• Recovery phase of ATN or post-obstructive ARF • Tubulotoxicity as cisplatin, amphotericin • Diabetic hyperglycaemia B- Gastrointestinal loss 1- Prolonged or severe diarrhoea 2- Laxative abuse 3- Prolonged vomiting 4- Ileus with massive intestinal dilatation. C- Redistribution of K+ into cells 1- Metabolic alkalosis 2- Periodic muscle paralysis 3- Beta-adrenergic agonists e.g. salbutamol 4- Insulin. D- Inadequate K+ intake Intravenous fluid without K+ in patient without oral intake. Bartter’s Syndrome is a rare disease characterized with hypokalaemic alkalosis, hyperreninaemic hyperaldosteronism, high urinary prostaglandin E and prostacyclin concentration and normal blood pressure. Kidney biopsy will show hypertrophied juxtaglomerular apparatus. In the non renal causes of hypokalaemia when the kidney is intact, it can decrease urinary K+ to <20 mmol/day: Clinical features: Usually appear when plasma K+ is less than 2.5 mmol/L
1- Muscle weakness especially proximal muscles. Tendon reflexes are depressed. In severe cases, muscle necrosis may occur. 2- Gastrointestinal hypomotility up to paralytic ileus may occur with further K+ loss into dilated intestinal loops. 3- In chronic hypokalaemia, renal tubular damage with chronic tubulointerstitial nephritis may occur. 4- With severe hypokalaemia fatal cardiac arrhythmia may cause death. ECG will show the following: • Depressed T waves and S-T segments • Appearance of U waves • Widening of the QRS • Finally, ventricular ectopics and fibrillation may occur. Treatment: 1- Treatment of the etiology 2- Potassium supplement either oral or parenteral according to the severity of hypokalaemia. As a rule, we have not to give KCL intravenous more than 10 mmol/hour.
IV. Disorders of Plasma Calcium Concentration Generally, the kidney, the gastrointestinal tract and the skeleton play a key role in body calcium and phosphate homeostasis. The contribution of the kidney in calcium and phosphate metabolism includes: 1- Synthesis of 1,25 dihydroxycholecalciferol Inactive vitamin D (cholecalciferol) is activated in the liver by hydroxylation to 25, hydroxycholecalciferol, the second step of its activation is in the kidney to be 1, 25, dihydroxycholecalciferol. The active vitamin D promotes the gut calcium absorption and the normal calcification of bone. 2- Renal excretion of calcium 85-90% of the filtered Ca2+ is reabsorbed by the PCT while the rest is reabsorbed by the DCT, under the influence of PTH, only <2% of filtered calcium is excreted in the urine (equals about 5.5 mmol/day). 3- Renal excretion of phosphate Urinary excretion of phosphate varies from 5-40 mmol/day. 80-95% of the filtered load is absorbed in PCT (as Ca2+, glucose, aminoacids and low molecular weight proteins). Phosphate is the major buffer for H+ excretion. Hypercalcaemia Is a total plasma Ca2+ concentration more than 2.6 mmol/litre (10.5 mg/dl) Causes of hypercalcaemia
1- Malignancy • Multiple myeloma. • Boney metastasis • Hormonal factors (PTH-like substance) secreted by tumour cells. 2- Hyperparathyroidism 3- Sarcoidosis 4- Bone disease • Paget’s disease • Aluminium osteodystrophy 5- Calcium or vitamin D related • Vitamin D intoxication • Thiazide diuretics • Milk-alkali syndrome • Renal failure 6- Endocrine disease • Thyrotoxicosis • Addison’s disease 7- Hyperproteinaemia (only non-ionised calcium is raised) Clinical features 1- Manifestations of the etiologic cause 2- Renal manifestations • Polyuria and polydepsia resulting from urinary concentration defect • Stone disease and nephrocalcinosis • Acute renal failure may occur with severe hypercalcaemia and the associated dehydration owing to polyuria • Chronic renal failure due to stone disease, nephrocalcinosis and chronic tubulointerstitial nephritis. 3- Gastrointestinal manifestations
• Nausea and vomiting which are central effects of hypercalcaemia. These may aggravate dehydration induced by polyuria • Peptic ulcer disease • Pancreatitis 4- Nervous system Nausea, vomiting, malaise, fatigue, and even psychosis are all central effects of hypercalcaemia. 5- Tissue deposition of calcium may lead to nephrocalcinosis, vascular calcification, pruritis, conjunctival calcification (red-eye) and band keratopathy. Treatment: A- Treatment of the etiologic cause B- Treatment of hypercalcaemia 1- Saline diuresis in patients with reasonable kidney function. If there is no response we can inforce diuresis by furosemide and intravenous saline. Loop diuretics in contrary to thiazide diuretics increase urinary calcium excretion. 2- Glucocorticoids are effective in all conditions other than hyperparathyroidism. In sarcoidosis and Vit. D intoxication 10 mg prednisolone may be sufficient while in malignancy doses up to 60 mg/d may be required. 3- Others: • Methramycin is particularly useful in malignancy related hypercalcaemia, a dose of 20-30 ug/kg may induce fall in serum Ca2+ within hours and last for few days. • Calcitonin 50-100 units S.C. • Phosphate oral or intravenous, but carries the risk of metastatic calcification.
• Diphosphonate will suppresses hypercalcaemia in hyperpara- thyroidism 4- Dialysis in renal failure especially on using low Ca2+ dialysate will be very effective in decreasing serum calcium. Hypocalcaemia It is plasma calcium concentration less than 2.20 mmol/litre (8.5 mg/dl). Causes of hypocalcaemia 1- Renal failure 2- Hypoparathyroidism (surgical, idiopathic, pseudohypoparathyroidism) 3- Vitamin D deficiency 4- Hypoalbuminaemia 5- Acute pancreatitis In renal failure, hypocalcaemia is due to the lack of activation of vitamin D and to the hyperphosphataemia which will cause drop of serum calcium. The presence of acidosis will delay the manifestations of hypocalcaemia by increasing serum ionised calcium. Vitamin D deficiency may be due to decreased intake, decreased exposure to sun light, defective gut absorption or lack of its activation. Hypovitaminosis D is characterized with hypocalcaemia, hypophosphataemia and hyperparathyroidism. Clinical features of hypocalcaemia 1- Manifestations of the etiologic cause.
2- Neuromuscular; in acute hypocalcaemia it takes the form of tetany, tingling, numbness, parasthaesia, even convulsions. While in chronic hypocalcaemia the main features are depression, irritability, intracarnial calcification. 3- Bone disease as osteomalacia in vitamin D deficiency and renal failure and hyperparathyroid disease in hyperparathyroidism 4- Cataract may be seen with chronic hypocalcemia Treatment: 1- Treatment of the cause 2- Calcium and vitamin D supplementation
DISORDERS OF ACID-BASE BALANCE Plasma pH is normally 7.35-7.45 which represents a H+ concentration of 36-44 mmol/litre. The normal plasma HCo3- concentration is 20 to 30 mmol/litre. The lowest urinary pH is 4.5 units (with severe metabolic acidosis in presence of normal kidneys) and the highest urinary pH is 10 units (with severe metabolic alkalosis). Metabolic Acidosis Metabolic acidosis can result from the generation or the ingestion of acid; or from the loss of bicarbonate ions with consequent accumulation of H+ in the circulation. This will be compensated for by the increase in ventilation with a consequent drop in the level of Co2 and HCo3-. The term acidaemia is sometimes used when compensatory mechanisms fail to maintain the pH level within the normal range. But in practice, the term acidosis is usually used whether the pH level is within the normal range or lower. Features of metabolic acidosis: • Low plasma HCo3- concentration (< 20 mmol/litre). • Low arterial Co2 concentration (< 40 mmol/litre). • Low plasma pH (< 7.35). Causes of metabolic acidosis:
First we have to know about the concept of anion gap which is the difference between plasma concentration of Na+ and the sum of chloride and bicarbonate [Na+ — (CL + HCo3-) = 6 — 16 mmol]. This gap represents substances which combine with Na+ other than CL- and HCo3- which are not measured in routine chemistry such as amino acids. We may classify metabolic acidosis into those with high anion gap [Na+ — (CL + HCo3-) > 16 mmol] and those with normal anion gap: I- Metabolic acidosis with high anion gap: The high anion gap is due to the addition of anionic toxic substances into the circulation which combine with Na+ at the expense of chloride and HCo3-. Since these substances are not measured, the anion gap will be high. Causes of metabolic acidosis with high anion gap are: • Lactic acidosis; the anion toxic substance here is lactate • Diabetic ketoacidosis with accumulation of acetoacetic acid; B-hydroxybuteric acid • Intoxication with methyl alcohol; Ethylene glycol, paraldehyde and salicylates. • Renal failure with accumulation of sulfates; phosphates and phenols. II- Metabolic acidosis with normal anion gap (hyperchloraemic metabolic acidosis). This could be due to renal, gastrointestinal or other defects. A. Renal causes of metabolic acidosis with normal Anion gap:
1- Diamox, a diuretic which causes bicarbonate wastage (bicarbonaturia). 2- Renal tubular acidosis (RTA); resulting from either: a. Type I, classic (Distal) RTA: In this condition, there is inability to secrete H+ load. b. Type II, proximal RTA: In this condition, the PCT is unable to reabsorb HCo3- as there is a set up of HCo3- Tm at low level e.g. HCo3- Tm of 16 mmol/l, so any HCo3- above this concentration will be lost in urine. c. Type III RTA: There is both inability to secrete H+ load and proximal HCo3- wastage. d. Type IV RTA: There is hyperkalaemic hyperchloraemic metabolic acidosis with hyporeninaemic hypoaldosteronism. This is usually seen in diabetics with mild renal impairment. B- Gastrointestinal causes of metabolic acidosis with normal anion gap: 1- Diarrhoea; There is loss of K+ and HCo3-, every litre of diarrhoea fluid contains 30-50 mmol of HCo3-. 2- Fistula or tube drainage: Each litre of the small intestinal fluid contains 60 mmol HCo3- while pancreatic fluid contains 120 mmol/litre. 3- Ureterosigmoid or ileal loop urine diversion: In these conditions there is loss of mucosal HCo3- (normally present in high concentration in intestinal mucous) in exchange with the urinary CL- (hyperchloraemia).
4- Anion exchange (CL- versus HCo3-) as with the use of cholestyramine. 5- Ingestion of Ca and Mg chlorides. Treatment of metabolic acidosis: 1- Treatment of the cause and compensate for the deficit 2- In distal RTA, NaHCo3 should be provided 1-3 mmol/kg/d, sometimes K+ supplementation is required. In children NaHCo3 will be provided in a dose of 5-15 mmol/kg/d. 3- In proximal RTA large amounts of alkali are provided (10-25 mmol/kg/d) and K+ supplementation. Respiratory Acidosis In respiratory acidosis, Co2 retention occurs and the reaction (Co2 + H2O ∅ H2Co3 × H+ + HCo3-) results in accumulation of H+ in circulation and acidosis. The kidney compensates by the secretion of H+ and reabsorption of HCo3-. In acute respiratory acidosis blood Hco3- increases by 1 mmol/L for every 10 mmHg increase in PCo2 while in chronic respiratory acidosis HCo3- increases by 3.5 mmol for very 10 mmHg increase in PCo2. Features of respiratory acidosis: • high PCo2 • low pH • high HCo3- • urine pH is low <5.4 Etiology:
• Severe respiratory disease e.g. obstructive air way disease and severe obesity. • Central depression of respiratory drive. Clinical features: 1- Manifestations of the cause. 2- Confusion, hyperreactivity, headache, tremor, stupor and coma in severe cases. 3- Papilloedema and increased CSF pressure due to V.D. 4- Pulmonary and splanchnic V.C. Treatment: 1- Treatment of the etiologic cause 2- If there is respiratory failure, assisted respiration (ventilator) should be provided. Metabolic Alkalosis Because of the high capacity of the kidney to secrete HCo3-, metabolic alkalosis can only persist if there is a renal dysfunction with a reduction in HCo3- excretion or enhanced renal generation of HCo3-. Features: • High plasma HCo3- (> 30 mmol/litre) • High plasma pH (pH > 7.45) • High Pco2, for every 1 mmol/litre increase in plasma HCo3- there will be a 0.6-0.7 increase in Pco2. Hypoxaemia stands as a limiting factor for the respiratory compensation. So, if it exists, we have to give oxygen support.
• Chloride and K+ are also usually low. K+ is low as a result of the renal loss and the intracellular shift. Causes: A- Renal: 1- Adrenocorticoid and adrenocorticoid-like effect (HCo3- retention with K+ and H+ excretion). • Secondary aldosteronism (e.g. cirrhosis) • Primary aldosteronism • Cushing’s syndrome • Bartter’s syndrome • Liquorice ingestion 2- Volume depletion (Cl- depletion and HCo3- reabsorption) • diuretics • diarrhea • cirrhosis B- Gastrointestinal loss of acid: • Vomiting • Gastric aspiration C- Ingestion of alkali: • NaHCo3 • Milk-alkali syndrome
Hyperaldosteronism stands as a common mediator in metabolic alkalosis as it lead to enhanced K+ and H+ excretion, with sodium and bicarbonate retention (hypokalaemic alkalosis). Diuretic therapy, secondary aldosteronism in cirrhotics and severe vomiting are the common causes of metabolic alkalosis. Clinical features: 1- Manifestations of the cause 2- Manifestations of neuromuscular irritability owing to the decreased ionized calcium. Treatment: 1- Of the cause 2- Support respiratory and renal compensatory mechanisms. 3- If there is renal failure with severe metabolic alkalosis, dialysis may be provided. Respiratory Alkalosis Excessive pulmonary wash of Co2 will result in alkalosis owing to directing the reaction (H2O + Co2 ´ H2CO3 ´ H+ HCo3-) to the left with consequent reduction in H+. The renal defence mechanism will include the increase in HCo3- secretion and retention of H+. This mechanism is relatively slow. It needs 24 hours to be established. For each 10 mmHg increase in PCo2, there is a 2.5 mmol/L decrease in plasma HCo3.
Features: • ↓ PCo2 • ↑ pH • ↓ HCo3 Causes of respiratory Alkalosis: 1- Iatrogenic in patients under ventilatory support. 2- Liver cirrhosis, salicylate intoxication, exercise and hypotension. 3- Hyperventilation syndrome in neurotic patients 4- Cerebral hypoxia and intracranial disease Clinical features: 1- Manifestations of the cause 2- Parasthesia, tinnitus, neuromuscular irritability and/or cerebral vasoconstriction Treatment: 1- Of the cause 2- Breathing into a mask (rebreathing of expired air with its high level of Co2).
HYPERTENSION AND THE KIDNEY Most physicians, consider the blood pressure above 140/90 mmHg in patients under the age of 50 years as hypertension thus deserves treatment. Etiology And Classification Of Hypertension: Hypertension, according to severity and target organ damage (of retina, kidney, heart) could be classified into benign or malignant. Etiologically, hypertension may be classified as essential (primary) or secondary. Secondary hypertension may be: 1- Renal: a- Renovascular hypertension: • Renal artery stenosis • Polyarteritis nodosa • Renal artery aneurysm • Renal artery malformation b- Renoparenchymal: • Glomerulonephritis • Polycystic kidney disease • Analgesic nephropathy • Renal tumour as Wilms’ tumour • Other renal parenchymal diseases
2- Endocrinal: a. Adrenal cortex: • Cushing’s syndrome • Conn’s syndrome b- Adrenal medulla and splanchnic sympathetic chain: • Pheochromocytoma c- Others: • Acromegaly • Hyperparathyroidism 3- Iatrogenic: • Oral contraceptives • Sympathomimetic amines (nasal decongestants and bronchodilators) • Corticosteroids • Cyclosporine • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Tricyclic antidepressants • Liquorice • Pregnancy-associated hypertension • Acute intermittent porphyria Secondary Hypertension A- Renal Hypertension: Renal hypertension is the commonest type of secondary hypertension. This may be due to diseases of the renal artery as renal artery
stenosis (renovascular hypertension) or disease of the renal parenchyma as glomerulonephritis (Renoparenchymal hypertension). Pathogenesis: Hypertension may develop owing to either: • Excess secretion of renin with a consequent more angiotensin II activity. • Vasopressor substances as Endothelin will be released by the diseased kidney. Endothelins are cyclic peptides released by arteriolar endothelium. They may have a vasoconstrictor action and strong platelet activation. • Failure to secrete salt and water load because of the decreased nephron mass. This will lead to the expansion of the extracellular volume and hypertension. • Failure to secrete vasodilator substances such as prostaglandins, platelet activating factor and kinins due to decreased nephron mass. Treatment: 1- Treatment of renal disease as renal artery stenosis by balloon dilatation or bypass surgery and SLE by steroids and immunosuppressive drugs. 2- Control of hypertension in renal patients may be a part of the treatment of the renal disease as it is known that uncontrolled hypertension is one of the major factors causing progression of renal damage and scarring. 3- Any drug which controls hypertension will be valuable but it seems that, in the presence of significant proteinuria, ACEIs may be superior in the prevention of glomerular scarring. On the contrary, in the
presence of renal artery stenosis this group of drugs are contraindicated. B- Conn’s Syndrome-Primary hyperaldosteronism: This is characterized with excess aldosterone which is due to excess secretion by adenoma or hyperplasia of the zona glomerulosa of the adrenal cortex. This will result in hypokalaemia and metabolic alkalosis. Plasma sodium will be high and bicarbonate will be above 30 mmol/L, also plasma renin will be low. Patients with Conn’s syndrome usually present with muscle weakness and mild hypertension. In few cases with Conn’s syndrome, the course of this disease will be marked with malignant hypertension and stroke. Treatment depends mainly on surgical excision and in bilateral cases steroid replacement may be needed. C- Pheochromocytoma: This is a tumour of chromaffin cells occurring in all age stages. In children, the tumour is always highly malignant (neuroblastoma and medulloblastoma), while in adults the tumour is always benign. Yet, hypertension will have a sinister prognosis if untreated properly. In 90% of cases the tumours is in adrenal medulla while in 10% the tumour is extra-adrenal affecting the sympathetic chain. It could be multiple and malignant. The extra-adrenal tumour could be abdominal or even thoracic.
Beside the clinical criteria of this tumour, serum and urinary catecholamine assay will confirm the diagnosis. Localization of tumour site is mandatory for surgical excision. This is usually carried out by isotope scanning using the tracer meta-iodo benzaguanin (MIBG). The tumour is extremely sensitive to X-ray contrast media, on exposure it will secrete a huge amount of catecholamine with fatal outcome. So, in hypertensive patient if pheochromocytoma is expected, this should be excluded first; by catecholamine assay before the patient is subjected to the contrast media. Treatment is by hypotensive drugs having A and B-adrenergic blocking properties as labetalol and carvedilol. They are the drugs of choice. The definitive treatment is surgical excision. RENAL DISEASES IN HEPATIC PATIENTS There are many renal disorders which are known to occur in cirrhotic patients. These are: 1- Hepatorenal syndrome 2- Cirrhotic glomerulopathy 3- Glomerulopathy induced by infection common in cirrhotic patients such as: • Malaria • Bilharziasis • HBV • HCV 4- Tubulointerstitial disorders that are due to: • Infection (brucellosis, mononucleosis, tuberculosis) • Systemic disease (sarcoidosis, Sjogren’s syndrome, lymphoma) • Drugs (methicillin, ampicillin, penicillin, sulfonamides, rifampicin, acetaminophen, Allopurinol).
5- Drugs and toxins producing combined Hepatic and Renal damage. A- Drugs causing hepatic injury and acute tubular necrosis: • Hallogenated hydrocarbons as carbon tetrachloride, chloroform and chlorethylene • Hallogenated anaesthetics as Halothane and Methoxyflurane • Tetracycline • Sulfonamides • Rifampicin • Acetaminophen • Methotrexate • Arsenic • Copper sulphate B- Hepatic injury and acute interstitial nephritis • Sulfonamides • Phenindione • Rifampicin • Allopurinol Hepatorenal Syndrome (HRS) Definitions :- HRS is an unexplained, functional renal failure occurring in patients with advanced liver disease. The diagnosis of HRS is considered when there is no laboratory or anatomic evidence of other known cause of renal failure. HRS occurs in patients with cirrhosis, acute hepatitis, fulminant hepatic failure and with hepatic malignancy.
Etiology :- HRS usually develops in hospitalized patient, indicating that iatrogenic factors are playing important role in the pathogenesis of this disorder. Abdominal paracentesis, vigorous diuretic therapy and bleeding- especially gastrointestinal-are known precipitating factors. Sometimes HRS is idiopathic. Clinical features of HRS The patient usually presents with manifestations of advanced liver disease and on development of HRS, there will be further progression of the bad general condition, disturbance of consciousness, mental concentration, increase in oedema, ascites and progressive oliguria and even anuria. Laboratory assessment will show a progressive increase in serum creatinine and blood urea. Differential Diagnosis: HRS should be differentiated from other causes of azotaemia in patient with advanced liver disease especially prerenal azotaemia and acute tubular necrosis. The following table presents the important differentiating points.
Pre renal azotemia Hepatorenal syndrome Acute tubular Necrosis Urinary sodium (mmol/L) <10 <10 >20 Urine/plasma creatinine ratio >30/1 >20/1 <20/1 Urine osmolarity (mosmol/l) ≥200 higher than plasma >200 higher than plasma Relatively similar to plasma (isothenuric) Urine sediment Normal Unremarkable Casts, cellular debris Treatment of Hepatorenal Syndrome • Treatment of HRS is largely supportive. • Prevention is more important. Toxic agents as NSAIDs, demeclocycline, aggressive diuresis or aggressive paracentesis have to be avoided. • If azotaemia is discovered in hepatic patient, the precipitating factor as volume contraction, cardiac decompensation and urinary tract obstruction have to be discovered and promptly treated. • If prerenal azotemia is possible we have to give a volume expander (colloid as albumin or crystalloid as saline) . • Abdominal paracentesis with plasma volume expansion (e.g. by salt free albumin) may decrease the intra-abdominal pressure, decrease
inferior vena cava obstruction and may increase the cardiac output and the renal perfusion. • Dialysis may be indicated in selected patients with HRS. Mainly those with potentially reversible acute liver disease and those awaiting orthotopic liver transplantation. • Orthotopic liver transplantation is the definitive line of treatment in patients with end stage liver disease and HRS. The renal function is resumed immediately after transplantation. PROTEINURIA Proteinuria is a rare presenting complaint of patients. Yet, when severe enough, it may cause hypoalbuminaemia and oedema. As protein in urine decreases the surface tension, it causes frothy urine which may be observed by some patients (bile salts and detergents used in toilets do the same). The urine is tested for proteinuria by dip stick test. Dipstick is a plastic strip, attached to it is a paper impregnated with chemical substance (tetrabromophenol) which is normally yellow in colour and changes according to amount of protein in urine (0, +, ++, +++). It can detect a protein down to a concentration of 300 mg/l. Proteinuria detected by dip stick test should be confirmed by collecting the 24 hours urine and testing for quantity of proteinuria using chemical methods. Definitions: • Proteinuria is a secretion of an abnormal amount of protein in urine. Normal protein excretion per 24 hours in adults is less than 200 mg.
Most of this protein is albumin and Tamm Horsfall protein with smaller amounts of immunoglobulins. • False positive proteinuria by dip stick occurs mainly when urine is alkaline and very concentrated; or if the stick test is left in urine for long time. False negative proteinuria is observed when protein excretion is mainly Bence Jones proteinuria and when urine is very diluted. • Bence Jones protein which is the light chain fraction of immunoglobulin appears in abnormal amounts in urine in cases of multiple myeloma, clots at temperature 45-55°C, above and below that range it dissolves in urine. Presence of Bence Jones proteinuria should be confirmed by immunoelectrophoresis. • The causes of Bence Jone’s proteinuria include: multiple myeloma, amyloidosis, adult Fanconi syndrome, benign monoclonal gammopathy and hyperparathyroidism. Mechanism of proteinuria: There are four known mechanisms for proteinuria. These are: 1. Abnormality in permeability of the glomerular basement membrane because of glomerular disease or abnormal glomerular hemodynamics. 2. Increased concentration of small molecular weight protein in blood (MW 60000- 70000) e.g. hemoglobin, myoglobin and immunoglobulin light chains. These will pass easily through the normal GBM 3. Tubular disease with inadequate reabsorption of normally filtered proteins of MW <60000 e.g. B2-microglobulin. 4. Secretion by renal tubular cells of Tamm-Horsfall protein (urinary glycoprotein).
Differential Diagnosis of Proteinuria: I. Functional proteinuria: There is no organic change in the kidney tissue: it is usually less than 1 gm/d and is reversible. Possibly, it is due to hemodynamic changes or to minor glomerular disease which are reversible. a. Strenuous exercise b. Fever c. Orthostatic proteinuria d. Miscellaneous (Thyrotoxicosis, severe anaemia, CNS lesions) II. Patients with proteinuria of 0.5-3.5 gm/d: a. Acute interstitial nephritis. b. Chronic interstitial nephritis such as bacterial (pyelonephritis), gouty nephropathy, analgesic nephropathy or nephrolithiasis. c. Tubular proteinuria such as Fanconi syndrome, heavy metal intoxication (lead, cadmium), multiple myeloma, hypokalaemic nephropathy, polycystic kidney disease and medullary cystic kidney disease. III. Patients with proteinuria of more than 3.5 gm/d: Usually caused by glomerular disease. a. Primary glomerular disease: refers to all types previously discussed under glomerulonephritis. b. Secondary glomerular disease is Previously discussed under glomerulonephritis.
Investigations of a case of proteinuria: 1. Characterization of proteinuria: After diagnosis of proteinuria by dip stick test, it should be confirmed by quantitative estimation of 24 hours proteinuria. Further assessment may include electrophoresis or immunoelectrophoresis to determine the type of abnormal protein excreted. 2. Urine analysis: For pus cells (to diagnose U.T. infection), RBCs and casts (to diagnose glomerular disease), also urine volume (oliguria or polyuria), pH of urine, specific gravity and test for glycosuria; and aminoaciduria and B2 microglobulin (may help in the diagnosis of tubular disease). 3. Blood and serologic examination: a. Kidney function tests: serum creatinine, creatinine clearance, electrolytes (Na, K, Ca, Po4). b. Total protein, albumin, cholesterol to diagnose nephrotic syndrome. c. Serologic examination e.g. for anti-DNA and complement component C3 and C4 for diagnosis of lupus erythematosus. 4. Radiologic assessment including: a. Examination of the kidney for its size, state of parenchyma, the presence of stone, back pressure change or pyelonephritic changes. It is achieved through ultrasound examination, plain X-ray, and IVP (if the kidney function is normal). b. Investigations to discover malignancy which could be the etiologic cause of proteinuria e.g. skeletal survey for multiple myeloma, X-ray chest and bronchogram or CT scan for bronchogenic carcinoma.
- Renal biopsy will give the final answer for the diagnosis of the kidney lesion causing proteinuria. HAEMATURIA Definitions • Normally the number of RBC’s in urine should not be more than 5 RBCs/high power field on microscopic examination of fresh centrifuged urine sample. So, haematuria is defined as a secretion of more than 5 RBCs/HPF in urine. • Haematuria may be the only symptom or associated with other symptoms, according to the etiologic cause e.g. loin pain and fever with infection and renal colic with renal stones. • Haematuria could be gross (causing red-coloured urine) or microscopic (urine appears normal. But RBCs are seen on microscopic examination). In gross hematuria, urine looks red if alkaline, but brown or coca-cola like if urine is acidic due to denaturation of the hemoglobin. • Also, hematuria could be glomerular (because of glomerular disease, sometimes called medical); or non glomerular (sometimes called surgical). Glomerular could be differentiated from non glomerular haematuria by: 1. The shape of RBCs in urine is dysmorphic in cases with glomerular haematuria while it will be normal in case of non glomerular haematuria. 2. The size of RBCs whose mean corpuscular volume in urine of patient with glomerular haematuria which is smaller than it is in peripheral blood. But in non glomerular cases it is equal.
- Proteinuria is present in most cases of glomerular hematuria but not in cases of non glomerular hematuria. 4. Casts such as proteinuria. 5. Blood clots indicate non-glomerular bleeding and can be associated with pain & colic. Differential Diagnosis of Hematuria: A. First, hematuria should be differentiated from other causes of red or brownish urine: - Microscopy will show RBC’s only with hematuria. - Dipsticks (Hemastix) will be positive with hemoglobinuria (hemolysis) and myoglobinuria (muscle damage) but negative with other causes e.g. porphyrins (in porphyria), bile (in jaundice), melanin (in melanoma), alkaptonuria, food dyes and drugs as PAS or phenylphthalein. B. Hematuria may be of renal, ureteral, bladder or urethral origin. I. Haematuria of renal origin: a. Glomerular haematuria: Either primary glomerular disease (e.g. IgA nephropathy, mesangial proliferative glomerulonephritis or crescentic glomerulonephritis); or secondary glomerulonephritis i.e. renal involvement is a part of systemic disease (e.g. post-streptococcal glomerulonephritis, Henoch-Schönlein purpura, SLE, polyarteritis nodosa). b. Renal infection: Pyelonephritis (especially with papillary necrosis) or renal tuberculosis. c. Renal neoplastic disease: Renal cell carcinoma, transitional cell carcinoma of the renal pelvis and others. d. Hereditary renal disease: Medullary sponge kidney or polycystic kidney disease.
e. Coagulation defect: Use of anticoagulant, liver disease and thrombocytopaenia. f. Renal vascular disease: Renal infarction, renal vein thrombosis or malignant hypertension. g. Exertional haematuria. II. Hematuria of ureteral origin: a. Malignancy. b. Nephrolithiasis c. Ureteral inflammatory condition secondary to nearby inflammation e.g. diverticulitis, appendicitis or salpingitis. d. Ureteral trauma e.g. during ureteroscopy. III. Hematuria of bladder origin: a. Infection: schistosoma, viral or bacterial cystitis. b. Neoplasms. c. Foreign body in the bladder e.g. stones. d. Trauma: During instrumentation or accidental. e. Drug: e.g. cyclophosphamide induced haemorrhagic cystitis. IV. Hematuria of urethral or associated structures: a. Prostate: acute prostatitis, benign prostatic hypertrophy. b. Urethritis, foreign body or local trauma to the urethra.
Investigations of a case of hematuria: 1. First exclude haemoglobinuria and myoglobinuria since both of them can also cause positive dipstick test for haematuria. This is done by microscopic examination of fresh urine sample. In case of haematuria, RBCs could be seen while in the other two conditions no RBC’s could be seen. In case of myoglobinuria, clinical examination may show manifestations of muscle disease and the examination of urine by immunoelectrophoresis may show myoglobin. In case of haemoglobinuria, manifestations of haemolysis may be evident. 2. Examination of urine for proteinuria and casts (to diagnose glomerular disease), pus cells and urine culture (for diagnosis of infection), Zeil-Nelson stain and specific media (for diagnosis of T.B.). 3. Plain X-ray, I.V.P. (if serum creatinine is normal), ultrasound and possibly angiography, for the diagnosis of surgical diseases e.g. stone, malignancy or infection. 4. RBCs in urine could be examined for its shape to differentiate glomerular from non glomerular causes (by phase contrast microscopy). 5. Kidney function tests. 6. Specific investigations for diagnosis of systemic diseases causing haematuria e.g. SLE. 7. Kidney biopsy for glomerular haematuria.
VALUE OF URINE EXAMINATION IN MEDICAL DIAGNOSIS Normal Urine Characters: 1. Volume is 600-2500 ml/24 h (average is 1200 ml/24 h). 2. Colour is umber yellow. 3. Specific gravity is 1003-1030 (represents amount of solids in urine). 4. pH is 4.6-8.8 (average 6.0) 5. Protein: The amount as detected by semiqualitative methods is 0.0-0.1 gm/24 hr urine. 6. Cells and casts: - R.B.C.s and W.B.C.s. < 5 by H.P.F. - Hyaline casts occasionally present (protein collected in the renal tubules taking a cylinderical shape producing occasional hyaline casts). 7. Glucose: should be negative. 8. Some other substances may be present e.g.: - Calcium < 150 mg/24 hr. - Phosphate : 1mg/24 h. - Amylase: 260-950 mg/24h. - Creatinine: 1.6 gm/24 h (15-25 mg/kg/24h). - Porphyrin: 50-300 mg/24h. - Ketones: qualitative amounts. How to examine urine: We have to comment on the following items: - Volume/24 h - Specific gravity (osmolality)
- Colour of urine - Dip stick examination of urine - Microscopic examination. 1. Volume of urine: Changes in urine volume may be oliguria or polyuria: Polyuria: (Urine volume > 2500 ml/day) may occur with: - Diuretics - Excessive water intake (within the normal range). - Compulsive water drinking in psychological cases (psychogenic polydepsia). - Uncontrolled D.M. - Diabetes insipidus which may be central or nephrogenic. • In central D.I. there is a decreased A.D.H. secretion. • In nephrogenic D.I. the renal response to A.D.H. is defective as in analgesic nephropathy and medullary cystic kidney disease. - Early stage of chronic renal failure. - Diuretic phase of acute renal failure. (for more details see chapter on hypernatraemia) Oliguria: (Urine volume < 600 ml/day), may occur with: i. Obstructive causes: Mainly produce anuria i.e. no urine at all, should be differentiated from urine retention by detecting urine in the bladder (suprapubic dullness, by U.S., or by urethral catheter). - Removal of solitary functioning kidney.
- Bilateral ureteric obstruction (or unilateral ureteric obstruction of a solitary functioning kidney). - Retro-peritoneal fibrosis blocking ureteric flow. ii. Nonobstructive causes: Mainly produce oliguria: - Inadequate renal perfusion e.g. with vomiting, or diarrhea will cause depletion of body salts and fluids. - Intravascular volume depletion e.g. with internal haemorrhage or rapidly developing ascites. iii. Oliguria with intrinsic renal disease: - Oliguric phase of acute tubular necrosis. - Rapidly progressive glomerulonephritis. - Bilateral cortical necrosis. - End stage renal failure. - Acute nephritic syndrome. - Nephrotic syndrome. 2. Specific gravity: Specific gravity represents the amount of solids in urine: - Specific gravity is measured by urinometer or by another special complicated apparatus which is more perfect (osmometer). - Specific gravity is one of the kidney function tests. In D.I. repeated measurement of urine specific gravity in face of water deprivation and after vasopressin administration is mandatory for proper diagnosis.
- Colour: - Normal: umber yellow - Examples of colour changes of urine: • Red urine: with hematuria, myoglobinuria and haemoglobulinuria (with haemoglobinuria the colour is red brown). • Pink: with rifampicin. • Orange: concentrated normal urine, urobilin, bilirubin, • Deep yellow: Mepacrine. • Milky: Chyluria. • Smoky: acute glomerulonephritis. 4. Dip stick examination of urine: - Dip stick is a plastic strip with squares of paper impregnated with enzymes which change in colour on exposure to target chemicals. - Dip stick is used for detection of protein, ketones, glucose, pH, haemoglobin, bile, bacteria, pus cells and leucocytes i. Proteinuria: - Normal protein in urine (by quantitative assessment) is <0.1 gm/d by dip stick. It is mainly albumin and Tamm Horsfall protein which is synthesized by renal tubules. - Abnormal proteinuria may contain albumin, globulin, Bence Jones protein and low molecular weight protein (e.g. B-microglobulin). - Proteinuria may be of: • Glomerular origin e.g post infectious G.N., drug induced G.N., collagen disease and idiopathic G.N. • Tubular origin (usually low molecular weight proteins) e.g. heavy metals intoxication, analgesic nephropathy. - For more details see chapter on proteinuria (page 122 )
ii. pH: - Normal urine is acidic, average 6. - Highly acidic in uric acid stones. - Alkaline in stones caused by infection and in renal tubular acidosis. - pH is important in: • The treatment of stones, it is advised to give alkalies e.g. Na HCo3 in acidic stones, or acids e.g. vitamin C in alkaline stones. • Drug intoxication, it is advised to give alkalies in acidic drug intoxication as salicylates and acids in alkaline drug intoxication as pethidine. • Increase potency of some antibiotics in urinary tract infection, alkalies with aminoglycosides and acids with tetracyclines are given. iii. Haemoglobinuria: - Haemoglobin may be present in urine in haemoglubinuria or haematuria (differentiated by presence of R.B.C.s in case of haematuria). - RBCs may rupture in cases of hypotonic urine but RBCs ghosts could still be seen. - Ascorbic acid may produce false test for haemoglobinuria.