The Ad Hoc Cimmittee Reports on Estimating
the Future Workforce and Training
Requirements for Nephrology
J. of ASN; 5(Suppl 9) May, 1997.
Number of ESRD in USA:
-has been growing by 12% per year since 1970s because of:
- ~9% increase in prevalance (number of
cases/million population)
- ~2% increase in size of population
- shift towards to non-white population
-reason of increase in prevalance:
- increase in rate of incidance (new cases/million
population)
- less importantly slight decline in mortality
History
Richard Bright (1789-1858):
- causal relationship between intrinsic renal disease
and the complex abnormalities of uremia (1827)
Alexander V. Korányi (1866-1944):
- concept of renal insufficiency based upon
hyposthenuria (1898)
- measurement of urine freezing point depression
during water restriction makes possible to detect a
clinically latent stage of uremia before its full
symptomitic development (1907)
Neal S. Bricker:
- adapted nephrons of remnant kidney are similar to
the normal nephrons in controlateral kidney –
„Intact nephron hypothesis”
History
Robert Platt (1900-1978):
- „There are two ways of looking at renal failure. The first is
to consider the kidney to be so disorganized that almost
anything can happen. This is convenient, usual, but rather
unproductive way of looking at renal failure. The other
concept is that of a kidney which has largely been destroyed
by disease but in which a small proportion of the nephrons are
left and are functioning under a stress and load to which a
normal kidney is never subjected. The second concept seems
to me to provide a much more satisfactory basis for
consideration of renal function in disease.” (1951)
- suggestion that secundary hyperparathyroidism is
due to the acidosis and phosphate retention led to a
lowering of serum calcium
- „adapted nephrons”
Causes of chronic renal failure
1. Glomerulonephritis
Diffuse proliferative
Focal proliferative
Mesangio-capillary
Focal glomerulosclerosis
Epimemranous nephropathy
Henoch-Schönlein disease
Polyarteritis nodosa
Systemic lupus erythematosis
Wegener’s granulomatosis
Goodpasture’s syndrome
2. Chronic pyelonephritis
3. Renal vascular disease
Hypertensive nephrosclerosis (small vessels)
Accelerated hypertension
Renal artery obtruction (large vessel)
Renal vein thrombosis
Systemic sclerosis
Diabetes mellitus
4. Metabolic causes
Diabetes mellitus
Gout
Hypercalcaemia
Hyperoxaluria
Cystinosis
Angiokeratoma corporis diffusum (Fabry’s disease)
5. Nephrotoxins
Analgesic abuse
Heavy metal poisoning – lead, gold, cadmium
Worcestershire sauce
6.
Obstructive
Urethral strictures or valves
Bladder neck obstruction
Neurological bladder
Prostatic enlargement
Vesico-ureteric reflux
Uretero-vesical obstruction
Calculi
Tumours
Retroperitoneal fibrosis
Pelvi-ureteric obstruction
7.
Renal tuberculosis
8.
Sarcoidosis (Bolton et al. 1976)
9. Dysproteinaemia
Myeloma
Amyloidosis
Mixed IgA-IgM cryoglobulinaemia
Waldensröm’s macroglobulinaemia
10. Miscellaneous
Balkan nephropathy
Sickle-cell haemoglobinopathy
Japanese cadmium-nephropathy
Radiation
11. Hereditary or congenital
Polycystic disease
Nephronophthisis (medullary cystic disease)
Alport’s syndrome
Cystinosis
Hyperoxaluria
Chronic tubular acidosis
Infantile nephrotic syndrome
Dysplastic kidneys
Course of chronic renal
failure
months, years, decades
renal
disease
nephron
damage
remnant
nephrons
hypertrophy
damage of
hypertrophic
nephrons
uremia
months, years, decades
renal
disease
nephron
damage
remnant
nephrons
hypertrophy
nephron tissue
volume
medullary
osmotic
concentration
H2O and urea
rediffusion in
remnant
collecting ducts
polyuria
damage of
hypertrophic
nephrons
uremia
months, years, decades
renal
disease
nephron
damage
nephron tissue
volume
remnant
nephrons
hypertrophy
SNGFR 
damage of
hypertrophic
nephrons
uremia
change in glomerulotubular balance
prox. tubular
reabsorption
increased distal
osmotic load
(Na , urea )
medullary
osmotic
concentration
osmotic diuresis
(10-20 x per nephron)
H2O and urea
rediffusion in
remnant
collecting ducts
polyuria
months, years, decades
renal
disease
remnant
nephrons
hypertrophy
nephron
damage
nephron tissue
volume
damage of
hypertrophic
nephrons
uremia
change in
glomerulo-tubular
balance
SNGFR
prox. tubular
reabsorption
medullary osmotic
concentration
increased distal
osmotic load
(Na , urea )
H2O and urea
rediffusion
in remnant
collecting ducts
osmotic diuresis
(10-20 x per nephron)
polyuria
hyposthenuria
isosthenuria
(concentrating oblity )
obligate fluid and salt loss in spite
of reduction in total GFR
tubular
damage
no distal Na transport
(diluting oblity )
oligo-anuria
Isosthenuria in relation to the number of
nephrons
Specific gravity of urine
1050
1040
Concentrating ability
Diluting ability
1030
Isosthenuria
1020
1010
Specific gravity of
glomerular filtratum
1000
2 000 000 1 500 000 1 000 000
500 000
Number of the nephrons of two kidney
0
Dynamism of retention
First phase: 100-20% GFR
(„reserve”)
Second phase: 25-5% GFR
(„transitional”)
protein intake:
52.5
150 g/ die
100 g/ die
50 g/ die
35
17.5
0
30
GFR
60
90
120 ml / min
75
100 %
GFR
0
Na, Mg, PO4, etc
Third phase: <5%
(„end stage”)
70
Blood carbamid- N mmol/l
Stages of CRF based on GFR
changes
25
50
100%
30 60 90 120
GFR, ml/min
Signs and Symptoms of Uremia
Behavioral, mental or neurological
Depressive: fatigue, asthenia, malaise, mental dullness,
shortening of concentration, memory defects
sluggishness or „heaviness”, anorexia
drowsiness by day, suicidal thoughts,
thanatophobia, stupor
precoma
coma
Irritative: anxiety, fasciculations, twitching, headache,
cerebellar signs of ataxia, asterixis, abnormal
gait, vertigo, compulsive actions, central
nausea, convulsions
Psychiatric: personality change, bizarre behavior
(e.g. compulsive, paranoid, etc.), phobias
organic psychosis, selective amnesia, denial,
food and drug kleptomania
Peripherial: pruritus, paresthesias, burning foot, restless
leg syndrome, foot flap and drop, monoplegia
paraplegia, sensory and motor defects,
bladder atony and dysfunction
Ophthalmic: nystagmus, miosis, asymmetric pupils
(anisocoria), blurring, amaurosis, the red eye
sydrome due to conjunctival irritation from
calcium deposits, band keratopathy
Gastrointestinal
Membrane problems: cheilitis, glossitis, stomatitis,
parotitis, esophatigis, enteritis,
pancreatitis, colitis, ileus
Functional problems: anorexia, dysgeusia and ageusia,
nausea, vomiting, hematemesis,
constipation, diarrhea, abdominal
distention
Structural problems: peptic and colonic ulceration
Cardiovascular-pulmonary
Pericarditis, acute and constrictive
Cardiomegaly
Pleuritis
Congestive heart failure
Change in blood pressure
Arrhytmias
Vascular calcification
Accelerated atherosclerosis
Cheyne-Stokes and/or Kussmaul breathing
Hematological
Anemia (normochromic normocytic)
Bleeding abnormality (prolonged bleeding time,
abnormal platelet aggregation)
Lymphopenia, mild thrombocytopenia
Dermatological
Pallor
Excoriations and pruritus
Urea frost
Purpuraand ecchymosis
Rash
„Pseudo-clubbed” fingers of severe hyperparathyroid
bone disease
„Brown nail” of uremia
Cutaneous and subcutaneous calcification
Peripheral tissue necrosis and ulceration
Metabolic
Musculoskeletal muscle pain and weakness, proximal
myopathy, bone pain, bone pain, bone fractures, aseptic
necrosis of bone
Disturbances in multiple endocrine systems
Carbohydrate intolerance
Hyperlipidemia
Gout and pseudogout
Wasting and abnormalities in protein metabolism
Sexual and reproductive
Impotence
Decreased libido
Reduced nocturnal penile tumescence
Infertility
Amenorrhea
Frigidity
Gynecomastia
Galactorrhea
Immunological
Reduced T-cell-mediated immune function
Impaired phagocytosis and chemotaxis
Atrophy of the lymphoid system including thymus
Reduced immune surveillance of neoplasia
Miscellaneous
Reduced wound healing
Hypothermia
Impaired response to pyrogen
Uremia
Excretory
failure
-H2O
-Na+
-H+
-HPO24-, SO24-urea, kreatinin
-toxins (?!)
Renal biosynthetic
failure
-erythropoietin
-prostaglandins
-kinins
-1.25 (OH)2, vitamin D3
-HCO3
-NH3
Regulatory failure
(disruption of
homeostatically useful
hormonal feedback
sontrol systems)
1. distribution of
hormonal control
system
-PTH 
-natriuretic hormone 
2. disturbed renal (or
extrarenal) catabolism
of polypeptide hormones
-insulin, glucagon
-PTH, STH secretion
3. end-organ resistance
at the receptor or
postreceptor level
-insulin
-PTH
List of suspicious agents
Urea
2,3- Butylene glycol
Creatinine
Lipochromes
Methylguanidine
Glucagon
Guanidinosuccinic acid
Growth hormone
Other guanidines
Gastrin
Uric acid
Renin
Pyridine derivatives
ß2 – microglobulin
Amino acids
Lysozymes
Aliphatic amines
Retinol-binding protein
Polyamines
ß2 – glucoprotein
Indoles
Ribonuclease
Myoinositol
Natriuretic hormone
Mannitol
Middle molecule
Glucuronic acid
PTH
Parathyreoid hormone and the uremie manifestations
Nephron loss
Phosphate
retention
Se-Ca++ 
Renal production Responsiveness Decreased PTH
of 1.25 (OH)3
of bone to PTH  metabolism in
vitamin D3 
kidney
Absorption of
Ca in gut 
Se-Ca++ 
Secunder hyperparathyreodism
Effects of PTH
++
1. Ca - content of cells
2. Cell membrane permeability changed
3. Cyclic AMP activity
4. Soft tissue calcification
5. Increased protein catabolism
(protein- kinase )
Parathyreoid hormone and the uremie manifestations
Excess
PTH
Inhibit
Bone marrow
Hemolysis
Reduction in
red marrow
RNA Heme
Synthesis by
erythroid precursors
Anemia
Uremic anemia: parathyreoidectomy
improvement
PTH decrease utilization of iron
Ca- channel blokkers decrease the hemolysis induced by PTH
Experimental and clinical evidences for neurotoxicity of
PTH
Uremia: - increased Ca – content of brain tissue (EEG slows down) and
periferial nerves (decreased conduction)
- Endogen PTH may induced similar phenomen in dogs.
- Adenoma of parathyreoid glands
similar phenomen
- In uremia the disturbance of renal motor nerves are in
correlation with the concentration of PTH in the blood
Increased PTH may play a role
in the development of:
Hypertension
Myocardiopathia
Hyperlipidemia
Leukocytosis, dysfunction of thrombocytes
Disturbance of insulin secretion
Myopathia
Sexual dysfunction
Hypertrophy of the remnant kidney
Nephrectomy
(partial)
remnant
nephrons
hypertrophy
afferent 
vascular
resistance 
SNGFR 
efferent
e.g.: removal of 60% of renal mass
adaptation ?!
SNGFR 
increased
by 200%
Suggested mechanism for glomerulosclerosis
Reduced renal mass
Decrease in
total GFR
Systemic
hypertension
Endothelial
damage
Intraglomerular
hypertension
Microaneurysm
formation
Intraglomerular
thrombosis
Further in
total GFR
mesangial traffic
of macromolecules
Increased number
of macrophages
Mesangial
expansion
Liberation of
growth factors
Fibrosis and liberation
of growth factors
(platelet DGF)
hyalin formation
Glomerulosclerosis
Observation in human medicine
1, ARF
„recovery”
later on: uremia
2, Painkiller induced renal dysturbances
progression of renal disease continued
3, Glomerulonephritis + renal artery stenosis
4, Pregnancy RBF , GFR
drugs stopped
uremia
better prognosis
accelerated progression of renal disease
Questions:
1, One „Kidney people” ( trauma, kidney donor etc.):
Future prospect:
How much of the kidney is lost to get hyperfiltration?
2, May hyperfiltration cause progressive renal lesion in „normal person?”
(- number of nephrons decrease by age:
30 years
80 years old GFR number of nephrons ~50%
- protein intake?)
3, GFR in type I diabetes increased at the beginning but only 50% gets
serious renal damage
Kidney disease
Number of nephrons
Hypertrophy of the
remaining nephrons
Glomerularsclerosis
Hyperfiltration
Agents
increasing
glomerular
pressure
Conditions deteriorating kidney function
Hypertension (untreated)
Hyperuricemia
Generally known
Ca – deposit
Hyperlipidemia (triglicerid, preß lipoprotein
(type IV) lipoprotein lipase
Diet with high protein
Diabetes mellitus
Sever anemia
Other important
factors
Chronic vasodilatory therapy ( fe. Steroids)
Pregnancy
Diastolic pressure > 70 mmHg
Sever proteinuria
Uremia
1, GFR < 10-20 %
2, H2O, Na retention
oedema, circulation disturbancy
3, H+- secretion, buffer capacity metabolic acidosis ( death cc. 6.9 pH)
4, K+ - conc. (acidosis, catabolism ): 8 maeq/l
5, Urea, creatinin
6, Anemia: hemolysis , production
7, Hypertension: R-A System hypervolemia
8, Osteomalacia
9, Uremic coma
death
Maximal urinary osmotic
concentration
glomerulonephritis
1000
Intestitial
nephritis
800
600
papillanecrosis
400
200
0
50
GFR (ml/min)
100