Renal Pathology PDF

Renal physiology: Kidneys - The kidneys serve many important homeostatic functions, including the following: ▪ Excretion of metabolic waste products and foreign chemicals, include: ➔ Urea (protein metabolism), Creatinine (muscle metabolism) & Uric acid (nucleic acids metabolism)...

Renal physiology: Kidneys - The kidneys serve many important homeostatic functions, including the following: ▪ Excretion of metabolic waste products and foreign chemicals, include: ➔ Urea (protein metabolism), Creatinine (muscle metabolism) & Uric acid (nucleic acids metabolism) ➔ Most toxins & other foreign substances (by the body or ingested: pesticides, drugs, food additives). ➔ Hemoglobin breakdown products (i.e., bilirubin) ➔ Metabolites of various hormones. ▪ Regulation of body fluid osmolality and electrolyte concentrations ▪ Regulation of water and electrolyte balances ▪ Regulation of arterial pressure ➔ Kidneys play main role in long-term BP regulation by excreting variable amounts of Na & H2O. ➔ Kidneys contribute to short-term BP regulation by secreting renin from juxtaglomerular apparatus that lead to the formation of vasoactive products (e.g., angiotensin II). ▪ Regulation of acid-base balance ➔ Organs for acid-base balance: Kidneys, Lungs & Body fluid buffers. By excreting acids (H+) and HCO3-. It is responsible for the long-term regulation of acid base balance. ➔ Kidneys are the only way of elimination certain types of acids, (sulfuric acid & phosphoric acid) ▪ Regulation of erythrocyte production ➔ 90% Erythropoietin is secreted by Kidneys, which stimulates RBCs production from BM. ➔ Hypoxia is the main stimulus for erythropoietin secretion. ➔ People with severe kidney disease or who removed his kidney or on hemodialysis, Severe anemia develops because of decreased erythropoietin production. ▪ Secretion, metabolism, and excretion of hormones ➔ Hormones produced in the kidney: Erythropoietin, Vitamin D and Renin ➔ Hormones metabolized and excreted by kidney: Insulin, Angiotensin II, Most peptide hormones. ▪ Gluconeogenesis: glucose synthesis from amino acids ▪ Regulation of vitamin D activation. ➔ Kidneys produce active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol): By hydroxylating this vitamin at the “number 1” position. By α1-Hydroxylase enzyme. ➔ Calcitriol plays an important role in calcium and phosphate regulation. Normal calcium deposition in bone Calcium reabsorption by the gastrointestinal tract.  Notes: Azotemia (uremia) is a common condition that occurs when you have too many waste products in your blood (elevation of blood urea nitrogen (BUN) & serum creatinine levels.) General organization of the kidneys - Kidneys lie on the posterior wall of the abdomen, outside the peritoneal cavity (Retroperitoneal). - Anatomy: ▪ Hilum: indented region in the medial side of kidney ➔ Renal artery & vein, lymphatics, nerve, and ureter will pass through it. ▪ Kidney: ➔ Fibrous Capsule: for protection. ➔ Outer cortex ➔ Inner medulla: Divided into 8 to 10 renal pyramids (cone-shaped). Renal pyramid:  Base: originates at the border between the cortex and medulla.  Apex: terminates in the papilla which projects into the renal pelvis. ➔ Renal pelvis: Minor calyces: collect urine from the tubules of each papilla. Major calyces: collect urine from the Minor calyces. ▪ Ureter: carries the urine from renal pelvis to the bladder. ▪ Bladder: where urine is stored until the bladder is emptied. Renal blood supply - Blood flow to the two kidneys is normally about 22 % of the cardiac output. - Renal artery: ▪ Enters the kidney then branches progressively: Interlobar arteries → Arcuate arteries → Interlobular arteries → Afferent arterioles → Glomerulus → Efferent arteriole → Peritubular capillaries → Empty into the vessels of the venous system → Interlobular vein → Arcuate vein → Interlobar vein → Renal vein. - Afferent & Efferent arterioles help regulate the hydrostatic pressure in both sets of capillaries. ▪ Glomerular capillaries: ➔ High hydrostatic pressure (60 mmHg) → Filtration ▪ Peritubular capillaries: ➔ Low hydrostatic pressure (13 mm Hg) → Reabsorption - As Response to body homeostatic demands: ▪ There will be changes in the arterioles' diameter (resistance). ➔ Regulate hydrostatic pressure in glomerular & peritubular capillaries. ➔ Thus, changing the rate of glomerular filtration, tubular reabsorption. Nephron ▪ Each kidney has about 1M microscopic nephrons (The functional unit of the kidney). ❖ Tubular Components - Glomerulus: Have high hydrostatic pressure (60 mmHg). ▪ Glomerular capillaries covered by: Epithelial cells of Bowman’s capsule. ▪ Filtered fluid from the glomerular capillaries flows into Bowman’s capsule. - Bowmans’s capsule - Proximal convoluted tubule (in the cortex). ▪ Most of reabsorption occurs here. - Loop of Henle (in the medulla) ▪ Ascending limb = thick segment. ▪ Descending limb = thin segment. - Distal convoluted tubule (in the cortex). ▪ Will form juxta-glomerular apparatus. - Collecting duct ▪ Collects the final form of urine from many nephrons. - Macula Densa ▪ Elongated cells of the distal tubule. ▪ Senses any change in NaCl concentration & filtrate volume in DCT. Urine formation - The rates of substance excretion in the urine depends on: 1. Glomerular filtration ▪ Plasma is filtered from glomerular capillaries into Bowman’s capsule ▪ All substances are filtrated Except: ➔ Large size & negatively charged substances as plasma proteins. ▪ Normally about 20% of the plasma in glomerulus is filtered. ▪ The other 80% of plasma is not filtered and passes into the efferent arteriole to peritubular capillaries. ▪ Glomerular Filtration Rate (GFR): ➔ Equals to: 180L/day or 125ml/min, ➔ Why huge GFR? To filtrate the plasma 60 times per day!!! Filtration barrier Layer Notes: Endothelium Very fenestrated & allow only the small substances to pass through Basement Has -ve charge membrane Epithelium Inner layer of Bowman’s capsule (podocytes) Form filtration slit ▪ The factors that influence the filtration rate: ➔ The size of the molecule. ➔ The charge of the molecule. 2. Tubular reabsorption: ▪ Filtered substances are transferred from tubules to peritubular capillaries. ▪ This process is highly selective and variable. ➔ 99% for water, 100% for glucose & AA, 99.5% for salt, 50% for urea and 0% creatinine. ➔ Most substances that must be cleared are poorly reabsorbed → High amounts in urine. ➔ Electrolytes (Na, Cl, HCO3-) are highly reabsorbed → only small amounts in urine. ➔ Nutritional substances, (AA & glucose), are completely reabsorbed → do not appear in urine. 3. Tubular Secretion: ▪ Secretion plays an important role in determining the amounts of K+ & H+ & drugs' waste products that are excreted in the urine. - Each of the processes is regulated according to the needs of the body. ▪ Excess sodium in the body → Rate of Na filtration increases, and rate of Na reabsorption decreases, causing increased urinary excretion of sodium. Renal handling of four hypothetical substances. - Substances are categorized as the following: ▪ Freely filtered but is neither reabsorbed nor secreted. ➔ Excretion rate = Filtration rate (Figure A). ➔ Examples: Creatinine (Endogenous) & Inulin (Exogenous). ▪ Freely filtered but partly reabsorbed. ➔ Excretion rate less than Filtration rate (Figure B). ➔ Examples: Electrolytes (Na & Cl) & Urea. ▪ Freely filtered but completely reabsorbed. ➔ Excretion rate = Zero (Figure C). ➔ Examples: Amino acids and glucose. ▪ Freely filtered not reabsorbed but secreted. ➔ Excretion rate more than Filtration rate (Figure D). ➔ Examples: para-aminohippuric acid (PAH) & organic acids and bases  Notes: Creatinine is a very important indicator of renal failure.  Renal pathology Symptoms of renal pathology Quantity of urine excretion - Urine volume with waste products (1 - 1.5 liters/day) - Polyuria: Urine output/ 24 hours > 3 L/day in adults ▪ Causes: Diabetes mellitus, Diabetes insipidus, Diuretics, Excess fluid intake, lithium. - Oliguria: Urine output/ 24 hours < 400 mL/day ▪ Causes: Acute kidney injury - Anuria: no urine excretion ▪ Causes: Shock, Urinary tract obstruction, Vascular occlusion. Changes in urine - Dysuria: Pain or discomfort during micturition, ▪ Cause: Lower urinary tract infection, Prostate gland enlargement. - Glycosuria: Glucose in the urine ▪ Occurs when blood glucose levels exceed 180 mg/dL (renal threshold for glucose reabsorption) ▪ Causes: Diabetes mellitus - Proteinuria: > 150 mg protein/day in the urine → (Froth urine!) ▪ Normally low MW proteins are filtered at glomeruli, but they are reabsorbed. ▪ Proteinuria of low MW proteins more than 2g/day indicates significant glomerular disease. - Hematuria: Red blood cells in the urine ▪ Normally: Few RBCs are detected by microscope ▪ Causes ➔ Bleeding from anywhere in renal tract: Kidneys: Clotting disorders, Cyst, Tumor, Glomerular disease, Interstitial disease, Infarction Ureter: Cancer, Stone Urinary Bladder: infection Urethra: Trauma in urethra. ▪ Microscopic (only evident on microscopic) or macroscopic/gross (evident on visual exam). ▪ Beeturia: red discoloration of urine after eating beetroot ▪ Drug-induced urine discoloration: ➔ Rifampin: harmless red-orange discoloration of bodily fluids (urine, sweat, tears)  Notes: ▪ Examination of urine is helpful in establishing the cause of hematuria: ➔ Presence of WBCs and micro-organisms suggests infection. ➔ Presence of RBC casts suggests glomerular bleeding. Obligatory urine volume: - It is the minimum amount of urine that must be produced which is about 500ml. - Which is needed for the elimination of waste products. - If the person is not drinking water, he will still produce 500ml of urine daily. - What is the source of water? Plasma - After some days (2-3days) after this state of use plasma to eliminate the urine he will enters dehydration state. - In which the urine volume will be decreased below 500ml, thus the waste products will accumulate. - The accumulated waste products may cross BBB & cause delusions. 1. NEPHROTIC SYNDROME - It is due to loss large quantities of protein in the urine. - Caused by increase the filterability & permeability of the nephron for large substances like proteins. - The signs and symptoms start to appear when proteinuria is about 3.5 grams/day. - Affects any age. - Characteristics of nephrotic syndrome: ▪ Proteinuria of more than 3.5 g/24 hours. ▪ Serum albumin less than 3 grams/100 ml. ▪ Signs of edema. - Clinical features of nephrotic syndrome 1. Edema ▪ Due to hypoalbuminemia. ▪ Edema is seen in upper limbs, lower limbs and face (periorbital). ▪ May extends to genitalia and lower abdomen (Ascites). ▪ Anasarca is a severe and generalized form of edema, with subcutaneous tissue swelling throughout the body. 2. Hyper coagulopathy Nephrotic range proteinuria ▪ Due to loss of anticoagulants. (Hallmark) ▪ Tendency for clot formation. ▪ It may lead to venous thrombosis and emboli formation. 3. Infection ▪ Due to hypogammaglobinemia. 4. Hypercholesterolemia ▪ Due to loss Enzymes involved in cholesterol metabolism. ▪ This leads to arterial occlusion. - Causes of nephrotic syndrome: ▪ The diseases causing nephrotic syndrome always affect the glomeruli. ▪ Primary causes: ➔ Focal segmental Glomerulosclerosis (FSGS). Affects old age groups. Doesn’t respond to treatment. Ends with end stage renal failure. ➔ Minimal change diseases (MCD): Affects children & young age group. Responds well to steroids. Good prognosis. ➔ Membranous glomerulonephritis (nephropathy). ➔ IgA glomerulonephritis (nephropathy). ▪ Secondary causes: ➔ AIDS (HIV infection), Hepatitis, Syphilis, Sarcoidosis, ➔ SLE (Systemic lupus erythematosus)‫ مرض الحمى الذؤابية‬, "Diabetic nephropathy, amyloidosis" 2. NEPHRITIC SYNDROME - Nephrotic syndrome + Hematuria. ▪ Protein + RBCs in the blood. ▪ We will see RBC casts. 3. Glomerulonephritis (GN) - Inflammation of glomeruli which is mostly immunologically mediated. - Associated with: Deposition of anti-glomerular basement membrane antibodies. ▪ Which came after streptococcal infection (post-strep). ➔ Example: upper respiratory tract infection followed by glomerulonephritis. - Signs and symptoms: ▪ Na+ retention, Edema, Hypertension. ▪ Proteinuria, Hematuria, Reduced renal volume.  Note: Differentiated from nephrotic & nephritic syndromes by history of upper RT infection. 4. Acute tubular necrosis (ATN) - Necrosis of cells of kidney tubules. - It is the most common cause of acute renal failure. - Tubular cell death: Make nephron unable to do its function temporarily (reversible disease). Pathophysiology: - Reduce blood flow to tubular cells: ▪ O2 to tubular cells specially to cells of thick ascending loop of Henle (mostly affected). ▪ Death of the cells → Cells' Shedding into the lumen → Tubules occlusion. ▪ OR breaks the basement membrane → Leakage of tubular content into renal interstitial tissues. - Toxins ▪ Chemical "Drugs": - Gentamycin- Cytotoxic drugs - Amphotericin B ▪ Bacterial Toxins: Shiga bacteria. 5. Cystinuria: - An inherited (AR) disease characterized by high cystine levels in the urine. - Cystine Amino acid normally filtrated & reabsorbed completely in PCT. - The reabsorption is done by SLC3 & SLC39 channels. - Pathophysiology: ▪ Loss of function mutation in SLC3A1 & SLC7A9 genes. ▪ That will lead to no expression of SLC3 & SLC39 channels. ▪ Thus, no reabsorption of cystine → Excreted in the urine. ➔ This cystine will aggregate to form a cystine crystals & stones. ➔ Alonge with Cystine there will be other AA: Ornithine, Lysine, Arginine.  Notes: ◼ Cystine is insoluble in acidic media (urine). ◼ Thus, more acidic urine → Cystinuria → Cystine Stones. ◼ Low urine volume → Cystine concentration → Cystine Stones 6. Cystine stones: - Etiology: Cystinuria - Clinical features: recurrent kidney stones (manifesting with e.g., flank pain) starting in childhood. - Prevention ▪ Hydration, Diet low in sodium, Urine alkalinization, Tiopronin ▪ Chelating agents (e.g., penicillamine) for refractory cases - Treatment: ▪ Surgery (not the optimal) ▪ Reduce the amount of cystine (oxidized form) ➔ By reducing the cystine into cysteine. ➔ Thus,  blood cystine,  cysteine & Glutathione (Antioxidant) 7. Renal failure: - Failure of kidneys functions: ▪ Acid-base balance stimulates RBCs synthesis, Vit D synthesis. ▪ Azotemia → Cross BBB (NS problems). ▪ Affects osmolarity and electrolytes. - When Creatinine is more than 200 µmol/liter → biochemical of ARF (Normal 55-120 µmol/liter). - Either Acute renal failure (ARF) Or chronic renal failure (CRF). Acute renal failure (ARF) - Sudden loss of kidneys function develops over a short period and stay for a short period. ▪ ARF is usually reversible (the renal function usually returns). ▪ If renal function is not restored rapidly, a temporary renal replacement therapy may be required. Chronic renal failure (CRF) - Loss of kidneys function develops over a long period and stays for a long period. ▪ It is usually irreversible due to loss of large number of functioning nephrons. ▪ Number of functioning nephrons about 20-30% - Atrophic kidney. - Causes: Same as those leads to ARF, in addition to: ▪ Diabetes mellitus, atherosclerosis, pyelonephritis, polycystic kidneys. - Effect of Failure of kidneys functions: ▪ Acid-base balance: metabolic acidosis = Respiratory rate. ▪ Vit D synthesis: Hypocalcemia. ▪ EPO synthesis: Anemia. ▪ Electrolytes: Hyperkalemia. ▪ Nitrogen: High urea & creatinine concentrations.  Note: ◼ Normal kidney in young adults have about 70-90% functioning nephrons. ◼ Normal kidney in elderly have about 40-60% functioning nephrons. ◼ Normal creatinine concentration = 55-120 µmol/liter ◼ Normal urea concentration = 2.5-6.5 mmol/L. ◼ Normal K+ concentration = 3.5-5 mmol/L Causes of renal failure: Prerenal (Perfusion) causes: - Any condition that leads to decreased renal perfusion (∼ 60% of cases of AKI). ▪ Renal artery stenosis ▪ Hypovolemia: Hemorrhage, vomiting, diarrhea, sweating, burns, diuretics, poor oral intake, dehydration. ▪ Hypotension: due to sepsis, cardiogenic shock (decreased cardiac output), anaphylactic shock ▪ Drugs that affect glomerular perfusion: e.g., cyclosporine, tacrolimus, NSAIDs, ACE inhibitors. Renal causes: - Any condition that leads to severe direct kidney damage (∼ 35% of cases of AKI). ▪ Glomerulonephritis: e.g., rapidly progressive glomerulonephritis ▪ Acute tubular necrosis: Ischemia, Nephrotoxic drugs, Endogenous toxins ▪ Acute interstitial nephritis: infection or medication Postrenal (Obstructive) causes: - Causes include any condition that results in obstruction of urinary flow (∼ 5% of cases of AKI). ▪ Acquired obstructions ➔ Stones ➔ Benign prostatic hyperplasia (BPH) ➔ Iatrogenic: e.g., catheter-associated injuries ➔ Tumors: e.g., bladder, prostate, cervical, metastases ➔ Bleeding with subsequent blood clot formation ▪ Neurogenic bladder: e.g., due to multiple sclerosis, spinal cord lesions, or peripheral neuropathy ▪ Congenital malformations: e.g., posterior urethral valves  Note: one of the complications is Hydronephrosis: ◼ Hydronephrosis: When the kidney become swollen as the result of a build-up of urine inside them. - Pathophysiology: ▪ Due to this stone the urine will still found in the ureter. ▪ Then it will accumulate in the renal pelvis. ▪ Accumulation of bad substances → loss of functioning nephrons. ▪ Decrease of the kidney's excretory ability. ▪ Renal failure. Clinical features of Renal failure: - The signs and symptoms are combination of underlying condition that causes the renal failure. 1. Abnormalities of urine volume ▪ Oliguria, Anuria (rare, severe), normal or increased. 2. Blood chemistry abnormalities ▪ Acid-base balance: metabolic acidosis = Respiratory rate. ▪ Vit D synthesis: Hypocalcemia & Hyperphosphatemia. ▪ EPO synthesis: Anemia. ▪ Electrolytes: Hyperkalemia. ▪ Nitrogen: High urea & creatinine concentrations. ▪ Bleeding tendency (poor platelets function) ▪ Immunity depression ▪ Infections. Clinical Features of CRF (‫)مهمات جدا‬ - Early: Asymptomatic or SOB or tiredness, Nocturia. - Later: Systemic manifestations. - Nervous system: ▪ Neuropathy: ➔ Due to demyelination of nerve fibers. ➔ Manifest as: Paresthesia (Restless leg ‫)لما اجرك تنمل‬ Foot drop → motor neuropathy Absent of reflexes. Autonomic neuropathy cause: delayed gastric emptying, diarrhea, postural hypotension (defect in baroreceptors) ▪ Drowsiness and coma - Endocrine system: ▪ Hyperparathyroidism→ is due to hypocalcemia and hyperphosphatemia. ▪ Hyperprolactinaemia → causes a decrease in libido and sexual function in female and male ▪ Relative insulin resistance. ▪ Amenorrhea. - Respiratory system: ▪ Respiration is strongly stimulated by metabolic acidosis to reduce H+. ▪ Rate & depth of respiration → (deep breathing = Kussmaul’s breathing). - Cardiovascular system: ▪ Hypertension (in 80% of CRF patients). ▪ Atherosclerosis. ▪ Vascular calcification. ▪ Pericarditis is seen in end-stage renal failure. ▪ Pulsus paradoxus: ➔ Pathological decrease in the pulse wave amplitude and systolic blood pressure > 10mmHg during inspiration. ➔ Physiology During inspiration: Intrathoracic pressure → venous return → RV filling → bowing of ventricular septum into the left ventricle → LV volume→ LV contraction → Systolic blood pressure ▪ Hypertension: ➔ Causes further damage to glomeruli and renal blood vessels (severe renal failure). ➔ Leads to increase jugular venous pressure (JVP) or due to pericardial tamponade. ➔ Caused by:  Aldosterone: Na absorption → water retention.  Angiotensin II: vasoconstriction. Renal artery stenosis Chronic glomerulonephritis. (Due to thickening of glomerular capillary membrane) - Musculoskeletal system: ▪ Renal osteodystrophy: ➔ Osteomalacia (failure of bone mineralization) ➔ Osteoporosis (reduction in bone mass) ➔ Osteosclerosis (increased bone density) ▪ Myopathy: ➔ Poor nutrition, hyperthyroidism, vitamin D deficiency and electrolytes disturbances ▪ Muscle twitching - Blood: ▪ H+ & HCO3- leads to Metabolic acidosis. ▪ RBCs leads to severe anemia. ▪ Platelets. - Skin: ▪ Pruritus (due to hyperphosphatemia). ▪ Pallor skin (due to anemia). ▪ Easily bruises. ▪ Nails: brown line pigmentation. - Gastrointestinal system: ▪ Anorexia, nausea, hiccough, vomiting. Replacement of renal function in renal failure - When kidneys stop working temporarily or permanently, waste products accumulate in the blood. - It is also important to replace the endocrine function of the failing kidneys. - To replace the excretory function of the failed kidneys → hemodialysis or peritoneal dialysis. ▪ In acute renal failure: Used to replace kidney function until the kidneys back to work. ▪ In chronic renal failure: Used permanently until successful kidney transplant is done. ▪ Dialysis cannot replace the endocrine and metabolic functions of the kidney. ▪ This function could be resumed by kidney transplant.  Notes: ◼ Hematuria: Hemoglobinuria: red urine Myoglobinuria: very dark or black urine Porphyria → urine darkens on standing ALKAPTONURIA → Dark brown or dark urine Drugs: Senna (orange), Rifampicin (orange) L. Dopa (urine darkens on standing) ◼ Proteinuria: Orthostatic proteinuria: Occurs only during the day. Bence Jones proteinuria: Seen in myeloma. Immunoglobulin light chains appear in the urine. Poorly detected by dipstick test and needs special procedure. The End ْ ُ ‫السالمةُّيثنيُّهمُُّّصاحبه‬ ُّ ُُّّ‫حب‬ ُ ُّ ‫املرءُّبالك‬ ‫سل‬ ُّ ُّ‫عنُّاملعايلُّويغري‬