Renal Physiology & The Urinary Tract Flashcards
What adult structures are formed by the urachal structures?
Urachal remnant: middle ligament of the bladder
Umbilical arteries: round ligaments of the free border of the paired lateral ligaments of the bladder
Where in the urethra are the various ducts located in males?
- Colliculis seminalis (common openings of the ductus deferens and ducts of the seminal vesicles) is a dorsal papilla immediately caudal to the urethral opening.
- Prostatic ducts are two small papilla lateral to the colliculus seminalis.
- Bulbourethral glands open in paired dorsal lines 2-3c, caudad to the colliculis seminalis.
- Lateral urethral glands are smaller ducts at the same level as the bulbourethral glands, but they are laterally located.
What are the two types of nephrons?
- The superficial or cortical nephrons with short loops of Henle.
- The juxtamedullary nephrons with long loops of Henle.
List the effects of stimulation of the renal nerves.
- Predominantly sympathetic
- Control of renal vascular resistance (vasoconstriction or dilation)
- Increased proximal tubular sodium reabsorption and renin release by activation of a1adrenoceptors (with low frequency stimulation of the nerve)
- Increased perfusion of the outer renal medulla (dopamine D1 receptors) - presence of these receptors is the basis for use of dopamine and DA-1 receptor agonist fenoldopam to improve renal blood flow in acute renal failure.
Where does the sympathetic and parasympathetic innervation to the bladder arise?
Sympathetic: hypogastric nerve with pre-ganglionic fibres from spinal segments L1-L4 to synapse in the caudal mesenteric ganglion. Post-ganglionic fibres supples the bladder (B2adrenergic receptors) and proximal urethra (primariily A1 and some A2adrenergic receptors).
Parasympathetic: sacral segments of the spinal cords with neurons joining to form the pelvic nerve.
Somatic innervation of the lower urinary tract is primarily to the striated muscle of the external urethral spincter via a branch of the pudendal nerve from S1-S2.
What other abnormalities commonly accompany congenital defects of the kidney such as renal agenesis or dysplasia?
- Ureteral dysgenesis or ectopic ureters
- Cryptorchidism/urogenital defects
What is the most common site of renal cysts?
Most often in the cortex but can occur from any portion of the nephron.
What are the treatment options and considerations for unilateral renal vascular anomalies?
- Unilateral nephrectomy
- Selective renal embolisation
- Conservative treatment (only if bleeding is minor and not associated with anaemia)
Treatment is only likely to be effective if the defect is not associated with azotaemia.
Ectopic ureters are more commonly reported in females than males - what could influence this finding?
The longer length of the male urethra makes retrograde urine flow more likely in males, hence urinary incontinence doesn’t occur. Likewise urinary incontinence is more easily identified in females than males.
What are the diagnostic methods for ectopic ureteral location?
IV dyes (sodium fluorescein, indigo carmine, azosulfamide etc may discolour the urine to help with endoscopic localisation.
Ultrasound guided pyelography with contrast agent may be useful.
Contrast enhanced CT in small patients.
What surgical options are available for ectopic ureter/ureters and what may need to be measured first?
- Ureterocystotomy (unilateral or bilateral) - prior to this, measure the intra-vesicular pressure response to progressive distention until voidance to ensure competency of the urethral sphincter prior to reimplantation.
- Unilateral nephrectomy - ensure the other kidney is functional and the ureter is patent and in a normal position.
What factors would lead you to suspect a ureteral tear rather than a bladder or urachal tear in a case of uroperitoneum?
- Delayed onset of clinical signs/slower progression
- Mild protrusion of the vagina in fillies if the peritoneum is intact
- Continued development of peritoneal effusion and ongoing/refractory electrolyte derangements despite placement of a urinary catheter/bladder drainage
What therapies are available for an enlarged bladder in a sick, recumbent neonate?
- Bethanecol (cholinergic drug) to improve detrusor function (no reports of true efficacy with this medication).
- Acepromezine (A-adrenergic blocker) to decrease urethral sphincter tone (no reports of true efficacy with this medication).
- Indwelling urinary catheter +/- use of phenazopyridine as a local analgesic to reduce lower urinary tract discomfort and spasm and allow relaxation of the bladder sphincters.
What non-renal factors may influence urea and creatinine concentrations in blood?
Urea: Protein catabolism with fasting/weight loss (except in ponies), protein supplementation in the diet, prolonged exercise (secondary to protein catabolism; reduced renal blood flow may also influence).
Creatinine: Placental insufficiency in newborns, fasting, rhabdomyolysis or muscle wasting caused by disease or exercise.
What is the role of vasopressin/ADH?
- Principle controller of renal water reabsorption.
- Vasopressin acts on V2 receptors on the basolateral membrane of collecting duct epithelial cells, leading to insertion of water channels in the apical membrane.
- Channels increase the water permeability and lead to increased water reabsorption.
- V2 receptor activation can be antagonised by activation of adjacent A2 adrenoceptors and PGE2 effects - the A2 effects may be responsiblel for diuresis associated with their administration.
What is the proposed mechanism for why horses don’t always drink when they become dehydrated due to prolonged exercise or colitis?
Loss of water is in proportion to loss of osmoles (in sweat and diarrhoea) hence plasma osmolality doesn’t increase and osmotic thirst stimulus is not produced.
What percentage of cardiac output do the kidneys receive at rest?
15-20%
Why is the renal medulla typically hypoxic?
Renal blood flow is delivered preferentially to the cortex; medullary flow is derived largely from the vasa recta that arise from the efferent arterioles of juxtamedullary glomeruli (<20% renal blood flow).
What are the protective mechanisms to preserve medullary blood flow and oxygenation and how do NSAIDs influence these?
During renal hypoperfusion there is a preferential reduction in cortical blood flow and redistribution of renal blood flow to the corticomedullary region. In addition production of PGE2 and PGI2 as well as nitric oxide cause vasodilation. Administration of NSAIDs in patients with poor renal perfusion exacerbates hypoxic injury as it prevents these protective mechanisms.
What is the rationale for administration of dopamine infusions in acute renal failure?
Dopamine receptors are located on most renal arteries so blood flow increases in the renal cortex and medulla in response to activation of these receptors, hence they increase renal blood flow and urine output in normal horses and may be of benefit in horses with ARF.
What is the glomerular filtration rate (GFR) of horses?
1.6-2mL/kg/min or filtration of the total plasma volume 60-70 times per day.
Why does glomerular filtration rate (GFR) reduce less so than renal blood flow with renal vasoconstriction?
Greater vasoconstrictive effects of angiotensin II on efferent arterioles compared with afferent arterioles.
Which segments of the nephron are most susceptible to hypoxic injury with reduced renal perfusion and why?
Proximal tubule: these cells have a high metabolic rate so despite being predominantly in the relative more highly perfused cortex you get a relative hypoxia around these cells due to ongoing metabolic activity, so the proximal tubule is highly susceptible to injury with reduced cortical flow.
Medullary thick ascending loop: As the renal medulla only receives a relatively small fraction of total renal flow it is normally in a relatively hypoxic environment so any degree of renal hypoperfusion leads to exacerbation of medullary hypoxia, particularly in the inner stripe which has a high metabolic activity (primarily of the epithelial cells lining the medullary thick ascending loop of Henle). Tx with CRI of furosemide may help reduce the metabolic rate of these cells and may protect against hypoxic injury.
What are the main causes of hyponatraemia?
Ruptured bladder
Diarrhoea
Defective water excretion (pre-renal eg hypovolaemia)
Oliguric renal failure after reduction of GFR
Loop diuretics (blockade of the apical Na/K/2Cl cotransporter)
Inappropriate vasopressin/ADH secretion (not documented in equids)
What is the biphasic effect of efferent arteriolar constriction on GFR?
At moderate levels of constriction there is a slight increase in GFR due to increased resistance to outflow from the glomerular capillaries, raising hydrostatic pressure.
A more marked vasoconstriction reduces renal blood flow, hence the filtration fraction and glomerular colloid osmotic pressure increases beyond the glomerular capillary hydrostatic pressure and decreases the force for filtration.
What are the effects of angiotensin II on GFR, water and sodium dynamics?
Angiotensin II preferentially constricts effeerent arterioles thereby increasing glomerular hydrostatic pressure (its usually released in response to decreased arterial pressure or hypovolaemia) therefore protecting against reduced GFR. So angiotensin II helps maintain normal GFR and excretion of wastes while also increasing tubular reabsorption of sodium and water to help restore blood volume and pressure.
What do the macula densa cells sense and what effects does this have?
Macula densa cells detect changes in volume delivery to the distal tubule. Decreased GFR causes reduced flow rate in the loop of henle and increased reabsorption of Na and Cl in the ascending loop, hence decreasing the concentration of NaCl at the macula densa cells which iniatiates a signal from these cells with 2 effects:
1. decreases resistance to blood flow in the afferent arterioles, raising glomerular hydrostatic pressure, returning GFR toward normal; 2. increases renin release from juxtaglomerular cells of the afferent and efferent arterioles. Renin is an enzyme that increases formation of angiotensin I which is converted to angiotensin II which constricts efferent arterioles, hence increasing glomerular hydrostatic pressure and returning GFR toward normal.
How does the Na/K ATPase pump facilitate sodium reabsorption in the tubule?
Pumping of sodium out of the cell to the interstitium and potassium into the cell from the interstitium creates a negative charge of ~-70mv within the cell. This then favours passive diffusion of Na across the luminal membrane of the cell from the tubule because of the concentration gradient (low intracellular concentration of Na) and because the negative charge intracellularly attracts the positively charged Na. This occurs in most parts of the tubule.
In addition to the Na/K ATPase pump, what other mechanisms are there for Na reabsorption?
In the proximal tubule the extensive brush border increases the surface area for reabsorption by ~20fold.
Sodium carrier proteins bind Na on the luminal side and release them intracellularly (facilitated transport) and may also provide important secondary active transport for other substances eg glucose and amino acids.
Na, H2O other substances are also reabsorbed from the intesrtitial fluid into the peritubular capillaries by ultrafiltration which is passive, driven by the hydrostatic and colloid osmotic pressure gradients.
Secondary active transport one substance moves down its concentration gradient (eg Na) and the energy released by this process is used to drive another substance (such as glucose) against its electrochemical gradient.
How does water move across the tubular epithelium of the nephron?
As solutes move to the interstitium (either passively or by active transport) they create a concentration gradient that enables osmotic movement of water to the interstitium. The proximal tubule is highly permeable and water reabsorption occurs rapidly here (and brings some solutes with it via solvent drag). In the more distal tubule (loop of Henle through to the collecting tubule) the tight junctions are less permeable to water and solutes and the epithelial cells have reduced membrane surface area, which reduces movement of water. However ADH increases permeability in the distal and collecting tubules. Water permeability remains low in the ascending loop of Henle, but in the presence of ADH it can be high in the distal tubules, collecting tubules and collecting ducts (controlled essentially by ADH).
How is chloride reabsorbed in the tubule?
The transport of Na out of the tubule leaves the tubule negatively charged compared to the interstitial fluid which causes passive diffusion of Cl through the paracellular pathway.
In addition as water is reabsorbed the Cl in the tubular lumen becomes concentrated, causing transport down the concentration gradient. Hence active reabsorption of Na is closely coupled to passive reabsroption of Cl.
Cl can also be reabsorbed by secondary active transport, most commonly with Na across the luminal membrane.
How does osmolarity and concentration of Na remain fairly constant in the proximal tubule despite reabsorption?
The amount of Na decreases markedly but the concentration remains the same due to marked water reabsorption in this segment.
Describe the permeability along the different segments of the loop of Henle.
Thin descending limb: highly permeable to water and moderately permeable to most solutes, including urea and sodium. Allows simple diffuseion of substances through its wall and almost all of the ~20% filtered water that is reabsorbed in the loop of Henle occurs in his segment.
Thin ascending limb: virtually impermeable to water, and minimal reabsorption of solutes.
Thick ascending limb: thick cells with high metabolic rate, capable active reabsorption of Na, Cl and K. Most of the ~25% filtered load of Na, Cl and K that are reabsorbed in the loop of Henle, are reabsorbed in this portion. Ca, bicarbonate and Mg are also reabsorbed in this segment. Movement of Na across the luminal membrane is mediated primarily by Na/K/2Cl co transporter and this is the site of action of frusemide (loop diuretics). Also significant paracellular reabsorption of Mg, Ca, Na and K due to the slight positive charge of the tubular lumen relative to the interstitial fluid. There is a slight back leak of K into the lumen which creates the positive charge that forces diffusion of Mg and Ca from the lumen. There is also a Na/H counter transport mechanism that mediates Na reabsorption and H secretion in this segment. Virtually impermeable to water, hence the fluid becomes dilute as it flows towards the distal tubule.
Describe the function & permeability of the distal tubule & collecting ducts.
The first portion provides part of the juxtaglomerular complex giving feedback control of GFR and blood flow.
The convoluted part has similar characteristics of the TAL (reabsorbs most of the ions incl Na, K and Cl; relatively impermeable to water and urea). Na/Cl cotransporter moves NaCl out of the tubular lumen (thiazide diuretics inhibit this transport system)
The second half of the distal tubule and cortical collecting tubule are composed of principal cells and intercalated cells. Principal cells reabsorb Na and H2O and secrete K into the lumen (facilitated by high intracellular K and low intracellular Na concentrations due to Na/K ATPase pumps on the basolateral membrane). The intercalated cells reabsorb K and secrete H into the lumen.
Collecting ducts: Final site for processing urine. Permeability of the medullary collecting duct to water is controlled by the level of ADH. This segment is permeable to urea so some urea is reabsorbed into the medullary interstitium, helping to raise the osmolality in this region. The medullary collecting duct is capable of secreting hydrogen ions against a large concentration gradient as occurs in the cortical collecting duct, hence these regions play an important role in regulating acid-base.
How do Na-channel blockers and aldosterone antagonists decrease urinary excretion of K and act as K sparing diuretics?
The principle cells of the distal tubule and cortical tubule have Na/K ATPase pumps on the basolateral membrane that maintains the high K/low Na intracellular environment that facilitates Na reabsorption and K secretion in this segment. These diuretics inhibit entry of Na into the Na channels of the luminal membranes, thereby reducing the amount of Na that can be subsequently exchanged for K via the Na/K ATPase pumps and ultimately the amount of K available for secretion into the tubular fluid.
How is BUN : Cr used to differentiate different times of azotaemia (ie pre-renal and post-renal from renal causes and acute from chronic kidney disease)?
Pre-renal and post-renal azotaemia: BUN : Cr should be higher due to increased reabsorption of urea with low tubule flow rates in pre-renal and preferential diffuseion of urea across peritoneal membranes in post-renal cases such as uroperitoneum.
Acute renal failure and chronic kidney disease: BUN : Cr will often be less than 10:1.265 for ARF due to a proportionately higher increase in Cr compared with BUN. In contrast, with CKD the BUN : Cr often exceeds 10:1. The explanation for why is not clear but one theory is that urea is a nonpolar molecule that diffuses freely into all body fluids whereas Cr is a charged molecule that likely takes longer to diffuse out of extracellular fluid hence a sudden decrease in renal perfusion leads to a greater increase in Cr than in BUN.
What measurements can help differentiate pre-renal failure from intrinsic renal failure?
- Maintenance of adequate concentrating ability and osmolality (USG >1.020, osmolality >500mOsm/kg)
- Urine : serum creatinine ratios >50:1 (concentrated urine) and fraction Na clearance <1% (indicating adequate tubule function) would be expected with pre-renal failure.
- Urine : serum creatinine ratios <37:1 and clearance values >0.8% my be seen with intrinsic renal failure.
Progression from pre-renal failure to intrinsic renal failure is associated with decompensation of the intrarenal responses to hypoperfusion.
What degree of increase in peritoneal fluid creatinine relative to serum creatinine concentration do you expect with uroperitoneum?
Two-fold or greater increase in the peritoneal creatinine concentration relative to the serum creatinine concentration.
Differentiate Ca and P concentrations in horses with ARF versus CKD
Hypercalcaemia and hypophosphataemia often occurs with CKD (although can also be hyperphosphataemia:
- Osteodystrophy of CKD has been associated with aluminium deposition in skeletal muscle which may inhibit buffering capacity for increases in hypercalcaemia.
- Impaired tubular function in the face of ongoing intestinal absorption of Ca.
Hypocalcaemia and hyperphosphataemia with ARF:
- Resistance to parathyroid hormone
- Down regulation of renal calcitriol (Vit D)
- Damage to tubular epithelial cells may result in reduced absorption of Ca.
Differentiate the likely source of pigment with pigmenturia at different stages in urination.
Start or end of urination: lesions of the urethra or accessory sex glands in males.
Throughout urination: myonecrosis or a bladder or kidney lesion.
An exception is blood clots with cystitis which may occasionally be passed more frequently at the end of urination due to sedimentation of the clot with time.
Explain paradoxic aciduria.
Instead of reflecting metabolic acidosis, paradoxic aciduria reflects hypochloraemic metabolic alkalosis. After all Cl has been reabsorbed from the glomerular filtrate further Na reabsorption occurs by exchange with K and H ions, hence paradoxic aciduria occurs with concomitant hypokalemia.
How do you differentiate between different causes of pigmenturia?
Evaluation of serum for haemolysis and urine sediment for red blood cells to differentiate between haemoglobin and whole red blood cells and perform an ammonium sulphate precipitation test to detect myoglobin.
List the causes of bilirubinuria
Intravascular haemolysis, hepatic necrosis and obstructive hepatopathies.
What is the significance of identification of casts and crystals on urine sediment examination in equids?
Casts: molds of Tamm-Horsfall glycoprotein and cells that form in the tubules and pass into the bladder. They can be associated with both inflammatory and infectious processes but are rare in normal equine urine. They are also unstable in alkaline urine so may not be detected.
Equine urine is rich in crystals, most of which are calcium carbonate (CaCO3) and to a lesser degree calcium phosphate and calcium oxlatate. These are normal findings.
Explain the benefit of measuring urinary enzyme concentrations.
Inflammation or necrosis of tubular epithelial cells can result in elevated urinary activity of lysosomal and brush border enzymes. Determination of the activities of certain urinary enzymes can provide evidence of tubular damage several days before azotaemia develops. Different enzymes are present or more prevalent in certain regions of the nephron and as such assessment of changes in the urinary activity of selected enzymes may assist the clinician in identifying the segment of the nephron suffering the greatest dysfunction or damage. However, it is not considered a routine measure of renal damage and is probably of limited use as a single measure.
