Mezei201_lecture_2012_2013

Mezei201_lecture_2012_2013

URINARY TRACT SYSTEM

Z s f ia M e z e i, M D 2013.

ANATOMY
KIDNEYS: 1./ Capsule 2./ Renal cortex: Nephron: (Cortical 85 %, Juxtamedullar 15 % /reach into the medulla) Bowmans capsule Glomerulus: Afferent arteriole (artery to the glomerulus) Capillary: Endothelial cells Basement membrane Podocyte foot processes Efferent arteriole (artery from the glomerulus): This vessel supplies the tubules, as well. The efferent arteriole ends in capillaries, the capillaries are joined into venules and the venules return to the renal vein. Mesangial cells Tubule: Proximal convoluted tubule Loop of Henle: Descending limb of loop of Henle Ascending limb of loop of Henle Distal convoluted tubule JGA / Juxtaglomerular apparatus Collecting tubule

3./ Renal medulla 4./ Renal pyramid 5./ Renal pelvis URETERS BLADDER URETHRA

Mezei201_lecture_2012_2013

Mezei201_lecture_2012_2013

STRUCTURE OF GLOMERULUS

PHYSIOLOGY:
KIDNEYS: Urine formation: As a result of glomerular function - Filtration / Filtrate formation As a result of tubule function - Reabsorption - Secretion / Excretion - Concentration and dilution Removal of pathological metabolic products Hormone production: Renin-Angiotensin-Aldosterone System, Erythropoietin, Prostaglandins, Hydroxylation of Vitamin-D Regulation of salt and water homeostasis Regulation of acid-base balance Forward urine URETERS: BLADDER: Store urine Void urine URETHRA:
FUNCTION OF GLOMERULUS - FILTRATION

Afferent arteriole

Efferent arteriole Oncotic pressure 30 mmHg

Glomerulus

http://herkules.oulu.fi/isbn9514264290/html/x782.html
Bowmans capsule

Hydrostatic pressure 75 mmHg

Intersticial pressure 10 mmHg

Tubular pressure 10 mmHg

Proximal convulated tubule Effect Effectv filtration pressure 7575-3030-1010-10=25 mmHg

FUNCTION OF THE NEPHRON

GLOMERULUS FILTR FILTRCI CI

FILTRATION
SECRETION

TUBULUS

REABSORPTION

PROXIMAL TUBULE

NaCl, water, K, glycose, Aminoacids, PO43-, HCO3-, Ca2+, Mg2+, urate, urea water

H+, NH4+, organic anion, organic cation

LOOP OF HENLE

DISTAL TUBULE

NaCl, K+, Ca2+, Mg2+, NH4+, NaCl, water, K+,

renin

COLLECTING DUCT
http://www.colorado.edu/intphys/Class/IPHY3430-200/image/19-4d.jpg

H+, K+, NH3

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Mezei201_lecture_2012_2013 BILIRUBIN: ROSINS TEST How to perform: 1 % alcoholic iodine solution layered on top of urine Positive result: green ring at the border of urine and iodine Only direct bilirubin can be detected!!!!!! Associated disease: hepatocellular jaundice obstructive jaundice THE MICROSCOPIC EXAMINATION OF THE URINE SEDIMENT IS AN INTEGRAL PART OF THE URINANALYSIS: 1./ SEMIQUANTITATIVE: For this examination, the standard volume of urine (10 ml is centrifuged in a low speed centrifuge. The supernatant is decanted and the urine is gently resuspended in a standard volume (0.5 ml) of urine supernatant. A drop of the resuspended urine is placed on a slide, coverslipped and examined under a light microscope using the 10x and 40x objectives low and high magnification (this is frequently called a wet prep). Results: I. Organic substances A./ Cellular - Epithelial cells - Leukocytes - Spermium B./ Casts - Hyaline - Granular (degraded leukocytes, epithelial cells and proteins) - Leukocyte - RBC - Epithelial cell - Waxy C./ Microorganisms - Bacteria - Fungi II. Anorganic substances A./ In acidic urine: - Urate crystal - Calcium-oxalate crystal - Amorphous urate granule - Cholesterol crystal B./ In alkaline urine - Ammonium-magnesium-phosphate - Calcium-phosphate - Ammonium-urate - Calcium-carbonate 2./ QUALITATIVE: ADDIS COUNT 10 ml from collected (12 h) urine specimen is centrifuged for 5 min. Discard 9 ml supernatant and gently resuspend pellet in 1 ml supernatant. Counting takes place in hemocytometer (Brker chamber). The cells should be counted in 1 mm3 of urine and the result expressed as number of cells per mm3, or cell number per a day. RBC: 1 million, WBC: 2 million/day.

MONITORING OF URINARY TRACT FUNCTIONS:

A./ URINE SAMPLING First morning urine or urine stored for 4 hours on 2-8 oC is used Collecting of urine sample: 1./ Spontaneous void following to a hexachlorophene wash of genitals Mid-stream specimen of urine: First 15-30 mL is discarded and the following 50-100 mL is collected 2./ With catheter 3./ Transcutaneously, suprapubically (Transcutaneous urine specimen collection from urinary bladder) B./ URINE ANALYSIS Color, smell, transparency and specific weight TESTS FOR SUBSTANCES IN THE URINE: PROTEIN: SULPHOSALICIC ACID How to perform: Urine+ a few drops of 20 % sulphosalicic acid Positive result: Precipitation of protein GLUCOSE: NYLANDERS TEST How to perform: 2/3 part urine +1/3 part Nylanders solution Boiling Positive result: Dark brown or black discoloration KETON BODIESS: LEGAL SOLUTION (SODIUM NITROPRUSSIDE) How to perform: 5 ml urine + 5 drops of Sodium nitroprusside (supersaturated in water) + a few drops of 20 % NaOH until becomes light red + 96 % acetic acid until becomes burgundy red PUS: DONNS TEST How to perform: 2/3 urine + 1/3 20 % KOH shake well, once never repeat shakes Positive result: Slowly ascending bubbles BLOOD: BENZIDINE TEST How to perform: 0.5 mL benzidine (supersaturated in concentrated acetic acid solution) + 3 mL 3% hydrogen-peroxide +3.5 mL urine Positive result: Blue discoloration UBG: EHRLICHS TEST How to perform: 5 mL urine+ 5 drops of Ehrlichs solution Evaluation: In transmitted light yellowish discoloration Normal In top view light red discoloration Discoloration increases with warming Increased In transmitted light: red discoloration never at room temperature Associated diseases: hepatocellular jaundice hemolytic jaundice Decreased There is no discoloration even after warming Associated disease: obstructive jaundice

Mezei201_lecture_2012_2013 C./ FUNCTIONAL TESTS I./TESTS FOR GLOMERULAR FILTRATION (GFR=GLOMERULAR FILTRATION RATE):
WITH CLEARANCE TECHNIQUES

Mezei201_lecture_2012_2013 3./ With radioactive metal complexes - isotope clearance The radioisotopes (Cr51-inulin, Co57-B12) given intravenously is distribute quickly and evenly in the extracellular compartment and excreted only by the kidneys. If a substance is used that is excreted via filtration only, the GFR is determined. It must be observed that the distribution compartment should not be changed. (Water homeostasis) Advantage: There is no need for extra fluid intake There is no need for urine collection Thus it can be used in case of all kind of urine collecting difficulties. Retention Incontinency Cooperation inability Oliguria Conditions with decreased GFR: Decreasing blood pressure: Decrease of hydrostatic pressure: Dehydration, exsiccosis, hypotension and shock In renal diseases: Increase of interstitial pressure due to inflammatory cells and accumulation of connective tissue In glomerulonephritis (GN) In increase of tubular pressure: Occlusion of tubules; e.g. cylinders Occlusion of lower urinary tract; e.g. calculus II. TESTS FOR TUBULAR FUNCTION: Urinary concentration test: Salt enriched dinner without fluid intake Subsequent morning specific gravity of urine is determined: Normally the specific gravity of urine is > 1.025 pond/cm3 (or 1.025 kilopond/dm3 or 1025 pond/dm3) The kidney concentrating function decreases earlier than the diluting one in: Pyelonephritis / inflammation of renal pelvis Early phase of renal failure Urine dilution test: The fasting patient has to drink 20 mL/kg body weight of water in 15 mins. Subsequent morning the urine specific gravity is measured in 30 min for 4 h. In normal diluting function urine specific gravity is under 1,004 pond/ cm3 at least in one sample. Found later in renal failure.

Main point: Clearance is a hypothetical volume of plasma from which an examined substance is completely removed per second. The received value depends on the type of the clearance substance, which is given for 1,73 m2 body surface and in mL/s. GFR = (UxV)/P U = concentration of substance in urine P = concentration of substance in plasma V= amount of voided substance per 1 second Types: 1./ Classic inulin clearance: Constant inulin plasma level should be maintained with infusion Urine sampling with catheter Disadvantage: Burdens the body with extra volume and foreign substance Risk for infections Normal value: Men - 2.10.37 mL/s/1.73 m2 Women - 1.940.27 mL/s/1.73 m2 2./Endogenous creatinine clearance: In case of normal plasma creatinine clearance (60-100 mmol/L) creatinine is excreted only via the glomerular filtration. Glomerular filtration is calculated from the creatinine amount in the urine and the creatinine concentration in the plasma. Venous blood sampling in the middle of urine collection Creatinine determination of serum and urine is done by the Jaffe reaction. Disadvantage: In case of high plasma creatinine concentration creatinine is filtrated and excreted, as well. Urine collection is necessary in this case also. Advantage: There is no extra volume burden There is no foreign substance intake Suitable for follow-up of renal diseases Normal value: Men: 20.4 mL/s/1.73 m2 Women: 1.80.4 mL/s/1.73 m2

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Mezei201_lecture_2012_2013 c./ Overflow proteinuria Occurrence: In hemolysis - high amount of hemoglobin is filtrated (if there is no more Hgb binding haptoglobin in the plasma) In muscle contusion - much myoglobin get into the filtrate Paraproteinemia - Bence Jones protein (Light chain of Ig) Pathomechanism: Glomerular function: intact Tubular function: intact but the highly filtrated low molecular weight protein cannot be reabsorbed by the tubules d./ Postrenal proteinuria Occurrence: Inflammation or tumor of the lower urinary tract Pathomechanism: Glomerular function: intact Tubular function: intact Protein detection tests are positive due to the increased amount of exfoliated epithelial cells and leukocytes during inflammation and not because of the increased amount of plasma proteins in urine

ABNORMAL URINE:
PROTEINURIA Healthy adult 80-150 mg protein is voided per day Distributed: 40% is albumin, 20% is globulin IgG, IgA, IgD and secreted IgA, 40% is protein originated from the kidney tissue - Tamm-Horsfall protein Glomerular filtration layers are inhibiting protein loss endothelial cells - small pores between - fenestrae basement membrane - negatively charge surface i nhibits passing of protein Podocyte processes -Their negatively charged surface inhibits protein loss Filtered proteins are reabsorbed in tubules Proteinuria Definition of proteinuria: The term proteinuria is used when: The protein content of urine is greater than 150 mg/day Types: a./ Glomerular proteinuria Causes: nephritic and nephrotic syndrome (protein excretion > 3.5 g/day) Pathomechanism: Glomerular permeability increases: filtration layer damage of glomerulus (endothelial cells, BM and podocyte foot processes) induced by glomerular immune deposits and sensitized T-cells Tubular function is intact: unable to reabsorb the high amount of filtrated protein Types: Benign: exercise, high body temperature, pregnancy and heart failure Moderate: the amount of excreted protein is more than 1g/day Selective: mainly albumin is excreted b./ Tubular proteinuria Causes: acute tubular necrosis: Due to nephrotoxic drugs transplant rejection chr. interstitial nephritis / chr. pyelonephritis Pathomechanism: Glomerular function is intact, thus only low molecular weight proteins (microglobulin and lysosim) pass through the glomerular filtration layer, therefore the poteinuria is not more than 2-3 g/day function is impaired, thus filtrated protein are not Tubular reabsorbed 9

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Mezei201_lecture_2012_2013 Laboratory tests: Qualitative detection: sulphosalicylic acid test (moderate 1+, significant precipitation 2+, flaky 3+ curdy 4+) Salicylates and penicillin disturb the detection Semiquantitative Quick test In the presence of proteins tetra-bromophenol blue test dipstick turn to greenish blue from yellow Quantitative detection: From 24-hour collected urine With Biuret reagent and photometry With turbidimetric method With protein electrophoresis and immunoassay Result in: Results of serum protein loss: Se albumin - oncotic pressure edema formation Se transport protein - deficiency diseases Se coagulant factor - disorders of the coagulation system Se immunoglobulin - susceptibility to infections Se apoprotein (HDL) -synthesis in the liver (all) hyperlipoproteinemia ( VLDL and LDL) Results of high amount protein in the tubules: Cylinder (cast) formation urine congestion - infection - increased pressure - GFR Amyloidosis impairment of renal function GLUCOSURIA Glucosuria is the excretion of glucose into the urine. Normally glucose is detected in the urine only in traces. Causes: Conditions with high blood sugar level: Diabetes mellitus Hyperthyroidism Cushing Phaeochromocytoma Injury of renal tubules Detection: Qualitative: Nylander test (can detect only reductive sugar) Bismuth nitrate turns to metal bismuth (black in color) due to the reductive effect of sugar in alkali environment Semiquantitative: Quick test glucose oxidase-peroxidase reaction, +: the test strip turns to greenish blue false +: as an effect of vitamin C and aspirin Quantitative: - Ortho-toluidine photometry detection Pathomechanism: a./ When the blood sugar level approximately doubles its normal value the amount of excreted glucose into the ultrafiltrate exceeds the maximal reabsorbing capacity of tubule cells. b./ In normal serum glucose level impaired tubule function causes glucosuria. Result in: Osmotic diuresis, polyuria and urinary tract infection Definition:

Mezei201_lecture_2012_2013 KETONURIA Definition: is a condition in which ketone bodies (acetone, acetoacetic acid, betahydroxybutyric acid) are present in the urine Causes: Diabetes mellitus glucose supply of cells due to insulin deficiency, which cause gluconeogenesis, lipid degradation and free fatty acid / FFA, and these can be metabolized in the way of ketone body formation only because in the absence of the activation effect of insulin lipid and energy cannot be synthetised from FFA. Glucagon excess enables the FFA transport via carnitine into the mitochondrium, where ketone bodies are synthetised. Alkalosis, thyrotoxicosis and acetonemia

Detection: Qualitative:

Legals test In the presence of ketone bodies and in alkali environment the Sodium nitroprusside turns to burgundy red Semiquantitative: Quick test High anion gap metabolic acidosis

Result in and concomitant sign:

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Mezei201_lecture_2012_2013 HEMATURIA Definition: In urine precipitation test RBC count is > 3 / HPF Causes: Renal Glomerulonephritis, renal infarction, trauma, tumour, TB and calculus Bladder Inflammation, trauma, tumour, TB and calculus Urethra Calculus and trauma Prostate Tumor and TB Localization of source of bleeding: Guyons three glass test: Blood in first urine fraction - The source is in the terminal urinary tract Blood in the third fraction - The source is in the bladder Blood in all three fractions - The source is in the kidney Detection: Qualitative: Benzidine test Benzidine is oxidized by hydrogen peroxide and the process is catalyzed by hemoglobin - positive result: Prussian blue Semiquantitative: Quick test Microscopic test Dysmorphic urinary RBCs indicate renal source of bleeding Quantitative: Microscopic urine precipitation test Addis count: RBC count in 24h urine > 1 million Types: Macroscopic hematuria: visible to the unaided eye that urine is tinged with blood Microscopic hematuria: It can be detected by microscope only Isolated hematuria: There is RBC in the urine only (not WBC or protein) Result in: casts and anemia RBC cast

Mezei201_lecture_2012_2013

HEMOGLOBINURIA Detection:

Causes: Result in:

Supernatant of decantated urine is red Qualitative:Benzidine test (positive in case of hematuria and hemoglobinuria as well) Quick test Hemolytic anemias (Causes of hemolytic anemias see later) Proteinuria might occur because reabsorption of plasma proteins and hemoglobin from the filtrate take place on the same transporter

UBG/UROBILINOGEN IN URINE Normally there is only small amount of urobilinogen in urine Detection (fresh urine sample is needed for the detection): Qualitative: In the presence of UBG urine turns to red with Ehrlichs reagent Semiquantitative: Quick test UBG with diazonium salt produces reddish azo-dye Abnormally increased UBG excretion: In hepatocellular injury In hemolysis Abnormally decreased: In bile tract obstruction BILIRUBIN (BI) Definition: Occurrence of bilirubin in urine. Normally there is no bilirubin in urine. If there is Bi in urine, water soluble Bi occur in urine only. Pathomechanism: See inserted figures Detection: Qualitative: Rosins test Semiquantitative: Quick test Abnormally increased: In biliary obstruction In hepatocellular injury

RBC

Dysmorph RBC

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Mezei201_lecture_2012_2013 PYURIA - PURULENT URINE Definition: The term pyuria is used if 3-5 WBC/HPF/high power field are detected in the urine precipitation Normally: 1-2 WBC/HPF are detected. Causes: Pyelonephritis, cystitis, urethritis (NOT in glomerulonephritis!!) Sterile pyuria: Pyuria, although the repeated bacteria cultures are negative. Cause: The used standard cultures are not suitable for the growing of the given bacteria; e.g. Mycobacterium/TB, Chlamydia, Mycoplasma Detection: Qualitative: Donns test Mucin is released from WBC as an effect of KOH; increases the viscosity BACTERIURIA Definition: The term significant bacteriuria is used when the number of bacteria colonies is >105/mL. Causes: pyelonephritis / Inflammation of the pelvis of the kidney, cystitis urethritis Detection: Nitrite test: Bacteria turns nitrate found in the urine into nitrite Positive result: red Uroculture: Thorough urine sampling Inoculation with a calibrated loop (0.01 or 0.001 mL) Culturing for adequate length and reading the results.

Mezei201_lecture_2012_2013 ABNORMAL URINE SEDIMENT: Semiquantitative Microscopic field of view test Organic substances: Epithelial cells WBCs (1-2 WBC/HPF in men and 5 WBC/HPF in women) pyelitis RBCs (>3-5 RBC/HPF, see before) GN, hematurias Casts (tubule moulds) Hyalin -Glomerulonephritis Granular -Glomerulonephritis -Pyelonephritis Wax -Chr. renal failure WBC -Chr. pyelonephritis RBC -Acute glomerulonephritis Kullzs coma-cast -Diabetic coma Hemoglobin -Hemoglobinuria Myoglobin -Crush (bruised great muscle) Lipid/ Maltese cross -Nephrosis Anorganic substances: Acud urine: Urate crystalls Calcium oxalate crystals Amorphous urate granules Cholesterol crystals Cystine crystals Alkali urine: Ammonium-magnesium-phosphate crystals Calcium-phosphate crystals Ammonium-urate crystals Calcium carbonate crystals Addis count From collected urine (which volume is known) 10 mL is taken, decantated and the precipitate is suspended in 1 mL. From this, samples are put into the Brker's chamber and the elements are counted exactly. Then it is counted back onto the daily voided volume: RBC: 1 million/24 hours, WBC: 2 million/24 hours Time consuming and there is a lot of source of errors.

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Mezei201_lecture_2012_2013 CHANGES IN THE AMOUNT OF URINE: A./ OLIGURIA: Definition: Oliguria: urine volume < 400 mL/day Anuria: urine volume < 100 mL/day Causes: Prerenal: Central circulatory disturbance: -heart failure Peripheral circulatory disturbance: -shock and collapse Dehydration, exsiccosis and edema formation Renal circulatory disturbance: Constriction and obstruction of the renal artery It is reflectory in case of a calculous attack Renal: Glomerular injury: Glomerulonephritis Renal infarction Renal TB Tubular injury Acute tubular necrosis: Drug induced e.g. Sulphonamide Toxic CCl4, mercury, lead, methyl alcohol Trauma caused by the big amount of released myoglobin DIC Ischemia Postrenal: Urine void is difficult Obstruction: calculus and tumour Innervation disorders: spinal cord injury and multiple sclerosis B./ POLYURIA: Definition: urine volume > 3000 mL/day Types/Causes: 1./ Hyperosmolar polyuria / osmotic diuresis Main point: Osmotically active substances are excreted by the urine, which carry water as well (app. 3-4 L urine per day) Urine osmolarity > 300 mosmol/Kg Causes: Glucose - Diabetes mellitus Urea - Diuretic phase of acute renal failure Mannitol - Used to release edema in the CNS NaCl - diuretics - Renal salt loss - Compensatory phase of chr renal failure Bicarbonate -alkalosis 2./ Hypoosmolar polyuria Main point: Urine osmolarity < 250 mosmol/Kg Causes: a./ Primary polydipsia = increased water intake Psychogenic schizophrenia Abnormally increased thirstiness/dipsogen Central nervous system: Granuloma Inflammation Demyelinisation Myeloma multiplex Drug induced

Mezei201_lecture_2012_2013 b./ Diabetes insipidus (app. 20 L urine daily) A./ Central/sensitive to vasopressin Main point: AVP production or secretion of Hypothalamus, Causes: Acquired: head trauma, tumor, granuloma, inflammation and aneurism Congenital: Undeveloped hypothalamus Genetic disorders B./ Peripheral Main point:V2 receptor disorder of tubules, thus AVP effects cannot be expressed Acquired: Medicine Causes: Vessel obstruction Sickle cell anemia Renal infiltration Amyloidosis Congenital: Genetic causes X-linked AVP R2 gene mutation Aquaporin 2 gene mutation C./ Gestational Cause: release of vasopressinase by the placenta or the liver SPECIFIC GRAVITY OF URINE Normal value: End values -1,001-1,040 pond/cm3 Mean values -1,017-1,020 pond/cm3 1./ Hyposthenuria: Main point: Specific gravity of urine cannot rise above 1,025, due to the decreased concentrating function of tubules. GFR < 30 mL/min Causes: 1./Renal: a./ Glomerular Glomerulonephritises b./ Tubular Conditions with decreased active sodium transport 2./ Neurohumoral: Diabetes insipidus (Central or peripheral) 2./ Asthenuria or isosthenuria: Main point: Specific gravity of urine is 1,010; i.e. the same as the specific gravity of plasma ultrafiltrate, because tubules are unable to concentrate and to dilute. GFR < 20 mL/min Renal failure Causes: AZOTEMIA Definition: Increase of non-protein nitrogen in blood (BUN). Non-protein nitrogen: Total of nitrogen containing substances (ureaN=carbamide, creatinine) in plasma except proteins Prerenal: Prerenal anuria Causes: Increased protein degradation Renal: Renal anuria Postrenal: Postrenal anuria

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Mezei202lecture2012-2013

Mezei202lecture2012-2013

URINARY TRACT DISORDERS II.

GLOMERULAR DISEASES A./ PATHOMECHANISM: MAIN POINT: Lesion of nephrons: 1./ Glomerular lesion: a./ Increased permeability: Due to lesion of filtration barrier (Components: endothel, BM and podocyte foot processes) b./ Intracapsular (within the Bowmans capsule) pressure increases 2./ Tubular lesion CAUSES: IMMUNOCOMPLEX MEDIATED LESION Local (in situ) immunocomplex formation Endogenous Ag: tissue Ag; e.g. BM - Goodpastures sy Exogenous Ag: bacterial Ag: Similar to anionic glomerular components Circulating immunocomplex formation Endogenous Ag: DNA and tumor Exogenous Ag: Staphylococcus, Streptococcus and viral antigen NON-IMMUNOCOMPLEX-MEDIATED LESION Toxic damage of podocytes Activation of the alternative pathway of the complement system Necrotic lesion As an effect of free radicals and proteolytic enzymes released from leukocytes Hyperfiltration injury of intracapillary hydrostatic pressure due to resistance (vasodilatation) of the afferent artery Atubular glomerulus Proximal tubules are sensitive to hypoxia (ischemia or tubulointerstitial disorders) B./ EFFECT OF DECREASING NEPHRON NUMBER: Short term: Long term: Hyperfiltration of the intact glomerulari are responsible for the GFR Glomerular lesion results in: Proteinuria Hypertension: Due to TGF-, angiotensin II, PDGF and endothelin Increase of EC matrix that leads to Glomerular hypertension Progressive renal failure 1 2

Mezei202lecture2012-2013 C./ CLASSIFICATION: I./ NEPHROTIC SYNDROME

MAIN POINT:

Mezei202lecture2012-2013

damage of glomeruli without leukocytes proliferation and infiltration

SIGNS AND SYMPTOMS: Proteinuria/albuminuria > 3.5 g/kg/1.73 m2/day Hypoalbuminemiahypoonciaedema Edema formation decreases blood volume, which results in: Activation of sympathetic nervous system, and RAAS causing salt and water retention and activation of AVP leading to water retention Less Atrial Natriuretic Peptide/ANP release leads to increased Na and water retention Increased blood clotting / hypercoagulation: a./ Permeability(-) surface platelet/PLT activation - PLT adhesion - PLT secretion - PLT aggregation Facilitate thrombus formation and increases blood clotting b./ Loss of endogenous anticoagulants (AT III, Protein C and S); c./ hepatic protein, blood clotting factor and fibrinogen synthesis blood clotting d./ Renal vein thrombosis, deep vein thrombosis, and pulmonary embolism are frequent Arterial thrombosis, although less common Secondary hyperlipoproteinemia 1./ HDL excretion 2./ Increased protein and therefore increased apoprotein synthesis in the liver, due to decreased albumin level: Apo B synthesis hepatic VLDL formation Apo C III (LPL inhibitor) synthesis and ApoC-II (LPL activator) loss in the urine VLDL degradation IDL and LDL As a result of the 1./ and 2./ processes: Increased risk of atherosclerosis Lipid casts in urine (with a shape of a Maltase cross) 3./ Increased Lp(a) fibrinolysis Secondary hyperparathyroidism: Level of cholecalcipherol binding protein due to the increased urinary loss, and thus amount of activated D vitamin and intestinal calcium absorption . parathyroid activation due to Se Ca2+ level. Increased risk of infections As a consequence of immunoglobulin loss in the urine Iron resistant hypochromic microcytic anemia develops Mechanism: Loss of transferrin in the urine 3

TYPES: PRIMARY 1./ Minimal change: Cause: a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows. Pathomechanism: IgM and IgA deposition and complement activation 2./ Membranous nephropathy Cause: diffuse thickening of glomerular basement membrane Pathomechanism: Immune mechanism IgG against BM, nucleus, WBC cytoplasm complement activation

3./ Focal segmental glomerulosclerosis: Cause: The extent of lesions varies in different portions of the kidney, ranging from normal unaffected glomerulus to segmental sclerosis Pathomechanism:
not immune mediated glomerulus permeability

mesangial dysfunction: persistent glomerular vasodilatation hyperfiltration sclerosis 4./ Membranoproliferative or mesangiocapillary glomerulonephritis Cause: proliferation of mesangial and endothelial cells and expansion of the mesangial matrix, thickening of the peripheral capillary walls by subendothelial immune deposits and/or intramembranous dense deposits Pathomechanism: immunocomplex deposition - subendothelially and - mesangially complement activation SECONDARY NEPHROTIC SY: DM, amyloidosis, SLE, NSAIDs, heroin, HCV, HBV, HIV

Mezei202lecture2012-2013 II./GLOMERULONEPHRITIS: MAIN POINT: Inflammation of glomeruli: Leukocyte infiltration Antigen - antibody complex deposition Complement activation Proliferation: Originating from glomerular cell matrix or leukocytes intra /endocapillary proliferation
(endothelial cells)

Mezei202lecture2012-2013 TYPES: Acute nephritic syndrome Endocapillary proliferative glomerulonephritis (GN) -hemolytic Streptococcus (Type 12)
Nephritis-associated streptococcal cationic protease and its zymogen precursor (NAPR) have been identified as a glyceraldehyde-3-phosphate dehydrogenase that functions as a plasmin(ogen) receptor. This binds to plasmin and activates complement via alternate pathway. Antibody levels to NAPR are elevated in streptococcal infections (of group A, C, and G)

extracapillar proliferation
(originating from Bowmanns capsule, epithelial cells and/or monocytes)

Membranproliferative GN Dense deposit disease Rapidly progressive glomerulonephritis Semilunar-type GN Necrotizing and semilunar-type GN Granular immune deposit GN Linear immune deposit GN

COURSE: EXTENSION: SYMPTOMS:

acute, subacute or chronic focal or diffuse Oliguria < 400 ml Intracapsular pressure increases due to proliferative processes in the Bowmans capsule. This pressure is opposite to that of the filtration one, therefore GFR decreases. Proteinuria/albuminuria Less than in nephrotic syndrome, because proliferation reduces filtration surface Hypoproteinemia Edema Partially due to reduced onkotic pressure and permeability increase Hypo- or asthenuria Reduced tubular function is the consequence of decreased renal tubular blood supply due to glomerular damage Hematuria (deformed/dysmorphic RBCs), Casts: granular, hyalin and RBC Hypertension Azotemia Renal failure

Asymptomatic hematuria and/or proteinuria IgA nephropathy the most common GN Diffuse mesangial proliferative GN Focal proliferative and necrotizing Thin basement membrane GN Alport nephropathy Chronic GN and renal failure SLE (WHO)

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Mezei202lecture2012-2013 NEPHROPATHIES T U B U L O I N T E R S T I T I A L DISEASES DEFINITION: These diseases generally involve tubules and/or the interstitium of the kidney and spare the glomeruli TYPES: I./ Acute: Causes: a./ Drugs: NSAID, sulphonamide, diuretics, anticonvulsives, antiepileptics, ACE inhibitors, H2 (histamine) blockers b./ Acute infections: Bacteria: Streptococcus, Staphylococcus, E. coli Viral: Ebstein-Barr, Cytomegalo and HIV Idiopathic Pathological signs: Interstitial edema Cortical and medullary leukocyte infiltration Focal tubular cell necrosis Clinical picture: - A c u t e p y e l o n e p h r i t i s Cause: Signs: Infection (hematogenous or ascending)

Shivering, high body temperature, tachycardia Diarrhea, nausea and vomitus Pain (costovertebral) Blood: Leukocytosis (shift to the left), Increased red blood cell sedimentation rate Bacteria (in haematogenous infections) Urine: Bacteriuria (105 colonies/mL) Pyuria WBC and WBC casts Microscopic hematuria Renal function: Intact Blood pressure: Normal - complete recovery or later - chr. pyelonephritis

Course:

Mezei202lecture2012-2013 II./ Chronic Causes:

Mezei202lecture2012-2013 PATHOGENESIS AND CONSEQUENCES OF NEPHROLITHIASIS PREDISPOSING FACTORS FOR NEPHROLITHIASIS: 1./ Organic core formation: fibrin, mucopolysaccharides, bacteria and inflammatory cells (WBCs) 2./ Concentration of stone forming substance exceeds solubility in the urine: urates, phosphates and oxalates 3./ Obstruction of urinary outflow: congenital disorders, tumors and pregnancy 4./ Alterations in the urine: concentrated due to insufficient fluid intake pH acidic basic (due to genitourinary infection) decreased inhibitory factor for nephrolithiasis: Mg, pirophosphate, citrate and peptides 5./ Other risk factors: genetic, climatic, dietary, mineral content of water, exercise and age

a./ Hereditary renal disease: polycystic kidney, Fanconi sy. with tubular damage b./ Toxic agents: Exogenous toxins: - Drugs: analgesics and aspirin - Lead - Lithium Endogenous toxins: Uric acid gout Hypercalcemia Hypokalemia (polyuria, polydipsia) Malignant tumor c./ Recurrence of acute infections Pathologic signs: Interstitial - nephritis - fibrosis Propagation of mononuclear cells Tubular damage: - atrophy - dilatation - thickening of basement membrane Chronic pyelonephritis Clinical picture: Cause: Acute pyelonephritis or Chronic beginning of a bacterial infection Signs: Fatigue, anemia, nausea, vomiting Blood: leukocytosis is absent Increased red blood cell sedimentation rate normal Se creatinine Urine: proteinuria (tubular) a significant fraction of the protein is low molecular weight microscopic hematuria WBC in urine, with leukocyte casts Urine might be sterile, as well (bacteria cannot be detected) pyuria Renal function: tubular dysfunction specific gravity of the urine is reduced Blood pressure: high retinal vessel alterations

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Mezei202lecture2012-2013 TYPES OF STONE: 1./ CYSTINE STONE autosomal recessive In physiological conditions: Dibasic amino acids (lysine, ornithine, arginine and cysteine): Amino acids are readily filtered by the glomerulus and undergo nearly complete reabsorption by proximal tubular cells.
At least 2 transport systems are responsible for cystine reabsorption, as follows:

Mezei202lecture2012-2013 4./ CALCIUM STONE: 70% of kidney stones are calcium stones, from which 60% is oxalate and 10% phosphate containing stone a./ calcium-oxalate formed in acidic urine and gives well defined X-ray shadows characteristic for renal calculi

CAUSE:

The high-affinity system mediates uptake of 10% of L-cystine and the dibasic amino acids at the apical membrane of the straight third segment of the proximal tubule (Type I cystinuria).
Low-affinity system: is present in the S1-S2 part of the proximal tubule and is responsible for 90% of L-cystine reabsorption (Type II and III cystinuria).

hyperuricosuria: - formes urea stone core hypercalcuria: - hyperparathyroidism - stone metastases hypocitrateuria (citrate and Ca form a soluble complex) - metabolic acidosis, renal tubular acidosis - hypokalemia - bacteria degrade citrate content of urine hyperoxaluria: - increased oxalate intake: sorrel, spinach, chocolate with nuts and parsley - increased oxalate absorption in the colon (passive process): physiology: Ca binds to intestinal oxalate, which is not absorbed but defecated there is increased oxalate absorption: if lipid content of faeces is high: Calcium soap is formed, excreted with faeces Oxalate cannot bind to Ca and thus cannot be excreted via faeces and it is absorbed if permeability of colon increases - increased oxalate formation: glycine metabolism disorder, congenital enzyme defects: type 1: 20 OH 3oxo adipate carboxylase defect: glyoxalate cannot be formed to CO2 but oxalate type 2: due to D-glycerate dehydrogenase defect amount of OH pyruvate elevates - that encourage fomation of glyoxalate into oxalate - formed to L-glycerate: metabolic dead end voided via urine

The genetic defect impairs intestinal absorption and renal reabsorption of cystine, causing elevated urinary levels of cystine and subsequent crystallization and cystine stone formation. 2./ URATE STONE Urate is a nucleic acid break down product (purinehypoxanthinexanthineurate) Urate: is filtered at the glomerulus. The renal tubule can reabsorb (movement of urate from tubule lumen to peritubular fluid) or secrete (movement of urate from peritubular fluid into tubular lumen) urate. Uric acid is a relatively water insoluble end-product of purine metabolism Uric acid stones are produced when the urinary uric acid concentration is increased secondary to overproduction, increased renal tubular urinary uric acid secretion, decreased renal tubular urinary uric acid reabsorption, decreased urinary water content, increased hydrogen ion concentration in the urine. 3./ STRUVITE STONE Mg-AMMONIUM-PHOSPHATE Struvite stones are associated with urinary tract infections. Specifically, the presence of urease-producing bacteria, Ureaplasma urealyticum Proteus species (most common), leads to the hydrolysis of urea into ammonium and hydroxyl ions. Increase in ammonium and phosphate concentrations combined with the alkaline urine (pH >7.2) is necessary for struvite and carbonate apatite crystallization, so magnesium ammonium phosphate crystals (MgNH4 PO4 6H2 O) formation. Stones are large, coral-shaped and expand also to smaller chalices

b./ calcium phosphate formed in alkaline urine, in urinary tract infection big, roughed and take up the shape of the cavity cause: hypercalcuria D hypervitaminosis Hyperparathyroidism Milk-alkali syndrome

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Mezei202lecture2012-2013 CLINICAL SIGNS OF STONES: pain, spasm vomitus anuria paralytic ileus hematuria COMPLICATIONS OF STONES: Urine stagnation: Urinary tract infection Decrease of filtration and anuria Tubule damage RENAL FAILURE DEFINITION: Kidneys fail to adequately function: Urine is not formed anuria Do not detoxicate azothemia TYPES: ACUTE RENAL FAILURE Sudden decrease of glomerular filtration (in hours) CHARACTERISTICS: 50% decrease of creatinine clearance Anuria occur Increase of Se creatinine is 44 micromol/L (50% increase) Sudden deterioration of renal function that requires dialysis CAUSES: I./ Prerenal: 1./ Condition with hypovolemia (exiccosis): External loss (intestinal tract, kidney and skin) Internal loss (into interstitium, abdominal cavity and intestines) 2./ Conditions with decreased cardiac output : Myocardium disorders: MI Pericardial tamponade, fibrosis Vitiums Arrhythmias Pulmonal hypertonia 3./ Disturbed renal filtration: Renal vessel constriction: In hepatorenal syndrome: renal perfusion due to abdominal vessel dilatation Macroglobulinemia Myeloma Polycystic kidney

Mezei202lecture2012-2013

II./Renal: 1./ Renovascular occlusion: a./ renal artery occlusion: atherosclerosis, thrombosis, embolia and vasculitis b./ renal vein occlusion: thrombosis and external occlusion 2./ Glomerular and microvessel disorders: glomerulonephritis vasculitis microangiopathy: hemolytic uremic syndrome /HUS, thrombotic thrombocytopenic purpura /TTP, disseminated intravascular coagulation /DIC) toxemic pregnancy malign hypertension 3./ Acute tubular necrosis a./ toxic: endogenous -myoglobin - rhabdomyolisis hemoglobin - hemolysis urea cell lysis these substances are filtrated via glomeruli, precipitated in the tubules and cause epithelial cell degradation exogenous toxins: ethylene glycol chemotherapy medicines antibiotics (aminoglycosides) radiological contrast media 14

A and NA effect and Hypercalcemia

Hyperviscosity syndrome:

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Mezei202lecture2012-2013 b./ interstitial nephritis: Allergy -immune origin, medicines: antibiotic-riphampicin, thrimetoprin, NSAID, Diuretics Infection: Bacterium - E. coli Virus - Cytomegalo Fungus - Candida Cellular infiltration: Lymphoma, Leukemia and Granuloma Tubule occlusion: Exogenous toxins: Acyclovir, Sulphonamide and Oxalate Rejection following to an acute renal transplantation III./ Postrenal: Ureter occlusion: renal calculi, blood clot and external pressure (tumor and fibrosis) Bladder neck: prostate hypertrophy, renal stone, tumor and blood clots Urethra occlusion: scarring, fibrosis, congenital (phimosis) SIGNS: In hypovolemia: Decrease of blood pressure, dizziness and unconsciousness Tachycardia Oligo-, anuria Elevation of remnant nitrogen in blood Renal origin beside previous: Hematuria (RBC casts) Porteinuria Postrenal origin: Hypogastrial pain and macroscopic hematuria might occur Tubule injury due to renal ischemia: Detachment of tubule cells, Pathologic substances might get back to the circulation via the injured tubules COURSE: If eliciting factors are relieved: renal circulation, perfusion and tubular function might be recovered (tubular epithelial cells might be regenerated)

Mezei202lecture2012-2013 CHRONIC RENAL FAILURE MAIN POINT: Occur due to decrease of nephron number and function. GFR is 20% under the physiologic value. (normal value 120 mL/min). CAUSE: 1./ glomerulonephritis 2./ diabetic nephropathy (the most frequent) 3./ hypertension 4./ polycystic kidney ADAPTATION: with decreased tubular reabsorption a./ phosphate excretion increases: Due to mild/moderate renal failure Se phosphate Se Ca Se calcitriol synthesis ( inhibitory effect of PTH) PTH secretion Ca reabsorption phosphate excretion Severe renal failure - hyperphosphatemia is always presented - amount of active D-vitamin decreases - amount of circulating hormone and receptor decrease inhibitory effects cannot be expressed - hypocalcemia develops due to decreased intestinal absorption - PTH level rises because site of PTH metabolism, the renal parenchyma, decreases and osteal PTH resistance develops b./ Na excretion increases in advanced renal failure Due to nephron loss NaCl and water reabsorption ability of proximal tubules aldosterone is ineffective NaCl excretion and decreased reabsorption increase of urea and creatinine level osmotic diuresis level of natriuretic factor increase In tubules in remaining nephrons fractionated water excretion increases isosthenuria decreased tolerance to water load and withdraw nycturia is frequent With increased tubular secretion K excretion Ammonia excretion: 25% GFR - 4x increase of ammonia production manifest pH divergence / bones buffer, bicarbonate level is low then mild non-anion gap acidosis (sulphate and phospate do not increase) anion gap acidosis sulphate and phosphate increase

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Mezei202lecture2012_2013 MALADAPTATION: Adaptive (i.e. compensatory) mechanisms deplete, in 90% decrease of GFR. Uremia, clinical syndrome of chronic renal failure, develops LABORATORY TESTS: Azotemia: Se RN (rest nitrogen) is elevated (Se carbamide and creatinine) Increase of other elevated metabolic substances Electrolyte disorders: hyperphosphatemia Hypocalcemia Se Na might be low or elevated as well Se K might be low or elevated as well UREMIA CLINICAL SIGNS I./ Signs of osseous system: Due to renal parenchyma damage: 1./ Decreased renal 1-OH-ase activity: Outcome: Decreased amount of 1-25 OH vitamin D and thus decreased intestinal calcium reabsorption and thus hypocalcemia develops that increases PTH release, and as a result (secondary hyperparathyroidism) calcium mobilization from bones increases generalized osteitis fibrosa cystica (Recklinghausens disease) 2./ Decreased renal excretion function: a./ Decreased phosphate excretion, and thus elevated Se phosphate and hypocalcemia (Se Ca decreases) develops see outcome in 1./ b./ Decreased ammonium ion synthesis and thus H+ cannot be excreted adequately, this cause increased anion gap metabolic acidosis, and as a result phosphate excretion and calcium reabsorption of renal tubules decrease this cause elevation of Se phosphate and decrease of Se calcium Calcium and phosphate excretion from bones increases as well, thus osteoporosis is developed c./ Toxic substances might remain in the body, with a result of decreased vitamin D effect that cause decrease of Se Calcium level Osteomalacy or in children rachitis occur

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II./ Hematologic signs: 1./ RBC formation a./ normocytic normochrom anemia: due to decreased renal erythropoietin production b./ hemolytic anemia: due to metabolic acidosis c./ microcytic hypochrom iron deficiency anemia due to frequent gastrointestinal hemorrhages and inadequate absorption 2./ coagulation disorders: a./ protrombin synthesis decreases -with an outcome of hemophilia b./ disorders of thrombocyte (PLT) function guanidinosuccinate binds to thrombocyte surface, thus thrombocyte adhesion, aggregation and secretion becomes disturbed 3./ WBC count decreases: Decreased number and function of lymphocytes, neutrophil granulocytes monocytes Outcome: increased susceptibility to infections

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Mezei202lecture2012_2013 III./ Neuromuscular signs: Dementia due to aluminium intoxication Decreased concentrating ability Muscle spasm (restless leg) Peripheral neuropathy, due to elevation of remnant nitrogen Enecephalopathy, Cerebral hemorrhage, Cerebral edema, Sensory and motory nervous system disorders IV./ Cardiovascular system: hypertension, heart failure, pericarditis, rhythmic disorders V./ Pulmonary disorders: pleuritis, dyspnoe

VI./ Gastrointestinal signs: Nausea, vomitus, hiccup Anorexia Gastrointestinal hemorrhage Uremic halitus Uremic ulcus: due to defense Helicobacter pylori infection VII./ Endocrine system: Secondary hyperparathyroidism Hyperglycemia Amenorrhea Oligospermia, decreased testosterone Decreased growth

VIII./ Skin: Anemic skin Yellow deposits due to urochrom Purpuras due to thrombocyte function disorders Pruritus due to increase of pathological metabolic substances IX./ Metabolic changes: Hypothermia due to decreased metabolism Hypertrigliceridemia Metabolic acidosis Hypo- or hypernatremia and hypo- or hyperkalemia might occur as well Glucose intolerance

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