A. Overview of Function

1. Resorption of filtered electrolytes
   1. Uncontrolled resorption
   2. Regulated resorption
2. Regulation of acid-base status
   1. Reclamation and/or regeneration of bicarbonate
   2. Recycling of ammonium (NH4+)
   3. Secretion of protons (H+)
3. Resorption of blood urea nitrogen

B. Sodium

1. Normal blood Na+ 135-145mM
2. An abnormal sodium level is indicative of an abnormality in volume regulation
3. Calculated Na deficit = (144-[Na])x0.6x(kg wt) where kg wt is desired weight (kilogram)
4. The kidney initially filters all sodium into the urine
5. About 85% is resorbed in the proximal tubule
6. Remainder absorbed in:
   1. Ascending Loop of Henle
   2. Distal tubule (aldosterone sensitive Na/K ATPase)

C. Potassium

1. Serum K+ level is controlled tightly from 3.5 to 5.5mM
2. All K+ filtered out by kidney and resorbed in the Loop of Henle
3. Secretion of K+ can also occur in the distal tubule/collecting duct
   1. This is mediated by the aldosterone (mineralocorticoid) sensitive Na/K+ ATPase
   2. Spironolactone is an aldosterone antagonist which blocks this pump

D. Chloride

1. Normal chloride levels are 98-110mM
2. In normal persons, chloride transit is essentially passive
   1. Follows along its own gradients
   2. These include both chemical and net electrochemical gradients
3. Cystic Fibrosis is a disease of an abnormal chloride channel

E. Bicarbonate [4]

1. Normal serum HCO3- concentration is 23-28mM
2. All filtered out by kidney through glomerulus
3. Resorption (~85%) by proximal tubule only for tubule [HCO3-] > 24mM
4. Some drugs can increase this threshold such as carbonic anhydrase inhibitors
5. The remaining 15% of the bicarbonate is regenerated by the distal tubule

F. Blood Urea Nitrogen (BUN)

1. Normal serum levels are ~8-15mg/dL; all BUN is filtered
2. Resorption by the proximal tubule occurs
   1. Degree of resorption is dependent on the renal sensor of volume (perfusion) status
   2. This sensor appears to be in the juxtaglomerular complex
3. In states of renal hypoperfusion, BUN is efficiently resorbed
   1. This leads to increases in serum serum BUN levels
   2. Creatinine is not resorbed, so that BUN to creatinine ratios increase
   3. BUN : Creatinine ratios >15 generally indicate renal hypoperfusion
4. If tubular dysfunction is present, BUN is poorly resorbed, leading to a drop in serum levels

G. Creatinine

1. All creatinine is filtered into the urine and not resorbed at all
2. Thus, serum creatinine level [Cr]s is a good measure of glomerular filtration rate (GFR)
3. Estimation of Male is GFR ~ {(140-Age) x Weight(kg)}/(72 x [Serum Creat])
4. This estimation is multiplied by 0.85 for Females
5. Normal creatinine levels are ~0.6 to 1.2 mg/dL

H. Calcium

1. Calcium resorption is increased by 1,25 dihydroxy-vitamin D in the distal tubule
2. Kidney is responsible for hydroxylation of 25 hydroxy-vitamin D to dihydroxy form
3. PTH (parathyroid hormone) stimulates the hydroxylation of 25-OH vitamin D
4. Normal Calcium levels are ~8.5-10.5mg/dL (correction for serum albumin required)

I. Phosphate

1. Regulated by vitamin D and PTH and affected by calcium levels
2. Vitamin D increases phosphate resorption from the gut, but decreases renal reabsorption
3. PTH decreases renal reabsorption
4. Normal phosphate levels are ~2.5-4.5mg/dL
5. Major phosphate regulation occurs in distal tubule
6. Hyperphosphatemia is major problem in acute and chronic renal failure
7. Hypophosphatemia occurs in refeeding syndrome

J. Acid-Base Handling [2,4]

1. Physiologic production of acids must be balanced by renal removal
2. Two main sources of acidosis:
   1. Conservation of filtered HCO3-
   2. Excretion of 50-100mmol (~1mmol/kg) noncarbonic acid each day
3. Mechanisms of normal acid handling
   1. Proximal reclamation of filtered HCO3-
   2. Proximal synthesis and medullary recycling of NH4+ (ammonium)
   3. Distal secretion of hydrogen ions (H+, aldosterone sensitive)
4. Normal Acid Excretion (NAE)
   1. Titratable acids + NH4+ - HCO3- = NAE
   2. In healthy adults, normal acid excretion is about ~1mEq/kg/day

K. Susceptibility to Ischemia

1. Renal tubular cells, particularly outer medulla, are at high risk of hypoxic injury
2. Blood supply comes from a second arterial bed
3. Partial pressure of oxygen in medulla is 20-30mm less than that of the cortex [1]
4. Reduction in renal perfusion and/or oxygenation leads to acute tubular necrosis

L. Renal Tubular Channels [3]
[Figure] "Renal Tubular Cells"

1. Renal Collecting Duct Na+ Channel
   1. Found mainly in apical membranes of principal cells of collecting duct
   2. Provides Na+ entry for aldosterone regulated Na+/K+ pump use (basolateral membrane)
   3. Activating mutations in ß or gamma cause Liddle's syndrome (pseudoaldosteronism)
   4. Inactivating mutations cause pseudohypoaldosteronism (salt wasting, dehydration)
2. Glucose Transporter
3. Proton Transporter
4. H+/K+ Antiporter
5. HCO3-/Cl- Antiporter
6. Potassium (K+) Channel
7. K+ Pump
8. Na+/K+ Antiporter - ATP dependent
9. Water Transporters (aquaporin channels)
   1. Found mainly in erythrocytes and in apical membranes of kidney collecting ducts
   2. Permit very high water permeability
   3. Six different aquaporin genes, AQP0 to AQP5, have been identified

M. Normal Urinary Values

1. Normal volume 2-2.5 Liters
2. pH 5.5-7.0
3. 24 Hour Values
   1. Normal 24 hour urine creatinine 15-25 mg/kg
   2. Normal 24 hour calcium <200 mg/day
   3. Normal 24 hour citrate <320 mg/day
   4. Normal 24 hour cysteine <200 mg/day
   5. Normal 24 hour oxalate <44 mg/day
   6. Normal 24 hour uric acid <600 mg/day

References

1. Brezis M and Rosen S. 1995. NEJM. 332(10):647
2. Smulders YM, Frissen PH, Slaats EH, Silberbusch J. 1996. Arch Intern Med. 156(15):1629
3. Herbert SC. 1998. Am J Med. 104(1):87
4. Gluck SL. 1998. Lancet. 352(9126):474