Pathophysiology

of renal system

Pathogenesis of acute and chronic

renal failure

KIDNEY STRUCTURE and FUNCTIONS

Filtration Reabsorption Secretion Excretion Incretion

proximal tubule

Bowman’s space

Basal membrane

Visceral Epithelium podocytes

Mesangial cell

Endothelium

JGA

The structure of nephron

Epithelial Podocyte

Major functions of the kidney

EXCRETORY - Maintain plasma osmolality near 285 mosm by varying the excretion of water - Maintain plasma concentration of each electrolyte with normal range -Maintain the plasma pH (7.35-7.45) eliminating excess H+ or reabsorption HCO3

-Excrete the nitrogeeous and products of protein metabolism: -Urea, uremic acid, creatinine

NONEXCRETORY -Produce renin - regulation of blood pressure -Produce erythropoietin – stimulation of erythropoiesis -Metabolize vitamin D -Degrade insulin (20%)

--Produce prostaglandin

Normal blood chemistry levels

Substance Normal value

Blood urea nitrogen (BUN) 8.0-25.0 mg/dl Creatinine 0.7-1.5 mg/dl Sodium 135 – 147 meq/l Chloride 100 – 106 meq/l Potassium 4.2 - 5 meq/l Carbon dioxide 24 – 29 meq/l Calcium 8.5 – 10/3 mg/dl Phosphate 3 – 4.5 mg/dl Uric acid 2.6 – 7.2 mg/dl pH 7.35 – 7.45

concentration of urine descending loop reabsorption of water NaCL diffloses in Ascending loop Na reabsorps ,water stays in Urea secretion in thin segment

reabsorption of: Nacl H 2 O (ADH ) HCO3

SECRETION of: K H NH3 some drugs

reabsorption of water (ADH) reabsorption or secretion : Na, K, H, NH3

Renal investigations 1. Examination of urine evaluation of color, turbidity (clear), pH, specific gravity (1.016-1.022), sediments 2. Blood urea 3. Serum creatinine 4. Glomerular filtration rate (GFR) 5. Blood urea nitrogen (BUN) 6. Radiology, isotopic studies computerized tomography 7. Ultrasound 8. Renal biopsy PROTEINURIA - up to 150 mg/day Trace < 30 mg/100ml in urin HEAVY PROTEINURIA ≥ 3.5 g/day ( up to 20-30 g/day)

Calculation of clearance GFR (renal filtration velocity )

a x (creatinine in serum : b) x (0,993) age

sex a b

Women 144 61,9

Men !$$ 79,6

GFR = (140-age) x body mass Kg x (1,23 for men or 0,5 for women) creatinine in serum (mkmol/l)

GFR = 39,1 x [height/creatinine] 0516 x [1,8/cystitis] 0,294 x x [30/BUN]0,169 x 1099 male x [height/1.4]0188

Cystain C in serum can secrets by all nucleated cells and appears in blood , is filtrated freely and reabsorbed completly

CASTS in urine

red cell casts

hyaline casts

waxy casts

epithelial casts

granular casts

Daily DIURESIS

Normal diuresis - 1.0 – 1.5 l ( diet dependent)

Oliguria less then 1.0 l up to 300 ml (hypotension,

hypovolemia, intrinsic renal diseases

Polyuria more then 1.5 l up to 10 – 20 l

(usually with nocturia) - excessive intake of water - ↑ excretion of solute (hyperglycemia) - ↓ ADH production - intake diuretics - ↓ osmolality of blood

Classification of Renal failure

ACUTE: - abrupt of onset

- often is reversible ( if recognized early)

CHRONIC: - develops slowly

- end – result of irreparable damage to the kidneys

DUE TO PATHOGENESIS: PRERENAL failure RENAL failure POSTRENAL failure

DUE TO ETIOLOGY: infectious, autoimmune, ets.

PRERENAL FAILURE (ARF)

impaired blood flow

↓ GFR, ↑ BUN

tubular necrosis

hypovolemia dehydration septicemia, shock, heart failure, surgery, (ets.)

CAUSES:

Intrarenal failure (ARF)

Glomerular : - acute GN acute pyielonephritis Tubular (most common) - Ischemia, - toxic agents -obstruction

Interstitial Tubular obstruction (casts, myoglobin, cellular debris Hb)

Postrenal failure

Obstruction of urine output from the kidney ureter (calculi, stridures) bladder (tumor, neurogenic) urehtra (prostatic hypertrophy / hyperplasia)

kidney stone, scar tissue

pregnancy, abnormal growth

bladder outflow obstruction

Examples of kidney pathology

Acute renal failure (ARF)

ARF is an abrupt reduction in renal function. - is usually associated with oliguria - sufficient to increase nitrogenous wastes - impaired fluid and electrolyte balance - ↓ GFR - Azotemia - ↑ blood levels of nitrogenous wastes: urea, uric acid, creatinine

RISK FACTORS FOR ARF: impaired renal blood flow - diabetes, - administration of nephrotic drugs, which alter intrarenal hemodynamic, -elderly age

ACUTE RENAL FAILURE

pre renal causes renal causes (intrinsic)

postrenal causes

tubular necrosis interstitial necrosis ( 10% of cases)

acute glomerulonephritis (5% of cases)

ischemia ( 50% of cases)

toxins ( 35 % of cases)

CAUSES of ARF: • intravascular volume depletion and hypotension due to GI, renal, dermal losses, hemorrhage, shock, congestive heart failure, cirrhosis, nephrosis • Medications : cyclosporine, radiocontrast agents • Hepato -renal syndrome

• Large-vessel renal vascular disease: renal arterial thrombosis or embolism , renal artery stenosis • Small – vessel renal vascular disease: vasculitis, arterioembolism, sclerodermia hemolytic-uremic syndrome, sickle cell anemia, hypocalcemia • Sepsis

•Generalized or localized reduction in renal blood flow

To control acute renal failure – monitoring of:

- urine osmolality - urine concentration Na ( Na reabsorbtion is maintained in prerenal azotemia, is lost in acute tubular necrosis ) - proteinuria - hemoglobinuria - casts in the urine - blood creatinine, BUN – blood urea nitrogen

STAGES of ARF: - initial, - oliguria, - poyiuri (restoration of diuresis), -recovery

ACUTE RENAL INJURY

STAGES: 1) Risk 2) Injury 3) Renal failure 4) Loss of functions 5) End stage of renal disease (terminal)

chronic renal diseases = Chronic renal failure

The main criteri0ns for ARI are decreased diuresis and decreased GFR less then 60 ml/min.

The stages of chronic renal disease define due to GFR but Not to concentration of plasma creatinine.

TYPICAL urine finding in ARF CONDITION DIPSTICK TEST SEDIMENT urine Fractional analysis osmol excretion

Prerenal Trace or no A few hyaline > 500 < 1% Azotemia proteinuria casts possible mosm/kg

Renal azotemia Tubular injury Mild to Pigmented < 350 > 1% Ischemia moderate granular mosmol/kg proteinuria casts Acute intrstinal + hemoglobin RBC, > 500 < 1% nephritis leukocytes RC casts ACUTE Glomerular- Nephritis +hemoglobin -- “ -- POSTRENAL Trace or no Crystal <350 >1% Azotemia proteinuria RBC, WBC

Mechanism of oliguria in ARF ischemia or nephrotoxins

glomerular injure

tubula r injure

vasoconstriction

decreased permeability decreased surface area

cellular cast formation

decreased GFR

OLIGURIA

obstruction

increased untraluminal pressure

tubular back leak

Symptoms and signs of ARF

• Diminished urinary output – urine may be dark from concentration of BR or presence of free Hb • Total anuria – no urine at all suggest postrenal obstruction • Thirst and dry mouth – dehydration, i.e. Prerenal • Hiccough, drowsiness from acute uremia • Dyspnea due to pulmonary edema from over hydration

ARF complicatons: -hyperkaliemic cardiac asystole, -pulmonary edema and respiratory failure, - secondary sepsis, - DIC-syndrome, - hypophosphatemia and hypokalemia during diuretic recovery stage

CHRONIC RENAL FAILURE -

progressive and irreversible loss of renal function

Causes: -uncontrolled hypertension, - urinary tract obstruction and infection - disorders of the glomeruli - systemic diseases (diabetes mellitus)

4 stages for progression: 1) diminished renal reserve 2) renal insufficiency 3) renal failure 4) end-stage-renal disease (terminal)

4 stages for progression

number of nephrons in %

months or years

1-00 - 75 - 50 - 25 - 0

1--↑ risk of azotemia 2 – hypertrophy of remainding nephrons. Isostenuria. 3 – The kidney cannot regulate volume and solute composition ; - edema - metabolic acidosis; - hypercalcemia 4 - ↓ renal capillaries; - scaring in the glomeruli; - atrophy and fibrosis in the tubules; - ↓ kidney mass

1

2

3

4

TO control renal function they find out: - GFR

- creatinine clearance - Creatinine in serum - Cystatin C

Chronic renal failure • Body fluid changes

• Inability to concentrate and dilute urine

• ↓ ammonia synthesis, ↓HCO3 conservation

• ↓ potassium excretion

• hyperphosphatemia and inability to activate vitamin D

• ↓ synthesis of erythropoietin, uremic toxins

• impaired platelet formation

• Manifestations

• fixed specific gravity of urine, polyuria, nocturia

• Metabolic acidosis

• Hyperkalemia

• hypocalcemia, ↑parathyroid hormone

• Anemia

• Bleeding tendencies epistaxis, hemorrhagia, gastrointestinal bleeding bruising of the skin

CHRONIC RENAL DISEASE

STAGES: 1. Symptoms and signs of renal injury (nephropathy) with

normal GFR ≥ 90 ml/min/1,73 m3 2. Nephropathy (Renal injury) with initial decreased GFR GFR < 60 – 89 ml/min 3. Moderate nephropathy decreased GFR Bb = 30 – 59 ml/min 4. Severe decreased GFR = 15 – 29 ml/min 5. Terminal renal failure

Chronic renal failure – from decreased GFR Less then 30 -59 ml/min/m3

Chronic renal disease STAGES: 1) the features of renal injury GFR ≥ 90 ml/min /1,73 m 2 2) renal injury with initial ↓GFR (60 – 89) 3) moderate decrease d GFR (30 – 59) 4) SEveare decreased GFR ( 15- 20) 5) Terminal renal failure

Stages base on the changes of GFR, but not on the concentration of plasma creatinine

CHRONIC RENAL FAILURE Systemic effect of uremia

• Cardiovascular function

- Activation of RAAS

- ↑ vascular volume

- ↓ vasodilator proataglandins

- Metabolic toxins

- Fluid retention, hypoalbuminemia

- ↑ extracellular fluid volume

- Gastrointestinal function

- Increased metabolic wastes:

- decomposition of urea by intestinal flora → ↑NH3 ,

- ↑ gastric acid secretion

• Manifestations

• Hypertension

• Uremic pericarditis

• Edema

• Congestive heart failure, pulmonary edema

• Anorexia, nausea, vomiting;

• Ulceration and bleeding of GI mucosa

CHRONIC RENAL FAILURE • Altered immune function

• Impaired cellular and humoral

immunity

• Impaired skin and mucosal barriers

• Neurologic function

• Uremic toxins → atrophy and demyelination of nerve fibers

• Fluid and electrolyte imbalance ↑ metabolic acids and other small, diffusible particles (urea)

• Manifestations

• Infections

• Peripheral neuropathy

• Headache

• Encephahlopathy: loss of recent memory, lethargy ,coma, seizures, asterixis, muscle twitching

RENAL OSTEODYSTROPHY

CRF →↓ P excretion→↑ P plasma levels →↓ Ca +2 → ↑ PTH (parathormon)

→bone tissue → ↑Ca+2 reabsorbtion from bone tissue

additional factors: cytokines, persistent hypogonadism

CRF→ ↓vitamin D → → ↓Ca +2 absorbtion in intestine ↓*Ca+2 ] in plasma Hyperparathyroidism

↓ vitamin D

Renal syndromes and symptoms CHANGES IN DIURESIS: Polyuria - increased daily diuresis more then 1,5 liter Loss of tubular function; Conn’s syndrome; pyelonephritis

Olygouria - decreased daily diuresis low then 1 liter

Decreased number of functional nephrons; sclerosis or thrombosis of renal vessels; obstruction of collecting duct, ureter,

ANuria - daily diuresis not more then 30 -50 ml

Decreased Arterial blood pressure low then 50 mm Hg, ARF; CRF Creatinine cLearance provides a good mesure of GFR . GFRcr = ( Ucr x V) : Pcr. GFR = 100 -120 ml/min. CREATININE - a substance ,produced by muscles, is measured in plasma and urine to calculate GFR. Plasma creatinine concentration = 0,7 – 1,2mg/dl

Blood urea nitrogen - normal range = 10- 20 mg/ dl of blood

BUN increases when ↓ GFR Changes of specific gravity and pH of urine: normal SG = 1.016 –1.022 pH < 6 Urine sediment - casts, red blood cells, white blood cells, crystalls,

Renal syndromes and symptoms

Uremic syndrome -occur the most frequently in patients with renal

pathology. Characterized by protenuria, hematuria, leukocyturia

Proteinuria - loss of proteins with urine more then 300 mg/daily.

Selective proteinuria - in urine appear protein s with molecular mass less then 70000 (albumins) IS = 15 30% Unselective proteinuria - in urine appear proteins with molecular mass more then 70000. IS > 30% Index selectivity (IS) =( clearance IgG : clearance alb) x 100% Hematuria – increased number of red blood cells in urine. ( Normal: 1 ml of urine - not more then 1000 erythrocytes) Renal ← glomerulonephritis, tuberculesis. Postrenal ← cistitis, urethritis, trauma.

EXTRA renal syndromes

AZOTEMIA - blood urea nitrogen > 30 mmol/l (urea >6 mmol/l, creatitine > 0,1 mmol/l )

EDEMA - disturbance of water –electrolyte balance

NEPHROTIC syndrome - secondary aldosteronism,

↓ oncotic pressure in blood lymphtic failure

RENAL ARTERIAL HYPERTANSION - activation of RAAS

Nephritic syndrome

Causes: -acute proliferative glomerulonephritis Ig A nephropathy Rapidly progressive glomerulonephritis

Primary Secondary disease of the glomeruli effect of systemic vasculitis SYNDROME can be initiated by: -Immune complexes, -Antiglomerular BM-antibodies, -Leukocytes

Clinical manifestations : - Hematuria with red blood cells - ↓ GFR -Azotemia, -Oliguria -Hypertension

Pathophysiology of nephrotic syndrome

Altered glomerular permeability and loss of negative charge

increased function of plasma protein

proteinuria

hypoalbuminemia

edema hepatic synthesis of lipoproteins

hyperlipoproteinemia

lipiduria

NEPHROSIS Primary disorder Secondary to systemic diseases: (mainly in children younger then 15 year0s Diabetes Mellitus -Minimal change disease -Focal sclerosis -- Membranous glomerulopathy --Membranoproliferative glomerulonephritis

1) diffuse loss of processes from epithelial layer 2) sclerosis of some glomeruli 3) diffuse thickening of BM due to deposition of immune complexes 4) BM thickening + cellular proliferation ( primarily of mesangium cells)

Pathophysiology of nephrotic syndrome Glomerular damage

↑ permeability of glomerular capillaries

PROTEINURIA ( ≥ 3,59g/24 hr)

HYPOPROTEINEMIA (albumin < 3g/d )

↓ plasma oncotic pressure Compensatory ↑ synthesis of proteins and lipoproteins by liver

HYPERLIPIDEMIA

↓ plasma volume

↓ GFR Fluid escapes into tissue

EDEMA ↑ aldosteron secretion

Nephrotic syndrome shows the total damage of kidney

Nephrotic syndrome is characterized by proteinuria -hypoproteinemia - edema

Nephritic syndrome shows the inflammation in nephrons

UREMIC syndrome

The main features of UREMIC SYNDROME are proteinuria and hematouria. Some times leukocytemia and casts.

Characterized by increased blood urea and creatinine levels accompanied by systemic effects.

Glomerulonephritis

Glomerulonephritis is a number of renal disorders in which proliferation and inflammation of the glomeruli are secondary to immune mechanism.

GLOMERULAR INJURY: immune origin: antibody, AB-Ag complexes Antigens: endogenous (DNA in epithel .cells) exogenous ( hemolytic streptococci )

GLOMERULAR DISEASES: -proliferative - sclerotic -membranous: diffuse, focal, segmental, mesangial

PATHOGENESIS OF GLOMERULONEPHRITIS

sensibilation t o infections

Ag-AB complexes in blood

deposition of immune complexes in glomeruli

AB –synthesis to Ag of glomerular basal membrane

Ag-AB complexes on glomerular basal membrane

complement activation

proliferation of macrophages and mesangial cells

release , mediators, proteases, oxidants

thrombosis in capillaries

↓ renal blood flow

activation of RAAS ↑ Art. blood pressure edema

↑ permeability

uremic syndrom

↓ GFR

↓ diuresis, azotemia

renal failure

Acute pyelonephritis

CAUSES: microorganisms: E coli, proteus, pseudomonas. Fungus, virus. RISK Factors: Urinary obstruction and reflux of urine from the bladder Neurogenic bladder, female sexual trauma

The infection is spread by ascending microorganisms along Ureters ( by bloodstream, lymphstream)

CLINICAL MANIFESTAIONS: fever, chills, pain, dysuria , polikuria, may be nausea, vomiting as a result of toxicity. IN BLOOD : NP leukocytosis, ↑ESR, anemia. IN URINE CULTURE : microorganisms