Renal Physiology and Transport Mechanisms

kidney functions

excretory, endocrine, and metabolic functions

nephrons

primary functional excretory units

200 L

How many L of blood is filtered through a healthy adult kidney each day?

1) glomerular filtration

2) reabsorption

3) tubular secretion

What are the key processes of the excretory function of the kidney?

renal impairment

major determinant of dosing adjustments

glomerular filtration

Passive movement of water, ions, and small (<10-20 kDa) molecules across the glomerular-capillary membrane into the Bowman capsule and then the proximal tubule

size and charge

Glomerular filtration is ___________ selective.

Glomerular Filtration Rate

GFR

GFR

rate of plasma flow from glomerulus into Bowman's space

poorly charged

Are poorly or highly charged molecules more likely to be reabsorbed in glomerular filtration?

reabsorption

-rescuing molecules that we want to maintain in the body

-Passive or Active

-Recovery of water and solutes

limited

Water absorption is ______ beyond the loop of henle.

tubular secretion

-facilitate elimination of undesirable molecules

-Active process (transporter-mediated) to remove

molecules from the renal circulation and/or parenchyma into the tubular lumen

-includes secretion of molecules lost in exchange for a reabsorbed molecule

-includes re-routing substances that were passively reabsorbed

proximal tubules

Where does tubular secretion mostly occur?

aldosterone

stimulates excess K+ secretion in the distal convoluted tubule and collecting duct

proximal tubule

reabsorbs about 70% Na+/water; secrets drugs

loop of henle

concentrates urine

distal tubule

Na+/Cl- reabsorption

collecting duct

water balance (ADH)

furosemide MOA

Primarily inhibits reabsorption of sodium and chloride in the ascending loop of Henle and proximal and distal renal tubules, interfering with the chloride-binding cotransport system, thus causing its natriuretic effect (Rose 1991)

5 mins

What is the onset of action for IV furosemide?

30-60 mins

What is the onset of action for sublingual Furosemide?

15 to 20 mins

How long before symptomatic improvement with acute pulmonary edema with furosemide?

6-8 hrs

What is DoA with oral furosemide?

about 2 hours

What is the DoA with IV furosemide?

91-99%

Furosemide is __________ protein bound.

Albumin

What is Furosemide primarily bound to?

solute linked carriers and ATP binding cassettes

What are the highly efficient transport pathways in the proximal tubule?

solute linked carriers

-OATs (organic anion transporters)

-OCTs (organic cation transporters)

-OATPs (organic anion transporting polypeptides)

-MATEs (multidrug and toxin extrusion proteins)

ATP-binding cassettes (ABC) transporters

-P-gp or MDR1 (multidrug resistance protein 1)

-MRP1

-MRP2

OATs

-important for secretion into the tubule

-Penicillins, NSAIDs, Methotrexate, Loops, Thiazides, Uric Acid

OCT

Metformin, Cimetidine

size and charge

The role of urine pH and drug ionization depends on what?

tubular secretion (carriers)

majority of drugs enter kidney tubule by what

nonionized drugs

may be passively reabsorbed into the systemic circulation, but tubular cells are less permeable to the ionized forms→ highly ionized compounds not reabsorbed

pH

Passive reabsorption depends on the _____

weak acids

Acidic urine favors reabsorption of:

weak bases

Alkaline urine favors reabsorption of:

ion trapping

Weakly acidic drugs are susceptible to _________ in the urine.

altering urinary pH

How can you enhance the excretion of charged species?

ionized

For a weak base, when the pH is less than the pK, the ________ form (protonated) predominates.

nonionized

When the pH is greater than the pK, the __________ (unprotonated) form predominates.

-Total available surface area for filtration

-Filtration membrane permeability

-Net filtration pressure

How is GFR determined:

net filtration pressure

-Glomerular capillary hydrostatic pressure (PGC)

-Plasma oncotic pressure (πGC)

-Bowman's capsule hydrostatic pressure (PBS)

NSAIDs

-afferent arteriole constriction

-decrease GFR

Angiotensin II

-efferent arteriole constriction

-increase GFR

ACE inhibitors

-dilate efferent

-decrease GFR

kidney function in kidney disease

net result of a reduced number of appropriately functioning nephrons

loss of nephrons

compensatory hyperfunction of remaining nephrons (glomerular hyperfiltration, secretion, reabsorption) and renal hypertrophy

increased individual workload

increased single-nephron GFR) aims to preserve kidney function as much as possible

bc the surviving nephrons can still compensate for the loss

Why does kidney function appear preserved early in CKD?

renal functional reserve (RFR)

-The capacity of the kidney to increase GFR in response to physiological or pathological stress (e.g., protein load)

-By afferent vasodilation and increased filtration surface area

liver

What is the major organ for drug metabolism?

renal enzymes

-peptidases

-CYP enzymes (phase 1, limited)

-UDP-glucuronosyltransferases (phase 2)

peptidases

-In brush border of proximal tubules

-Essential for amino acid reabsorption

-Degradation of peptide hormones & drugs (e.g., insulin, enkephalins, imipenem)

CYP enzymes

Contribute to the metabolism of some drugs

UDP-glucuronosyltransferases

Glucuronidation to increase drug hydrophilicityfor excretion

excreted

hydrophilic

reabsorbed

lipophilic

renally cleared drugs

obvious impact of kidney disease (dose-adjustment)

non renally cleared drugs (<30% renal excretion)

Kidney disease → uremia (accumulation of waste products in the blood) → Circulating uremic toxins affect extra-renal drug metabolism and transporter function

enzyme inhibition

Directly inhibit the activity of hepatic CYP and UGT enzymes →Reduced metabolism of the drug and prolonged half-life

CYP enzyme down regulation

Decrease gene expression and protein levels of certain hepatic CYP isoforms (e.g., CYP2C9) → reduction in drug metabolism

transporter inhibtion

Inhibit function of hepatic and intestinal drug transporters (e.g.,OATPs, P-gp) → Reduced uptake into the liver for metabolism or reduced efflux from the intestine → altered bioavailability and clearance

probenecid and penicillin both compete for OATs which keeps Penicillin active longer

Probenecid is a competitive inhibitor of OATs. Why is it used together with penicillin?

these drugs are excreted into the tubule and uric acid does too so they will both be competing for the same transporter resulting in hyperuricemia

What potential adverse effect of thiazides and loop diuretics is related to their tubular secretion?

alkalize urine

Salicylates (like aspirin) are weak acids. In the case of acute salicylate poisoning, how can renal excretion of the drug be increased?

HTN increases vasoconstriction and pressure on efferent

-Lisinopril will result in vasodilation and decreased pressure

How does chronic hypertension increase glomerular workload and lead to kidney damage? Howdoes lisinopril help specifically the glomerulus?

not enough to contract

Explain how ACE inhibitor affects GFR in renal artery stenosis.

Cilastatin inhibits renal peptides and allows Imipenem to work

Imipenem is always administered with cilastatin. Why?

transporters

play key roles in drug elimination and interactions

urine pH and drug ionization

affect passive reabsorption and urinary drug trapping

renal functional reserve

reflects the kidney's adaptability to stress or injury

CKD

alters both renal and hepatic drug clearance (dose adjustment and monitoring)