Estimating Future Workforce & Training Requirements for Nephrology

1. 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

2. 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”

3. 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”

4. 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. 5. Nephrotoxins • Analgesic abuse • Heavy metal poisoning – lead, gold, cadmium • Worcestershire sauce • 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 • Renal tuberculosis • 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

6. Course of chronic renal failure months, years, decades remnant nephrons hypertrophy damage of hypertrophic nephrons renal disease nephron damage uremia

7. months, years, decades remnant nephrons hypertrophy renal disease nephron damage damage of hypertrophic nephrons uremia nephron tissue volume medullary osmotic concentration H2O and urea rediffusion in remnant collecting ducts polyuria

8. months, years, decades renal disease nephron damage remnant nephrons hypertrophy damage of hypertrophic nephrons uremia nephron tissue volume SNGFR  change in glomerulo-tubular 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

9. months, years, decades remnant nephrons hypertrophy damage of hypertrophic nephrons renal disease nephron damage uremia change in glomerulo-tubular balance nephron tissue volume SNGFR prox. tubular reabsorption medullary osmotic concentration increased distal osmotic load (Na , urea ) osmotic diuresis (10-20 x per nephron) H2O and urea rediffusion in remnant collecting ducts oligo-anuria 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 )

10. Isosthenuria in relation to the number of nephrons Concentrating ability 1050 Diluting ability 1040 1030 Specific gravity of urine Isosthenuria 1020 Specific gravity of glomerular filtratum 1010 1000 2 000 000 1 500 000 1 000 000 500 000 0 Number of the nephrons of two kidney

11. Dynamism of retention 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”) 70 protein intake: 150 g/ die 100 g/ die 50 g/ die 52.5 35 Blood carbamid- N mmol/l 17.5 0 30 60 ml / min 90 120 GFR 0 75 100 25 50 % 100% Na, Mg, PO4, etc 30 60 90 120 GFR, ml/min

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. Nephron loss Renal production of 1.25 (OH)3 vitamin D3 Responsiveness of bone to PTH  Decreased PTH metabolism in kidney Phosphate retention Se-Ca++  Absorption of Ca in gut  Se-Ca++  Secunder hyperparathyreodism Parathyreoid hormone and the uremie manifestations Effects of PTH • Ca++- content of cells • Cell membrane permeability changed • Cyclic AMP activity • Soft tissue calcification • Increased protein catabolism • (protein- kinase )

19. 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

20. Increased PTH may play a role in the development of: Hypertension Myocardiopathia Hyperlipidemia Leukocytosis, dysfunction of thrombocytes Disturbance of insulin secretion Myopathia Sexual dysfunction

21. Hypertrophy of the remnant kidney Nephrectomy (partial) remnant nephrons hypertrophy afferent  vascular resistance  SNGFR  efferent SNGFR  increased by 200% e.g.: removal of 60% of renal mass adaptation ?!

22. Suggested mechanism for glomerulosclerosis Reduced renal mass Decrease in total GFR Further in total GFR Systemic hypertension Intraglomerular hypertension Endothelial damage Increased number of macrophages Microaneurysm formation mesangial traffic of macromolecules Mesangial expansion Liberation of growth factors Intraglomerular thrombosis Fibrosis and liberation of growth factors (platelet DGF) hyalin formation Glomerulosclerosis

23. 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

24. Kidney disease Number of nephrons Hypertrophy of the remaining nephrons Glomerularsclerosis Agents increasing glomerular pressure Hyperfiltration

25. Conditions deteriorating kidney function Hypertension (untreated) Hyperuricemia Ca – deposit Hyperlipidemia (triglicerid, preß lipoprotein (type IV) lipoprotein lipase Generally known Diet with high protein Diabetes mellitus Sever anemia Chronic vasodilatory therapy ( fe. Steroids) Pregnancy Diastolic pressure > 70 mmHg Sever proteinuria Other important factors

26. 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

27. glomerulonephritis 1000 Intestitial nephritis 800 Maximal urinary osmotic concentration 600 papillanecrosis 400 200 0 50 100 GFR (ml/min)