Patho 2 test 2: The Renal System

The Renal System

• The kidney is the main organ responsible for maintaining homeostasis, controlling the composition of body fluids and excretion of metabolic waste and foreign substances.
• The kidney regulates body fluid volume, osmolality, and acid-base balance, and also produces hormones such as erythropoietin and activates vitamin D.

Gross Anatomy of the Kidney

• The kidney is a retroperitoneal organ located alongside the vertebral column at T12-L3.
• The kidney is divided into the outer cortex and inner medulla, with the hilum being the point where the renal artery and nerves enter and the renal vein exits.
• The ureter exits the kidney to drain urine into the bladder.

Renal Perfusion

• The kidney is one of the most well-perfused organs in the body, receiving 25% of cardiac output.
• The right and left renal arteries branch off the abdominal aorta and enter the kidney through the hilum.
• The blood flow through the kidney is divided into two capillary beds: glomerular and peritubular.

The Nephron

• The nephron is the functional unit of the kidney, with approximately 1 million nephrons per kidney.
• The nephron is divided into the glomerulus, proximal tubule, loop of Henle, and distal tubule.
• The nephron is responsible for filtering plasma, reabsorbing and secreting substances, and regulating the amount of substance excreted in the urine.

Glomerular Filtration

• Glomerular filtration is a passive process that occurs through the glomerular capillaries, driven by hydrostatic and osmotic pressures.
• The filtration rate is influenced by the surface area available for filtration, membrane permeability, and net filtration pressure.
• The glomerular filtration rate (GFR) is the volume of plasma filtered per unit time, with a normal rate of 125 mL/min.

Autoregulation of Renal Blood Flow

• The kidney can autoregulate blood flow in response to changes in systemic blood pressure, maintaining a constant GFR.
• Autoregulation occurs through two mechanisms: myogenic autoregulation and feedback from the juxtaglomerular apparatus.

Regulation of Renal Blood Flow and GFR

• The kidney can regulate GFR by adjusting the diameter of the afferent and efferent arterioles.
• The kidney can increase GFR by dilating the afferent arteriole and constricting the efferent arteriole, and decrease GFR by constricting the afferent arteriole and dilating the efferent arteriole.

Clinical Correlations

• Estimating GFR is an important indicator of kidney function.
• Creatinine is a commonly used substance to estimate GFR, as it is freely filtered in the glomerulus but not reabsorbed in the tubules.
• GFR can be influenced by age, gender, and muscle mass.

Tubular Pathway Review

• The tubular pathway consists of the proximal tubule, loop of Henle, and distal convoluted tubule.
• Transport (reabsorption and secretion) occurs in every part of the tubule.
• The proximal tubule is responsible for reabsorbing most of the filtered sodium, water, and other solutes.

Tubular Reabsorption

• Tubular reabsorption is the process of transporting substances from the tubular lumen back into the peritubular capillaries.
• Transport can be active or passive.
• The tubules have a transport maximum, beyond which they cannot reabsorb any more substances.

Tubular Secretion

• Tubular secretion is the process of transporting substances from the peritubular capillaries into the tubular lumen.
• Important for disposing of drugs and drug metabolites, eliminating undesirable substances, removing excess potassium, and controlling pH.

Pathophysiology of the Kidney

• Each function of the kidney can be compromised, leading to various disorders.
• The result of the compromised function will depend on the location, etiology, and chronicity of the damage.

Classifying Renal Disease

• Renal disease can be classified based on chronicity, location, and etiology.
• Acute kidney injury (AKI) and chronic kidney disease (CKD) are two common classifications.

Causes of Kidney Injury

• Prerenal causes: inadequate renal blood flow, leading to decreased GFR.
• Intrarenal causes: nephron damage, glomerulotubular diseases.
• Postrenal causes: obstruction or structural defects blocking urine from draining.

Chronic Kidney Disease

• Slow, progressive loss of renal function and decrease in GFR.
• Causes: systemic diseases, intrinsic kidney disease, and obstructive uropathies.
• Defined in stages based on GFR and whether the patient is dialysis-dependent.

End-Stage Renal Disease

• Dialysis is needed to sustain life.
• Can be caused by various diseases, including hypertension, diabetes, and autoimmune conditions.

Hypertensive Nephropathy

• Can affect both glomerular and peritubular capillaries.
• Microvascular damage from constant exposure to high systemic blood pressure.
• Leads to tissue fibrosis, ischemia, and small/fibrotic glomeruli.

Diabetic Nephropathy

• Hyperglycemia over time causes microvascular damage to renal arteries and direct glomerular damage.
• Leads to decreased GFR, proteinuria, and eventually end-stage renal disease.

CKD and Renal Adaptation

• The kidney has a remarkable ability to adapt to chronic insults, allowing for preservation of renal function.
• However, eventually, the kidneys can no longer compensate, and dialysis may be needed.

Dialysis

• Hemodialysis and peritoneal dialysis are two common methods of dialysis.
• Hemodialysis uses an external glomerular membrane and tubule system to filter undesired substances, remove volume, and maintain a normal balance of solutes.
• Peritoneal dialysis uses the peritoneal membrane to filter plasma and remove waste products.

Glomerular Diseases

• Impairment of glomerular filtering properties leads to decreased GFR
• Can be primary or secondary
• Molecules like blood cells and Albumin can pass into urine and be excreted

Nephrotic and Nephritic Syndromes

• Syndromes are constellations of signs and symptoms with multiple causes
• Depend on amount and type of damage
• Not all glomerular damage causes syndromes, and some diseases can cause both

Nephritic Syndrome

• Inflammatory cells accumulate in the mesangium
• Caused by antigen deposition, leading to damage to endothelial cells
• Damage thins the glomerular basement membrane and podocytes, allowing proteins and red cells through into the filtrate
• Signs: Hematuria, Hypertension, Oliguria, Edema, RBC casts and red blood cells, Protein (to a lesser degree), White blood cells
• Associated with: Infection-related Glomerulonephritis, Rapidly Progressive Glomerulonephritis (RPGN)

Nephrotic Syndrome

• Damage to the glomerular basement membrane/podocytes leads to loss of negative charge and increased permeability
• Plasma proteins are lost, decreasing plasma oncotic pressure
• Can be primary or secondary
• Diabetic nephropathy is the most common cause of secondary, HTN is the second most common
• Signs: Proteinuria (>3.5 gm/day), Hypoalbuminemia, Ascites and peripheral edema, Hyperlipidemia, Lipiduria

Glomerulopathy

• Disease of the glomeruli
• Group of autoimmune disorders involving inflammation of glomerular capillaries
• Present with various combinations of hematuria, proteinuria, oliguria, hypertension

Types of Glomerulonephritis

• Acute Glomerulonephritis: Primary glomerular injury from immunologic responses, ischemia, drugs, toxins, infection
• Post-Streptococcal Glomerulonephritis: One of the causes of Acute Glomerulonephritis
• Rapidly Progressive Glomerulonephritis (RPGN): Autoimmune, can be secondary to post-strep GN or unknown causes, always autoimmune
• Membranous Glomerulonephritis: One of the most common causes of Nephrotic syndrome in adults
• Minimal Change Glomerulonephritis: One of the most common causes of Nephrotic syndrome in children
• Chronic Glomerulonephritis: Slow progression, can be asymptomatic, often an incidental finding on a routine physical
• Secondary Glomerulonephritis: Most common cause of chronic renal failure, often due to DM, HTN, or both

Path of Damage in Obstructive Uropathy

• Collecting system dilates, triggering smooth muscle hypertrophy in the ureters
• Flow slows down or stops, decreasing GFR and elevating hydrostatic pressure in Bowman's Capsule
• Collecting system stretches and enlarges, damaging tubular cells and leading to fibrosis
• Fibrosis signals tissue repair, bringing in cytokines, proteases, and causing cell damage and apoptosis
• Irreversible tubular damage can result

General Timeline

• < 1 week: Hydronephrosis and hydroureter are present
• ~ 1 week: Distal tubules show evidence of damage
• ~ 2 weeks: Proximal tubule damage
• ~ 4 weeks: Glomeruli are damaged
• > 4 weeks: Cell death begins to occur
• > 3 months: Doubtful that any function can be regained

Clinical Correlation: Signs/Symptoms

• Flank pain
• Fever
• Nausea/vomiting
• Hematuria (especially in intrinsic causes like stones)
• Symptoms of glomerular disease like edema if the obstruction persists

Acute Tubular Necrosis (ATN)

Ischemic ATN

• Hypoperfusion leads to hypoxia, causing cell death
• Cellular debris of dead cells (casts) fall into the tubules, causing physical obstruction
• Obstruction lowers GFR more due to initial hypoperfusion
• Ischemia in tubular cells stops production of vasodilators, leading to more vasoconstriction
• Tubules are affected in an interrupted and "patchy" way
• Debris from dead tubular cells can be seen as granular "casts" in the urine, which looks "muddy"

Etiology of Ischemic ATN

• Renal hypoperfusion
• Tubule cell injury
• Tubule cell death
• Cellular debris → Tubular occlusion
• Lowered GFR
• More vasoconstriction

Nephrotoxic ATN

• Occurs due to exposure to toxic agents
• Nephrotoxic drugs (e.g., antibiotics, chemotherapy, contrast dye)
• Bacterial toxins
• Large amounts of circulating hemoglobin or myoglobin
• Toxic non-drug substances (e.g., antifreeze, mercury, arsenic)

Phases of ATN

Initiation Phase

• Drastic decrease in GFR
• Big "jump" in BUN/creatinine levels
• Clinically, suspect ATN if creatinine rises sharply in the first 24-48 hours

Maintenance Phase

• GFR remains low
• BUN/Cr continue to rise
• Oliguria or anuria
• Hemodialysis may become necessary

Clinical Correlation: Indications for HD in the Acute Setting

• Volume overload
• Hyperkalemia
• Severe acid-base disturbances
• Uremic encephalopathy
• Toxin/medication removal

Recovery Phase

• Tubule cells begin regenerating
• Tubular function can slowly recover
• First indication is usually increasing urine output and then gradual decrease in BUN/Cr
• Similar to obstruction, there can be "post-ATN diuresis" due to dilute urine from regenerating tubular cells
• Recovery can be complete, partial, or never, and some patients end up with life-long ESRD and remain dialysis-dependent

Clinical Correlation: Why should we care about ATN?

• 22.7% incidence of AKI in hospitalizations
• AKI is associated with a more than fourfold increased likelihood of death
• ATN is the most common cause of AKI

Body Fluid Compartments

• Total body fluid is divided into ⅔ intracellular fluid (fluid within cells) and ⅓ extracellular fluid
• Extracellular fluid is further divided into ¾ interstitial fluid (between cells) and ¼ plasma fluid (in capillaries)
• Plasma fluid is responsible for transporting materials between cells and capillaries through interstitial fluid

Osmoregulation

• Osmolality is the concentration of solutes in body fluids, critically important for organ function
• Normal plasma osmolality is maintained by:
  • Excreting excess water
  • Replenishing lost water
  • Maintaining normal amounts of solutes in the body
• The brain and kidneys are the main organs involved in osmoregulation

Maintaining Body Water

• Water reabsorption occurs passively through osmosis, but is ultimately determined by the movement of sodium and the presence of aquaporins
• Sodium is the most abundant extracellular cation
• Aquaporins are surface proteins that form "holes" in the cellular membrane, allowing water to pass through
• Aquaporins are present throughout the tubules, with high concentrations in the proximal tubules and descending limb of the loop of Henle
• No aquaporins are present in the collecting ducts unless vasopressin (ADH) is present, making water reabsorption dependent on ADH

Vasopressin/ADH Control of Water Reabsorption

• Vasopressin is released by the posterior pituitary in response to elevated osmolarity and stimulates water reabsorption in the collecting ducts
• Decreased osmolarity inhibits vasopressin secretion, leading to decreased water reabsorption
• Baroreceptors in the atria and carotid arteries also affect vasopressin production, with low blood pressure stimulating release of vasopressin

Disorders of Vasopressin

• Diabetes Insipidus (DI):
  • Central DI: brain produces too little ADH, often due to pituitary or hypothalamic damage
  • Nephrogenic DI: kidneys don't respond to circulating ADH, often due to chronic lithium use or hypercalcemia
• SIADH (Syndrome of Inappropriate ADH):
  • Body is unable to suppress ADH secretion, leading to excessive water reabsorption and hyponatremia
  • Caused by CNS issues, malignancy, or certain medications

Sodium Homeostasis

• Sodium reabsorption from tubule cells to interstitial fluid is almost always active transport
• Active transport generates an electrochemical gradient, allowing for the reabsorption of other substances like glucose
• Na+/K+ ATPase is the enzyme responsible for active sodium reabsorption

Sodium Reabsorption

• Sodium is actively pumped out of the tubule and back into the blood, allowing other substances to be reabsorbed
• Energy is expended to "pull" sodium from the tubular lumen into the cell, creating an electrochemical gradient
• Sodium is then actively transported out of the cell to maintain low intracellular Na+ concentrations

Disorders of Sodium Regulation

• Hypernatremia: too much sodium (Na >145 mg/dL), causing fluid to shift from intracellular fluid to extracellular fluid
• Causes of hypernatremia:
  • Hypovolemic hypernatremia: dehydration, osmotic diuresis
  • Hypervolemic hypernatremia: excessive sodium intake, iatrogenic administration of normal saline
  • Diabetes Insipidus: loss of free water
• Hyponatremia: too little sodium (Na <135 mg/dL), often caused by SIADH, heart failure, or liver disease

Juxtaglomerular Apparatus

• JG cells around the afferent arteriole are specialized smooth muscle cells that secrete renin and control blood flow into the glomerulus.
• Mechanoreceptors in JG cells sense changes in the vessel diameter, and when blood pressure is low, they release more renin.
• Macula densa, located in the distal convoluted tubule, senses changes in sodium concentration of the filtrate and signals to the JG cells to release more renin when sodium levels are low.

Potassium Regulation

• Potassium is the major intracellular cation, and its distribution is maintained by Na+/K+ ATPase pumps.
• K+ sensors in the adrenal gland respond to changes in potassium levels, and high potassium levels stimulate the release of aldosterone, which promotes potassium excretion and sodium retention.
• Low potassium levels lead to decreased aldosterone release, resulting in potassium retention and sodium excretion.
• Normal intracellular potassium levels are crucial for maintaining resting membrane potential, and changes in potassium levels can affect muscle contraction and neuronal activity.

Renal Regulation of Potassium

• Bulk reabsorption of potassium occurs in the proximal tubule and the loop of Henle.
• The distal tubule and collecting duct are responsible for regulating potassium levels in response to aldosterone.
• Aldosterone stimulates the production of proteins that activate the Na+/K+ ATPase, leading to sodium reabsorption and potassium secretion.

Factors Affecting Plasma K+

• Factors that increase plasma potassium levels include:
  • Dietary intake
  • Cellular breakdown
  • Acidosis
• Factors that decrease plasma potassium levels include:
  • Stool losses
  • Increased cellular uptake
  • Insulin and acid-base status

Potassium and Serum pH

• Potassium is an important buffer in the intracellular fluid.
• When there is high plasma H+ (acidosis), H+ ions move into the cell, and potassium ions move out of the cell, leading to increased plasma potassium levels.
• Alternatively, when there is high plasma pH (alkalosis), H+ ions move out of the cell, and potassium ions move into the cell, leading to decreased plasma potassium levels.

Pathophysiology of Hyperkalemia

• Hyperkalemia is typically defined as plasma potassium levels > 5.5 mmol/L.
• Causes of hyperkalemia include:
  • Decreased renal excretion due to decreased filtration or secretion
  • Acute renal failure
  • Hypoaldosteronism
  • Medication effects
  • Cellular breakdown
• Clinical correlations:
  • Treatment of hyperkalemia includes calcium gluconate, insulin + D50, Kayexalate, and IV sodium bicarbonate.
  • Patients with end-stage renal disease on hemodialysis must be mindful of dietary potassium intake.

Pathophysiology of Hypokalemia

• Hypokalemia is not as life-threatening as hyperkalemia.
• Causes of hypokalemia include:
  • Excess urinary losses
  • Excess stool losses
  • Increased cellular uptake
  • Alkalosis
  • Pregnancy
• Treatment of hypokalemia includes potassium replacement, either orally or intravenously.

Renal Acid-Base Buffering

• Acids tend to give up hydrogen ions, while bases combine with hydrogen ions to neutralize them.
• The shape of a protein determines its action, and protein shape is dependent on pH.
• Derangements in serum pH can lead to significant dysfunction throughout the body and ultimately death.

Hydrogen Ion Buffering

• The lungs and kidneys work together to maintain a balance of H+ and HCO3 ions to maintain normal pH.
• Excess hydrogen in the blood is buffered by bicarbonate, which combines with hydrogen to form carbonic acid.
• Not enough hydrogen in the blood leads to the dissociation of carbonic acid into hydrogen and bicarbonate ions.

Acidosis and Alkalosis

• Acidosis pushes the equation towards the left, forming more carbonic acid, while alkalosis pushes it towards the right, promoting the dissociation of carbonic acid into hydrogen and bicarbonate ions.
• Respiratory compensation occurs quickly, while renal buffering takes more time.
• The kidneys and lungs work together continuously to regulate serum H+ concentrations.

Bicarbonate Reabsorption

• Bicarbonate is freely filtered in the glomerulus and must be reabsorbed in the tubule.
• The majority of bicarbonate reabsorption occurs in the proximal tubule.
• Within a tubule cell, water and CO2 combine to form carbonic acid, which dissociates into bicarbonate and hydrogen ions.
• H+ moves into the tubular lumen, and bicarbonate moves out of the cell and back into the plasma.

Renal pH Control

• To increase serum pH, the kidneys reabsorb more bicarbonate.
• To decrease serum pH, the kidneys excrete more bicarbonate.

Renal Compensation for Acidosis

• If the plasma is too acidic, the kidneys reabsorb more bicarbonate, but the bloodstream still wants more.
• This leads to the renal compensation for chronic respiratory acidosis.
• Within a tubule cell, water and CO2 come together to form bicarbonate, which is reabsorbed.
• H+ moves into the tubular lumen, where it binds to an anion, usually phosphate, and is excreted into the urine.