored purposely. Fat is stored most abundantly as adipose tissue. Carbohydrate as glycogen. Protein is available from the breakdown of any existing proteins when in need of this substrate. Proteins can be recycled. If a protein is broken down into amino acids and used to build an enzyme that is needed; it can be broken down again and used to build another enzyme. Fat and carbohydrate utilized in structures can be recycled. Macronutrients utilized for energy lose their structure and cannot be recycled, they must be replaced. The digestion of food to extract and absorb usable substrates ultimately yields waste that remains in the gastrointestinal (GI) tract (for example, insoluble fiber) and is removed as feces.

The lining of the GI tract not only absorbs all nutrients (macro and micro), but there is some incidental loss of micro-nutrients (electrolytes and minerals) such as $C{a}^{2+}$ in the feces from the GI secretions and normal wear and tear of the cells and tissue that line the GI tract. A small amount of incidental loss of micronutrients such as $N{a}^{+}$ and $K^{+}$ occurs in the sweat and urine. Since the input of these micronutrients can easily exceed the incidental loss, there can be intentional (regulated) loss through the renal filtration and secretion processes to maintain $N{a}^{+}$, $K^{+}$ and $C{a}^{2+}$ homeostasis.

Water is the source of the fluid environment that the biochemical processes of life occur, and transport of essential nutrients flow through the circulation and micro-circulation. Without water the blood plasma, interstitial fluid and intra-cellular fluid would not be fluid. The fact that they are fluid enables nutrient movement. The amount of water in the body also influences the concentration (and therefore osmolarity) of these fluid spaces. The amount of water influences the blood volume. If blood volume is too high, blood pressure increases and edema may result. If blood volume is too low due to a loss of water, viscosity increases which increases resistance to circulation. Problems occur when there is too little water (dehydration) or too much water (elevated blood volume, edema). The water in the body is always in use, being filtered between compartments in support of the movement of nutrients and electrolytes as well as by-products (waste). In this way it is recycled - there is no need for a complete overturn of water in the course of a day. However, the amount of water that must be taken in (input) should equal the amount of water that is lost in a day (output). Water loss occurs through four routes, two incidental and two intentional. Incidental water loss occurs with ventilation of air out of the body; and a small amount of water is routinely lost in the feces. Evaporation of water from the skin is a mechanism of cooling the body and sweating is a route of loss. Intentional loss of water in sweat is highly variable based on the temperature and activity levels which influence the need for cooling. Renal filtration and excretion requires a loss of water in urine for the removal of metabolic waste. Of these four routes for the output of water sweating is highly variable and can be partially regulated through behavioral adaptations. Renal is also highly variable and is regulated through physiological processes. The maintenance of normal water volume, and as a result plasma volume, is buffered by fluctuations in renal output in response to water input. Because there is a continual regular loss of water (breathing and sweating), and a necessary regular loss of water for waste removal (feces and urine), there is a regular need (demand) for water input. While the kidneys can make more or less concentrated urine which includes less or more water (respectively), the body must make urine regularly to filter the blood and keep it free from the toxicity of metabolic waste products.

The kidneys are in the retroperitoneal cavity of the body. Given their location and the high prevalence of back pain in physical therapy practice it is important to consider the possibility that back pain is related to the kidneys.

Background: Kidney Pain

Kidney pain is pain from disease or injury to a kidney. Kidney pain or discomfort may manifest as a dull, one-sided ache in the upper abdomen, side or back. Back pain that includes upper abdomen or side components and that does not respond to provocations that would typically provoke a musculoskeletal source of pain such as movements (active & passive tension) should be considered. The patient should be questioned regarding a history of the common causes of kidney diseases such as alcohol use, diabetes, high blood pressure, family history or a history of kidney stones. Fever and changes in urinary habits or urinary symptoms often accompany kidney pain and are therefore important considerations when ruling out a kidney as a source of back pain.

Each kidney is divided into two regions: the outer cortex and the inner medulla. Comprising these two region are tube-like structure called nephrons - the functional unit of the kidney. Each kidney can contain a million individual nephrons with each nephron serving a vital role in reabsorption, secretion, and filtration of solutes. At its simplest, each nephron contains a renal corpuscle (glomerulus surrounded by Bowman’s Capusle) and renal tubule. The glomerulus is a capillary network and the primary site for plasma filtration and the formation of urine. Distributed on both ends of the glomerulus are the afferent and efferent arterioles, which provide inflow of filtrates to the glomerulus and outflow of filtrates to the upper portion of the nephron - the Bowman’s Capule (or Bowman’s Space).

From this region the ultrafiltrate (which will become urine) travels through a looping tubular structure where the functions of re-absorption and secretion occurs. The segments of the nephron tubule that emerge from Bowman’s capsule includes several distinct functional units (in order): the proximal convoluted tubule, the proximal straight tubule, the loop of Henle (which contains a thin descending limb, a thin ascending limb, and a thick ascending limb), the distal convoluted tubule, and the collecting ducts. The distinct reabsorption and secretion functions across the tubule are based on a highly specialized epithelial cells lining each segment. The collecting ducts drain regionally into pouches which then drain larger pouches eventually reaching the renal pelvis which proceed into the ureter. Through this collecting duct system the urine from each kidney drains into a ureter and is transported to the bladder for storage and eventual elimination.

There are two types of nephrons, superficial cortical nephrons and juxtamedullary nephrons, which are distinguished by the location of their glomeruli and the length of their loops of Henle. The superficial cortical nephrons have their glomeruli in the outer cortex (which is more superficial) and have relatively short loops of Henle. The juxtamedullary nephrons have their glomeruli deeper in the kidney with larger glomeruli and therefore have higher glomerular filtration rates. The juxtamedullary nephrons also have long loops of Henle that go deep into the kidney that are essential for the concentration of urine.

Renal clearance is the volume of plasma cleared of a substance per unit time and is determined by filtration, reabsorption and secretion.

1. 1.

   Filtration (indiscriminate elimination): pushing filtrate (plasma) out of the capillary into Bowman’s capsule

2. 2.

   Reabsorption (selective): selectively pulling substances (including water) back into the capillary

3. 3.

   Secretion (selective): selectively pushing substances out of the capillary into the renal tubule

Substances with the highest clearances are both filtered and secreted and may be completely removed on a single pass of blood through the kidneys. Substances with the lowest clearances either are not filtered or are filtered and subsequently reabsorbed and may not be removed at all. Renal clearance is based on the rate substances are removed (cleared) from plasma in the kidneys. The higher the renal clearance of a substance, the more plasma that is cleared of the substance.

For example, kidneys regulate the renal clearance of $N{a}^{+}$ to match what is absorbed so that people do not have to adjust what they ingest. In situations of reduced or impaired renal function dietary modification of $N{a}^{+}$ may be necessary. The general principle is that normal physiology provides individuals lots of freedom since it can make adjustments to buffer the consequences of behavior. As that physiological capacity is lost with aging and various chronic conditions, behavior must be adjusted to avoid the consequences.

Urine is formed by anything (including water) that is filtered and not reabsorbed, or not filtered and then secreted. Urine leaves the kidneys and flows through the ureters into the bladder. Peristaltic contractions of smooth muscles in the ureter, enhanced by parasympathetic activation, force urine from the kidneys toward the bladder which help maintain the flow of urine from the kidneys even as pressure rises in the bladder.

The bladder is a smooth muscle chamber with two parts. The bladder body collects urine and the neck is a funnel-shaped extension that connects with the urethra. The smooth muscle of the bladder can increase bladder pressure to 40-60 $mmHg$ and play a major role in emptying the bladder during micturition.

The smooth muscle of the bladder wall is influenced by the autonomic nervous system and a spinal cord stretch reflex. Micturition (urination) is the process of emptying the bladder when it is filled. Filling of the bladder increases its pressure and therefore wall tension rises. Pelvic nerves connect with the spinal cord through the sacral plexus include sensory and motor nerve fibers. The sensory nerve fibers detect when the bladder wall tension rises above a threshold level that activates the micturition reflex to empty the bladder or, if this fails, creates a conscious desire to urinate. The motor nerves transmitted to the pelvic nerves are parasympathetic fibers.

Background: Urinary Semantics

The terms micturition and urination are equivalent and can be used interchangeably. However, the reflex that triggers urination is the micturition reflex. Though, if you heard someone say urination reflex, I’m quite sure you’d know what they meant.

The bladder neck includes the internal sphincter muscle interlaced with a large amount of elastic tissue. The natural tone of the internal sphincter muscle keeps the bladder from emptying until the pressure in the main part of the bladder rises above a critical threshold. Beyond the neck of the bladder the urethra passes through the urogenital diaphragm, which includes a layer of muscle called the external sphincter. This muscle is a voluntary skeletal muscle and is used to prevent urination even when the micturition reflex is attempting to empty the bladder.

Glomerular filtration is the first step in the formation of urine. The rate of glomerular filtration is appropriately called the glomerular filtration rate (GFR). As blood enters the glomerular capillaries, a portion of that blood is filtered into Bowman’s capsule. The fluid that is filtered is similar to interstitial fluid and at this point is called an ultrafiltrate. Ultrafiltrate contains water and all of the small solutes of blood, but not proteins and blood cells. The pressures responsible for glomerular filtration are similar to the pressures operating for micro-circulation filtration in systemic capillaries (Chapter 7). However, the characteristics and surface area of glomerular capillaries result in a much higher GFR than filtration in systemic capillaries (glomerular capillaries have a higher filtration coefficient than systemic circulation capillaries). The ultrafiltrate of glomerular filtration renters the peritubular capillaries through reabsorption and can be more selective. The ultrafiltrate that does not re-enter the vascular fluid does not enter lymph vessels, but rather proceeds through the renal tubules for urine formation and excretion.

Glomerular filtration results in the production of large quantities of ultrafiltrate each day (approximately 180 L/day). If all of this ultrafiltrate were excreted as urine the following quantities would be lost each day: 180 $L$ of water; 25,200 $mmol$ of $N{a}^{+}$; 19,800 $mmol$ of $C{l}^{-}$; 4320 $mmol$ of $HC{O}_3^{-}$; and 14,400 $mg$ of glucose. Each of these losses is 10 times more than the amount present in the entire ECF. This is clearly not a sustainable approach to mass balance.

There are a set of reabsorption mechanisms in the epithelial cells lining the renal tubule that return these (and other) substances to the peritubular capillaries. The details of these mechanisms are beyond the scope of this text. Overall, reabsorption includes the return to capillaries through several different transport proteins that either selectively and directly transport substances, or through the transport of substances which then manipulate the osmolarity between the renal tubule and the peritubular capillaries. Water and many solutes ($N{a}^{+}$, $C{l}^{-}$, $HC{O}_3^{-}$, glucose, amino acids, urea, $C{a}^{2+}$, $M{g}^{2+}$, phosphate, lactate, and citrate) are reabsorbed from ultrafiltrate back into the peritubular capillaries. If reabsorption did not occur, most of these constituents of ECF would be rapidly lost in the urine.

This approach, the generation of a large quantity of ultrafiltrate and the selective reabsorption back into the capillaries, is a highly efficient way to filter and clear waste products (urea, creatinine that have limited reabsorption), and regulate the blood and ECF content of other substances. For example, even though glucose is filtered and then reabsorbed, in certain hyperglycemic situations with diabetes, glucose cannot be fully reabsorbed which results in glucose in the urine (glycosuria). Glycosuria contributes to an upper limit of blood glucose and its acutely deleterious effects, but it is not a healthy long term homeostatic mechanism for glucose control.

Reabsorption is adjusted based on ECF fluid volume. Increased ECF volume inhibits tubule reabsorption which results in loss of ECF fluid volume, and decreased ECF volume stimulates tubule reabsorption which results in an increase in ECF. Different diuretics (drugs that promote water removal in urine) work at different points along the renal tubule to reduce reabsorption of water.

Secretion mechanisms in the epithelial cells can remove selected and specific substances from the peritubular capillary blood and add them to urine. Organic acids, organic bases, and $K^{+}$ are secreted from peritubular capillary blood into tubular fluid as needed. In addition to filtration, secretion provides a mechanism for excreting substances in the urine. Compared to filtration secretion is selective like reabsorption. The secretion mechanisms involve transporters in the membranes of the epithelial cells lining the renal tubule.

Excretion rate refers to the amount of a substance excreted per unit time and is related to the clearance rate. However the excretion rate is in terms of the amount of a substance excreted per time frame ($mmol/day$) whereas the clearance rate is in terms of the volume of plasma cleared of the substances ($mmol/L$). The overall reabsorption or secretion rate of a substance is the difference between the amount filtered and its excretion rate. The excretion rate reflects the overall result of glomerular filtration, tubular reabsorption, and tubular secretion. It can be compared with the amount filtered to determine whether a substance has been reabsorbed or secreted. The difference between the amount filtered and the excretion rate is the rate of net reabsorption or net secretion. When the amount filtered is greater than the excretion rate, there has been reabsorption of the substance. If the amount filtered is less than the excretion rate, there has been secretion of the substance.

The kidneys maintain a normal body $N{a}^{+}$ content by ensuring that $N{a}^{+}$ excretion equals $N{a}^{+}$ intake, a matching process called $N{a}^{+}$ balance. $N{a}^{+}$ balance is achieved by variations in the reabsorption of $N{a}^{+}$. If $N{a}^{+}$ excretion is less than $N{a}^{+}$ intake, then there is positive $N{a}^{+}$ balance. Extra $N{a}^{+}$ is retained, primarily in the ECF. When the $N{a}^{+}$ content of ECF is increased, there is increased ECF osmolarity and thus volume; blood volume and arterial pressure also increase, and there may be edema. If $N{a}^{+}$ excretion is greater than $N{a}^{+}$ intake, then a person is in negative $N{a}^{+}$ balance. When excess $N{a}^{+}$ is lost from the body, there is a decreased $N{a}^{+}$ content of ECF, decreased ECF osmolarity and volume, increased ICF volume, and decreased blood volume and arterial pressure.

$K^{+}$ balance is maintained by shifts of $K^{+}$ across cell membranes and by renal regulation. The renal mechanisms for $K^{+}$ balance include filtration, reabsorption, and secretion. Secretion is influenced by dietary $K^{+}$, aldosterone, acid-base balance, and flow rate. With low $K^{+}$ intake, more $K^{+}$ is reabsorbed and less is secreted; with high $K^{+}$ intake less is reabsorbed and more is secreted. The secretion of $K^{+}$ in the distal tubule and collecting ducts allows the fine-tuning of $K^{+}$ excretion to maintain $K^{+}$ balance.

Acid-base disturbances can effect blood $K^{+}$ concentration due to alterations in $K^{+}$ secretion. Alkalosis increases $K^{+}$ secretion, and acidosis decreases $K^{+}$ secretion. Therefore, conditions such as chronic pulmonary disease that increase blood carbon dioxide and decrease blood pH (respiratory acidosis) can be accompanied by hyperkalemia.

Commonly used diuretics, the loop diuretics and the thiazide diuretics, cause increased $K^{+}$ excretion. Therefore, an important side effect of diuretic therapy is hypokalemia. The $K^{+}$-sparing diuretics (e.g., spironolactone, amiloride, triamterene) do not cause increased $K^{+}$ excretion because they inhibit all of the actions of aldosterone and inhibit $K^{+}$ secretion. The most common use of $K^{+}$-sparing diuretics is in combination with the loop or thiazide diuretics to offset hypokalemia produced by those drugs.

Calcium regulation involves kidney reabsorption in response to parathyroid hormone. The overall coordinated process of calcium regulation involves variations in intestinal absorption and release from bones. Therefore, it is best considered with an understanding of intestinal absorption.

There are three ways the kidneys influence acid base balance. First, the secretion of $H^{+}$; second the reabsorption of $HC{O}_3^{-}$; and third, the production of new $HC{O}_3^{-}$. It is best to consider kidney (metabolic) causes and compensations of acid-base balance along with respiratory causes and compensations of acid-base balance. Therefore, clinical interpretation of acid-base imbalance is in the chapter on respiration.

Blood volume is regulated based on two primary factors: 1. impact on BP, RBF and subsequently GFR; 2. impact of water in plasma on ECF osmolarity. These are not completely separate regulatory pathways (there is overlap). The overlap is clear when considering the integration of the hormonal mechanisms underlying the regulation of blood pressure and osmolarity. The primary hormones to be considered include: renin, angiotensin II, anti-diuretic hormone (ADH) and aldosterone. The influence of these three hormones on renal function is summarized in Table 8.2. How these hormones and renal function is involved in long term blood pressure regulation is covered in Chapter 9 on Circulation.

Diarrhea results in a large volume loss of fluid from the gastrointestinal tract. The osmolarity of the fluid lost is approximately equal to that of the ECF (isosmotic). ECF volume decreases, but there is no accompanying change in ECF osmolarity. Therefore there is no need for a fluid shift across cell membranes and ICF volume remains unchanged. In the new steady state, ECF volume decreases and the osmolarities of ECF and ICF are unchanged. The decrease in ECF volume means that blood volume (a component of ECF) also is reduced, which produces a decrease in arterial pressure. Other consequences of diarrhea include increased hematocrit and increased plasma protein concentration.

Water deprivation (negative mass balance of water) in situations with sweating (hot environments and/or high metabolism) results in net losses to both NaCl and water in sweat. Sweat is hyposmotic relative to ECF. Sweat contains relatively more water than solute. When sweating hyposmotic fluid is lost from the ECF. ECF volume decreases and ECF osmolarity increases. ECF osmolarity is transiently higher than ICF osmolarity, and this difference in osmolarity causes water to shift from ICF into ECF until ICF and ECF osmolarity equalizes. In the new steady state, both ECF and ICF volumes are decreased and ECF and ICF osmolarities increased. In hyperosmotic volume contraction, the plasma protein concentration is increased but the HcT is unchanged. The explanation for the increase in plasma protein concentration is straightforward: Fluid is lost from ECF, and the plasma protein remaining behind becomes concentrated. It is less obvious, however, why the hematocrit is unchanged. Loss of fluid from ECF alone would cause an increase in the concentration of red blood cells and an increase in HcT. However, there also is a fluid shift in this disturbance: Water moves from ICF to ECF. Because RBCs are cells, water shifts out of them, decreasing their volume. Thus, the concentration of red blood cells increases, but red blood cell volume decreases. The two effects offset each other, and HcT is unchanged. The shift of water from ICF to ECF offsets the loss of ECF from water loss.

Adrenal insufficiency includes a deficiency in aldosterone, a hormone that promotes $N{a}^{+}$ reabsorption. Aldosterone deficiency results in excess NaCl excreted in the urine. Because NaCl is an ECF solute, ECF osmolarity decreases. ECF osmolarity is less than ICF osmolarity and causes water to shift from ECF to ICF until osmolarity equilibrium. In the new steady state, both ECF and ICF osmolarities are lower than normal. The shift of water results in decreased ECF volume and increased ICF volume. In hyposmotic volume contraction, both plasma protein concentration and HcT will be increased because of the decrease in ECF volume. HcT also increases because of the shift of water into red blood cells, increasing cell volume.

An infusion of isotonic NaCl presents the opposite clinical picture of losing isotonic fluid through diarrhea. Because NaCl is an extracellular solute, all isotonic NaCl solution is added to the ECF, causing an increase in ECF volume but no change in ECF osmolarity. There is no shift of water between ICF and ECF because there is no difference in osmolarity between the two compartments. Both plasma protein concentration and HcT decrease because of the increase in ECF volume.

Ingesting dry NaCl (for example, eating a salty snack) increases the total amount of $N{a}^{+}$ in the ECF and osmolarity increases transiently as the higher ECF osmolarity causes water to shift from ICF to ECF, decreasing ICF volume and increasing ECF volume. In the new steady state, both ECF and ICF osmolarities are higher than normal and equal to each other. Because of the shift of water out of cells, ICF volume will decrease and ECF volume will increase. In hyperosmotic volume expansion, both plasma protein concentration and hematocrit will decrease due to the increase in ECF volume. Hematocrit also will be decreased because of the water shift out of the red blood cells.

Syndrome of inappropriate antidiuretic hormone (SIADH) secretes inappropriately high levels of ADH, which promotes too much water reabsorption. The excess water is retained and distributed throughout the total body water. ECF is diluted and transiently has a lower osmolarity. Water shifts into the ICF since it has higher osmolarity. When compared with the normal state, ECF and ICF volumes are both increased and ECF and ICF osmolarities will be decreased. In hyposmotic volume expansion, plasma protein concentration is decreased by dilution. The hematocrit is unchanged as a result of two offsetting effects: The concentration of red blood cells decreases because of dilution, but RBC volume increases because water shifts into the cells. But this increase in RBC volume (due to water) does not necessarily increase oxygen carrying capacity of HbG so maintaining HcT in the situation of hyposmotic volume expansion does not necessarily mean oxygen carrying capacity is normal.

Older adults have reduced thirst sensation and the ability to concentrate urine, together this results in increased ECF osmolarity (hyperosmotic stress) [lorenzo_role_2019]. Hyperosmotic stress leads to cell dehydration (reduced ICF), which has consequences for the intracellular protein structure and function. In severe situations this can result in cell damage. There is also some evidence to suggest that cell volume may act as a signal, with cell swelling acting as an anabolic signal (promotes hypertrophy) and cell shrinkage acting as a catabolic signal (promotes atrophy). One possible reason, or contributing factor, for the age related progressive loss in muscle mass and strength may be impaired ECF - ICF water homeostasis that originates from mild kidney insufficiency and a loss of thirst. Intracellular water content in lean mass has been related to muscle strength, functional capacity, and frailty risk, and has been proposed as an indicator of muscle quality and cell hydration [lorenzo_role_2019]. Muscle weakness can promote further decreases in fluid (and nutrient) intake due to challenges in ADLs. This can occur directly with difficulty attaining the necessary muscle tension for performing ADLs (either basic ADLs or instrumental ADLs), or with the accumulation of objective fatigue (difficulty sustaining ADLs)[collins_heart_2015]. Several chronic conditions that include renal insufficiency such as diabetes, high blood pressure, chronic heart failure, obstructive pulmonary disease and renal failure all share a common feature of muscle catabolism, atrophy and weakness. With these conditions the atrophy and weakness seem to go beyond disuse atrophy [adams_skeletal_2006]. A common, and plausible, feature of these conditions may be water homeostasis.

Rhabdomyolosis is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms include muscle pain; signs include weakness, muscle stiffness and edema. Signs may also include tea-colored urine, an irregular heartbeat, vomiting, and confusion. A positive urine myoglobin test provides supportive evidence. Myoglobin is harmful to nephrons so if rhabdomyolysis is severe it may lead to kidney failure. Common causes of muscle damage include crush injury, strenuous exercise, medications (including statins for lowering blood cholesterol), or substance abuse. Less common causes include infections, electrical injury, heat stroke, prolonged immobilization, lack of blood flow to a limb, or snake bites.