Functions of the kidneys

A. Main function: regulation of volume & composition of body fluids, done by : - Filtration of plasma at the glomeruli at rate of 120 ml/minute (170 L/day) GFR. - Absorption of selected amounts of water, electrolytes, glucose and amino acids. Also secretion of certain substances. - Excretion of urine with waste products (1 - 1.5 liters/day)

Functions of the kidneys

B. Endocrine (hormonal) function: 1. Production of: i. Renin: From juxtglomerular Apparatus Generates Angiotensin II. ii. Erythropoietin: From interstitial Peritubular cells Stimulate RBCs formation. 2. Vitamin D metabolism hydroxylation of 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol "Active form of Vitamin D.

Function of the kidney

The basic functional unit is the nephron. Each kidney contains ~106 nephrons. The kidneys receive 20-25% of the cardiac output. Glomerular filtration rate depends on filtration pressure at the glomerulus which is regulated by: A- Efferent arteriole constriction by angiotensin II. B- Afferent arteriole dilatation by Prostaglandin. C- Mechanical autoregulation. The epithelial cells are not dividing cells. The filtration barrier allows water, electrolytes, glucose, amino acids to pass. *Proteins below MW 20000 can freely pass. *Proteins above MW 65000 can NOT pass through the barrier. - Afferent arteriole = Pre-glomerular - Efferent arteriole = Post-glomerular

Disorders of urine volume

Normally urine volume/24 hours ~ 1-1.5 liter Anuria (no urine excretion) is due to either: a. Total urinary obstruction. b. Vascular occlusion. Oliguria - urine output / 24 hours is below 500 ml. Polyuria - urine output / 24 hours is above 3 liters. Causes: 1. Excess fluid intake. 2. Hyperglycemia. 3. Diabetes inspidus (decreased or absence of antidiuretic hormone) 4. Drugs diuretics Toxins lithium

Haematuria
Means urine contains blood or RBCs. Causes -Bleeding from anywhere in renal tract: A. Kidneys: i. Clotting disorders ii. Cyst iii. Tumor iv. Glumerular disease v. Interstitial disease vi. Infarction B. Ureter: i. Cancer ii. Stone C. Urinary Bladder: Infection D. Urethra: Trauma in urethra.

Haematuria
Haematuria: a. Frank Bleeding b. Microscopical bleeding RBCs detected in urine by microscope Normally: Few RBCs are detected by microscope. * Dipstick test can detect microscopical bleeding. * +ve Dipstick test is positive during menstruation. Examination of urine is helpful in establishing the cause of hematuria: 1. Presence of WBCs and micro-organisms suggests infection. 2. Presence of RBC casts suggests glomerular bleeding.

Haematuria
Glomerular bleeding suggests fracture in the glomerular basement membrane (GBM). Glomerular bleeding may develop after strenuous exercise. Recurrent episodes of gross haematuria associated with respiratory tract infection indicates IgA nephropathy: Glomerulonephrits with deposition of IgA in mesangial cells.

Haematuria
Red urine due to haematuria must be differentiated from other causes of red or black urine: 1. Hemoglobinuria: red urine
Myoglobinuria: very dark or black urine

*Both show positive dipstick test but no RBCs on microscopy. 2. Food dye beetroot 3. Porphyria urine darkens on standing 4. ALKAPTONURIA Dark brown or dark urine 5. Drugs : * Senna (orange urine) * Rifampicin (orange urine) * L. Dopa (the urine darkens on standing)

Proteinuria
Presence of abnormal concentration of proteins in the urine . *Proteinuria makes urine froth easily! 1. Low molecular weight Proteins: * Normally low MW proteins are filtered at glomeruli, but are absorbed by tubular cells * Less than 150 mg/day should appear in the urine * Appearance of more than 150mg of low MW proteins in the urine 24 hours means failure of reabsorption by tubular cells and indicates tubular cell damage. * Proteinuria of low MW proteins more than 2g/day indicates significant glomerular disease.

Proteinuria
2. Albuminuria * Normally albumin is not filtered at glomeruli. * Presence of albumin in the urine is a positive sign of glomerular disease. - Albuminuria is seen in early stages of glomerular disease of diabetes mellitus "diabetic nephropathy. * Minor leakage of albumin into glomerular filtrate may occur temporarily after vigorous exercise, fever and heart disease.

Abnormal proteins in the urine

In myeloma (malignant proliferation of plasma cells) immunoglobulin light chains (MW ~ 25 KDa) appear in the urine. This is called Bence Jones proteinuria . This proteinuria is poorly detected by dipstick test and needs special procedure. The protein precipitates when urine is heated to 60o , and disappears when urine is boiled and reappears when the urine cools.

NEPHROTIC SYNDROME
Is due to loss large quantities of protein in the urine. The signs and symptoms start to appear when proteinuria is about 3.5 grams/day. Characteristics of nephrotic syndrome: 1. Serum albumin is less than 3 grams/100 ml. 2. Signs of fluid retention or edema. 3. Proteinuria of more than 3.5 g/24 hours. Causes of nephrotic syndrome: The diseases causing nephrotic syndrome always affect the glomeruli. 1. Glomerulonephritis. 2. Systemic diseases: "Diabetic nephropathy, amyloidosis"

Clinical features of nephrotic syndrome

1. Edema * Is due to hypoalbuminemia and Na+ retention. * Starts in lower limbs and extending to genitalia and lower abdomen (in severe case). Ascites occurs early in children * In the morning the edema is seen in upper limbs and face. 2. Hypercoagulability * tendency for clot formation . * Is due to loss of anticoagulants. * It may lead to venous thrombosis and emboli formation. 3. Infection * Is due to hypogammaglobulinemia 4. Hypercholesterolemia * Leads to arterial occlusion (Enzymes involved in cholesterol metabolism are lost in urine).

Glomerulonephritis (GN)
Inflammation of glomeruli It is mostly immunologically mediated evidence for this: 1. Deposition of anti-glomerular basement membrane antibodies 2. Response of several types of GN to immunosuppresive drugs. * The antibody - Antigen complexes are deposited in the glomeruli. These complexes are formed from reaction of the antibodies against glomerular antigens or with antigens deposited in the glomeruli.

Glomerulonephritis (GN)
Acute post - infection glomerulonephritis *Mostly seen after streptococcal infection Signs and symptoms: - Na+ retention - Edema - Hypertension - Proteinuria - Hematuria - Reduced renal volume

Acute tubular necrosis (ATN)

* Necrosis of cells of kidney tubules. * It is the most common cause of acute renal failure. Tubular cell death is Caused by: a. Reduce renal blood flow b. Toxins i. Chemical Drugs: - Gentamycin - Cytotoxic drugs - Amphotericin B ii. Bacterial Toxins

Acute tubular necrosis (ATN)

Reduce blood flow to tubular cells leads to less O2 delivery to tubular cells specially to cells of thick ascending loop of Henle (they are very active metabolically) Death of the cells Shedding of the cells into the lumen of the tubules leading to occlusion . Also reduction in O2 delivery to tubular cells leads to breaks in tubular basement membrane causing leakage of tubular content into interstitial tissues of the kidney. Note: Tubular cells can regenerate function. *In ATN there is period of diuresis ( Increased urine output). This is due to loss of concentration gradient of kidney medulla.

Renal failure
Failure of kidneys functions. Primarily failure of excretory function Leads to retention of nitrogenous waste products that produced by body metabolism. Also other functions of the kidneys may Fail: 1. Regulation of fluid and electrolytes balance 2. Regulation of acid - base balance 3. Endocrine function Renal failure is either Acute renal failure (ARF) Or chronic renal failure (CRF)

Acute renal failure

Sudden entire or almost entire loss of kidneys function which develops over a period of days or weeks. * A plasma creatinine concentration of more than 200 mol/liter is used as a biochemical definition of ARF. Also K+ and urea concentrations in the blood are also increased in acute renal failure. * Normal creatinine level is between 55-120 mol/L * Normal urea concentration 2.5-6.5 mmol/L. [K+] = 3.5-5 mmol/L

Acute renal failure

ARF is usually reversible (the renal function usually returns) If renal function is not restored rapidly in ARF, a temporary renal replacement therapy may be required. Causes of ARF: 1. Pre - renal 2. Intrinsic renal disease 3. Post - renal

acute renal failure: Causes of

Acute renal failure

1. Pre - renal causes of ARF: Result in a decrease in renal blood flow. Causes: 1. Systemic Causes *Circulatory shock due to hemorrhage or excessive water loss as vomiting, diarrhea and burns. *Heart failure 2. Local causes like renal artery stenosis, renal artery occlusion and disease affecting renal arterioles.

Acute renal failure

2. Intrinsic renal causes (abnormalities within the kidney itself): could lead to ARF, these include: diseases affecting Glomeruli Blood vessels Renal tubules

Acute renal failure

*Acute glomerulonephritis: This is caused by immune reactions that damage glomeruli. It develops after streptococcal infection else where in the body (for ex. Tonsillitis or sore throat). Antibodies against streptococcal antigens Formation of antibodies-antigens complex Depositions of these complexes in glomeruli Destruction of the glomeruli from these immune reactions. Another mechanism for development of glomerulonephritis is the reaction of certain antibodies with glomerular antigens. This reaction causes damage of the glomeruli leading to ARF.

Acute renal failure

*Diseases affecting tubules (85% of ARF due to intrinsic renal diseases are of this type) Either severe ischemia of renal tubules Or toxic chemical substances and bacterial toxins affecting tubules lead to Death of renal tubules epithelial cells Tubular cells slough off blockage of renal tubules

Acute renal failure

3. Post-renal causes of ARF are due to obstruction of renal flow. *Sites of obstruction: a. Bilateral obstruction of ureters or renal pelvices. b. bladder obstruction c. uretheral obstruction *Causes of obstruction could be 1. stones 2. tumor 3. inflammation Obstruction of urine flow leads slowly progressive destruction of renal tissues. Also leads to infection which results in rapid decrease in renal function.

Causes Systemic (shock, hypotension)

Reversible pre-renal ARF

This may be due to blood loss or loss of intravascular fluid into tissues as in cases of burns, crush injuries, sepsis Local ( renal artery stenosis or occlusion and renal arteriols abnormalities) * Renal blood flow is 1200 ml/min. This high blood flow is essential to keep high GFR (120ml/min). *High GFR is needed for effective regulation of body water and electrolytes. A decrease in blood flow leads to a decrease in GFR and thus decreasing the ability of the kidneys to excrete excess water and electrolytes

Reversible pre-renal ARF

* Normally the kidneys can regulate their blood flow and GFR over wide range variation in blood pressure. The mechanisms of this regulation are: a. Vasodilatation of afferent arteriols through liberation of prostaglandins. b. A decrease in stretching of renal blood vessels (in case of a decrease in BP) leads to vasodilatation. This is called auto-regulation of renal blood flow. c. A vasoconstriction of efferent arteriols by Angiotensin II: This effect is mediated through the release of renin from juxtaglomerular apparatus. When the above mechanisms fail to maintain blood Flow, then GFR decreased and this leads to formation of a low urine volume (oliguria).

Established acute renal failure:

1. Causes : prolonged kidneys under perfusion (i.e. prolonged ischemia of renal tubules which follows circulatory shock). Because of high metabolic activity of tubular cells, a decrease in blood flow reduces delivery of oxygen to them and this causes acute tubular necrosis and shedding of tubular cells into tubular lumens obstructing them. Toxic effects of drugs and chemicals Conditions affecting intra-renal arteries and arteriols like vasculitis, hypertension and disseminated intravascular coagulation. prolonged obstruction of urine flow.

2. 3.

4.

Clinical features of established ARF:

The signs and symptoms are combination of underlying condition that caused the renal failure and those of renal failure itself. 1. abnormalities of urine volume *Oliguria *Anuria it is rare and indicates acute urinary tract obstruction or vascular occlusion. *Sometimes urine volume is normal or increased (seen in 20% of patients). This is due to low GFR and poor tubular absorption and does not mean normal kidney excretory function.

Clinical features of established ARF:

2. blood chemistry abnormalities * High plasma urea and creatinine concentrations. The rate of the increase of these substances depends on catabolic state of the body. for ex. If there is severe infection, trauma and surgery, then the rate of increase is high. * Hyperkalemia is common specially if there massive break down of tissues, hemolysis and acidosis. *Hyperkalemia must be corrected because of its effect on heart function (causes ventricular arrhythmia). *If plasma K+ concentration is more 7 mmol/l, cardiac arrest may occur. *Dilutional hyponatremia (reduced plasma Na+) occurs if water intake is free or inappropriate amount of intravascular water is given.

Clinical features of established ARF:

2. blood chemistry abnormalities (Cont.) *Hypocalcaemia: is due to less 1,25-dihydroxycholicalciferol which is formed in the kidney. * Acid-base disturbances Metabolic acidosis. * Signs and symptoms of waste products retention. These include anorexia, vomiting, nausea, drowsiness, apathy, confusion, muscle twitching and coma. * Respiratory rate is increased (due to metabolic acidosis) * Pulmonary edema may develop (due to retention of fluid or inappropriate administration of excess fluid). * Anemia (due to blood loss and less erythropoietin production). * Bleeding tendency * Immunity depression and infection.

Chronic Renal failure (CRF)

An irreversible deterioration in renal function resulted from irreversible loss of large number of functioning nephrons. CRF occurs over a period of years. In CR, there is loss of excretory, metabolic and endocrine functions of the kidney. The clinical signs and symptoms of CRF are sometimes referred to as UREMIA. Causes: Any factor or condition which destroys the normal function and structure of the kidneys (i.e. decreasing the no. of functional nephrons) may lead to CRF. In most cases, serious symptoms do not occur until the no. functioning nephrons decreased below 20-30% of normal.

Chronic Renal failure (CRF)

Among conditions that lead to CRF are: 1. Metabolic disorders Diabetes mellitus 2. Immunological disorder glomerulonephritis 3. Renal vascular disorder atherosclerosis 4. primary tubular disorder nephrotoxins like analgesics and heavy metal 5. Infection pyelonephritis 6. Urinary tract obstruction 7. congenital disorders polycystic kidneys 8. Hypertension

Clinical Features of CRF

*Early stage: CRF is often asymptomatic. Biochemical examination shows an elevated blood urea and creatinine concentration. Nocturia may be an early symptom and it is due o loss of concentration ability of the kidneys. **Sometimes, patient with CRF may present with complaints which are not renal in origin like breathlessness or tiredness. * In late stage of CRF, the patient looks ill, anemic. The respiration is deep (Kussmauls breathing). Anorexia, nausea, hiccough, pruritis, vomiting, muscle twitching drowsiness and coma are among late signs and symptoms of CRF. Actually, in late stage of CRF almost every body system is affected.

Physical signs in CRF

Anemia of CRF:
This anemia may be caused by: 1. decrease in erythropoietin production 2. Inhibition in erythropoiesis by toxic effect of metabolic waste products on bone marrow. 3. An increase in blood loss due to increased capillary fragility and poor platelets function. 4. Reduction in dietary intake and absorption of iron and other substances needed for erythropoiesis. 5. Shortening of RBC life span *The severity of anemia in CRF is proportional to the severity of renal failure and anemia contributes to many non-specific symptoms of CRF.

Bone abnormalities of CRF (renal osteodystrophy)

These abnormalities are mixture of: *Osteomalacia (failure of bone mineralization) *Osteoporosis (reduction in bone mass) *Osteosclerosis (increased bone density) *In CRF there is less 1,25-dihydroxycholecalciferol(active form of vitamin D) decrease absorption of Ca+2 from intestine hypocalcaemia, this causes: A. Reduction in bone calcification. B. Hyperparathyroidism Increased bone resorption. * Excretion of phosphate is decreased in CRF leading to hyperphosphotaemia which stimulates the parathyroid glands. * Osteoporosis of CRF is probably due to malnutrition.

Chronic Renal Failure

Myopathy of CRF is due to a combination of poor nutrition, hyperthyroidism, vitamin D deficiency and electrolytes disturbances. Neuropathy of CRF Is due to demyelination of nerve fibers (the longer fibers being involved at earlier stage). *parasthesia sensory impairment *foot drop motor neuropathy *delayed gastric emptying} diarrhea } Autonomic postural hypotension } neuropathy

Chronic Renal Failure

Endocrine disorders of CRF Hyperprolactinaemia causes a decrease in libido and sexual function in and Hyperparathyroidism is due to hypocalcaemia and hyperphosphotaemia Amenorrhea ( means absence of menstrual cycle in ) There is also relative insulin resistance in CRF. However a decreased renal metabolism of insulin in CRF may reduce the daily requirements of insulin in Diabetics.

Chronic Renal Failure

Metabolic acidosis The increased H+ leads to exchange of H+ instead of Ca2+ in the bone and this aggravating the metabolic disease of the bone of CRF. The respiration is strongly stimulated by metabolic acidosis. The increased respiratory activity is an attempt to reduce H+ concentration by blowing of CO2. Plasma PH less than 6.8 leads to coma and death.

Chronic Renal Failure

Cardiovascular disorder of CRF: 80% of patients with CRF develop hypertension. The increase in BP is due to retention of Na+ and fluid. It is also due to production of renin, angiotensin II and aldosterone. These hormones are increased in CRF specially if there is under-perfusion of renal tissues due to vascular diseases. * Atherosclerosis is common and it is accelerated by the hypertension. * Vascular calcification may also occur in CRF * Pericarditis is seen in end-stage renal failure.

Chronic Renal Failure

CRF and body fluid If water and food are not restricted in complete CRF, the following may occur: 1. Generalized edema. 2. High urea and creatinine plasma concentration. 3. High K+ and PO43- plasma concentration. 4. Acidosis. 5. Low HCO3 plasma concentration. Infection and CRF Due to decreased cellular and humoral immunity, the CRF patients are susceptible to infection.

Chronic Renal Failure

Hypertension and CRF * hypertension is seen in 80% of CRF patients. When hypertension develops, it will increase the severity of renal failure because hypertension causes further damage to glomeruli and renal blood vessels. *Conditions like renal artery stenosis reduce renal blood flow and therefore reducing GFR and this leads to retention of water and development of hypertension. *Chronic glomerulonephrirtis causes thickening of glomerular capillary membrane and therefore decreasing GFR and subsequently development of hypertension.

Chronic Renal Failure

Hypertension and CRF (Cont.) * Conditions that increase aldosterone secretion will lead to increased tubular Na+ absorption which leads to water retention and subsequently development of hypertension. * Conditions that increase renin secretion leads to formation of angiotensin II, which causes retention of Na+ and water and vasoconstriction and this will lead to hypertension.

Replacement of renal function in renal failure

**When kidneys stop working temporarily or permanently, metabolic waste products accumulate in the blood. It is essential to get rid of these toxic substances which worsen the condition and affect other body systems. It is also important to replace the endocrine function of the failing kidneys. **It is possible to replace the excretory function of the failed kidneys by hemodialysis or peritoneal dialysis. **Dialysis is used to replace kidney function in acute renal function until the kidneys resume their function. **In chronic renal failure, dialysis is used permanently until successful kidney transplant is done. **Dialysis can not replace the endocrine and metabolic functions of the kidney. These function could be resumed by kidney transplant.

Basic principle of dialysis

Please see Textbook of medical physiology by Guyton and Hall 10th edition page 378