CSR Renal Physiology & Pathophysiology 2 — Questions and Answers

Question 1: Which segment of the nephron is primarily responsible for the reabsorption of approximately 65% of filtered sodium?

Proximal convoluted tubule (Correct answer)
Loop of Henle
Distal convoluted tubule
Collecting duct

Correct answer: Proximal convoluted tubule

The proximal convoluted tubule reabsorbs roughly 65% of filtered sodium via sodium-hydrogen exchangers and sodium-coupled transporters, making it the nephron's primary sodium reabsorption site.

In the proximal convoluted tubule, sodium is actively reabsorbed through multiple mechanisms including the Na+/H+ exchanger (NHE3), Na+-glucose co-transporter (SGLT2), and Na+-amino acid co-transporters. Water follows passively, preserving osmolality. This segment also handles the bulk of bicarbonate, glucose, and amino acid reabsorption. Damage here, as seen in Fanconi syndrome, causes renal wasting of multiple solutes.

Question 2: In chronic kidney disease, decreased production of which hormone by the peritubular cells leads to anemia?

Renin
Erythropoietin (Correct answer)
Calcitriol
Angiotensin II

Correct answer: Erythropoietin

Erythropoietin (EPO) is produced by peritubular interstitial cells in the renal cortex. CKD leads to fibrosis and loss of these cells, reducing EPO production and causing normocytic normochromic anemia.

Erythropoietin is a glycoprotein hormone synthesized primarily by peritubular fibroblasts in the renal cortex in response to hypoxia via HIF-2α signaling. As CKD progresses, nephron loss and interstitial fibrosis reduce EPO-producing cells, causing anemia of chronic kidney disease. This is distinct from iron-deficiency anemia and is managed with erythropoiesis-stimulating agents (ESAs) and iron supplementation. Hemoglobin target in CKD patients on ESA is typically 10–11.5 g/dL.

Question 3: The renin-angiotensin-aldosterone system (RAAS) is activated when renal perfusion pressure falls. Which renal cells are responsible for renin secretion?

Mesangial cells
Podocytes
Juxtaglomerular cells (Correct answer)
Macula densa cells

Correct answer: Juxtaglomerular cells

Juxtaglomerular (JG) cells in the afferent arteriole wall are specialized smooth muscle cells that synthesize, store, and secrete renin in response to reduced perfusion pressure.

The juxtaglomerular apparatus (JGA) consists of juxtaglomerular cells, the macula densa, and extraglomerular mesangial cells. JG cells detect reduced stretch in the afferent arteriole (low BP) and also respond to signals from the macula densa (low NaCl delivery) to secrete renin. Renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by ACE. Angiotensin II raises blood pressure and stimulates aldosterone release. In CKD, chronic RAAS activation contributes to hypertension and progressive fibrosis.

Question 4: Which pathophysiological mechanism primarily explains the metabolic acidosis commonly seen in advanced CKD (GFR < 30 mL/min)?

Increased bicarbonate secretion in the proximal tubule
Reduced ammoniagenesis and net acid excretion by the failing kidney (Correct answer)
Excessive lactic acid production from uremic toxins
Hyperventilation causing CO2 retention

Correct answer: Reduced ammoniagenesis and net acid excretion by the failing kidney

Advanced CKD impairs ammoniagenesis in the proximal tubule and reduces functioning nephrons, resulting in decreased net acid excretion and retention of fixed acids, causing metabolic acidosis.

The kidneys excrete approximately 50–100 mEq of non-volatile acid daily, primarily as ammonium (NH4+). In CKD, loss of proximal tubular mass reduces glutamine metabolism and NH3 production. With fewer nephrons, total ammonium excretion falls. Retained hydrogen ions titrate bicarbonate, causing progressive metabolic acidosis. This acidosis accelerates protein catabolism, worsens bone disease (buffering by calcium carbonate from bone), and increases potassium release from cells. Bicarbonate supplementation targeting serum HCO3 ≥ 22 mEq/L is recommended in CKD guidelines.

Question 5: In nephrotic syndrome, massive proteinuria leads to hypoalbuminemia and edema. What is the primary mechanism of edema formation?

Increased lymphatic obstruction from protein accumulation
Reduced plasma oncotic pressure leading to fluid shift into interstitium (Correct answer)
Direct sodium retention by the renal tubules independent of oncotic pressure
Increased capillary hydrostatic pressure from hypertension

Correct answer: Reduced plasma oncotic pressure leading to fluid shift into interstitium

Loss of albumin reduces plasma oncotic pressure (colloid osmotic pressure), allowing hydrostatic pressure to push fluid into the interstitial space, causing edema.

In nephrotic syndrome, glomerular barrier damage allows massive albumin loss (>3.5 g/day in adults). Serum albumin falls below 2.5 g/dL in severe cases. Starling forces govern fluid exchange: reduced plasma oncotic pressure (normally ~25 mmHg) tips the balance toward filtration at capillaries. Additionally, sodium retention by the kidney (via aldosterone and reduced ANP sensitivity) exacerbates fluid accumulation. Dietary management focuses on moderate sodium restriction (2–3 g/day), adequate but not excessive protein intake, and addressing the underlying glomerular disease.

Question 6: Which of the following best describes the role of the loop of Henle in urine concentration?

It reabsorbs glucose and amino acids to concentrate the filtrate
It creates a hyperosmotic medullary interstitium via countercurrent multiplication (Correct answer)
It secretes hydrogen ions to acidify the filtrate directly
It senses systemic blood pressure and adjusts sodium excretion

Correct answer: It creates a hyperosmotic medullary interstitium via countercurrent multiplication

The loop of Henle uses countercurrent multiplication: the descending limb is water-permeable (concentrating the filtrate), while the thick ascending limb actively pumps NaCl without water, building a hypertonic medullary gradient.

The juxtamedullary nephrons have long loops of Henle that extend deep into the medulla. The thin descending limb is highly permeable to water but not salt, so water exits as fluid descends into the hypertonic medulla. The thick ascending limb (TAL) actively transports Na+/K+/2Cl- via NKCC2 (the target of loop diuretics like furosemide) but is impermeable to water, diluting the tubular fluid while building the medullary gradient. This gradient enables the collecting duct, under ADH influence, to concentrate urine to up to 1200 mOsm/kg. In CKD, loss of juxtamedullary nephrons impairs concentrating ability, causing isosthenuria.

CSR Renal Physiology & Pathophysiology 2

Which segment of the nephron is primarily responsible for the reabsorption of approximately 65% of filtered sodium?