Download Effects of Nephron Loss on Renal Excretory Mechanisms

Disturbances of Renal Function
Jinn-Yuh Guh, M.D.
Kaohsiung Medical College
Introduction
Renal blood flow accounts for 20% of cardiac output which is the largest for all
organs. The kidneys reabsorb >99% of glomerular ultrafiltrate to produce urine.
Despite variations in daily intake of food and water, the kidneys precisely regulate
extracellular fluid volume and composition (and ICF indirectly). There are three
principles in Nephrology whereby the kidneys accomplish this task with fidelity:
1.Homeostasis (Balance)
Internal
Extracellular & intracellular
External
Input (production+intake)=output
2. Adaptation
Compensation takes time.
3. Steady-state
The state where homeostasis is maintained in wellness or sickness.
Renal function
I. Definition of renal function:
廣義:
1. Homeostasis of body fluids
2. Homeostasis of electrolytes and acid/base
3. Excretion of (nitrogenous) waste products and detoxification
4. Endocrine (Active Vitamin D, Erythropoietin, Renin, Kinin-kallikrein, etc.)
5. Metabolism
狹義:
Glomerular filtration rate (GFR)
II. Anatomic correlations:
1. Glomerular (GFR)
2. Tubular: Reabsorption and secretion
Active transport
Energy-dependent, e.g. basolateral Na-K-ATPase is the most
important energy source
Passive transport
Driven by concentration or electrical gradients
Effects of Nephron Loss on Renal Excretory
Mechanisms
Glomerular ultrafiltration (GFR)
Ultrafiltrate (no blood cells, no large molecular weight solutes)
Formed by plasma ultrafiltered through glomerular capillaries into
Bowman's space
GFR
=(difference in hydrostatic pressure-difference in oncotic pressure) x
permeability x glomerular plasma flow x glomerular capillary surface
area
Filtration barriers to large molecular weight solutes
1. Size barrier
Solutes with M.W. albumin (68,000) will not be filtered
2. Charge barrier
Negatively charged solutes (e.g. albumin) will not be filtered
GFR will decrease if:
Glomerular hydrostatic pressure decrease
e.g. shock
Tubular hydrostatic pressure increase
e.g. urinary tract obstruction
Plasma oncotic pressure increase
e.g. dehydration, dysproteinemia
Renal blood flow decrease
e.g. hypovolemia, heart failure
Glomerular permeability decrease
e.g. glomerular diseases
Filtration surface area decrease
e.g. progressive renal failure
Glomerular adaptations to nephron loss
Hypertrophy, hyperfiltration, intrarenal hypertension
Glomerulotubular balance
Fractional reabsorption remains constant (e.g. 60% in PT for Na)
despite differences in GFR
Intact nephron hypothesis
In CRF, remnant nephrons are distributed such that some are
hypofunctioning, while some others are hyperfunctining. However,
glomerulotubular balance is retained and reset at a lower level
(e.g. 40% in PT for Na), thereby creating a "magnification
phenomenon".
Progressive nature of chronic renal failure
When GFR<50%, glomerular compensation by hyperfiltration will cause
glomerulosclerosis and end-stage renal disease. This may be the "final
common pathway" for CRF. This may also be the "trade-off" between
adaptation and progressive renal failure. Angiotensin converting
enzyme inhibitors and low protein diet may be effective in retarding this
progression.
Biologic Consequences of Sustained Reductions in GFR
Retention of solutes
Curve A (Substances excreted primarily by GFR, e.g. urea, creatinine,
etc.)
Serum creatinine will not increase until GFR falls below 50%.
However, serum creatinine still increases (although within "normal
limit") when GFR falls from 100% to 50%. Moreover, serum
creatinine increases at an exponential speed once GFR is
below 50%.
Curve B (Substances excreted primarily by tubular transport, e.g.
phosphate, urate, H, K)
These will not increase until GFR falls below 25%
Curve C (Na, Cl)
These solutes will maintain homeostasis until end-stage renal
disease. For example, if dietary salt 7 g (120 mEq)/day, urinary Na
120 mEq/day, Plasma Na 140 mEq/L, then:
1. Normal: GFR 125 ml/min, filtered Na 25,200 mEq/day,
FeNa=0.5%
2. CRF patients: GFR=2 ml/min, filtered Na 403 mEq/day,
FeNa=30%
This is called "magnification phenomenon"
Adaptations in Tubule Transport Mechanisms in
Response to Nephron Loss
Normal tubular transport of NaCl and water in proximal convoluted
tubules (PT)
PT is a "high capacity, low gradient" nephron segment. 2/3 of
glomerular ultrafiltrate is isosmotically reabsorbed here. Na is reabsorbed
with glucose, amino acids, organic solutes (e.g. lactate) and anions (HCO3,
Cl). Water is coupled to solute transport because:
1. "Leaky" membrane plus luminal hypotonicity.
2. Early PT preferentially reabsorbs HCO3 (formed by cytoplasmic
carbonic anhydrase) via luminal Na/H antiporter so that Cl increases in
late PT. Diffusion of NaCl is higher than backleak of HCO3 thereby
creating an effective osmotic pressue gradient favoring reabsorption of
water.
3. Lateral interstitial space hypertonicity
Reabsorption of fluid from PT
Peritubular Starling forces (physical factors)
Oncotic (colloid osmotic) pressure build up while hydrostatic pressure
decreases in peritubular capillaries because of glomerular ultrafiltration.
Therefore, Starling forces favor an uptake mode in renal tubules
(Please compare with the filtration mode in the glomerulus).
Tubular reabsorption will decrease if
Peritubular hydrostatic pressure increases or oncotic pressure
decreases.
Tubular reabsorption will increase if
Peritubular hydrostatic pressure decreases (increased efferent
arteriolar resistance) or oncotic pressure increases (increased
filtration fraction).
Hormones
e.g. angiotensin II
Descending limb of Henle's loop
Low permeability to Na, passive water reabsorption,
Ascending limb of Henle's loop
Water-impermeable, thus creating luminal hypotonicity. Hence, this is a
"diluting" segment.
1. Thin
Passive NaCl reabsorption
2. Thick
Na reabsorption
a. 1/2 of Na reabsorbed by an active furosemide-sensitive
electroneutral Na-K-2Cl cotransporter
b. 1/2 of Na reabsorbed passively by a positive lumen potential
Countercurrent mechanism
This creates medullary hypertonicity which, along with ADH,
accounts for urinary concentration.
Distal nephron (distal tubule distal to macula densa + collecting tubule) is a "low
capacity, high gradient" segment because it has tight junctions
Distal tubule
Water-impermeable in the absence of ADH, thus creating luminal
hypotonicity. Hence, this is also a "diluting segment".
Active thiazide-sensitive electroneutral Na-Cl cotransporter
Terminal connecting segment
Aldosterone-sensitive
Collecting tubules and ducts
Cortical and medullary collecting tubules
Water-impermeable in the absence of ADH
Electrogenic Na channel
Na reabsorption creates a lumen-negative potential
Aldosterone-sensitive
Determines final quantity and quality of daily urine
Efects of Nephron Loss on Fluid Transport in
Surving Nephrons
"Magnification phenomenon"
Increased fractional excretion of solutes due to
1. Increased peritubular hydrostatic pressure (e.g. hypertension)
2. Decreased peritubular oncotic pressure (e.g. hypoalbuminemia or
decreased filtration fraction)
3. Retention of organic acids (e.g. hippurates)
Tubular secretion accompanied by fluid secretion
4. Atrial natriuretic peptide, prostaglandins, Na-K-ATPase inhibitor
Increased natriuresis with generalized abnormalities of Na transport
across cell membranes is a "trade-off".
5. "Osmotic diuresis" in remnant nephrons
Due to retained plasma solutes which must be excreted in the
remnant nephrons
6. "Salt-losing nephropathy"
Chronic pyelonephritis, some tubulointerstitial diseases
7. Aldosterone is NOT contributory
NaCl
Narrowed "salt window" despite nephron adaptations. Therefore, if the
patient ingests much salt, hypertension and edema will occur. If the patient
ingests little salt, due to "obligatory natriuresis", dehydration will occur.
Water
Narrowed "water window" despite increased fractional water excretion.
Therefore, if the patient ingests much water, hyponatremia will occur. If
the patient ingest little water, hypernatremia and dehydration will occur.
For example
Osmolar intake=600 mOsm/day. If Uosm=300 mOsm/kg, then 2 L of
urine is required to excrete this osmolar load. This urine amount
represents 1% of GFR in normal (GFR 125 ml/min or 180 L/day) and
50% (GFR 2.78 ml/min or 4 L/day) in CRF patients, respectively.
Another example
Normal
GFR 125 ml/min, Uosm=40-1200 mOsm/kg. UV=0.5-15 L/day
CRF
GFR 2.8 ml/min, Uosm=250-350 mOsm/kg. Uv=1.7-2.4 L/day
Decreased urine concentration and dilution capacity (isosthenuria) occurs
when GFR falls below 25%
Phosphate (P)
Normal
(PT) Tubular reabsorption of phosphate=80-90%
PTH inhibits this reabsorption in PT
CRF ("Trade-off hypothesis")
P retention decreases Ca, hypocalcemia increases PTH which returns
P towards normal. However, further successive decreases in GFR will
further increase PTH to induce phosphaturia to keep a normal P.
Secondary hyperparathyroidism (one form of renal osteodystrophy
) in CRF is due to
1. "Trade-off" hypothesis
2. Skeletal resistance to calcemic action of PTH
3. Active Vitamin D (1,25(OH)2D) and its receptor decreased
Decreased intestinal Ca absorption and decreased inhibition of PTH
secretion
H and HCO3
Normal renal acid handling
Net acid excretion1 mEq/kg/day=60 mEq/day
=NH4+ 30 mEq + titratable acid (H2PO4) 30 mEq -HCO3 0 mEq
H is formed within renal tubule by cytoplasmic carbonic anhydrase
and secreted by the luminal Na/H antiporter. The secreted H is buffered
by urinary buffers (minimal urine pH=4.4)
HCO3 reabsorptionH secretion
Proximal tubule (threshold 26 mEq/L)
Filtered HCO3 combines with secreted H to form H2CO3 which
yields CO2 and H2O under luminal carbonic anhydrase
HCO3 regenerationH secretion
Non-bicarbonate buffers
NH4+ : Ammoniagenesis (glutamine becomes NH4+) in PT
(increased in metabolic acidosis)NH4+ secretionNH4+
concentrated in the medulla by countercurrent
mechanismSecretion of NH3 in the collecting tubule
Titratable acid: Unable to compensate during metabolic acidosis
Effects of nephron loss on renal acid handling
Decreased ammoniagenesis despite amplification in surviving tubules
Chronic metabolic acidosis (HCO3 14-18 mEq/L) occurs when
GFR<25-30%
Stable (non-progressive) probably because of bone buffers (CaCO3,
Ca phosphate)
1. Early
Hyperchloremic
2. Late
High anion gap (due to retention of unmeasured anions, e.g.
sulfates, phosphates, etc.)
K (>95% intracellular)
Normal renal K handling
Fractional excretion=20% because of
1. Reabsorption
2/3 in proximal tubule, 20-25% in Henle's loop
2. Secretion
Distal tubule and collecting tubule
Depends on
1. Lumen negative potential (electrical gradient) created by Na
reabsorption by electrogenic Na channels
2. Distal flow rate
3. Concentration gradient of K
Renal K handling in nephron loss
Magnified distal fractional K secretion due to:
Increased aldosterone
Increased distal flow (osmotic diuresis in surviving nephrons)
Increased lumen negative potential
Increased non-reabsorbable anions
e.g. phosphates, sulfates
Increased colon K secretion by aldosterone