GFR
Each kidney contains approximately 1 million nephrons.
GFR is the sum total of the filtering rates of all 2 million nephrons in the kidneys.
Single nephron GFR x # of functioning nephrons.
Normal value for GFR depends on age, sex, and body size, and is approximately
130 mL/min/1.73 m2
for men and and 120 mL/min/1.73 m2
for women.
How much plasma does the kidneys filter in a day?
• 130 ml/min x 1440 min = 187 liters or roughly 180 liters per day.
• Average plasma volume is about 3 liters.
• 180 L/ 3 L= 60. Plasma gets filtered 60x in a day!
Pathophysiokogy of AKI
In hypovolemia, as RPF falls, kidney compensates to maintain a stable glomerular filtration pressure by 2 mechanisms.
1. Vasodilation of the afferent arteriole via local prostaglandin production.
2. Efferent vasoconstriction via angiotensin II.
Volume depletion from any etiology will decrease renal perfusion and renal plasma flow (RPF).
2. Decrease in RPF, if uncompensated by several autoregulatory mechanisms, will decrease GFR.
3. Result is prerenal AKI.
Prerenal AKI
kidney normal but perfusion low
BUN/Cr > 20
Normal BUN: Cr ratio is < 10. BUN:Cr ratio > 20 in prerenal AKI.
• Increased BUN reabsorption in prerenal AKI is caused by the increase in
the passive reabsorption of urea that follows the increased proximal
sodium reabsorption.
FeNa < 1% (avid Na reabsorption) falsely high with diuretics
Situations Where FENA < 1% Does not Indicate Prerenal AKI
• Contrast nephropathy
• Rhabdomyolysis
• Acute GN
• Hepatorenal syndrome
• ATN with CHF
• ATN with cirrhosis
• ATN with severe burns
FeUrea < 35%
Typical Features of Prerenal AKI
• Clinical history pointing to hypovolemia is most important clue.
• BUN/Cr ratio > 20:1. Normal BUN/Cr ratio is 10.
• UNa < 20 mEq/L
• FENa < 1%
• FEUrea < 35% (Useful if patient on diuretics)
• Urine sediment: bland or hyaline casts
Treatment of Prerenal AKI
• Pre-renal AKI is not pathology. It is physiology.
• Normally functioning kidneys are simply responding to volume depletion with end result being Cr rise.
• IVF replacement is treatment in patients who are volume depleted.
Intrarenal AKI
oliguric (urine output < 500 ml/24 hrs)
Most damage in ATN is to proximal tubule (where 70% of Na is normally reabsorbed)
Mechanism of Oliguria in ATN – Tubuloglomerular Feedback
• 70% of ATN cases will cause oliguria (UOP < 500 ml/day).
• Glomeruli are actually intact in ATN. So why are they not filtering enough plasma
to generate urine?
• Total body water (TBW) accounts for about 50% of body weight. So an 80 kg person has 40 L of TBW. 1/3 of this 40 L is ECF, so that’s 13 L. 1/3 of ECF is intravascular fluid. So the plasma volume is 13 L x 1/3 = 4L.
• Healthy kidneys can filter 100 ml/min of plasma. That means it takes about 4000/100 = 40 min to filter all the plasma in the body.
• 9% of the filtered plasma is reabsorbed by the tubules and returned to circulation.
• In ATN, tubular reabsorption is impaired. If the glomeruli keep on filtering while the tubules are not reabsorbing, then a person can become volume depleted.
• So oliguria is really an adaptive response in ATN. "Acute Renal Success"
Mechanism of Oliguria in ATN – Tubuloglomerular Feedback
• How does GFR get turned down in ATN?
• Tubuloglomerular feedback.
• ATN with tubular injury reduced NaCl reabsorption at the PCT increase NaCl delivery to macula densa at DCT chemoreceptor activated and releases vasoactive compounds afferent arteriolar vasoconstriction and a fall in GFR less filtration which in turn limits any further NaCl loss.
Treatment in ATN
• Supportive care only. IVF to keep MAP > 65 mmHg to ensure renal perfusion.
• Lasix does not make ATN better.
• Lasix can be used to control volume overload. Worth a try.
• When does a patient with ATN need dialysis? % fluid overload > 10% (about 8 kg
fluid up)
• Indications for acute hemodialysis:
1. Acidosis (refractory pH < 7.1)
2. Electrolyte (refractory K+ > 6.5, hypercalcemia > 13 with oliguria)
3. Intoxication (ethylene glycol, salicylate poisonings)
4. Overload of volume (unable to maintain O2 sat)
5. Uremia (MS change, nausea and vomiting)
Acute Interstitial Nephritis (AIN)
Etiology of AIN
• Medications account for 70% of AIN. Big offenders are:
1. Penicillins
2. Quinolones
3. Bactrim
4. PPIs
5. Diuretics
• Infections account for 10% of AIN
1. CMV
2. Legionella
3. HIV
• Rest from miscellaneous causes, such as:
1. Autoimmune disorders like SLE, Sjogren’s
2. TINU syndrome (tubulointerstitial nephritis with uveiitis)
3. Hypercalcemia (recent case at UNM)
Clinical Features of AIN
• Asymptomatic
• Constitutional symptoms (fever, chills, malaise, etc)
• Triad: Fever, Rash, Eosinophilia (5-10%)
• Flank tenderness
• Non oliguric AKI
• Eosinophiluria Neither sensitive nor specific
Treatment of AIN
• Discontinue suspected offending agent. Should see improvement within 3-7 days.
• If Cr does not improve 3-7 days after dc offending agent, consider biopsy and or a trial of steroid at 1 mg/kg up to 60 mg daily for one month with fast taper
• Patients with drug-related AIN should improve within 1-2 weeks after steroid therapy.
• Complete recovery may take up to 6 weeks.
Glomerular Nephritis
Clinical Features of Glomerulonephritis
Nephrotic syndrome:
1. Massive proteinuria > 3 g/day
2. Fluid overload: HTN, edema
3. Due to noninflammatory glomerular injury
Nephritic syndrome:
1. Mild proteinuria < 3 g/day
2. Prominent hematuria
3. Acanthocyte (dysmorphic RBC) on urine microscopy
4. RBC casts on urine microscopy
5. Due to inflammatory glomerular injury
Postrenal AKI
Pathogenesis of Postobstructive Nephropathy
1. How urine obstruction causes AKI is intuitive: renal function falls when urine flow is blocked.
2. Actual mechanism has to do with elevated pressure transmitting back into the glomeruli.
3. Important to keep in mind that only bilateral obstruction or unilateral obstruction of a solitary functioning kidney will cause renal failure.
4. Is renal failure from obstruction reversible?
• Maybe not completely if > 2 weeks. In animal models, obstruction > 2 weeks cause interstitial fibrosis. If prolonged, this is irreversible.
Dr. Alas - Calcium Phosphorus Magnesium
Plasma calcium is tightly controlled
– Total calcium 8.5-10.5 mg /dl
• Free (ionized) floating Ca is 45% of total Ca
- Approximately 4.5mg/dl-5.3 mg/dl
• Bound (reversibly) to plasma protein is 40% of total Ca
– 90% of bound Ca is to albumin
• Complexed to anions makes up 15% of total Ca
– Anions complexed to include (chloride, citrate, phosphate)
– Ca in this form is diffusable and available for filtration at the glomerulus
Ca homeostasis
• Increases serum calcium:
– Immediate release of Ca from skeleton is mediated by parathyroid hormone (PTH) acting indirectly on osteoclasts
– PTH is released to quickly restore a falling plasma calcium
– PTH also activates the vitamin D pre-hormone to increase Ca absorption from the intestine
• Decreases serum calcium:
– Calcitonin
• C cells of the thyroid
• Inhibits osteoclast bone resorption
(Dys)Functions of Calcium
• Necessary ion for metabolic processes
– Regulate ion channels
– Promote activation of enzymes
– Structural involvement (bone and teeth)
• Neuromuscular excitability
– Tetany and spasms
– Cardiac arrhythmias
– Lethargy (hypercalcemia)(Dys)Functions of Calcium(cont’d)
• Involved in alveolar surfactants
• Coagulation
– Prothrombin thrombin
– Fibrinogen fibrin
Renal Handling of Ca++
Proximal Tubule★
• Sodium is actively reabsorbed in the PT
• Calcium reabsorption occurs through passive diffusion
• Ca moves along the paracellular route in the PT!!!!
Thick Ascending Loop of Henle★
• Active reabsorption of NaCl and recycling of K in luminal membrane generates a lumen
positive potential difference (PD)
• This positive PD drives passive paracellular diffusion.
• Furosemide inhibits the Na-K-2Cl cotransporter leading to hypercalciuria.
Calcium Sensing Receptor
★CaSR & increased Ca intake★
• Suppression of PTH
– Decrease distal tubular calcium reabsorption
• Ca binds to CaSR => arachidonic acid metabolite => inhibits the luminal K channel and the basolateral NaK-ATPase
• K recycling halts the Na-K 2Cl as well thereby stopping paracellular reabsorption of Ca
★Distal Convoluted Tubule★
• In this segment Ca transport is an active process.
• Luminal transport initially is through TRPV5 channel then bound in cytosol to calbindin-D28K protein
• Finally it exits on the basolateral side through Ca/H or Na/Ca active exchangers
• PTH, vitamin D, and cAMP stimulate Ca absorption in the DCT.
• Thiazide diuretics cause hypocalciuria
• Thiazides inhibit the Na-Cl cotransporter; causing a natriuresis
• This ECF volume contraction causes increased Na absorption in the PT, and increased Ca
• Amiloride causes the same effect, but on the ENaC transporter in the collecting duct.
Acute treatment of hypercalcemia★
• It is important to assess volume status.
• Severe hypercalcemia will cause a diuresis
• Steps to removal of calcium in a volume depleted state:
– Hydrate well with saline (1-2 liters)
– Once hydrated give a loop diuretic
Phosphorus
Important as energy storage, a urinary buffer for H+, constituent of bone, and signal transduction.
• Many foods contain high amounts of PO4; especially deli meats, dairy products, nuts,
chocolate, and colas.
• Total PO4 content is 700 gm; 85% of which are in bone and teeth
Rise in Phosphorus is Associated with★★Increased Mortality★
• Normal serum range 3.0-4.5 mg/dL (Why is this important?)
• Ca x PO4 solubility product determines whether Ca and PO4 precipitate within the blood stream
• “The product”>70 places patient at risk for calciphylaxis
Brief Overview of Phosphate★Regulation
• Plasma concentration of phosphate is maintained by 1,25(OH)2D, PTH and FGF-23
• A rise in plasma PO4 stimulates PTH in 3 ways
• PO4 directly stimulates PTH synthesis
• Increased serum PO4 decreases serum Ca; stimulates the calcium sensing receptor (CaSR) on the parathyroid gland
• Increased PO4 decreases 1,25(OH) 2D decreasing it’s inhibition of PTH secretion
• Increased PO4 stimulates FGF-23 expression
Renal Handling of Phosphate
90% of PO4 is filtered by the glomerulus (10% protein bound)
• 85% of PO4 reabsorbed in proximal tubule
• FGF-23 and PTH inhibit renal tubular PO4 reabsorption (phosphatonin)
Proximal Tubule PO4 Handling★
• Na/H2PO4 cotransporter drives reabsorption
• A maximal absorption for this transporter exists (saturable)
• PTH causes endocytosis of the Na-PO4 cotransporter; inhibiting PO4 reabsorption
• Basolateral exit is not well understood
Magnesium -
Dr. Fisher - Nephritic Syndrome
IgA Nephropathy - Clinical Features (I)
• Most common glomerulonephritis worldwide
– very common GN in New Mexico!
• First described by Berger (Berger’s disease)
• Often triggered by upper respiratory infection
• Presents as nephritic syndrome with:
– hematuria and/or proteinuria
IgA Nephropathy - Pathogenesis
• Respiratory infection triggers production of antibodies
• antibodies typical of mucosal immune response are:
→ Immunoglobulin A (IgA)
→ IgA forms immune complexes with antigens in circulation
• IgA antibodies are deposited in mesangium
– incite inflammation
• In Henoch-Schönlein purpura (=systemic vasculitis):
– IgA antibodies also deposited in wall of small arteries
– incite inflammationIgA Nephropathy - Light mi
IgA Nephropathy - IF and EM
• By immunofluorescence:
– granular deposits of IgA in mesangium
– “mesangial” pattern of immunofluorescence
• By electron microscopy:
– elecron dense immune deposits in mesangium
– increased mesangial cells and matrix
Rapidly Progressive Glomerulonephritis
• Rapidly progressive glomerulonephritis is clinical term, NOT a pathologic diagnosis !!!
• Includes 3 different diseases:
– post-streptococcal glomerulonephritis
• a.k.a. post-infectious GN
– 1-4 weeks after streptococcal infection
– also caused by other bacterial infections (staphylococci, others)
• Most common in children 6-10 years
– much less common in adults
• In children prognosis typically excellent (i.e. complete recovery)
– prognosis tends to be worse in adults
Pathogenesis
• Immune-mediated - patients make antibodies against bacterial antigens
• Formation of immune complexes in serum
• Immune complexes get deposited in glomerulus and incite inflammation
• Pts have antibodies to streptococcal antigens in serum
– inc. ASO titer in serum as clinical lab test
(= antistreptolysin-O titer)
Post-streptococcal GN - IF and EM
• By immunofluorescence
– GRANULAR deposits of IgG and C3 along glomerular basement membrane
"lumpy bumpy or starry sky)
• By electron microscopy
– predominantly SUBEPITHELIAL deposits (i.e. on the epithelial side of the glomerular
basement membrane) = HUMPS
– (smaller subendothelial and mesangial deposits may be found)
– pauci-immune glomerulonephritis (=ANCA disease)
– anti-glomerular basement membrane glomerulonephritis (anti-GBM GM)
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