ACUTE AND CHRONIC RENAL FAILURE

A. ACUTE RENAL FAILURE *Characteristics: Sudden decrease in the GFR Azotemia Oliguria- often the initial oliguria leads to anuria High Mortality Rate *Three Principal Mechanisms that cause ARF 1. Pre-renal (25% of cases) a. Decrease in Blood Volume- in response to decreased blood pressure, the kidneys increase sodium and water reabsorption in an attempt to restore normal blood volume and perfusion; thus, there is low sodium concentration in urine b. Hemorrhage c. Burns d. Surgery e. Septicemia 2. Renal (65% of cases) a. Acute glomerulonephritis b. Acute Tubular Necrosis- leading cause of ARF; As ATN progresses, the renal tubular destruction results in loss of water and electrolytes, i.e. increase excretion of sodium c. Acute pyelonephritis d. Acute Interstitial Nephritis 3. Post-renal (10% of cases) - the ARF is caused by obstructions in urine flow. *How? The obstruction causes an increase in the hydrostatic pressure within the tubules and Bowmans space. As a result, the normal filtration pressures across the glomerular filtration barrier is disrupted and the glomerular filtration rate decreases. Eventually, the tubules become damaged and renal function is lost. a. Renal calculi b. Tumors c. Crystallization of ingested substances B. CHRONIC RENAL FAILURE *Characteristics: Progressive loss of renal function because of an irreversible and intrinsic renal disease Slow and silent-the GFR slowly but continuously decreases, the decrease becoming clinically recognizable only after 80 to 85% of normal renal function has been lost Azotemia Water and electrolyte imbalance Abnormal calcium and phosphorus metabolism *Causes: Glomerulonephropathies Diabetic nephropathy Chronic pyelonephritis Hypertension Collagen vascular diseases, e.g. Systemic Lupus Erythematosus Congenital abnormalities

I. PROTEINURIA
- presence of protein in urine is most indicative of renal disease and is often associated with early renal disease; although its presence is not always pathologic in nature NORMAL VALUE: 10 mg/dL 100 (150) mg/ day COMMON URINE PROTEINS a. Plasma derived

Primarily low molecular weight found in urine; from serum or genitourinary tract

**Small amounts of albumin, some globulins, and hormones can normally be found in the urine. b. Most plasma proteins (> 68,000 dalton's) are not filtered due to the glomerular barrier. Lower MW proteins are filtered, but are usually reabsorbed by renal tubules. ALBUMIN- major serum protein found in normal urine; majority is not filtered by the glomerulus and much of the filtered albumin is reabsorbed Small amounts of serum microglobulins

Urine derived The renal tubules (Tamm-Horsfall mucoproteins, Ig's), and urogenital tract may secrete small amounts of protein that are added to the urine. Tamm-Horsfall Protein (Uromodulin)- high molecular weight mucoprotein secreted by renal tubular cells that is not present in the plasma and forms the basic matrix of most urinary casts Proteins from prostatic, seminal and vaginal secretions

A. QUALITATIVE CATEGORIES OF PROTEINURIA 1. PRE-RENAL PROTEINURIA: protein loss in urine without renal disease a. Tubular overload proteinuria i. Occurs when elevated levels of small MW proteins (< 68K daltons) pass through the normal glomerulus and appear in urine. Excessive amounts of the same protein are found in blood and urine. ii. Examples: hemoglobinemia (from intravascular hemolysis) myoglobinemia- mostly due to muscle injury (from rhabdomyolysis - may see with heatstroke or seizures) Bence Jones proteinuria - excess light chain immunoglobulins associated with Multiple myeloma - BJP is screened in the lab based on its unique thermal coagulability: coagulates at temperatures between 40-60C and dissolves when the temperature reaches 100C

b. Functional proteinuria i. Transient alteration in glomerular function. ii. Sometimes transient proteinuria (usually albumin) is noted in association with hypertension, strenuous exercise, extremes of heat or cold, pregnancy, venous congestion, fever, or seizures. 2. RENAL PROTEINURIA: protein loss in urine due to renal disease a. Glomerular disease i. ii. Glomerular proteinuria results from a damaged glomerulus that allows for leakage of plasma proteins through the glomerulus. This form of proteinuria is usually profound and consists predominantly of albumin. When the glomerular membrane is damaged, selective filtration is impaired, and increased amounts of serum protein and eventually red and white blood cells pass through the membrane and are excreted in the urine.

iii.

iv.

v.

Conditions that present the glomerular membrane with abnormal substances are major causes of proteinuria due to glomerular damage. e.g. a. amyloid material b. toxic substances c. immune complexes found in lupus erythematosus and streptococcal glomerulonephritis Conditions that present the glomerular membrane with abnormal substances are major causes of proteinuria due to glomerular damage. e.g. a. amyloid material b. toxic substances c. immune complexes found in lupus erythematosus and streptococcal glomerulonephritis Increased pressure from the blood entering the glomerulus may override the selective filtration of the glomerulus, causing increased albumin to enter the filtrate. This condition may be reversible, such as a. occurs during strenuous exercise b. dehydration c. associated with hypertension d. pre-eclamptic state during the latter months of pregnancy

b. Tubular disease i. ii. iii. iv. Tubular proteinuria may occur due to tubular dysfunction (tubules fail to reabsorb filtered protein) or parenchymal inflammation. This form of proteinuria is usually mild. Increased albumin is also present in disorders affecting tubular reabsorption because the normally filtered albumin can no longer be reabsorbed. Other low-molecular-weight proteins that are usually reabsorbed are also present. Causes of tubular dysfunction include a. exposure to toxic substances and heavy metals b. severe viral infections c. Fanconi syndrome.

c. Orthostatic Proteinuria or Postural proteinuria i. ii. iii. iv. v. In this condition, proteinuria is found during the day but not at night when a recumbent position is assumed. Increased pressure on the renal vein when in the vertical position is believed to account for this condition. Persistent proteinuria may develop in some of these healthy subjects at a later date, and renal biopsies have shown abnormalities of the glomerulus in a few cases The total daily excretion of protein rarely exceeds 1 g, and in most instances, no other evidence of renal disease develops is apparent. To evaluate the possibility of postural proteinuria, the patient is instructed to empty his or her bladder upon going to bed in the evening. Immediately upon arising in the morning, the patient voids and saves this specimen. After 2 hours of standing and walking about, the patient voids again and saves the specimen. The two urine specimens are assessed for protein, and if the first is negative and the second positive, the patient may have postural proteinuria.

d. Microalbuminuria i. ii. iii. iv. v. used to predict Diabetic nephropathy and cardiovascular disorder some methods for microalbumin provide estimation of the 24 hour microalbumin excretion using AER (Albumin Excretion Rate) in micrograms/min. With these methods, microalbumin is considered significant when 30 to 300 mg of albumin is excreted in 24 hours or the AER is 20-200 micrograms/min. Several semiquantitative reagent strip methods have been developed so that patients at risk for renal disease can be monitored using random or first morning specimens. These methods are based on immunochemical assays for albumin or albumin-specific reagent strips that also measure creatinine to produce an albumin:creatinine ratio. (Why creatinine? Creatinine is produced and excreted at a consistent rate for each individual. Therefore, by comparing the albumin excretion to the creatinine excretion, the albumin reading can be corrected for overhydration and dehydration in a random sample.)

3. POST-RENAL PROTEINURIA: protein added to urine after it has been formed. a. b. c. Lower urinary tract or genital disease- this may occur when inflammatory exudates or blood proteins from the lower urinary or genital tract mix with urine (usually due to infection, hemorrhage, neoplasia, etc). Bacterial and fungal infectionsand inflammations produce exudates containing protein from the interstitial fluid. Protein can be added to a urine specimen as it passes throughnthe structures of the lower urinary tract (ureters, bladder, urethra, prostate, and vagina). The presence of blood as the result of injury or menstrual contamination contributes protein, as does the presence of prostatic fluid and large amounts of spermatozoa.

B.QUANTITATIVE CATEGORIES OF PROTEINURIA HEAVY PROTEINURIA >4g/day Nephrotic syndrome Minimal change disease RPGN-Rapidly Progressing, CGN Malaria, malignant HPN, amyloidosis, neoplasia, renal transplant rejection, heavy metanls (Au,Hg) poisoning, toxemia of pregnancy MODERATE 1-4g/day Nehprosclerosis Muliple myeloma Calculi MILD <1g/day CPN Chronic interstitial nepgritis Nephrosclerosis Poylcystic disease Medualay cysticdisease Glomerular or tubular and site of damage C. LABORATORY EVALUATION OF PROTEINURIA 1. URINE PROTEIN CONCENTRATION VERSUS URINE PROTEIN CONTENT a. Urine protein concentration Refers to the amount of protein per unit volume of urine. This amount may not accurately reflect total daily protein loss. b. Urine protein content: most accurate Refers to amount of protein in urine relative to the total urine volume produced. Is a much more accurate predictor of the magnitude of proteinuria present 2. SCREENING TESTS: evaluate urine protein concentration a. Urine dipsticks i. ii. iii. iv. Principle: PROTEIN ERROR OF INDICATOR A color change on test pad (tetrabromophenol blue) of dipstick indicates presence of protein in urine. These dipsticks are more sensitive to the detection of albumin than globulin or other proteins. An alkaline urine pH or chlorhexidine contamination may give a false positive reaction.

b. Sulfosalicylic acid (SSA) test i. ii. iii. An equal volume of urine (supernatant) and SSA is mixed together and the resultant turbidity is indicative of amount of protein present. Will detect albumin, globulins and BJ's proteins. False positive reactions may be noted with other factors which increase urine turbidity (radiopaque contrast agents, etc.).

iv. v.

Highly buffered alkaline urine produces false negative results. REPORTING OF SSA RESULT:

c. Effect of urine SG i. ii. iii. The urine SG will have an impact on protein concentration tests (e.g., dilute urine must contain larger amounts of protein before it will be detectable). Ex: A (1+) proteinuria in urine SG of 1.006 suggests greater protein loss than a (1+) proteinuria in urine SG of 1.040 (as a dilute urine sample implies a larger total urine volume than a concentrated sample). NOTE: For reasons stated above, these tests should be considered screening tests only - to determine the significance of proteinuria, a urine protein: creatinine ratio or a 24 hour urinary protein excretion test must be performed.

3. QUANTITATIVE TESTS: evaluate urine protein content a. Twenty-four hour urine protein excretion Urine is meticulously collected (catheterization typically necessary) for 24 hours. An aliquot is assayed for protein content and 24 hour urinary protein excretion determined. b. Urine protein/creatinine ratio (UPCr) i. ii. Basis: The UPCr is the test of choice for quantitating proteinuria. This test can be performed with a single random urine sample and provides a direct correlation to measured 24 hour urine protein loss. This test is often used to determine the significance of protein in the urine detected by routine screening methods. Technique: Urine protein (mg/dl) and urine creatinine (mg/dl) are measured in a single random urine sample. This test is not influenced by urine SG because while urine protein and creatinine levels are affected by total solute concentration (e.g., urine SG), their ratio is not.

c. Urine protein electrophoresis: used to evaluate type of protein in urine. Patients with glomerular disease will typically have an albumin peak, while those with tubular disease will have a globulin peak, and patients with Bence Jones proteinuria will have a monoclonal globulin spike.