Nephrology

The kidneys receive their blood supply from the renal arteries, which arise from the aorta approximately 3 cm above the umbilicus, and the renal veins return blood to the inferior vena cava. The urine produced by the kidneys is transported to the urinary bladder via the ureters, and then from the urinary bladder it travels out the body via the urethra (in the male, divided into the prostatic, membranous, and penile portions).

The kidneys themselves are divided into pyramids and calyces and other stuff that just isn't important today - what is important is the functional unit of the kidney, the nephron.

There are about 1,200,000 nephrons in the average kidney. Each one receives blood through an afferent arteriole, which breaks into little capillaries that feed blood to a glomerulus (the glomerulus is the beginning of the filtration pathway) - the capillaries then re-form into an efferent arteriole which supplies oxygen and nutrients to the rest of the kidney.

The action that gets started at the glomerulus is the clinically important part of this story. The blood that gets filtered into the glomerulus normally results in an "ultrafiltrate" that has little or no protein, but otherwise has the same composition as blood.

From the glomerulus, the fluid travels through the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, and finally into the collecting duct system (which becomes the ureter and so on).

Each portion of the nephron functions in unique ways and responds to different stimuli to change the contents and concentrations of the ultrafiltrate before it becomes urine. Understanding this segment-specific architecture regarding ion transport is essential to a good understanding of the kidney.

The glomerulus is where the initial filtration takes place, and it is the site where one of the basic concepts used to discuss kidney function occurs - the Glomerular Filtration Rate (GFR). This quantity, measured in ml/min, describes how much fluid is being filtered by the kidney at any given time, and it is a reliable marker of overall kidney function.

The principle of measuring GFR is that we look for a substance that is in the blood that is freely filtered by the kidney, and then purely excreted (the kidney neither absorbs, secretes nor metabolizes the matieral) - and then we measure how much of that substance is urinated compared to how much is in the blood. In other words, how much of something can get across the filters in the kidney? The best substance for the job is inulin, but the one that is easiest to use in clinical practice is creatinine - a breakdown product of muscle metabolism. When we measure creatinine clearance, we are applying the concepts just discussed, and so we are effectively measuring GFR.

The factors that effect GFR are anything that affect blood flow across the glomerulus - this includes the renal perfusion pressure (blood pressure to the kidney) and the resistance caused by the afferent and efferent arterioles.

In the proximal convoluted tubule, we first start to reabsorb substances back from the lumen of the nephron. In fact, about 2/3 of the transepithelial reabsorption of water, sodium, chloride, and potassium happens here, as well as just about all of the reabsorption of glucose and amino acids. Basolateral active transport by a Na⁺-K⁺ATPase pump creates the driving force necessary for the apical co-transport of substrates with sodium. In other words, sodium comes through the apical membrane holding the hand of other substances such as glucose, amino acids, etc.

The loop of Henle is often divided into the descending limb and the ascending limb. The descending limb absorbs another 15% of the free water. The ascending limb is impermeable to water, but does absorb many solutes. These include an additional 1/4 of the total Na⁺, Cl^-, Ca²⁺, and HCO₃^-. The mechanism in this portion of the nephron is active transport by a Na-K-2Cl symporter.

The distal convoluted tubule is responsible for reabsorbing a portion of whatever free water remains - the exact amount is controlled by the amount of ADH (vasopressin) present. It also reabsorbs another 7% of the total Na⁺ and Cl^-, and in its early portion also reabsorbs K⁺ and Ca²⁺. The latter portion of the distal tubule secretes K⁺, and also secretes either H⁺ or HCO₃^-, an option which is used to maintain acid-base balance.

Finally, the collecting duct system is responsible for reabsorbing Cl^- and some Na⁺, as well as for secreting some K⁺.

Craig's slides

In addition to diuretics, there are a wide variety of substances (and other forces) that influence the kidney to alter the way it processes fluid as it passes through the nephron. These include:

• ADH: Antidiuretic Hormone, aka vasopressin. This is made by the posterior pituitary as a response to either overconcentrated blood or too little volume. It influences the distal convoluted tubule (and to a lesser extent the collecting duct system) to reabsorb more free water. ADH water
• Aldosterone: Made in the adrenal cortex, it is released as a response to either increased plasma K⁺ or increased plasma angiotensin II. It influences the ascending loop of Henle to reabsorb more Na⁺ and Cl^-, and also influences the distal tubule and collecting duct to secrete more K⁺. Aldo Na⁺ Cl^-, K⁺
• Angiotensin II: Remember that the kidneys produce renin in response to low BP. Renin, in turn, causes the conversion of the hepatic enzyme angiotensinogen into angiotensin I, which is in turn converted to angiotensin II by the lungs. Angiotensin  II acts on both the brain to release ADH and the adrenals to release aldosterone. The result of Angiotensin II in the kidney is to influence the proximal tubule to reabsorb water, Na⁺, and Cl^-. Angiotensin II water Na⁺ Cl^-
• Atria of Heart: ANP (Anti-Natriuretic Peptide) is secreted by the atria in response to increased pressure, and results in inhibition of ADH secretion and activity, as well as direct blockage of reabsorption of Na⁺, Cl^-, and water from the collecting duct. ANP water Na⁺ Cl^- ADH
• Dopamine: The kidney itself releases dopamine in response to increased volume (BP). It influences the proximal tubule to reabsorb less water, Na⁺ and Cl^- (resulting in decreased concentrations of all of those things). Dopamine water Na⁺ Cl^-
• Epinephrine, Norepinephrine: These are released as a response to various sympathetic stimuli, including decreased volume. They influence most of the nephron (both tubules, the loop, and the collecting duct) to reabsorb more water, Na⁺ and Cl^- (resulting in increased concentrations of all of those things). Epi, Norepi water Na⁺ Cl^-
• Renal Artery Pressure: Low BP systemically is obviously reflected by low renal artery pressure, and the kidney responds to low pressure by releasing renin, which is intended to eventually raise pressure. The kidney has no way to communicate with other organs, however, and if it experiences low pressure for any reason (such as a stenosed or occluded renal artery, for example), it assumes that the problem is systemic and responds accordingly. It can thereby create systemic hypertension by inappropriately releasing renin in response to a local cause. renal artery pressure renin
• Renin: The afferent arterioles sense pressure and respond to low pressure by releasing renin and high pressure by suppressing it. Renin, in turn, converts angiotensinogen (a product of the liver) into angiotensin I. Angiotensin I is converted in the lung (by ACE, angiotensin converting enzyme) into angiotensin II (see above), which acts in various ways to increase blood pressure (has direct effect on kidneys, causes pituitary to release ADH, and causes adrenals to release aldosterone). Renin Angiotensin I and II ADH Aldosterone BP
• Urodilatin: This is secreted by the kidney itself in response to high pressure. It influences the collecting duct to reduce the reabsorption of water, Na⁺, and Cl^-. Urodilatin water Na⁺ Cl^-

Pre-renal - When we talk about "pre-renal," we're referring to anything that causes less blood to get to the kidney. Typically, the term is used to mean hypovolemia, but this is a gross oversimplification - there are actually four groups of conditions that can cause a pre-renal condition.

• Decreased Intravascular Volume (hypovolemia) can be caused by decreased fluid intake, third spacing, blood loss, or polyuria (typically from diabetes mellitus or insipidus).
• Decreased Systemic Vascular Resistance can be caused by a variety of drugs (vasodilators, such as digoxin), or by sepsis.
• Reduced Cardiac Output can be caused by myocardial infarction, ischemia, various arrhythmias, tamponade, PE, valvular disease (particularly aortic stenosis), or other causes.
• Renal Artery Blockage most commonly occurs as a result of renal artery stenosis, but can also occur from aortic dissection or by occlusion of the renal arteries by mass effect (tumor).

Post-renal - This refers to some sort of obstruction or increased pressure in the urinary outflow tract (ie anyplace that the urine goes after the kidney makes it). Eventually, the pressure backs up through the system and causes decreased GFR.

• Ureter: Blockage can occur here for a variety of reasons, most commonly a "kidney stone" or a clot, or occasionally renal tissue itself can clog the ureter (sloughed papillae). Also possible is occlusion by a tumor (inside or outside the ureter), or buildup of fungus or bacteria within the ureter. Finally, ureters are commonly ligated accidentally during obstetric, gynecologic, or other pelvic surgery, or abdominal surgery.
• Bladder: It is rare for anything to grow large enough to fill the entire bladder, but its outlet can easily be occluded by tumors, stones, clots, and fungal or bacterial masses. Also, the innervation of the bladder can be damaged, resulting in an inability to pass urine normally.
• Urethra: One of the most common causes of post-renal ARF is prostatic hypertrophy &/or cancer, which will impinge on the urethra. Similarly, stricture of the urethra itself may occur, or an abnormality of the genitalia (phimosis, reaction from STD, etc.) may be present.

Intra-renal (aka "renal") - This is the broadest category, and the most difficult to diagnose. It refers to any intrinsic disease or damage within the kidney itself.

• Vascular: Typically results from conditions in one of two categories:
  renal vasoconstriction - as seen in malignant HTN, scleroderma, TTP, or as a common reaction to contrast dye
  vasculitis - as seen in polyarteritis nodosa, SLE, Wegener's, temporal arteritis, Henoch-Shoenlein purpura (HSP), or other conditions.
• Glomerular Injury: Many diseases will injure the glomeruli, including post-infectious glomerulonephritis (typically strep), Goodpasture's, SLE, Wegener's, myeloma, or rapidly progressive glomeurlonephritis.
• Acute Interstitial Nephritis: Typically a reaction to either drugs or infection:
  Drugs - antibiotics, NSAIDS (including aspirin), diuretics, anticonvulsants, H2 blockers, gout drugs, others.
  Infections - acute pyelonephritis, strep, malaria, toxoplasmosis, salmonella, others.
• Primary Intratubular Obstruction: The tubules can be blocked by a variety of substances, including urate crystals, calcium oxalate crystals, methotrexate crystals, myeloma proteins.
• ATN: Probably the most common diagnosis in intra-renal failure. Generally caused by renal ischemia &/or nephrotoxins. Note that ischemia can occur as a result of many of the other causes of intra-renal or pre-renal causes of failure, or from prolonged azotemia. Common toxins include antibiotics, rhabdomyolysis, transfusion reactions, heavy metals, organic solvents, and animal venoms.

This refers to steady-state renal insufficiency (abnormal creatinine). it can cause acidosis, hyperparathyroidism, hyperphosphatemia (from hypoparathyroid) anemia, HTN, volume overload, etc.

The cause can be anything that causes acute renal failure.

Creatinine: Creatinine is a product of muscle metabolism that is typically released into the bloodstream at a fairly constant rate. Since it is typically removed at the same rate, it usually remains in the serum at a fairly predictable concentration. Its value to us lies in its characteristic of being a substance that is filtered into the kidney and then excreted, without the kidney altering what has entered it. In other words, when you measure urine creatinine, you're also measuring how much creatinine was filtered - you can assume that none has been reabsorbed, secreted, or metabolized by the kidney. So it's an effective marker for GFR (glomerular filtration rate), which is a good marker for overall kidney function.

Since there's assumed to be a fairly constant concentration of this stuff in the bloodstream, and since whatever gets filtered also gets excreted, it follows that if the kidney stops functioning, none will be excreted, and the concentration will build up in the blood. By itself, increased serum creatinine is no big deal, but it implies that other substances are also building up in the blood, including ammonia and other bad stuff. It also implies renal failure, which is something you don't want to have.

There are, of course, some problems with using creatinine as the only marker of renal function. The serum of a person with perfect kidneys will have elevated creatinine levels if something has happened to increase muscle metabolism or breakdown - this includes exercise and rhabdomyolysis, as only the two most common examples. In people with small muscle mass (elderly, bedridden), their circulating creatinine will naturally be lower, so creatinine values in the "normal" range may in fact represent an elevated level for these patients, suggesting renal damage.

The short version is that creatinine is generally used as a fairly reliable marker of overall renal function. As a rule of thumb, renal function has to decrease by 50% before creatinine goes up - an entire kidney could die and the value wouldn't change - so a rising creatinine is an important sign that you're dealing with a sick patient.

BUN: Blood Urea Nitrogen is another marker for overall renal function, which also can aid in the analysis of volume status. Urea, like creatinine, is freely filtered into the kidney, but it tends to be reabsorbed. Furthermore, its reabsorption is aided by ADH - when ADH influences the collecting ducts to reabsorb water, they also tend to reabsorb urea.

Therefore, urea (and BUN) are indirect markers of ADH, which is an indirect marker of volume status. Again: Low volume ADH reabsorption of water and urea more urea in the blood (remember that BUN = Blood Urea nitrogen).

In fact, the best way to really interpret these labs is by looking at the BUN:Creatinine Ratio. Since both are filtered and only one is reabsorbed, the ratio is a more specific marker for volume status than BUN is alone. Typically, if the ratio climbs above 20:1, we assume the patient is "pre-renal," in this context meaning hypovolemic. Always remember that the single best test for volume status remains clinical impression - it still remains infinitely more reliable than any lab value. Many authorities cite a ratio of > 30:1 as being highly suggestive of upper GI bleed.

Creatinine Clearance: Formula = (140-age*72)/serum creatinine. How much of the blood volume gets cleared of creatinine per minute. How well are we filtering? A more specific test for GFR.

Serum and Urinary Osmolarity: Used to understand tonicity disorders (disorders of water). If you suspect SIADH, DI - you would check these and apply some algorithm

Serum Sodium: Used also used as a proxy for tonicity disorders, in conjunction with osmolarity. For example, excess free water causes a low Nafluid balance for more on this.

Urinary Sodium: Used to tell us about volume - if <5, we say the patient is volume depleted and needing salt (saline).

Fractional Excretion: (Check formula) tells us about the amount of sodium excreted compared to how much is filtered. When less than 1, the patient is volume depleted. This is more specific than urinary sodium, since it takes into account the serum sodium. Very specific for the kidney's perspective on volume status.

• End stage renal disease
• Nephritic syndrome
• Nephrotic syndrome