Week 8 Flashcards
Describe the components of the glomerular filtration barrier and the determinants of glomerular filtration.
• Glomerular capillary endothelial cell layer: The fenestrations between the endothelial cells prevent filtration of blood cells and platelets but allow all components of plasma to pass through.
• Glomerular basement membrane (GBM): The fiber meshwork of GBM includes heparan sulfate, which creates a negatively charged barrier.
• Podocytes: Narrow filtration slits between the finger-like projections of podocytes are bridged by a membrane protein (nephrin), which is also a filtration barrier.
- Molecular size and electric charge are the two major determinants of solute filterability; Substances with molecular weights less than 7000 Daltons are freely filtered; as molecular weight increases from 7000 to 70,000 Daltons, there is a roughly linear decline in the amount of solute filtered. Albumin, with a molecular weight of 66,000 Daltons, is almost totally blocked by the filtration barrier.; Negatively charged macromolecules are less filtered compared to neutral molecules of the same size. At a physiologic extracellular fluid pH of 7.4, proteins carry net negative charges, which reduces their filtration.
Explain the glomerular pathophysiology of proteinuria in a diabetic patient.
This patient’s proteinuria (moderately increased albuminuria) is possibly due to both the increased number of large pores (limiting size selectivity) resulting in loss of size barrier and decreased heparan sulfate (major component of the charge barrier) on the GBM, leading to loss of the charge barrier. The loss of the size and charge barriers allows more albumin to pass through the glomerular filtration barrier resulting in the patient’s proteinuria (microalbuminuria).
Identify the underlying cause of a diabetic patient’s glucosuria and explain the causative mechanism with reference to renal threshold and transport maximum.
- It is evident from the laboratory findings (serum glucose level of 314) that the patient has diabetes. [The absence of ketones in the patient’s urine can be used to confirm a diagnosis of type II diabetes.] Her consistently elevated blood glucose level (due to her diabetes) is the cause of her glucosuria.
- Urinary excretion of glucose by the patient confirms the patient’s blood glucose level is above 200mg/dL (or 11 mmol/L) which is the renal threshold for glucose reabsorption. At a blood glucose level greater than the renal threshold, the rate of glomerular filtration exceeds the rate of glucose reabsorption at the proximal tubule by the sodium glucose transporters (SGLT2- 90%, and SGLT1 -10%). This leads to glucose accumulation in the glomerular filtrate. With a further increase of the blood glucose concentration, glucose excretion via urine (glucosuria) occurs, as observed in this patient.
- At blood glucose levels ≥400mg/dL, called the transport maximum (Tm), the rate of glucose excretion via urine may increase significantly as the sodium glucose transporters in the renal proximal tubule get saturated, and the glucose reabsorption rate at the proximal tubule plateaus.
Explain why the patient’s BUN-to-creatinine ratio and fractional excretion of sodium indicate prerenal acute kidney injury (AKI).
- Acute prerenal injury is associated with increased urea reabsorption due to enhanced passive proximal reabsorption of urea. This raises the BUN-to-plasma creatinine ratio to greater than 20:1. This patient’s BUN-to-plasma creatinine ratio is 26.
- In addition, this patient with prerenal disease and a decline in GFR demonstrates a FENa of less than 1%. This indicates that more than 99% of his sodium is being reabsorbed in an attempt to preserve proximal sodium and water reabsorption to improve his circulating volume (and therefore his blood pressure).
Elaborate on how a patient w/ acute pre-renal injury would affect his urinary excretion of urea. Justify your answer.
The patient is suffering from hypovolemic renal disease which has led to his decline in glomerular filtration rate (GFR), causing a decrease in urine flow or output, and an increase in plasma creatinine. Changes in urine flow inevitably affect renal urea handling. At a low urine flow, as seen in our patient, the kidney tubule would reabsorb considerable amounts of water, and therefore, a considerable amount of urea. Thus, the patient’s urinary excretion of urea would be low or subnormal [the kidneys would only excrete about 15% of filtered urea in this patient]. His elevated blood urea nitrogen levels (BUN) demonstrate this high urea reabsorption and thus decreased urea elimination via urine.
The patient is started on a continuous intravenous infusion of a medication that has a typical elimination half-life of 8 hours. Approximate the time to 75% steady state in a healthy patient and describe how the medication’s elimination half-life will be altered in this patient.
The elimination half-life of a drug is defined as the time required for the drug’s plasma concentration to be reduced exactly one-half (50%) after absorption and distribution are complete. It is also the time that a drug takes to reach 50% of steady state on infusion. Therefore, the pharmacokinetic convention is that it takes approximately 4-5 half-lives for an infused medication to reach steady state. Therefore, reaching 75% of steady state will take 2 half-lives, which with a typical half-life of 8 hours, will be 16 hours (8 hours x2). [The rule of thumb goes: 50% is 1 half-life, 75% is 2 half-lives, 85.5% is 3 half-lives, 94% is 4 half-lives and so on
The time course of a drug in the body (i.e., systemic clearance) depends on both the rate of elimination and the drug concentration. The equation for half-life is the natural log of 2 (the constant 0.7) multiplied by the volume of distribution divided by clearance, therefore reduced (renal) clearance will increase the elimination half-life of the infused medication.
[Half-life to percent steady state calculations:
(1) half-life is 100/2 = 50% steady state
(2) half-lives is 50/2 = 25% + 50% = 75% steady state
(3) half-lives is 25/2 = 12.5% + 75% = 87.5% steady state
(4) half-lives is 12.5/2 = 6.25% + 87.5%= 93.75% steady state
(5) half-lives is 6.25/2 = 3.125% + 93.75%= 96.9% steady state
(6) half-lives is 3.125/2 … etc. approaches 100% steady state]
Relate hypotension to possible ischemic injury of renal papillae.
Though the kidney receives 20 – 25% of cardiac output in a normal healthy adult, less than 10% of renal blood flow follows a course through the vasa recta to the renal medulla and only about 1% reaches the renal papillae. The low blood flow in the renal medulla causes it to be susceptible to ischemia.
In the setting of hypotension, the blood flow through the vasa recta to the renal medulla decreases further, resulting in ischemia of renal papillae and papillary necrosis.
Explain how the ischemia induced by hypotension could result in ischemic-tubular injury.
The first: ischemia induces a loss of cell polarity, inducing a redistribution of Na/K ATPase from the basolateral membrane to the luminal (apical) surface of the tubular cells. This increases sodium delivery to the distal tubules inducing tubuloglomerular feedback, thus causing vasoconstriction of the afferent renal arterioles, thus decreasing renal blood flow. This decreases GFR.
The second: ischemia initiates an inflammatory response that over time causes the injured tubular cells to detach from the basement membranes and cause luminal obstruction. This increases the hydrostatic pressure in the Bowman’s space, disrupting the tight junction in the glomerular capillaries. This can cause glomerular filtrate to leak back into the interstitium, increasing edema, damaging the tubule, and further reducing GFR.
Differentiate the pathophysiology of a condition that showed a renal biopsy w/ mesangial proliferation and IgA deposits vs nephrotic syndrome.
In nephrotic syndrome, the glomerular damage allows leakage of protein into the urine and patients present with proteinuria of >3.5 g/day, hypoalbuminemia, edema, and hyperlipidemia.
The damage to the glomerulus in this patient is much more severe than in nephrotic syndrome. In addition to proteinuria, this patient also has hematuria with RBC casts, which is suggestive of nephritic syndrome. The immune complex deposition triggers proliferation of glomerular cells (e.g., epithelial, endothelial, and mesangial) and stimulates arrival of neutrophils. These pathological changes lead to the leakage of proteins as well as red blood cells.
Explain how decrease urination and elevated plasma creatinine levels are indicative of glomerular filtration rate.
- Creatinine is an end-product of muscle metabolism and is constantly released into the blood. Creatinine clearance allows for an estimation of GFR
- Ccr (creatinine clearance) = [Urine creatinine] × ( urine flow rate/ [Plasma creatinine] )
- If a patient has low urine output and increased plasma creatinine levels, which is consistent with a low renal creatinine clearance and therefore indicative of a low GFR.
Describe the physiologic mechanisms of calcium reabsorption in the different segments of the nephron. Identify the location of impaired calcium reabsorption in a patient on furosemide.
- 67% in the proximal tubule (PT) where as H2O is reabsorbed it increases [Ca} in the lumen and drives it out through the tight junctions
- 20% in the thick ascending limb (TAL) of loop of Henle (LOH), because the positive lumen potential drives the passive reabsorption of Ca2+ through the tight junctions between the cells
- The rest in the distal convoluted tubule (DCT). Ca2+ reabsorption is active and uses an apical Ca2+ channel and basolateral Ca2+-ATPase and Na+-Ca2+ exchanger which are controlled by PTH.
- impaired calcium reabsorption occurs in the TAL (as a result of furosemide administration).
Why would physician discontinue furosemide in pt with kidney stone
Furosemide is a loop diuretic that inhibits the Na+-K+-2Cl- co-transporter in the thick ascending limb (TAL) of the loop of Henle (LOH). By inhibiting this transporter, furosemide reduces the reabsorption of NaCl and disrupts the positive lumen potential that builds up from K+ recycling. This positive potential normally drives the reabsorption of divalent cations (Ca2+ and Mg2+) in the TAL, and by reducing this potential, furosemide increases Mg2+ and Ca2+ excretion in the urine. Because furosemide promotes excretion of calcium from the kidneys and thus facilitates the formation of calcified kidney stones, the physician discontinued the patient’s furosemide.
Discuss the physiologic rationale for using a thiazide for a patient with h/o kidney stones
- thiazides enhance Ca2+ reabsorption, and act to reverse loop diuretic-induced hypercalciuria. Thiazides increase Ca2+ reabsorption from both the proximal tubule (PT) and distal convoluted tubules (DCT). In the PT, thiazide-induced volume depletion leads to increased Na+ and passive Ca2+ reabsorption. In the DCT, thiazide blocks the Na+-Cl- symporter resulting in low intracellular Na+ concentration, which increases Na+/Ca2+ exchange in the basolateral membrane and increases overall reabsorption of Ca2+.
Describe the three anatomical locations where the ureters narrow and how they may impact the movement of a stone through the ureter. Briefly describe how visceral afferents from the proximal portion travel from the ureter to convey pain sensation in this patient.
- There are 3 specific areas of narrowing along the ureter. The first is the ureteropelvic junction where the renal pelvis tapers into the proximal ureter. The second region of narrowing occurs where the ureter crosses the iliac vessels which is due to the extrinsic compression of the iliac vessels on the ureter and the angle of the ureter as it enters the pelvis. The ureterovesical junction is the third site of ureteral narrowing where the ureter is entering the muscular wall of the bladder. At each location the stone may become lodged more easily due to the narrowing.
- Visceral afferent fibers conveying pain sensation in the abdominal portion of the ureters (e.g., resulting from obstruction and consequent distension) follow the sympathetic fibers retrograde to spinal ganglia and cord segments T11–L2. Ureteric pain is usually referred to the ipsilateral lower quadrant of the anterior abdominal wall and especially to the groin.
