Step 1 Scores - How they determine your future

Acid Base Practice Problems

1 = normal

2 = uncompensated metabolic acidosis

3 = compensated respiratory acidosis

4 = uncompensated respiratory alkalosis

5 = uncompensated respiratory acidosis

6 = compensated metabolic acidosis

7 = compensated metabolic acidosis

8 = compensated respiratory acidosis

9 = compensated metabolic alkalosis

10 = mixed respiratory and metabolic alkalosis

Metabolic Acidosis due to Iron Overdose

Iron - the "I" in Mudpiles

Iron overdose as a cause of a high anion gap metabolic acidosis

Now, iron is usually mentioned as an important cause of metabolic acidosis, and there is a warm spot reserved for it in the “MUDPILES” mnemonic. An impressionable person might be inclined to believe that iron contributes to the high anion gap metabolic acidosis by dissociating into unmeasured anions, much like the toxic alcohols. However, that would be wildly inaccurate, because iron is a cation.

The acidosis here is multifactorial. Some textbooks (Fowler’s Handbook on the Toxicology of Metals) suggest that the acidosis is mainly due to the physicochemical effects of the iron ion itself. Other sources (Goldfranks Manual of Toxicologic Emergencies) attribute the acidosis to a raised lactate, of which not all is generated by direct effects of the iron, but rather due to the fluid loss (from an ulcerated gut), cardiogenic shock (due to the myocardial mitochondrial toxicity) and fulminant hepatic failure. On top of that, a fair portion of the lactic acidosis is due to the direct mitochondrial toxicity of iron in all tissues.

Hyperkalemia - extra lecture stuff

Fig. 3 Illustration of a normal action potential (solid line) and the action potential as seen in the setting of hyperkalemia (interrupted line). The phases of the action potential are labeled on the normal action potential. Note the decrease in both the resting membrane potential and the rate of phase 0 of the action potential (Vmax) seen in hyperkalemia. Phase 2 and 3 of the action potential have a greater slope in the setting of hyperkalemia compared with the normal action potential.

Phase 0 of the action potential occurs when voltage-gated sodium channels open and sodium enters the myocyte down its electrochemical gradient (Fig. 3). The rate of rise of phase 0 of the action potential (Vmax) is directly proportional to the value of the resting membrane potential at the onset of phase 0.7–9This is because the membrane potential at the onset of depolarization determines the number of sodium channels activated during depolarization, which in turn determines the magnitude of the inward sodium current and the Vmax of the action potential. As illustrated in Figure 4, Vmax is greatest when the resting membrane potential at the onset of the action potential is approximately −75 mV, and does not increase as the membrane potential becomes more negative. Conversely, as the resting membrane potential becomes less negative (that is, −70 mV), as in the setting of hyperkalemia (Fig. 3), the percentage of available sodium channels decreases. This decrease leads to a decrement in the inward sodium current and a concurrent decrease in the Vmax; therefore, as the resting membrane potential becomes less negative in hyperkalemia, Vmax decreases. This decrease in Vmax causes a slow-ing of impulse conduction through the myocardium and a prolongation of membrane depolarization; as a result, the QRS duration is prolonged.

In summary, the early effect of mild hyperkalemia on myocyte function is to increase myocyte excitability by shifting the resting membrane potential to a less negative value and thus closer to threshold potential; but as potassium levels continue to rise, myocyte depression occurs and Vmax continues to decrease.

Hyperkalemia also has profound effects upon phase 2 and phase 3 of the action potential. After the rapid influx of sodium across the cell membrane in phase 0, potassium ions leave the cell along its electrochemical gradient, which is reflected in phase 1 of the action potential. As the membrane potential reaches −40 to −45 mV during phase 0, calcium channels are stimulated, allowing calcium to enter the myocyte. The maximum conductance of these channels occurs approximately 50 msec after the initiation of phase 0 and is reflected in phase 2 of the action potential.7 During phase 2, potassium efflux and calcium in-flux offset one another so that the electrical charge across the cell membrane remains the same, and the so-called plateau phase of the action potential is created (Fig. 3). During phase 3, the calcium channels close, while the potassium channels continue to conduct potassium out of the cell; in this way, the electronegative membrane potential is restored.7 One of the potassium currents (Ikr), located on the myocyte cell membrane, is mostly responsible for the potassium efflux seen during phases 2 and 3 of the cardiac action potential.10 For reasons that are not well understood, these Ikr currents are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased so that more potassium leaves the myocyte in any given time period.10 This leads to an increase in the slope of phases 2 and 3 of the action potential in patients with hyperkalemia and therefore, to a shortening of the repolarization time. This is thought to be the mechanism responsible for some of the early electrocardiographic manifestations of hyperkalemia, such as ST-T segment depression, peaked T waves, and Q-T interval shortening.11,12

Urine Osmolarity in SIADH

Urinary Na excretion

In SIADH, urinary loss of Na⁺ continues despite significant hyponatremia. In these patients, as in healthy patients, urinary Na⁺ excretion is a reflection of Na⁺ intake and, therefore, usually is greater than 20 mmol/L. However, in the setting of Na⁺restriction in patients with SIADH or in patients with volume depletion due to extrarenal losses, the urinary Na⁺ concentration may be very low.

Urine Osmolarity
Patients with hyponatremia should turn off ADH and have a urine that is maximally dilute (ie, 50-100 mOsm/kg); however, in patients with SIADH, the urinary osmolality is usually submaximally dilute (ie, >100 mOsm/kg). One of the more common errors in recognizing SIADH is the failure to realize that the urine’s osmolality must be only inappropriately elevated and not necessarily greater than the corresponding serum osmolality.


Formative Quiz 2 has a case of SIADH with a urine osmolarity of 850.  I think this is incorrect for reasons state above.

Water Disorders - fill in the table . answers

Typical Causes of Hyperkalemia

•Increased release from cells:

•Hemolysis [leaking from mechanically damaged RBC]

•Metabolic acidosis

•Primary adrenal insufficiency

•Insulin deficiency

•Increased tissue catabolism

•Beta adrenergic blockade

•Exercise

•Reduced urinary excretion of K+

•Hypoaldosteronism (clinically important in the context of underlying renal disease)

•Renal failure

•Type 4 renal tubular acidosis

BUN/Cr

BUN/Cr Ratio

Urea handling by the kidney. The arrows indicate that urea is reabsorbed in the proximal tubule, secreted in the thin portions of the loop of Henle, and reabsorbed again in the inner medullary collecting ducts. The top halves of boxes indicate the percentage of the filtered load remaining in the tubule at a given location and the bottom halves indicate tubular concentration relative to plasma. Note that while the amount remaining in the collecting duct (and thus excreted) is half the amount filtered, the concentration is much higher than in plasma because most of the water has been reabsorbed. These numbers are highly variable, depending on several factors, particularly the hydration status.

BUN: Cr Ratio

The ratio of BUN to Cr can suggest hypovolemia because of differences in the way each is handled in the nephron. Both substances are passively filtered at the glomerulus, but whereas Cr remains within the tubule, the renal tubule is highly permeable to urea, which is passively reabsorbed with sodium. Therefore, in the setting of avid sodium retention, urea clearance is as low as 30% of GFR, whereas in the setting of adequate volume and sodium, urea clearance can increase to 70% to 100% of GFR. Thus, if the patient has normal concentrating ability, in the setting of prerenal failure, the serum ratio of BUN to Cr is typically >10. BUN level is depressed in patients with malnutrition and hepatic synthetic dysfunction and can be increased in the setting of protein loading, GI hemorrhage, or trauma. 

Decreased kidney function leads to an accumulation of urea and an inability to maintain electrolyte, water, and acid-base balance. The failure to adequately excrete urea, manifested as progressive elevation of blood urea nitrogen (BUN), serum creatinine, and other poorly defined toxins, results in uremia (see Chronic Kidney Disease below). Uremia is a syndrome characterized by a unique set of symptoms, physical examination findings, and laboratory abnormalities (see Table 16–7), presumably caused by a buildup of one or more uncharacterized toxins. In the absence of adequate renal clearance, ingestion of excess amounts of Na+, K+, water, or acids results in electrolyte, volume, and acid-base abnormalities that can be life threatening. Furthermore, excess Na+ ingestion in a patient with renal insufficiency results in intravascular volume expansion, which in turn can lead to hypertension and heart failure.

The clinical manifestations of acute kidney injury depend not only on the cause but also on the stage in the natural history of the disease at which the patient comes to medical attention. Patients with renal hypoperfusion (prerenal causes of acute kidney injury) first develop prerenal azotemia (elevated BUN without tubular necrosis), a direct physiologic consequence of a decreased GFR. With appropriate treatment, renal perfusion can typically be improved, prerenal azotemia can be readily reversed, and the development of acute tubular necrosis can be prevented. Without treatment, prerenal azotemia may progress to acute tubular necrosis. Recovery from acute tubular necrosis, if it occurs, will then follow a more protracted course, potentially requiring supportive dialysis before an adequate renal function is regained.

A variety of clinical tests can help determine whether a patient with signs of acute kidney injury is in the early phase of prerenal azotemia or has progressed to full-blown acute tubular necrosis. However, the overlap in clinical presentation along the continuum between pre-renal azotemia and acute tubular necrosis is such that the results of any one of these tests must be interpreted in the context of other findings and the clinical history.

Perhaps the earliest manifestation of prerenal azotemia is an elevated ratio of BUN to serum creatinine. Normally 10–15:1, this ratio may rise to 20–30:1 in prerenal azotemia, with a normal or near-normal serum creatinine. If the patient proceeds to acute tubular necrosis, this ratio may return to normal but with a progressively elevated serum creatinine.

Urinalysis is a simple and inexpensive test that serves as an important tool in the initial evaluation of the patient with acute kidney injury. The presence of hematuria and proteinuria should prompt an evaluation for GN. There are no typical abnormal findings in simple prerenal azotemia, whereas granular casts, tubular epithelial cells, and epithelial cell casts suggest acute tubular necrosis. Casts are formed when debris in the renal tubules (protein, red cells, or epithelial cells) takes on the cylindric, smooth-bordered shape of the tubule. Likewise, because hypovolemia is a stimulus to vasopressin release (see Chapter 19), the urine is maximally concentrated (up to 1200 mOsm/L) in prerenal azotemia. However, with progression to acute tubular necrosis, the ability to generate a concentrated urine is largely lost. Thus, a urine osmolality of less than 350 mOsm/L is a typical finding in acute tubular necrosis.

Finally, the fractional excretion of Na+

FENa+[%]=UrineNa+/PlasmaNa+UrineCr/PlasmaCr×100$FENa+[%]=UrineNa+/PlasmaNa+UrineCr/PlasmaCr×100$

is an important indicator in oliguric acute kidney injury to determine whether a patient has progressed from simple prerenal azotemia to frank acute tubular necrosis. In simple prerenal azotemia, more than 99% of filtered Na+ is reabsorbed, and the FENa+ will be less than 1% (except when the patient is on a diuretic). This value allows accurate identification of Na+ retention states (such as prerenal azotemia) even when there is water retention as a result of vasopressin release. With the progression of prerenal azotemia to acute kidney injury with acute tubular necrosis, this ability of the kidney to retain sodium avidly is generally lost.

Most damage in ATN is to proximal tubule (where 70% of Na is normally reabsorbed)

Mechanism of Oliguria in ATN – Tubuloglomerular Feedback

• 70% of ATN cases will cause oliguria (UOP < 500 ml/day).

• Glomeruli are actually intact in ATN. So why are they not filtering enough plasma to

generate urine?

• Total body water (TBW) accounts for about 50% of body weight. So an 80 kg person has 40 L of TBW. 1/3 of this 40 L is ECF, so that’s 13 L. 1/3 of ECF is intravascular fluid. So the plasma volume is 13 L x 1/3 = 4L.

• Healthy kidneys can filter 100 ml/min of plasma. That means it takes about 4000/100 = 40 min to filter all the plasma in the body. 

• 9% of the filtered plasma is reabsorbed by the tubules and returned to circulation. 

• In ATN, tubular reabsorption is impaired. If the glomeruli keep on filtering while the tubules are not reabsorbing, then a person can become volume depleted.

• So oliguria is really an adaptive response in ATN.  "Acute Renal Success"

Mechanism of Oliguria in ATN – Tubuloglomerular Feedback
• How does GFR get turned down in ATN?
• Answer: Tubuloglomerular feedback.
• ATN with tubular injury = reduced NaCl reabsorption at the PCT =increase NaCl delivery to macula densa at DCT = macula densa chemoreceptor activated and releases vasoactive compounds (adenosine)  = afferent arteriolar vasoconstriction and a fall in GFR = less filtration which in turn limits any further NaCl loss.

Renal Physiology Portion of RMR module

Renal Physiology Portion of RMR module

NBME Content Outline - Renal/Urinary System

NBME Content Outline - Renal/Urinary System.
(Step 1 item writers are assigned questions to write using this outline)

9.1 Normal processes
9.1.1 embryonic development, fetal maturation, and perinatal changes
9.1.2 organ structure and function
9.1.2.1 kidneys, ureters, bladder, urethra
9.1.2.2 glomerular filtration and hemodynamics
9.1.2.3 tubular reabsorption and secretion, including transport processes
and proteins
9.1.2.4 urinary concentration and dilution
9.1.2.5 renal mechanisms in acid-base balance
9.1.2.6 renal mechanisms in body fluid homeostasis
9.1.2.7 micturition
9.1.3 cell/tissue structure and function
9.1.3.1 renal metabolism and oxygen consumption
9.1.3.2 hormones produced by or acting on the kidney
9.1.4 repair, regeneration, and changes associated with stage of life

9.2 Abnormal processes
9.2.1 infectious, inflammatory, and immunologic disorders
9.2.1.1 infectious disorders
9.2.1.1.1 upper urinary tract
9.2.1.1.2 lower urinary tract
9.2.1.2 inflammatory and immunologic disorders
9.2.1.2.1 glomerular disorders
9.2.1.2.2 tubular interstitial disease
9.2.2 traumatic and mechanical disorders
9.2.3 neoplastic disorders
9.2.3.1 primary
9.2.3.1.1 renal
9.2.3.1.2 urinary bladder and collecting system
9.2.3.2 metastases
9.2.4 metabolic and regulatory disorders
9.2.4.1 renal failure, acute and chronic
9.2.4.2 tubular and collecting duct disorders
9.2.4.3 renal calculi
9.2.5 vascular disorders
9.2.6 systemic diseases affecting the renal system

9.3 Principles of therapeutics
9.3.1 mechanisms of action, use, and adverse effects of drugs for treatment of
disorders of the renal and urinary system
9.3.1.1 diuretics, antidiuretic drugs
9.3.1.2 drugs and fluids used to treat volume, electrolyte, and acid-base
disorders
9.3.1.3 drugs used to enhance renal perfusion
9.3.1.4 anti-inflammatory, antimicrobial, immunosuppressive, and
antineoplastic drugs
9.3.1.5 drugs used to treat lower urinary tract system
9.3.2 other therapeutic modalities

9.4 Gender, ethnic, and behavioral considerations affecting disease treatment and
prevention, including psychosocial, cultural, occupational, and environmental
9.4.1 emotional and behavioral factors
9.4.2 influence on person, family, and society
9.4.3 occupational and other environmental risk factors
9.4.4 gender and ethnic factors