The Residual Nephron Hypothesis

aaaNormal renal function represents the collective operation of a million or so nephrons. The function of each individual nephron requires the interdependence of four anatomic components:
  1. blood vessels - provide blood to glomeruli to be filtered
  2. glomeruli - filter blood to form a protein poor filtrate
  3. tubules - reabsorb about 99% of filtrate water and other substances and also reabsorb specific substances in a controlled manner
  4. collecting system - collects the formed fluid and excretes the end product as urine
aaaInitially, renal disease predominantly affects only one of the four anatomic components, and specific disease entities are named according to the anatomic component initially affected. For example, in acute poststreptococcal glomerulonephritis, the glomeruli are initially affected by an inflammatory reaction incited by the deposition of circulating immune complexes. Glomerular function diminishes as evidenced by reduced glomerular filtration rate. However, tubule function diminishes, as well, because of lack of glomerluar filtrate to act upon and because of reduced blood flow through inflamed glomeruli in affected nephrons. Likewise, in acute tubular necrosis, metabolically active tubular epithelial cells die because of anoxia or exposure to nephrotoxins. Tubule function is, of course, lost in affected nephrons. However, the consequent swelling of dead cells diminishes the bore of, and casts from sloughed, dead cells plug, the tubule lumen thereby diminishing the flow rate of filtrate and decreasing glomerular filtration rate. In general, though only one anatomic component is affected by injury, the functioning of the other anatomic components is also impaired.
aaa Renal function remaining during the course of renal disease is maintained by unaffected, residual nephrons. Functions are affected differently as the percentage of residual nephrons remaining diminishes during the course of renal disease. Functional impairment progresses in a fairly characteristic manner, regardless of the specific anatomic component initially affected.

Progression of Functional Impairment

The manner in which different renal functions diminish as renal disease progresses and increasing numbers of nephrons are affected is illustrated in the figure to the right and is discussed below.

Glomerular filtration rate decreases in direct proportion to the number of nephrons rendered nonfunctional.

Concentrating ability depends upon nephron density and is completely lost when there is only 15-25% functioning nephrons remaining.

Diluting ability (maximum free water clearance) is about 7 % of GFR and decreases correspondingly with GFR.

Excretion of phosphate, urate and acid by individual nephrons can increase to rates 3-5 times that normally required so that these functions are maintained until there is only 20-30% functioning nephrons remaining.

Elaboration of erythropoietin and active vitamin D by individual nephrons can increase 3-5 fold that normally required so that anemia and calcium deficiency do not develop until there is only 20-30% functioning nephrons remaining.

Sodium and potassium excretion by individual nephrons can increase enormously beyond rates normally required so that electrolyte disturbances do not occur until there is only a few percent functioning nephrons remaining.

Stages of Dysfunction

As renal disease progresses and different functions become more impaired, signs and symptoms become increasingly evident. Certain poorly defined terms are loosely used to describe the stage or severity of renal disease based upon the extent of signs and symptoms and each is associated with a range of % residual nephrons remaining:

100 - 50%aa Development of azotemia (or loss of renal reserve). As GFR decreases in proportion to the loss of functioning nephrons, waste products, (e.g., urea and creatinine) which are excreted primarily by glomerular filtration, begin to accumulate. Because the normal range for these substances is rather broad, definitely increased serum concentrations are not always found until the number of functional nephrons has diminished by about 50%. The term azotemia refers to the accumulation of nitrogenous waste products and is identified by serum creatinine and/or urea concentrations above the normal range. Concentrating ability and maximum free water excretion also diminish during this stage but not to the point where symptoms develop from reduced ability to regulate fluid volume. This stage is asymptomatic and azotemia is not yet definite.

75 - 20% aaRenal insufficiency. Azotemia is definite and progresses with the continuing loss of functioning nephrons as does diminished concentrating ability and maximum free water excretion. Ability to adequately regulate fluid volume is maintained, so long as water intake is normal. During this stage, symptoms are minimal except for continually increasing azotemia and development of nocturia as concentrating ability diminishes.

30 - 10%aaRenal failure. Concentrating ability is completely lost in the stage of renal failure and a minimum urine volume of 2 L/day (or greater if the osmotic load is increased) is excreted. Maximum free water excretion continues to diminish and regulation of fluid volume becomes severely limited. Dehydration or hypervolemia and hypertension may develop depending upon fluid intake. Excretion of phosphate, urate and acid become compromised and hyperphosphatemia, hyperuricemia and acidosis develop and progress. Elaboration of active vitamin D and of erythropoietin become inadequate. Vitamin D deficiency leads to calcium deficiency. Secondary hyperparathyroidism develops, with the intention of maintaining normal circulating calcium concentrations, but renal osteodystrophy (generally mild) also occurs as a consequence. Erythropoietin deficiency leads to anemia. During this stage, mild to moderate symptoms become evident.

15 - 2%aaa Uremia. During the uremic stage, the excretory and endocrine functional impairment worsen and consequent symptoms are more severe. Toxic metabolites accumulate to a sufficient degree to cause additional symptoms including pericarditis, esophagitis, gastritis, colitis, bleeding diathesis from effects on platelets, pruritis, sallow skin coloration and neuromuscular disturbances.

< 2 - 5%aaEnd stage (or terminal uremia). This stage is life-threatening and terminal unless dialysis is conducted or transplantation is performed. The functional impairment and consequent symptoms, which began in the renal failure stage and worsen during the uremic stage, are now severe. In addition, excretion of water and electrolytes is ineffective for maintenance of homeostasis.


Even though functional impairment progresses similarly in most cases of renal disease, the rate of progression, presenting symptoms and outcomes for different renal diseases are different. Syndromes are listed below:

  1. Nephrotic Syndrome
    (from increased glomerular permeability to proteins)
    1. characteristic features:
      • proteinuria > 3-4g/day; the protein loss may be
        "selective" - predominately albumin lost - or
        "nonselective" (large as well as small proteins lost)
      • hypoproteinemia and consequent edema (the protein synthesizing capacity of the liver is exceeded when protein loss is greater than 3-4g/day)
      • hyperlipidemia and elevated alpha-2 macroglobulin (from generally increased hepatic protein synthesis and retention of very large proteins)
    2. characteristic disease entities:
      • minimal change disease (lipoid nephrosis)
        - selective proteinuria
      • membranous glomerulonephritis
        - nonselective proteinuria

  2. Nephritic Syndrome
    (from inflammatory injury to glomeruli)
    1. characteristic features:
      • azotemia
      • decreased concentrating ability
      • hematuria
      • proteinuria (< 2g/day)
      • red cell casts
    2. characteristic disease entities:
      • acute post streptococcal glomerulonephritis
      • rapidly progressive glomerulonephritis

  3. Tubulointersitial Disease
    (from inflammation affecting tubules)
    1. characteristic features
      • cloudy urine from high WBC count
      • white cell casts
      • proteinuria (< 1g/day)
      • decreased concentrating ability
      • azotemia
    2. characteristic disease entities
      • pyelonephritis
      • analgesic induced interstitial nephritis

  4. Chronic Renal Failure
    • develops insidiously over a time course of years from nephritic or tubulointersitial disease.
    • may first be noticed from proteinuria or azotemia or in later stages from uremic symptoms
    • important to detect early when disease is treatable

  5. Acute Renal Failure
    (from anoxia or nephrotoxins)
    1. characteristic features
      • sudden oliguria
      • rapidly developing azotemia
      • broad waxy casts
      • loss of concentrating ability
      • diminished sodium reabsorption
    2. characteristic disease entities
      • acute tubular necrosis
      • diffuse cortical necrosis
    3. important to distinquish from cases of prerenal azotemia

    Progressive Impairment of Individual Functions

    A. Decrease in Glomerular Filtration Rate and Progression of Azotemia:

    As glomerular filtration rate decreases during the course of renal disease, substances, which are normally excreted, primarily by filtration, accumulate and serum concentrations increase. In the past, these substances were determined collectively as nonprotein nitrogen (NPN) components (thus, the term "azotemia") and included urea, creatinine and uric acid. The NPN assay is no longer conducted and the individual components are currently measured independently. Uric acid is excreted primarily by active secretion for which there is sufficient excess capacity so that hyperuricemia does not develop until the renal failure stage. Urea and creatinine, however, are excreted almost exclusively by filtration so that their serum concentrations increase in proportion to decreased GFR. For example, serum concentrations of urea and creatinine increase by a factor of two when GFR decreases by a factor of two, etc. Serum urea concentration is sufficiently great so that increases cause an increase in serum osmolality. Azotemia (increased serum concentrations of urea and creatinine) is not reliably found until GFR has decreased by about 50%.


    B. Diminished Ability to Regulate Fluid Volume:

    Regulation of fluid volume requires the ability to retain water and excrete a concentrated urine during periods of low water intake and to excrete excess water when fluid intake is high. Maximum water excretion is 6 - 7% of GFR and is normally about 10 L/day. This much water is excreted by patients with diabetes insipidus (ADH lack). As GFR decreases, so does the maximum water excretion rate. The ability to retain water depends upon concentrating ability which diminishes as the number of functioning nephrons decreases. Normal concentrating ability allows excretion of urine having an osmolality 3 - 4 times that of plasma, and a minimum urine volume of about 300 - 500 ml/day for a usual solute load to be excreted of about 600 mosmoles. Concentrating ability is completely lost at the renal failure stage and maximum urine osmolality is the same as plasma osmolality. Minimum urine volume is then about 2 L/day or greater if the osmolar load is greater than usual. Adequate volume regulation can be maintained during the course of renal disease only if water intake is between the limits imposed by the minimum and maximum urine excretion rates of the functionally impaired kidneys. If water intake is less than about 2 L/day (plus the amount required to compensate for insensible water loss) then dehydration results. If water intake is greater than the maximum amount which can be excreted, then hypervolemia and hypertension result. Because of the usual 300-500 ml capacity of the bladder, nocturia generally begins during the renal insufficiency stage and persists during the stages of renal failure and uremia as polyuria (urine volume > 2 L/day) develops. During end stage, water excretion is sufficiently diminished so that oliguria ( < 400 ml urine/day) occurs. Frank anuria ( < 50 ml/day) is rare.


    C. Decreased Excretion of Acid, Phosphate, Urate and Other Organic Anions:

    The normal kidneys can excrete 3 - 5 times as much acid (as NH4+) as usually required and, therefore, acidosis is not evident until the renal failure stage and is only mild until uremia develops. The acidosis is, of course, metabolic and there is an increased anion gap due to the accumulation of anionic, conjugate bases normally excreted with the ammonium ion.

    Phosphate excretion is regulated by the extent of tubular reabsorption from the filtrate which is controlled by parathyroid hormone. Normally, about 80-90% of filtered phosphate is reabsorbed with a normal positive calcium balance and basal levels of parathyroid hormone. Secondary hyperparathyroidism, which develops during the course of chronic renal disease from a negative calcium balance due to active vitamin D deficiency, diminishes phosphate reabsorption to a minimum of about 30% (a three-fold increase in excretion rate) so that hyperphosphatemia does not develop until the renal failure stage.

    Urate and other organic anions are excreted primarily by active secretion for which there is 3 - 5 times the capacity normally required. Hyperuricemia does not develop, therefore, until the renal failure stage and worsens during uremia. The increase in other unmeasured anions is responsible for the increased anionic gap associated with the metabolic acidosis of severe renal disease.


    D. Deficient Elaboration of Active Vitamin D and Secondary HyperParathyroidism

    Intestinal absorption of calcium, and of phosphate to a lesser extent, is regulated by circulating vitamin D3 concentrations. Active vitamin D (vitamin D3 or dihydroxy cholecalciferol) is elaborated exclusively by the kidneys. The elaboration rate of active vitamin D by individual nephrons is stimulated 3 - 5 fold by increased concentrations of parathyroid hormone. Adequate vitamin D3 concentrations can be maintained until the renal failure stage, after which intestinal absorption of calcium becomes deficient. Calcium deficiency then stimulates elaboration of parathyroid hormone the effects of which are to attempt to maintain normal serum concentrations of calcium by increasing bone resorption and increasing renal reabsorption of calcium. Near normal serum calcium concentration is thus maintained at the expense of increased bone resorption. The consequent bone wasting (renal osteodystrophy) generally presents as a mild form of osteomalacia.


    E. Deficient Elaboration of Erythropoietin and Anemia

    Individual nephrons have the capacity to elaborate erythropoietin 3 - 5 times the rate normally required, so that the normochromic, normocytic anemia associated with chronic renal disease does not occur until the renal failure stage. A decreased red cell lifetime may also contribute to the anemia.


    F. Sodium and Potassium Excretion

    Normally, from 0.5 to 2.5% of filtered sodium and about 20% of filtered potassium is excreted. Sodium excretion is determined by the extent of aldosterone controlled reabsorption in the collecting tubules and in the absence of aldosterone, a maximum of about 2.5% of filtered sodium is normally excreted. Factors responsible for controlling excretion of potassium are less well established. Quite surprisingly, normal serum concentrations of sodium and potassium are maintained until near end stage. The fraction of filtered sodium and potassium excreted per functioning nephron increases in proportion to the decrease in number of functioning nephrons.
    The factor accounting for the increased excretion rate/per nephron as renal disease progresses is atrial natriuretic hormone which inhibits both proximal and far distal tubular sodium reabsorption. Factors responsible for increased potassium secretion per nephron as renal disease progresses remain a mystery.

    Last Updated: 04/16/16