The Ad Hoc Cimmittee Reports on Estimating the Future Workforce and Training

Requirements for Nephrology

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

J. of ASN; 5(Suppl 9) May, 1997.

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. GlomerulonephritisDiffuse proliferativeFocal proliferativeMesangio-capillaryFocal glomerulosclerosisEpimemranous nephropathyHenoch-Schönlein diseasePolyarteritis nodosaSystemic lupus erythematosisWegener’s granulomatosisGoodpasture’s syndrome

2. Chronic pyelonephritis 3. Renal vascular disease

Hypertensive nephrosclerosis (small vessels)Accelerated hypertensionRenal artery obtruction (large vessel)Renal vein thrombosisSystemic sclerosisDiabetes mellitus

4. Metabolic causesDiabetes mellitusGoutHypercalcaemiaHyperoxaluriaCystinosisAngiokeratoma corporis diffusum (Fabry’s disease)

5. NephrotoxinsAnalgesic abuseHeavy metal poisoning – lead, gold, cadmiumWorcestershire sauce

6. ObstructiveUrethral strictures or valvesBladder neck obstructionNeurological bladderProstatic enlargementVesico-ureteric refluxUretero-vesical obstructionCalculiTumoursRetroperitoneal fibrosisPelvi-ureteric obstruction

7. Renal tuberculosis8. Sarcoidosis (Bolton et al. 1976)9. Dysproteinaemia

MyelomaAmyloidosisMixed IgA-IgM cryoglobulinaemiaWaldensröm’s macroglobulinaemia

10. MiscellaneousBalkan nephropathySickle-cell haemoglobinopathyJapanese cadmium-nephropathyRadiation

11. Hereditary or congenitalPolycystic diseaseNephronophthisis (medullary cystic disease)Alport’s syndromeCystinosisHyperoxaluriaChronic tubular acidosisInfantile nephrotic syndromeDysplastic kidneys

Course of chronic renal failure

renal disease

nephron damage

remnant nephrons hypertrophy

damage of hypertrophic nephrons

uremia

months, years, decades

renal disease

nephron damage

nephron tissue volume

remnant nephrons hypertrophy

damage of hypertrophic nephrons

medullary osmotic

concentration

uremia

H2O and urea rediffusion in

remnant collecting ducts

polyuria

months, years, decades

renal disease

nephron damage

nephron tissue volume

remnant nephrons hypertrophy

damage of hypertrophic nephrons

medullary osmotic

concentration

uremia

H2O and urea rediffusion in

remnant collecting ducts

months, years, decades

SNGFR

prox. tubular reabsorption

change in glomerulo-tubular balance

increased distal osmotic load(Na , urea )

osmotic diuresis (10-20 x per nephron)

polyuria

renal disease

nephron damage

nephron tissue volume

remnant nephrons hypertrophy

damage of hypertrophic nephrons

medullary osmotic concentration

uremia

H2O and urea rediffusion in remnant

collecting ducts

months, years, decades

SNGFR

prox. tubular reabsorption

change in glomerulo-tubular balance

increased distal osmotic load(Na , urea )

osmotic diuresis (10-20 x per nephron)

polyuria oligo-anuria

obligate fluid and salt loss in spite of reduction in total GFR

hyposthenuria isosthenuria (concentrating oblity )

tubular damage

no distal Na transport(diluting oblity )

2 000 000 1 500 000 1 000 000 500 000 0

1000

1010

1020

1030

1040

1050

Specific gravity of glomerular filtratum

Isosthenuria in relation to the number of nephrons

Concentrating ability

Diluting ability

Spec

ific

gra

vity

of

urin

e

Number of the nephrons of two kidney

Isosthenuria

Dynamism of retention

70

52.5

35

17.5

030 60 90 120 ml / min

0 1005025 75 %

protein intake:

150 g/ die 100 g/ die 50 g/ die

GFR

Blo

od c

arba

mid

- N

mm

ol/l

Stages of CRF based on GFR changes

First phase: 100-20% GFR(„reserve”)

Second phase: 25-5% GFR(„transitional”)

Third phase: <5% GFR(„end stage”)

Na,

Mg,

PO

4, et

c

30 60 90 120

100%

GFR, ml/min

Signs and Symptoms of Uremia

Behavioral, mental or neurologicalDepressive: 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 ulcerationCardiovascular-pulmonary

Pericarditis, acute and constrictiveCardiomegalyPleuritisCongestive heart failureChange in blood pressureArrhytmiasVascular calcificationAccelerated atherosclerosisCheyne-Stokes and/or Kussmaul breathing

HematologicalAnemia (normochromic normocytic)Bleeding abnormality (prolonged bleeding time, abnormal platelet aggregation)Lymphopenia, mild thrombocytopenia

DermatologicalPallorExcoriations and pruritusUrea frostPurpuraand ecchymosisRash„Pseudo-clubbed” fingers of severe hyperparathyroid bone disease„Brown nail” of uremiaCutaneous and subcutaneous calcificationPeripheral tissue necrosis and ulceration

MetabolicMusculoskeletal muscle pain and weakness, proximalmyopathy, bone pain, bone pain, bone fractures, asepticnecrosis of boneDisturbances in multiple endocrine systemsCarbohydrate intoleranceHyperlipidemia Gout and pseudogoutWasting and abnormalities in protein metabolism

Sexual and reproductiveImpotenceDecreased libidoReduced nocturnal penile tumescenceInfertilityAmenorrheaFrigidityGynecomastiaGalactorrhea

ImmunologicalReduced T-cell-mediated immune functionImpaired phagocytosis and chemotaxisAtrophy of the lymphoid system including thymusReduced immune surveillance of neoplasia

MiscellaneousReduced wound healingHypothermiaImpaired response to pyrogen

Excretory failure

-H2O

-Na+

-H+

-HPO24

-, SO24

-

-urea, kreatinin-toxins (?!)

Uremia

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

Renal biosynthetic failure

-erythropoietin-prostaglandins-kinins-1.25 (OH)2, vitamin D3

-HCO3

-NH3

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

Phosphate retention

Nephron loss

Responsiveness of bone to PTH

Renal production of 1.25 (OH)3 vitamin D3

Se-Ca++

Decreased PTH metabolism in

kidney

Absorption of Ca in gut

Se-Ca++

Secunder hyperparathyreodism

1. Ca++- content of cells

2. Cell membrane permeability changed

3. Cyclic AMP activity

4. Soft tissue calcification

5. Increased protein catabolism

(protein- kinase )

Effects of PTH

Parathyreoid hormone and the uremie manifestations

Bone marrow

Excess PTH

HemolysisReduction in red marrow

Inhibit

RNA Heme

Synthesis by erythroid precursors

Anemia

Uremic anemia: parathyreoidectomy improvementPTH decrease utilization of ironCa- 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

Nephrectomy (partial)

Hypertrophy of the remnant kidney

remnant nephrons

hypertrophy

e.g.: removal of 60% of renal mass

vascular resistance

afferent

efferent

SNGFR

SNGFR increased by 200%

adaptation ?!

Suggested mechanism for glomerulosclerosis

Systemic hypertension

Intraglomerular hypertension

Further in total GFR

Reduced renal massDecrease in total GFR

Endothelial damage

Microaneurysm formation

mesangial traffic of macromolecules

Increased number of macrophages

Intraglomerular thrombosis

Mesangial expansion

Liberation of growth factors

hyalin formationFibrosis and liberation of growth factors

(platelet DGF)

Glomerulosclerosis

Observation in human medicine

1, ARF „recovery” later on: uremia

2, Painkiller induced renal dysturbances drugs stopped

progression of renal disease continued uremia

3, Glomerulonephritis + renal artery stenosis better prognosis

4, Pregnancy RBF , GFR 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

Hyperfiltration Agents increasing glomerular pressure

Glomerularsclerosis

Conditions deteriorating kidney function

Generally known

Hypertension (untreated)

Hyperuricemia

Ca – deposit

Hyperlipidemia (triglicerid, preß lipoprotein

(type IV) lipoprotein lipase

Other important factors

Diet with high protein

Diabetes mellitus

Sever anemia

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 death

5, Urea, creatinin

6, Anemia: hemolysis , production

7, Hypertension: R-A System hypervolemia

8, Osteomalacia

9, Uremic coma

0

200

400

600

800

1000

50 100

GFR (ml/min)

Max

imal

uri

nary

osm

otic

co

ncen

trat

ion

glomerulonephritis

Intestitial nephritis

papillanecrosis