Week 9 Flashcards
Explain the major renal physiologic mechanism of antidiuretic hormone (ADH) in water balance.
The major renal effect of antidiuretic hormone (ADH) is antidiuresis (decreased urine formation due to increased water reabsorption). ADH acts on the principal cells in the collecting ducts. The basolateral membranes of the principal cells express vasopressin type 2 (V2) receptors and are different from the vascular (V1) receptors. The binding of ADH to V2 receptors results in activation of adenylate cyclase leading to increased intracellular production of cyclic adenosine monophosphate (cAMP).
This second messenger then induces, by a sequence of events, the incorporation of aquaporin 2 (AQP2) containing intracellular vesicles to the luminal (apical) membrane. The water can move into the collecting duct epithelial cells through the AQP2 channels, so the luminal membrane becomes highly permeable to water. The water permeability of the basolateral membranes of renal epithelial cells is always high due to constitutive presence of other aquaporin isoforms.
In the absence of ADH, the AQP2 channels are withdrawn from the luminal membrane by endocytosis
Outline the pathophysiology of a high-normal plasma sodium in a patient with nephrogenic diabetes insipidus.
This patient’s NDI is due to renal resistance to antidiuretic hormone (ADH). The patient’s kidneys are unresponsive to the ADH as indicated by her lack of response to an injection of desmopressin. Therefore, this patient’s kidneys reabsorb less water from the collecting tubules resulting in low urine osmolality, high plasma osmolality (due to low ECF volume), and high-normal sodium (to provide a stimulus for thirst).
Define diabetes insipidus, contrast nephrogenic diabetes insipidus from central diabetes insipidus, and explain how they were distinguished in this patient.
- Diabetes insipidus (DI) is a condition characterized by an inability of the kidneys to reabsorb free water from the collecting tubules secondary to impaired production of ADH or renal resistance to ADH.
- Central diabetes insipidus (CDI) is due to absent or insufficient release of ADH from the posterior pituitary, whereas nephrogenic diabetes insipidus is characterized by normal or increased plasma ADH level, but the kidneys are unresponsive to ADH (renal resistance).
- Injection of desmopressin increases urine osmolality in patients with CDI, whereas no change in urine osmolality is seen in this patient after an injection of desmopressin thus indicating NDI.
Explain the rationale for administration of hydrochlorothiazide and indomethacin to manage the patient’s symptoms.
The effect of thiazide diuretics such as hydrochlorothiazide is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the antidiuretic hormone (ADH)-sensitive sites in the collecting tubules and reducing the urine output.
NSAIDs such as indomethacin act to inhibit prostaglandin synthesis, which antagonize the action of ADH. Therefore, NSAIDs may provide an additional means to increase the patient’s urine concentration; NSAIDs inhibit prostaglandin-mediated inhibition of ADH, thereby increasing water reabsorption in the collecting tubule. [In addition, inhibition of renal prostaglandin synthesis can attenuate vasodilation of the afferent arteriole and result in decreased renal blood flow and thus decreased glomerular filtration rate. This role of prostaglandins in renal hemodynamics is minimal in healthy patients but is more pronounced in patients with chronic kidney disease or arterial volume depletion.]
Relat elevated ANCA levels to renal abnormalities
The clinical findings are consistent with ANCA-associated vasculitis which manifests in the kidneys as rapidly progressive glomerulonephritis (RPGN). Renal manifestations, including hematuria, mild proteinuria, and decreased renal function, occur as a result of autoimmune small vessel vasculitis (damage to renal capillary endothelial cells), leading to nephritic syndrome.
Describe the classic histologic (light microscopic) features you would expect to find on renal biopsy with elevated ANCA
ANCA-associated vasculitis results in nephritic syndrome, more specifically, pauci-immune rapidly progressive glomerulonephritis (RPGN). RPGN is also called “crescentic” glomerulonephritis due to the classic appearance of glomerular “crescents.” These crescents are composed of inflammatory cells, predominantly macrophages, that collect in Bowman’s space and compress the glomerular tuft.
Rationalize the ordering of an interferon gamma release assay in the workup of a patient with positive ANCA
Due to the clinical presentation and chest radiograph findings, tuberculosis is in the differential diagnosis and must be excluded rapidly. If the patient has tuberculosis, she must be isolated from other patients and would not receive steroid therapy (the first line therapy for ANCA-associated vasculitis)
Passage
A 50-year-old male is admitted to the Intensive Care Unit (ICU) with acute mental status changes and Kussmaul respirations. Arterial blood gas (ABG) analysis shows pH 7.08, HCO3- 10 mmol/L, pCO2 35 mmHg. His plasma electrolyte lab values include sodium 136 mmol/L (reference range 136-146) and chloride 100 mmol/L (reference range 96-106). Based on the ABG formulas, the physician calculates the predicted compensation value for the PCO2 to be 23 mm Hg.
Determine whether the primary acid-base disorder is being compensated for and whether a secondary acid-base disorder currently exists in the patient. Explain your rationale.
Analyze the laboratory values to identify the primary acid-base disorder.
The pH is severely acidotic (below reference range).
The PCO2 is within normal limits (toward the low side); this tends toward normal or slight alkalosis and so does not explain the pH change. The HCO3 is low; this tends toward acidosis and explains the pH change. The anion gap = Na – (Cl + HCO3) = 136 – (100 + 10) = 136 – 110 = 26. This anion gap is high, suggesting this is an anion gap metabolic acidosis.
For adequate respiratory compensation of the patient’s primary metabolic acid-base disorder, the predicted PCO2 would be significantly lower, near the 23 mm Hg calculated by the physician. The fact that this patient’s PCO2 is significantly higher than the calculated, predicted value suggests a second acid-base disturbance is occurring, specifically respiratory acidosis. Thus, this is a mixed acid-base disorder, consisting of two separate disorders. The “delta-delta” is 1.0, suggesting the metabolic acidosis is only a DKA and not an additional metabolic acidosis.
A 28-year-old male presents to the ED with a two-day history of fatigue, nausea, and emesis after “eating tuna that I probably left out too long.” On physical examination, his vital signs show T 99°F, HR 110 bpm, BP 95/58 mmHg, RR 12/min, BMI 28 kg/m2. He has dry mucous membranes and poor skin turgor. Lab values are sodium 145 mmol/L (reference range 135-145), potassium 4.4 mmol/L (reference range 3.6-5.2), chloride 102 mmol/L (reference range 98-107). The physician orders ABGs. The results are pH 7.47 (7.35 – 7.45), pCO2 47 mmHg (35 – 45), and HCO3- 33 mmol/L (22 – 29). The physician notes that the values closely match a calculated predicted compensation. Analyze the laboratory values to identify the primary acid-base disorder.
Determine whether the primary acid-base disorder is adequately compensated, whether there is a secondary acid-base disorder, and identify (i.e., name) any secondary acid-base disorder if one is present. Explain your rationale.
The pH is alkalotic (above normal range). The PCO2 is high, which would suggest acidosis and so does not explain the pH change. The HCO3 is high, indicating a metabolic alkalosis, consistent with the patient’s pH change, as the primary acid-base disorder. The high HCO3 value is due to acid loss from the stomach due to vomiting. The anion gap = Na – (Cl + HCO3) = 145 – (102 + 33) = 145 – 135 = 10. This anion gap is within the normal range, thus consistent with this primary acid-base diagnosis.
The patient’s increased PCO2 is due to a compensatory respiratory acidosis (corresponding to the patient’s bradypnea) for his metabolic alkalosis. The high pCO2 matches the predicted compensation, suggesting only a single acid-base disorder is present. Thus, the patient has a partially compensated metabolic alkalosis.
In the kidney, ammonium excretion accounts for the bulk of acid excretion by the nephron. Explain the roles of glutamine in the process of this acid excretion.
Glutamine, unlike toxic ammonium (NH4+), can be transported in the bloodstream at relatively high concentrations to the kidney. In the kidney, glutamine is taken up by cells in the proximal tubule. These cells break down glutamine into NH4+ and bicarbonate. The ammonium is excreted into the tubular lumen, and the bicarbonate is retained in the body. Thus, this process secretes acid, which is alkalinizing for the plasma because the bicarbonate is reabsorbed back into the plasma.
A 69-year-old male visits his primary care physician after discovering that his blood pressure is 168/104 mmHg during a health fair. His blood pressure was 140/88 mmHg last year. He also has a history of dyslipidemia. On physical examination, his blood pressure is 156/98 mmHg and his heart rate is 80 bpm. A systolic-diastolic abdominal bruit is auscultated in the epigastric region to the right of midline. Duplex Doppler ultrasonography reveals an elevated peak systolic velocity in the region of the right renal artery. Laboratory findings are significant for high serum sodium and low serum potassium levels.
Explain the most likely changes in renin secretion by each kidney, then predict the systemic level of renin in this patient.
Outline the pathophysiologic mechanism of increased plasma renin in causing this patient’s hypertension.
Describe the pathophysiology of this patient’s hypernatremia and hypokalemia.
This patient has renal artery stenosis on the right side. The renin secretion increases in the right kidney in response to a perceived decrease in arterial pressure due to decreased flow to the juxtaglomerular apparatus. This increased renin secretion results in hypertension. The left kidney responds to the resultant systemic hypertension by decreasing its renin secretion. Nevertheless, the systemic level of renin will be elevated in this patient because of the right kidney’s overcompensation for the right renal artery stenosis.
In the plasma, renin converts angiotensinogen (produced in the liver) to angiotensin I (AT I). This AT I is converted to angiotensin II (AT II) by angiotensin-converting-enzyme (ACE) secreted by pulmonary and renal endothelial cells. The angiotensin II has the following actions to increase blood volume and blood pressure: acts on AT1 receptors on vascular smooth muscles resulting in vasoconstriction and leads to increased blood pressure; acts on the adrenal cortex to stimulate the release of aldosterone, which increase renal reabsorption of Na+ to increase blood volume and thus blood pressure ; acts on the proximal convoluted tubule and increase Na+-H+ exchanger activity thereby increases Na+, HCO3-, and water reabsorption from the kidneys resulting in increased blood volume and pressure ; acts on the hypothalamus and stimulates thirst and thus increases water intake contributing to an increase in blood volume and pressure ; increases ADH release from the posterior pituitary gland, and this ADH increases water reabsorption from the kidney and results in increased blood volume and thus pressure
Activation of the renin-angiotensin-aldosterone system due to renal artery stenosis in this patient increases serum aldosterone levels resulting in increased aldosterone action in the kidneys. Aldosterone increases the activity of apical epithelial Na+ channels, apical K+ channels, and basolateral Na+-K+ ATPase in principal cells of the distal and collecting tubules. This increases Na+ reabsorption and K+ secretion in the kidneys; therefore, this patient’s hyperaldosteronemia is the cause of his hypernatremia and hypokalemia.
Justify the use of an angiotensin-converting enzyme (ACE) inhibitor in treating renovascular hypertension.
The ACE inhibitors (such as Captopril) inhibit the peptidyl dipeptidase (angiotensin converting) enzyme that converts angiotensin (AT) I to AT II and plasma kininase that inactivates bradykinin.
The inhibition of conversion of AT I to AT II results in an inhibitory action on the renin-angiotensin-aldosterone system (RAAS). Additionally, the inhibition of plasma kininase results in stimulatory action on the kallikrein-kinin system leading to an increase in the amount of active bradykinin which is a potent vasodilator that works partly by stimulating release of nitric oxide and prostacyclin. Thus, both mechanisms lead to decreased blood pressure in this patient, and act to manage the patient’s renovascular hypertension.
