Clinical Pharmacy iephrology. Symptoms and syndromes in major diseases of the kidney and urinary tract. Clinical pharmacology of drugs used to treat infectious diseases and immunoinflammatory urinary system diseases
Nephrology – is the science that studies the diagnosis and management of kidney disease, by regulating blood pressure, regulating electrolytes, balancing fluids in the body, and administering dialysis. Urology – is the science that studies the diagnosis and treatment of various diseases of the urogenital system in males, urogenital infections in women.
Chronic pyelonephritis – a nonspecific inflammation mainly tubules and interstitium in conjunction with the defeat of the urinary tract. Glomerulonephritis – genetically caused, multifactorial, immunologic, progressive inflammation of the kidneys with the defeat of initial glomerular apparatus. Urolithiasis – a chronic disease characterized by the formation in the kidneys and urinary tract urinary stones as a result of metabolic.
Cystitis – inflammation of the urethra, causes, predisposes factors are the same as prostatitis. Prostatitis – an inflammation of the prostate gland. Prostate adenoma – a benign tumor of the prostate gland usually occurs in older people.
Normal Kidneys and Their Function
The kidneys are a pair of bean-shaped organs that lie on either side of the spine in the lower middle of the back. Each kidney weighs about ¼ pound and contains approximately one million filtering units called nephrons. Each nephron is made of a glomerulus and a tubule. The glomerulus is a miniature filtering or sieving device while the tubule is a tiny tube like structure attached to the glomerulus.
The kidneys are connected to the urinary bladder by tubes called ureters. Urine is stored in the urinary bladder until the bladder is emptied by urinating. The bladder is connected to the outside of the body by another tube like structure called the urethra.
The main function of the kidneys is to remove waste products and excess water from the blood. The kidneys process about 200 liters of blood every day and produce about two liters of urine. The waste products are generated from normal metabolic processes including the breakdown of active tissues, ingested foods, and other substances. The kidneys allow consumption of a variety of foods, drugs, vitamins and supplements, additives, and excess fluids without worry that toxic by-products will build up to harmful levels. The kidney also plays a major role in regulating levels of various minerals such as calcium, sodium, and potassium in the blood.
As the first step in filtration, blood is delivered into the glomeruli by microscopic leaky blood vessels called capillaries. Here, blood is filtered of waste products and fluid while red blood cells, proteins, and large molecules are retained in the capillaries. In addition to wastes, some useful substances are also filtered out. The filtrate collects in a sac called Bowman’s capsule.
The tubules are the next step in the filtration process. The tubules are lined with highly functional cells which process the filtrate, reabsorbing water and chemicals useful to the body while secreting some additional waste products into the tubule.
The kidneys also produce certain hormones that have important functions in the body, including the following:
Active form of vitamin D (calcitriol or 1,25 dihydroxy-vitamin D), which regulates absorption of calcium and phosphorus from foods, promoting formation of strong bone.
METHODS OF URINE COLLECTION
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Random |
Taken at any time of day with no precautions regarding contamination. The sample may be dilute, isotonic, or hypertonic and may contain white cells, bacteria, and squamous epithelium as contaminants. In females, the specimen may contain vaginal contaminants such as trichomonads, yeast, and during menses, red cells. |
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Early morning |
Early morning collection of the sample before ingestion of any fluid. This is usually hypertonic and reflects the ability of the kidney to concentrate urine during dehydration which occurs overnight. If all fluid ingestion has been avoided since 6 p.m. the previous day, the specific gravity usually exceeds |
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Mid stream Clean catch |
Collected after cleansing the external urethral meatus. A cotton sponge soaked with benzalkonium hydrochloride is useful and non-irritating for this purpose. First half of the bladder urine is discarded and the collection vessel is introduced into the urinary stream to catch the last half First half of the stream serves to flush contaminating cells and microbes from the outer urethra prior to collection |
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Catheterization of the bladder |
Only in special circumstances, i.e., in a comatose or confused patient Risks introducing infection and traumatizing the urethra and bladder, producing iatrogenic infection or hematuria. |
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Suprapubic transabdominal needle aspiration of the bladder |
Provides the purest sampling of bladder urine |
MACROSCOPIC URINALYSIS
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Color |
Normal, fresh urine is pale to dark yellow or amber in color A red or red-brown (abnormal) color could be from a food dye, eating fresh beets, a drug, or the presence of either hemoglobin or myoglobin. If the sample contained many red blood cells, it would be cloudy as well as red. |
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Volume |
750 to 2000 ml/24hr |
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Clarity |
Turbidity or cloudiness may be caused by excessive cellular material or protein in the urine or may develop from crystallization or precipitation of salts upon standing at room temperature or in the refrigerator. Clearing of the specimen after addition of a small amount of acid indicates that precipitation of salts is the probable cause of tubidity |
COLOR. Normal urine is straw yellow to amber in color. Abnormal colors include bright yellow, brown, black (gray), red, and green. These pigments may result from medications, dietary sources, or diseases. For example, red urine may be caused by blood or hemoglobin, beets, medications, and some porphyrias. Black-gray urine may result from melanin (melanoma) or homogentisic acid (alkaptonuria, a result of a metabolic disorder). Bright yellow urine may be caused by bilirubin (a bile pigment). Green urine may be caused by biliverdin or certain medications. Orange urine may be caused by some medications or excessive urobilinogen (chemical relatives of urobilinogen). Brown urine may be caused by excessive amounts of prophobilin or urobilin (a chemical produced in the intestines).
TRANSPARENCY. Normal urine is transparent. Turbid (cloudy) urine may be caused by either normal or abnormal processes. Normal conditions giving rise to turbid urine include precipitation of crystals, mucus, or vaginal discharge. Abnormal causes of turbidity include the presence of blood cells, yeast, and bacteria.
SPECIFIC GRAVITY. The specific gravity of urine is a measure of the concentration of dissolved solutes (substances in a solution), and it reflects the ability of the kidneys to concentrate the urine (conserve water). Specific gravity is usually measured by determining the refractive index of a urine sample (refractometry) or by chemical analysis. Specific gravity varies with fluid and solute intake. It will be increased (above 1.035) in persons with diabetes mellitus and persons taking large amounts of medication. It will also be increased after radiologic studies of the kidney owing to the excretion of x ray contrast dye. Consistently low specific gravity (1.003 or less) is seen in persons with diabetes insipidus. In renal (kidney) failure, the specific gravity remains equal to that of blood plasma (1.008–1.010) regardless of changes in the patient’s salt and water intake. Urine volume below 400 mL per day is considered oliguria (low urine production), and may occur in persons who are dehydrated and those with some kidney diseases. A volume in excess of
URINE DIPSTICK CHEMICAL ANALYSIS
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pH |
The glomerular filtrate of blood plasma is usually acidified by renal tubules and collecting ducts from a pH of 7.4 to about |
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Specific gravity |
Any specific gravity > 1.022 measured in a randomly collected specimen denotes adequate renal concentration so long as there are no abnormal solutes in the urine. (which is directly proportional to urine osmolality which measures solute concentration) measures urine density, or the ability of the kidney to concentrate or dilute the urine over that of plasma. Dipsticks are available that also measure specific gravity in approximations. Most laboratories measure specific gravity with a refractometer. Specific gravity between 1.002 and 1.035 on a random sample should be considered normal if kidney function is normal. Since the sp gr of the glomerular filtrate in Bowman’s space ranges from 1.007 to 1.010, any measurement below this range indicates hydration and any measurement above it indicates relative dehydration. If sp gr is not > 1.022 after a 12 hour period without food or water, renal concentrating ability is impaired and the patient either has generalized renal impairment or nephrogenic diabetes insipidus. In end-stage renal disease, sp gr tends to become 1.007 to 1.010. Any urine having a specific gravity over 1.035 is either contaminated, contains very high levels of glucose, or the patient may have recently received high density radiopaque dyes intravenously for radiographic studies or low molecular weight dextran solutions. Subtract 0.004 for every 1% glucose to determine non-glucose solute concentration. |
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Protein |
Screening for protein is done on whole urine, but semi-quantitative tests for urine protein should be performed on the supernatant of centrifuged urine since the cells suspended iormal urine can produce a falsely high estimation of protein. Normally, only small plasma proteins filtered at the glomerulus are reabsorbed by the renal tubule. However, a small amount of filtered plasma proteins and protein secreted by the nephron (Tamm-Horsfall protein) can be found iormal urine. Normal total protein excretion does not usually exceed 150 mg/24 hours or 10 mg/100 ml in any single specimen. More than 150 mg/day is defined as proteinuria. Proteinuria > 3.5 gm/24 hours is severe and known as nephrotic syndrome. Dipsticks detect protein by production of color with an indicator dye, Bromphenol blue, which is most sensitive to albumin but detects globulins and Bence-Jones protein poorly. Precipitation by heat is a better semiquantitative method, but overall, it is not a highly sensitive test. The sulfosalicylic acid test is a more sensitive precipitation test. It can detect albumin, globulins, and Bence-Jones protein at low concentrations. In rough terms, trace positive results (which represent a slightly hazy appearance in urine) are equivalent to 10 mg/100 ml or about 150 mg/24 hours (the upper limit of normal). 1+ corresponds to about 200-500 mg/24 hours, a 2+ to 0.5-1.5 gm/24 hours, a 3+ to 2-5 gm/24 hours, and a 4+ represents 7 gm/24 hours or greater. |
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Glucose |
Less than 0.1% of glucose normally filtered by the glomerulus appears in urine (< 130 mg/24 hr). Glycosuria (excess sugar in urine) generally means diabetes mellitus. Dipsticks employing the glucose oxidase reaction for screening are specific for glucos glucose but can miss other reducing sugars such as galactose and fructose. For this reason, most newborn and infant urines are routinely screened for reducing sugars by methods other than glucose oxidase (such as the Clinitest, a modified Benedict’s copper reduction test). |
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Ketones |
Ketones (acetone, aceotacetic acid, beta-hydroxybutyric acid) resulting from either diabetic ketosis or some other form of calorie deprivation (starvation), are easily detected using either dipsticks or test tablets containing sodium nitroprusside. |
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Nitrite |
A positive nitrite test indicates that bacteria may be present in significant numbers in urine. Gram negative rods such as E. coli are more likely to give a positive test. |
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Leukocyte esterase |
A positive leukocyte esterase test results from the presence of white blood cells either as whole cells or as lysed cells. Pyuria can be detected even if the urine sample contains damaged or lysed WBC’s. A negative leukocyte esterase test means that an infection is unlikely and that, without additional evidence of urinary tract infection, microscopic exam and/or urine culture need not be done to rule out significant bacteriuria |
Nephrology/Urology Disorders
1. Nephrotic Syndrome
Symptoms:
Signs:
Peripheral Edema (Ascites & Pulmonary edema are possible.)
Complications:
· Atherosclerosis
· Venous Thrombosis
· Bacterial Infection
· Lab Presentation
Urinalysis: fixed proteinuria (> 3.5g / day / 1.73m2 body area), lipiduria with oval fat bodies seen on microscopy
Blood tests: hypoalbuminemia, dyslipidemia (↑ LDL, ↑ VLDL, ↓ HDL), hypercholesterolemia
The Nephrotic Syndrome is characterized by increased permeability of the glomerular capillary wall to proteins (loss of fixed negative charges on the basement membrane with or without other structural changes), leading to an increase in urinary protein excretion. Other characteristics include: hypoalbuminemia due to protein loss in the urine & ↑ catabolism of protein reabsorbed by the proximal tubule (even though hepatic production is ↑ed), peripheral edema with collection of fluid in the serous cavities, lipiduria seen on microscopic examination of urine due to ↑ed filtration of lipids & lipoproteins, and dyslipidemia caused by ↑ed lipoprotein synthesis and ↓ed lipoprotein catabolism. Hypoproteinuria is due to catabolic protein loss as well as urinary protein loss – dyslipemia & hypercholesterolemia are caused by hepatic overproduction of lipoprotein due to ↓ plasma oncotic pressure.
Sodium/water retention and edema occur as follows: 1) The “underfill” mechanism: urinary loss of albumin → ↓ intravascular oncotic pressure → ↑ movement of fluid into the interstitium (edema) → ↓ EABV → retention of Na/water (via RAAS, SNS activation, & non-osmotic release of ADH); the edematous state stabilizes when the decreased intravascular oncotic pressure is matched by the increased interstitial hydrostatic pressure, 2) The “overfill” mechanism: glomerular disease → primary ↑ in renal Na & water retention (this happens for reasons that are not yet clear) → ↑ ECFV → ↑ venular hydrostatic pressure → edema. It has been shown that only extremely low serum albumin levels (< 2.0g/dL) initiate edema via the underfill mechanism, and that the overfill mechanism is the major cause of edema in NS & is associated with aberrant RAAS activation.
Complications include atherosclerosis (related to the dyslipidemia), venous thrombosis (urinary loss of antithrombin III, protein C, and protein S in excess of loss of pro-coagulation factors), and bacterial infection (urinary loss of IgG). Depending on the cause of the NS, there may be a decreased GFR, hematuria, and clinical features associated with an underlying disease.
In assessing proteinuria, we must exclude functional proteinuria & orthostatic proteinuria: functional proteinuria is a transient increase in urinary protein (< 2-3x increase, up to 500mg/day) that occurs with exercise, febrile illness, emotional stress, or ↑
TREATMENT
1. To treat proteinuria, give occasional infusions of albumin or ACE–inhibitors (to ↓ GFR via reversal of angiotensinII-mediated constriction of the efferent arteriole).
– ACE-inhibitors are general therapy of choice for nephrotic pts. with HTN.
2. Reverse glomerular disease with corticosteroids or cytotoxic agents.
3. Na-restricted diet.
4. Give diuretics, but do so very cautiously to avoid avoid excessive ↓ of ECFV, acute kidney failure, metabolic alkalosis & hypokalemia.
– thiazides for mild edema; loops for severe edema
5. To treat dyslipidemia, use statins or bile-acid drugs
Major Forms of Primary Neprotic Syndrome
Minimal Change Glomerulopathy accounts for 70-90% of primary nephrotic syndrome in children under 10, with a peak incidence of 24-36 months and a strong male predominance in that population; MCG accounts for 10-15% of primary nephrotic syndrome in adults, and in adults it is often associated with underlying conditions (especially use of NSAIDs). MCG has no lesions on light microscopy or immunoflourescence; EM shows effacement of podocyte foot processes. MCG is thought to be mediated by a T-cell lymphokine that causes increased glomerular permeability; the cardinal clinical feature is abrupt onset nephrotic syndrome with HTN & renal insufficiency possible in adults (but rare in children). Treatment of MCG is with corticosteroids: 90% of pts. resolve within 6weeks, 25% achieve complete remission, 25-30% have < 1 relapse per year, and the remainder have frequent relapses (these may require treatment with cyclosporine).
Focal Segmental Glomerulosclerosis is a clinical-pathological designation that includes multiple etiologies & pathogenetic mechanisms (may be primarily renal or extra-renal); it is the most common cause of nephrotic syndrome among African Americans.
The pathogenesis of FSGS is poorly understood, but most theories suggest podocyte injury is involved; FSGS may result from a loss of nephrons which causes compensatory intraglomerular HTN and hypertrophy (although data in uninephrectomized pts. has shown only mild proteinuria and systolic HTN) – FSGS can occur as a result of increased glomerular hyperfiltration (as iephron loss or congenitally low nephric mass); it is also associated with syndromes of low oxygen delivery: sickle-cell disease, cyanotic heart disease, and obstructive sleep apnea.
The typical presentation of FSGS is asymptomatic proteinuria in the 2nd-3rd decade of life, most commonly in AAs; minimal microscopic hematuria can be seen in many pts., and about 33% present with renal insufficiency &/or HTN. The collapsing variant often presents with more severe proteinuria, ↓ed renal function, and poorer prognosis; the glomerular tip lesion often presents with rapid-onset edema similar to MCG.
Treatment of FSGS is controversial: with high-dose corticosteroids 40-55% of adult pts. attain remission, but the long-term risk/benefit of this treatment is unclear; cyclosporin has also been used with varying success and a high rate of relapse.
Membranous Glomerulopathy is the most common cause of nephrotic syndrome in Caucasian adults but is uncommon in children; peak incidence is in the 4th or 5th decade of life and it may occur as a primary or secondary ds with autoimmune and infectious causes more common in kids and underlying malignancies found in 20-30% of pts. >60yrs old.
Treatment of MG is with an alkylating agent such as chlorambucil or cyclophosphamide, which increase the chance of complete remission by 4-5x but may not affect long-term survival; cyclosporin A may give remission in 75% of cases but is associated with a high rate of relapse after drug is discontinued – corticosteroids do not work in MG.
2. Diabetic Nephropathy
Symptoms:
Signs:
· HTN
· Renal failure
· Lab Presentation
Blood tests: proteinuria, hyperglycemia
Histology: thickened GBM, exudative lesions, mesangial matrix expansion which when extreme produces Kimmelstien-Wilsoodules; linear staining of GBM for IgG (bound ionically due to abnormal glycation)
Treatment
1) Glycemic control
– definately helps in type I, may not help in type II
2) Treat the HTN
– BP goal: < 130/85
3) ACE-inhibitors or ARBs
– significantly delay the progression to ESRD
– have anti-proteinuric & renoprotective effect beyond that expected from lower BP alone
– block hemodynamic & non-hemodynamic effects of angiotensin II
4) Dietary protein restriction ( < 0.6g/kg/day)
– shown by several small studies to decrease rate of decline in GFR (phase III-IV disease)
Notes
Epidemiology of Diabetic Nephropathy:
● 40% of pts. with Type I; 30-50% of pts. with Type II
● leading cause of ESRD in North America
● worsens the prognosis of DM
● Measurement of albumin excretion should be done at rest, having excluded infection & other causes of proteinuria; if a short timed collection is done, measure creatinine also to be confident that a complete voiding has occured
● Persistant microalbuminuria is present when 2 out of 3 collections reveal an albumin excretion between 20-200ug/min, with collections done within 6mos & no less than one month apart.
● HTN occurs with 2x frequency in pts with DM (mostly
3. Glomerulonephritis
Symptoms:
Signs:
Peripheral Edema (excess Na/water retention)
Complications:
· HTN (fluid retention)
· Uremia (↓ filtration)
· CHF &/or Pulmonary Edema (fluid retention)
· Loss of GFR
· Lab Presentation
Urinalysis: proteinuria, hematuria (> 3 RBCs per high-power field)with dysmophic RBCs, RBC casts, oliguria/anuria. tea-colored urine.
Blood tests: azotemia, uremia (if renal failure is severe).
Acute and Rapidly Progressive Glomerulonephritis may lead to 50% or greater loss of renal function within weeks to months; uremia and its associated manifestations (nausea, hiccups, dyspnea, lethargy, pericarditis & encephalopathy) develop if renal failure is severe, and severe volume overload may cause CHF & pulmonary edema.
Proliferative glomerulonephritis may be focal (< 50% of glomeruli) or diffuse and is characterized histologically by the proliferation of glomerular cells (mesangial cells & endothelial cells), infiltration of leukocytes (especially PMNs & MPs), and possible necrosis & sclerosis. Mesangial hyperplasia alone is the least severe structural change and is usually associated with asymptomatic hematuria or proteinuria rather than active nephritis.
Lupus nephritis ranges from sub-clinical to severe (chronic nephritis with ESRD); the mildest expression (mesangioproliferative lupus glomerulonephritis) is induced by mesangial localization of immune complexes and usually causes only mild nephritis or asymptomatic hematuria & proteinuria – localization of substantial amounts of nephritogenic immune complexes in the subendothelial zones of glomerular capillaries induces overt inflammation (focal or diffuse proliferative lupus glomerulonephritis) and causes severe clinical manifestations of nephritis
Treatment
● Corticosteroids &/or immunosuppressives for immune-mediated inflammatory disease, with aggressiveness of treatment matching the aggressiveness of disease.
● Plasmapheresis is usually added for anti-GBM disease.
Notes
● Hematuria
Asymptomatic hematuria is hematuria that the pts. is unaware of & that is without azotemia, oliguria, edema, or HTN; it occurs in 5-10% of the general population. Recurrent gross hematuria (coke-colored urine) may be superimposed on asypmtomatic hematuria. Most hematuria is actually not of glomerular origin: 80% of hematurias in pts. with no proteinuria are caused by bladder, prostate, or urethral ds – hypercalciuria
& hyperuricosuria can cause asymptomatic hematuria, especially in children. Renal biopsy should be done in pts. with recurrent asymptomatic hematuria to save the pt. repeated invasive urological procedures; acanthocytes also suggest a glomerular ds, as osmotic trauma to RBCs as they pass through the nephron causes structural changes not seen in RBCs from a distal bleed. RBC casts in the urine also suggest a glomerular origin of bleeding.
4. Acute Renal Failure
Symptoms:
Signs:
Complications:
· Volume overload with Hyponatremia
· Hyperkalemia, Hyperphosphatemia, Acidosis (metabolic)
· Hyperphosphatemia
· Uremic Syndrome: anemia, pericarditis, coagulopathies,
· GI & CNS abnormalities.
· Peripheral &/or pulmonary edema
· Infections
· Lab Presentation
Urinalysis: oliguria (< 400 mL/day) RBC casts (glomerulonephritis) or pigmented epithelial casts (toxic or ischemic tubular damage) Prerenal (or glomerular ds) → low urine [Na] (< 20mEq/L) high urine osmolarity (> 500mOsm/L) urine specific gravity ~ 1.020 BUN/Cr ratio > 20/1
FENa < 1.0%
Intrinsic (tubular ds) → high urine [Na] (> 20mEq/L)
low urine osmolarity (<400mOsm/L)
FENa > 1%, proteinuria (glomerular ds)
Blood tests: ↑ creatinine, ↑ BUN, may show anti-GBM (Goodpasture’s), ANCAs, or ANAs (Lupus),
ARF is characterized by rapid onset of oliguria with ↑ing serum BUN & creatinine (with BUN increasing out of proportion to the increase in creatinine > 20:1 due to the fact that urea is produced more rapidly than creatinine). Causes of ARF may be pre-renal (↓ed blood flow), post-renal (obstruction of urine flow), or intrinsic : pre-renal causes include CHF, cirrhosis, sepsis and other causes of renal hypoperfusion. Post-renal causes are most often obstructions of the urine outflow tract (usually by a tumor or by prostatic hypertrophy in men) – the renal faliure is usually reversible if the obstruction is removed in time (so always do a renal ultrasound in ARF), and their is usually a syndrome of post-obstructive diuresis: removal of the obstruction causes the compensatory high glomerular pressures that developed to be unopposed; treatment of this is to give IV-fluids and monitor serum electrolytes. Intrinsic renal failure has multiple causes: medication-induced acute tubular necrosis (aminoglycosides, cisplatin, pentamidine, amphotericin, lithium, IV-contrast), nephrotic & nephritic glomerular syndromes (most are thought to be immunemediated), vascular disorders (such as microangiitis), and allergic interstitial nephritis. Intra-renal causes of ARF are associated with a higher mortality rate than pre-renal or post-renal causes. Severe proteinuria (3+ or 4+ on dipstick, >3g/day in urine) suggests a glomerular lesion. WBC casts suggest pyelonephritis or interstitial nephritis; fatty casts suggest nephrotic syndrome.
Tubulointestinal causes of ARF are the most common in the hospital and have the best outcomes if treated early.
Acute Tubular Necrosis is results from ischemic (↓ed perfusion) or toxic (drugs, rhabdomyolysis, tumor lysis syndrome) insult to the tubular epithelium – renal failure lasts 1-2 weeks during which ICU stay is required, survival correlates with severity of presentation, and most pts. survive and recover normal renal function (if the physiological insult is of short duration and the tubular epithelial basement membrane remains intact). If ATN in long-lasting (weeks), tubular injury results in tubular atropy & interstitial fibrosis.
Diagnostic findings are muddy-brown urine with tubular epithelial casts and high-urine [Na] with FENa > 1%. As the pt. recovers, urine output ↑es, BUN & creatinine plateau then fall, and the pt. is hypercalcemic. Pathologic changes may appear mild compared to the degree of renal failure. The pathophysiology of ATN proceeds in stages: in the intial stage, there is tubular epithelial cell injury and subsequent vasoconstriction; in the maintenance phase, obstruction occurs due to the sloughed-off injured tubular epithelial cells, and passive backflow of filtrate causes medullary congestion (seen on biopsy as dilated tubules with interstitial edema); in the recovery phase, new nephrons are recruited, and tubular integrity is restored with subsequent vasodilation. In addition to tubular occlusion by casts, backleak of filtrate across the damaged tubular epithelia & a primary reduction in GFR lead to renal failure – the decline in GFR results from arteriolar vasoconstriction & mesangial contraction. The decline in renal function in ATN has a variable onset, often beginning abruptly following a hypotensive episode, rhabdomyolysis, or the administration of IVcontrast media; when aminoglycosides are the cause, the onset is more insidious (initial rise in serum creatinine is at least 7 days after exposure). ATN is also often associated with disorders of divalent ion metabolism (hypocalcemia, hyperphosphatemia, hypermagnesemia), with altered PTH action & vitamin D metabolism playing a role in hypocalcemia & hyperphosphatemia (high PTH may occur in settings of ↓ serum [Ca]). Post-renal ARF is characterized by obstruction of the urinary tract leading to an acute rise in intratubular pressure – as a result, there is stimulation of the RAAS that → ↑ renal vasoconstriction (↑ renal vascular resistance) → ↓ GFR → ARF (if losses in GFR are severe). Post-renal ARF is also associated with normal urine sediment (no strange casts), intermittant anuria, and failure to void completely after catheterization; pre-renal disease is also associated with a normal-appearing UA. With continued obstruction over time in post-renal disease, tubular function may become impaired and findings may mimic intrinsic ARF (e.g. ATN).
In diseases that affect the glomerulus primarily (acute glomerulonephritis), the urinary and serum indices will more closely resemble those of pre-renal azotemia rather than intrinsic disease). This is because tubular reabsorbtion (and thus the ability to concentrate urine & conserve Na) may be normal in pts. with glomerular disease.
Treatment
1. Resuscitate, but be careful; the two most common causes of death in the resuscitation phase are hyperkalemia & pulmonary edema from attempts to restore urine output by giving fluids.
2. Post-renal failure → surgically remove obstruction &/or create a passage for urine drainage. Pre-renal failure →i. give fluids for true volume-depletion while constantly assessing pt. to prevent volume overload. ii. for advanced liver disease: dietary sodium restriction+ bed rest, give spironolactone to ↑ urine output; albumin may be given to prevent worsening of intravascular depletion, and paracentesis may be useful for tense ascites. iii. for CHF: diuretics, inotropics, ACE-inhbitors must be used with caution because they decrease GFR.
● Indications for dialysis: marked fluid overload, severe hyperkalemia, presence of uremic signs/symptoms (pericarditis, nausea/vomiting, confusion, bleeding with coagulopathy), severe metabolic acidosis, serum BUN > 100.
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Drugs removed from the body in significant quantities by dialysis or filtration |
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●IV-diuretics are often given in the early stages of ATN, though there is little evidence that they prevent progression of the disease.
● Cytoprotective agents such as free radical scavengers, xanthine oxidase inhibitors, CCBs and PGs may be given to help preserve tubular cell integrity.
● Treat infections aggressively.
● Treat severe metabolic acidosis, but correct slowly to prevent hypocalcemic complications (e.g. tetany).
● Dietary Interventions
Notes
.● Prerenal ARF is made worse by ACE-inhibitors, since they cause dilation of the efferent arteriole and a ↓ in GFR; NSAIDs similarly exacerbate pre-renal ARF because they inhibit the synthesis of prostaglandins (which cause vasoconstriction in the kidney).
● ½ of pts. with ATN have a less severe ds with normal urine output.
● 5% of hospital admissions to a med/surg ward will go on to develop ARF; this happens to 30% of ICU pts.
● Acute tubular necrosis is a misnomer, since overt tubular necrosis is rarely observed on biopsy; good terms are “post-ischemic” or “nephrotoxic” acute renal failure.
● Always look for a systemic disease in pts. who present with ARF.
● Factors other than GFR that effect serum BUN levels: protein intake, protein catabolism, GI bleeding, many others…
● A normal kidney with an intact tubular system can concentrate urine to ~ 1,200mOsm/kg.
Pathology of ARF
Acute Tubular Necrosis: Ischemic ATN → kidneys are swollen with a pale cortex & congested medulla; tubular injury is focal and
most pronounced in the proximal tubules & ascending limb of the LoH, and tubules show focal flattening with dilation of the
lumen and loss of the epithelial brush border. Toxic ATN → more extensive necrosis of the tubular epithelium, most often
involving all or specific portions of the proximal tubule; intra-tubular casts composed of necrotic debris are commonly seen.
Infectious ATN → be may caused by viruses that replicate in tubular epithelial cells (e.g. polyomavirus) with viral inclusion
bodies seen on biopsy; may also be caused by bacteria that replicate in the collecting ducts & distal tubules (pyelonephritis)
which show intratubular densely packed casts of PMNs.
Intra-tubular Occlusive Material: caused mostly by monoclonal Ig light-chains precipitating in the tubule & forming
obstructive/ & oxic casts: dense, hyaline casts with fractures &/or angular borders found in the distal tubules and collecting ducts;
these casts may be surrounded by cells (MPs & PMNs); immunoflouresce shows accumulation of kappa or lambda light-chains.
Hypersensitivity Tubulo-interstitial Nephritis: patchy infiltration of the cortex ( & to less extent, the medulla) with lymphocytes,
plasma cells, & eosinophils; proximal & distal tubules are focally invaded (tubulitis) and may show loss of brush border,
enlargement of nuclei, and mitotic activity; due to interstitial edema, adjacent tubules become separated from each other;
glomeruli & vessels are not affected; caused by NSAIDs, diuretics, sulfonamides, в-lactams.
Hemolytic Uremic Syndrome: characteristic changes are often found in glomerular vascular pole regions (larger arteries are
spared); injured arteries & arterioles show thrombi, activated endothelial cells, and a widened intimal zone due to fibrin
insudation, edema, and fibroblast hyperplasia; necrosis of myocytes may be seen in arterial media; glomerular capillaries may
show fibrin thrombi & cell-swelling; early changes are rapidly followed by fibrosis of the widened intimal zones and
subsequent severe stenosis; proteinuria may result from fibrous remodeling in the GBM (late changes); ischemia secondary to
the thrombic obstructions often causes ATN concurrent with HUS; frank gross necrosis of the cortex is possible.
Atheroemboli: “cholesterol clefts” seen on light microscopy (mostly in arteries) surrounded by MPs (early phase) then by fibroblasts
emboli cause arterial occlusion and eventual intimal fibrosis & stenosis; ischemia may → concurrent ischemic ATN
Bilateral Cortical Necrosis: focal or diffuse coagulative necrosis of the cortex involving all parenchymal elements; in pts. who
survive, dystrophic calcification of the necrotic areas may develop.
Acute Postinfectious Glomerulonephritis: acute phase begins 1-2weeks after the onset of infection; diffuse enlargement &
hypercellularity (↑ WBCs) of the glomerulus; subepithelial dense deposits on EM; immunoflourescence reveals granular
peripheral IgG & C3 deposits along the GBM; once infection clears, C3 is present without IgG because IgG is only produced
until the infection is cleared.
Crescentic Glomerulonephritis: light microsopy shows crescents (epithelial cells &MPs in Bowman’s space); the GBM is ruptured,
Nephrology / Urology 8 of 35
5. CHRONIC KIDNEY DISEASE
Chronic kidney disease occurs when one suffers from gradual and usually permanent loss of kidney function over time. This happens gradually, usually months to years. Chronic kidney disease is divided into five stages of increasing severity. The term “renal” refers to the kidney, so another name for kidney failure is “renal failure.” Mild kidney disease is often called renal insufficiency.
With loss of kidney function, there is an accumulation of water; waste; and toxic substances, in the body, that are normally excreted by the kidney. Loss of kidney function also causes other problems such as anemia, high blood pressure, acidosis (excessive acidity of body fluids), disorders of cholesterol and fatty acids, and bone disease.
Stage 5 chronic kidney disease is also referred to as kidney failure, end-stage kidney disease, or end-stage renal disease, wherein there is total or near-total loss of kidney function. There is dangerous accumulation of water, waste, and toxic substances, and most individuals in this stage of kidney disease need dialysis or transplantation to stay alive.
Unlike chronic kidney disease, acute kidney failure develops rapidly, over days or weeks.
Acute kidney failure usually develops in response to a disorder that directly affects the kidney, its blood supply, or urine flow from it.
Acute kidney failure is often reversible, with complete recovery of kidney function.
Some patients are left with residual damage and can have a progressive decline in kidney function in the future.
Others may develop irreversible kidney failure after an acute injury and remain dialysis-dependent.
Table 1. Stages of Chronic Kidney Disease
|
Stage |
Description |
GFR* |
|
1 |
Slight kidney damage with normal or increased filtration |
More than 90 |
|
2 |
Mild decrease in kidney function |
60-89 |
|
3 |
Moderate decrease in kidney function |
30-59 |
|
4 |
Severe decrease in kidney function |
15-29 |
|
5 |
Kidney failure |
Less than 15 (or dialysis) |
*GFR is glomerular filtration rate, a measure of the kidney’s function.
Chronic Kidney Disease Causes
Although chronic kidney disease sometimes results from primary diseases of the kidneys themselves, the major causes are diabetes and high blood pressure.
Type 1 and type 2 diabetes mellitus cause a condition called diabetic nephropathy, which is the leading cause of kidney disease in the United States.
High blood pressure (hypertension), if not controlled, can damage the kidneys over time.
Glomerulonephritis is the inflammation and damage of the filtration system of the kidneys, which can cause kidney failure. Postinfectious conditions and lupus are among the many causes of glomerulonephritis.
Polycystic kidney disease is an example of a hereditary cause of chronic kidney disease wherein both kidneys have multiple cysts.
Use of analgesics such as acetaminophen (Tylenol) and ibuprofen (Motrin, Advil) regularly over long durations of time can cause analgesic nephropathy, another cause of kidney disease. Certain other medications can also damage the kidneys.
Clogging and hardening of the arteries (atherosclerosis) leading to the kidneys causes a condition called ischemic nephropathy, which is another cause of progressive kidney damage.
Obstruction of the flow of urine by stones, an enlarged prostate, strictures (narrowings), or cancers may also cause kidney disease.
Other causes of chronic kidney disease include HIV infection, sickle cell disease, heroin abuse, amyloidosis, kidney stones, chronic kidney infections, and certain cancers.
If you have any of the following conditions, you are at higher-than-normal risk of developing chronic kidney disease. Your kidney functions may need to be monitored regularly.
Diabetes mellitus type 1 or 2
High blood pressure
Amyloidosis
Sickle cell disease
Systemic Lupus erythematosus
Vascular diseases such as arteritis, vasculitis, or fibromuscular dysplasia
Vesicoureteral reflux (a urinary tract problem in which urine travels the wrong way back toward the kidney)
Require regular use of anti-inflammatory medications
A family history of kidney disease
Chronic kidney disease is a growing health problem in the United States. A report by the Centers for Disease Control (CDC) determined that 16.8% of all adults above the age of 20 years have chronic kidney disease. Thus, one in six individuals has kidney disease. By disease stage, the prevalence is as follows:
stage 1, 3.1%;
stage 2, 4.1%;
stage 3, 7.6%;
stage 4; and
stage 5, 0.5%.
There are over 500,000 persons on dialysis or who have received kidney transplants.
The prevalence of chronic kidney disease has increased by 16% from the previous decade. The increasing incidence of diabetes mellitus, hypertension (high blood pressure), obesity, and an aging population have contributed to this increase in kidney disease.
Chronic kidney disease is more prevalent among individuals above 60 years of age (39.4%).
Kidney disease is more common among Hispanic, African American, Asian or Pacific Islander, and Native American people
Chronic Kidney Disease Symptoms
The kidneys are remarkable in their ability to compensate for problems in their function. That is why chronic kidney disease may progress without symptoms for a long time until only very minimal kidney function is left.
Because the kidneys perform so many functions for the body, kidney disease can affect the body in a large number of different ways. Symptoms vary greatly. Several different body systems may be affected. Notably, most patients have no decrease in urine output even with very advanced chronic kidney disease.
Effects and symptoms of chronic kidney disease include:
need to urinate frequently, especially at night (nocturia);
swelling of the legs and puffiness around the eyes (fluid retention);
high blood pressure;
fatigue and weakness (from anemia or accumulation of waste products in the body);
loss of appetite, nausea and vomiting;
itching, easy bruising, and pale skin (from anemia);
shortness of breath from fluid accumulation in the lungs;
headaches, numbness in the feet or hands (peripheral neuropathy), disturbed sleep, altered mental status (encephalopathy from the accumulation of waste products or uremic poisons), and restless legs syndrome;
chest pain due to pericarditis (inflammation around the heart);
bleeding (due to poor blood clotting);
bone pain and fractures; and
decreased sexual interest and erectile dysfunction.
When to Seek Medical Care
Several signs and symptoms may suggest complications of chronic kidney disease. Following symptoms:
Change in energy level or strength
Increased water retention (puffiness or swelling) in the legs, around the eyes, or in other parts of the body
Shortness of breath or change from normal breathing
Nausea or vomiting
Lightheadedness
Severe bone or joint pain
Easy bruising
Itching
The following signs and symptoms represent the possibility of a severe complication of chronic kidney disease and warrant a visit to the nearest hospital emergency department.
Change in level of consciousness – extreme sleepiness or difficult to awaken
Chest pain
Difficulty breathing
Severe nausea and vomiting
Severe bleeding (from any source)
Severe weakness
Chronic Kidney Disease is defined as the presence of renal dysfunction (↓ GFR) for > 3 months; serum creatinine alone frequently underestimates GFR, so the Cockcroft-Gault equation (see below) is used to estimate the GFR. The most common causes in the U.S. are DM & HTN, whereas the most common cause in underdeveloped nations is glomerulonephritis. Chronic kidney disease often follows an insidious course until the GFR declines to less than 10 ml/min, and pts. may initially present with severe azotemia. Regardless of the initial insult, the pathogenesis proceeds as follows: primary insult → ↓ total nephron mass →↑ glomerular BP (increased volume per nephron as well as resultant predominant vasodilation of the afferent arteriole) → epithelial cell injury & glomerular sclerosis → proteinuria → worsening glomerular HTN & sclerosis → eventual ESRD. Common anatomic & histologic features are: glomerular hypertrophy, focal segmental glomerulosclerosis with hyalinosis, interstitial fibrosis, vascular sclerosis, and epithelial foot process fusion. Control of systemic & glomerular HTN is the mainstay of treatment for CKD (target BP goal should be 125-130/75-80 rather than 140/90); treatment for HTN is indicated at any stage of disease, with drugs that lower the glomerular capillary pressure (ACE-inhibitors, ARBs) as the first-line agents. As GFR declines, Na excretion remains relatively constant to maintain a constant ECFV; to do this the remaining nephrons must proportionately increase their Na excretion (thus the fractional excretion of Na increases), mostly via excretion at the distal tubule. Although zero sodium balance may be maintained for some time, the ability of the nephron to increase sodium excretion when challenged with a large sodium load may be impaired in chronic renal failure. In the later stages of disease, there is transient net Na retention leading to an increased ECFV & subsequent increase in renal perfusion that causes a compensatory pressure natriuresis; although ECFV expansion is common is the later stages of disease, edema is not a consistant finding as the increase in interstitial space is often < 2-3L – patients with nephrotic syndrome will develop edema due to the associated increase in renal Na-reabsorbtion As GFR declines, there is also a progressive increase in the fractional excretion of potassium (to keep serum K levels normal), mostly occuring in the cortical collecting duct and at least partially due to elevated aldosterone & ↑ed activity of the Na/K pump on ductal epithelial cells; serum [K] does not begin to rise until GFR < 10% normal, however. As GFR declines, there is impairment in the capacity of nephrons to concentrate urine, as a higher solute load is imposed on each nephron & there is insufficient absorbtive surface-area to maintain medullary interstitial hypertonicity; since solute intake remains unchanged, the obligate urine volume increases and may manifest as polyuria &/or nocturia. The diluting ability of the nephron is also impaired, leading to ↓ed free water clearance and plasma hypoosmolality when water intake exceeds excretion & losses.
Metabolic acidosis develops as renal failure progresses; early in the course of chronic renal failure, hydrogen balance is maintained by increased ammoniagenesis. Eventually ammonia synthesis decreases as the decline iephron mass exceeds the increase in ammonia synthesis per functioning nephron. As renal mass decreases, the excretion of phosphorus decreases resulting in a rise in serum phosphorus, and since phosphorus binds Ca in the blood, this causes transient hypocalcemia (along with a concurrent ↓ in calcium absorbtion due to ↓ed levels of activated vitamin D caused by ↓ed activity of renal 1-α-hydroxylase). Hypocalcemia, hyperphosphatemia, and ↓ed activated vit.D lead to parathyroid hyperplasia and ↑ed secretion of PTH (secondary hyperparathyroidism), which restores serum [Ca] to normal at the expense of bone density. Osteitis Fibrosa Cystica is the bone disease that results from this process; once established, the bone destruction is essentially irreversible. Interventions are thus aimed at prevention of bone degredation: Calcium supplements have traditionally been given to bind the ↑ed serum phosphorus, but it is now known that this may worsen arterial calcification & increase the risk for cardiovascular disease – in order to avoid this, pts. with normocalcemia should be treated with non-calcium phosphorus binders. Vitamin D analogues (calcitrol) have also been used to suppress PTH secretion but may also worsen arterial calcification.
Care should be taken to avoid increasing the serum calcium x phosphorus to > 55 or the serum calcium > 9.4mg/dL. Parathyroidectomy may be needed if PTH > 800pg/mL, especially in pts. with severe hypercalcemia, progressive bone disease, or heavy vascular calcification, and whose hyperphosphatemia is refractory to phosphate binders. If serum [Ca] is very low, use cinacalcet which sensitizes parathyroid cells to serum Ca and causes them to halt PTH secretion at lower serum [Ca].
Anemia in chronic kidney disease results from ↓ed erythropoetin secretion from the kidney when GFR is < 30 ml/min. Uremic Syndrome results from impairment of the kidney’s ability to excrete toxins in the urine; it often occurs when GFR drops below 15ml//min Because the syndrome resolves with dialysis it is thought that low molecular weight toxins (0 3 kD) are responsible
Self-Care at Home
Chronic kidney disease is a disease that must be managed in close consultation with health care practitioner. Self-treatment is not appropriate.
There are, however, several important dietary rules one can follow to help slow the progression of kidney disease and decrease the likelihood of complications.
This is a complex process and must be individualized, generally with the help of health care practitioner and a registered dietitian.
The following are general dietary guidelines:
Protein restriction: Decreasing protein intake may slow the progression of chronic kidney disease. A dietitian can help determine the appropriate amount of protein for person.
Salt restriction: Limit to 4-6 grams a day to avoid fluid retention and help control high blood pressure.
Fluid intake: Excessive water intake does not help prevent kidney disease. In fact, doctor may recommend restriction of water intake.
Potassium restriction: This is necessary in advanced kidney disease because the kidneys are unable to remove potassium. High levels of potassium can cause abnormal heart rhythms. Examples of foods high in potassium include bananas, oranges, nuts, and potatoes.
Phosphorus restriction: Decreasing phosphorus intake is recommended to protect bones. Eggs, beans, cola drinks, and dairy products are examples of foods high in phosphorus. Other important measures that one can take include:
carefully follow prescribed regimens to control blood pressure and/or diabetes; stop smoking; and lose excess weight.
In chronic kidney disease, several medications can be toxic to the kidneys and may need to be avoided or given in adjusted doses. Among over-the-counter medications, the following need to be avoided or used with caution:
Certain analgesics: Aspirin; nonsteroidal antiinflammatory drugs (NSAIDs, such as ibuprofen [Motrin, for example])
Fleets or phosphosoda enemas because of their high content of phosphorus
Laxatives and antacids containing magnesium and aluminum such as magnesium hydroxide (Milk of Magnesia) and famotidine (Mylanta)
Ulcer medication H2-receptor antagonists: cimetidine (Tagamet), ranitidine (Zantac), (decreased dosage with kidney disease)
Decongestants such as pseudoephedrine (Sudafed) especially if you have high blood pressure
Alka Seltzer, since this contains large amounts of salt
Herbal medications
Treatment
There is no cure for chronic kidney disease. The four goals of therapy are to:
1. slow the progression of disease;
2. treat underlying causes and contributing factors;
3. treat complications of disease; and
4. replace lost kidney function.
Strategies for slowing progression and treating conditions underlying chronic kidney disease include the following:
Control of blood glucose: Maintaining good control of diabetes is critical. People with diabetes who do not control their blood glucose have a much higher risk of all complications of diabetes, including chronic kidney disease.
Control of high blood pressure: This also slows progression of chronic kidney disease. It is recommended to keep your blood pressure below 130/80 mm Hg if you have kidney disease. It is often useful to monitor blood pressure at home. Blood pressure medications known as angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) have special benefit in protecting the kidneys.
Diet: Diet control is essential to slowing progression of chronic kidney disease and should be done in close consultation with your health care practitioner and a dietitian. For some general guidelines, see the Self-Care at Home section of this article.
The complications of chronic kidney disease may require medical treatment.
Fluid retention can be treated with any of a number of diuretic medications, which remove excess water from the body. However, these drugs are not suitable for all patients.
Anemia can be treated with erythropoiesis stimulating agents such as erythropoietin or darbepoetin (Aranesp, Aranesp Albumin Free, Aranesp SureClick). Erythropoiesis stimulating agents are a group of drugs that replace the deficiency of erythropoietin, which is normally produced by healthy kidneys. Often, patients treated with such drugs require iron supplements by mouth or sometimes even intravenously.
Bone disease develops in kidney disease due to an inability to excrete phosphorus and a failure to form activated Vitamin D. In such circumstances, your physician may prescribe drugs binding phosphorus in the gut, and may prescribe active forms of vitamin D.
Acidosis may develop with kidney disease. The acidosis may cause breakdown of proteins, inflammation, and bone disease. If the acidosis is significant, your doctor may use drugs such as sodium bicarbonate (baking soda) to correct the problem.
● Dialysis at GFR < 15
Medical Therapy Heirarchy:
1. ACE-inhibitors to ↓ intra-glomerular BP and inhibit PAI-1 (a pro-fibrotic signalling molecule)
2. в-blockers & thiazide diuretics
– use of a diuretic with other meds is important
– use loop diuretic for serum creatinine levels > 2mg/dL
3. Vasodilator
– dihydropyridines are taken once per day and have a lower side-effect profile.
4. CCBs (may be third-line drug when used with ACEi)
● To treat Osteitis Fibrosa Cystica: cinacalcet
● To treat Anemia: erythropoetin
Notes
.● Renal ultrasound is the best test for distinguishing chronic kidney disease; it will show a small (fibrotic) kidney.
● Leading causes: DM, HTN
● Stages: I → kidney damage
II → mild ↓ in GFR (60-90 mL/min)
III → GFR 30-60 mL/min
IV → GFR 15-29 mL/min
V → kidney failure with GFR < 15mL/min
● There is a good correlation between development of diabetic nephropathy & diabetic retinopathy.
Cockcroft-Gault equation:
{GFR = [(140-age) x body weight (kg) x 0.85 (if female)]/[72 x serum creatinine]}
● AV fistulae (for dialysis access) take several months to form after the initial procedure, so ideally they are done before dialysis is absolutely necessary; create a fistula when the pts. GFR falls to less than 30ml/min/1.73m2.
Hyperkalemia
Clinical Presentation
GI: nausea, vomiting, diarrhea
Neuro: muscle cramps, weakness, parasthesias, paralysis, areflexia, tetany, focal neurologic deficits, confusion
Respiratory insufficiency
Cardiac arrest
Lab Presentation
Blood tests: [K+] > 5.5 mEq/L
ECG: 6.5 – 7.5 mEq/L → tall peaked T-waves, short QT interval, prolonged PR
7.5 – 8.0mEq/L → QRS widening, flattened P wave 10-12 mEq/L → “sine-wave” QRS V-fib., heart block, or asystole may occur
Hyperkalemia may be caused by acidosis (cells exchange K+ for H+ in the plasma to buffer the acidosis), ↓ insulin (insulin causes cellular uptake of K+), β-adrenergic blockade (β-receptors mediate cellular uptake of K+), digitalis (↓ed Na/K ATPase activity), hyperglycemia (osmotic drag of water/K+ into plasma), ↑↑ tissue injury (lysed cellular contents in plasma), renal failure (↓ K secretion, develops when GFR < 5 ml/min), ACE-inhibitors & amiloride/triamterene (↓ K secretion). Severe volume depletion may cause mild hyperkalemia via ↓ Na delivery to the CCD (and subsequent ↓ in K excretion), but this effect may be balanced by ↑ed aldosterone secretion from ↓ed ECFV resulting in ↑ed K-excretion. Factors that cause a decrease in aldosterone (chronic renal failure from diabetic nephropathy, NSAIDs, ACE-inhbitors, Heparin, & spironolactone) may cause or exacerbate hyperkalemia
Do a STAT ECG on any pt. with moderate to severe hyperkalemia to r/o life-threatening cardiac arrthymias.
Treatment
● If no ECG changes, no need for emergent treatment.
● If ECG changes are seen:
1. IV Ca2+ to stabilize membrane potential
2. Insulin, в2-agonist, IV bicarb → ↑ K-uptake into cells
3. loop diuretic, cation exchange resin → urinary & GI K-excretion
4. (maybe dialysis if hyperkalemia is severe)
Notes
● In diabetic ketoacidosis, pts. may have hyperkalemia even though total body potassium is decreased due to osmotic diuresis; these pts. usually develop hypokalemia after insulin therapy.
● K excretion in the CCD is increased by 3 major factors:
1. electronegativity of tubular lumen
2. enhanced flow & Na delivery to the CCD
3. aldosterone
– ↑ed # of Na channels on apical surface of principal cells
– ↑ed # of K channels here too
● In renal failure, as GFR worsens, there is a fractional increase in K-excretion per nephron; this is why there is no hyperkalemia in mild renal ds, though hyperkalemia develops when GFR < 5 ml/min.
● Pseudohyperkalemia develops when K is released during platelet aggreggation; so to avoid this take plasma samples with anti-coagulant.
Chronic tubulointerstitial nephritis
It is characterized by generalized chronic inflammatory cellular infiltation of the interstitium with tubular atrophy and generalized interstitial oedema or fibrosis. In many cases no cause is found. Chronic TIN changes evolve into progressive primary glomerular or vascular disease of the kidney, where its severity is a better predictor of long-term renal survival than the primary site of insult.
The patient usually presents with either polyuria and nocturia, or is found to have proteinuria or uraemia. Proteinuria is usually slight (less than 1 g daily). Papillary necrosis with ischaemic damage to the papillae occurs in a number of tubulointerstitial nephritides, for example in analgesic abuse, diabetes mellitus, sickle cell disease or trait. The papillae can separate and be passed in the urine. Microscopic or overt haematuria or sterile pyuria also occurs, and occasionally a sloughed papilla may cause ureteric colic or produce acute ureteric obstruction. The radiological appearances must be distinguished from those of reflux nephropathy or obstructive uropathy which is usually accompanied by tubular dilatation and atrophy and intense interstitial fibrosis with patchy inflammatory cellular infiltrate in the scarred areas.
Tubular damage to the medullary area of the kidney leads to defects in urine concentration and sodium conservation with polyuria and salt wasting. Fibrosis progressing into the cortex leads to loss of excretory function and uraemia.
Prostatitis
ABP → fever/chills, pelvic &/or perineal pain, dysuria suprapubic tenderness; “boggy” prostate, post-ejaculatory pain, urinary retention CBP → frequency, urgency, dysuria, pelvic/testicular ache, post-ejaculatory pain
NBP → pain anywhere in the pelvis, nocturia, dysuria,
Blood tests: ↑ed PSA
Urinalysis: WBCs in urine
Prostatitis ranges from life-treatening acute bacterial infection to non-infectious chronic inflammation. Acute bacterial prostatitis is defined as growth of bacteria from cultures of prostatic secretions; it is the least common form but is potentially fatal. Infection is usually a gram-negative rod (E.coli is the most common) though chlamydia may also cause ABP; pathogenesis is likely due to reflux of urine into the prostate during urination or urethral contamination during sexual intercourse. ABP is more likely to be seen in immunocompromised patients. Digital rectal exam should be done gingerly if at all to avoid causing a bacteremia. Diagnostic tests include urine culture (catheterize pts. with dysuria so severe they cannot void at all) and imaging to r/o prostatic abcess.
Chronic bacterial prostatitis is also defined by culture of bacteria from prostatic secretions, but the disease course is intermittant and more mild than ABP. Diagnosis is made by positive culture from post-massage prostatic secretions (don’t do massage if you suspect ABP, however) or post-massage urine. CBP is usually assoicated with a past UTI. Granulomatous prostatitis is usually due to an immune reaction to ruptured lumenal contents.
Non-bacterial prostatitis (chronic pelvic pain syndrome) is common & often presents in men 20-30yrs old; prostatic secretions show no bacteria & may or may not show WBCs. The four-glass test is used to rule out infectious causes; imaging tests to see if the patient can fully empty his bladder should also be done. NBP is a waxing/waning disease that causes intermittant exacerbations/resolutions of symptoms and may affect the patient for the rest of his life.
Treatment
ABP → flouroquinolone antibiotic (penetrates prostate well) for at least 4 weeks; hospitalization may be necessary
CBP → flouroquinolone or sulfa antibiotic for 4-6 weeks; anti-inflammatories for symptoms
NBP → anti-inflammatories, trial of antibiotics,
● б-blockers if pt. has difficulty voiding or other obstructive symptoms
● lifestyle changes, such as ↓ed stress, dietary change (there are numerous dietary triggers), and ↓ed activities that put pressure on the perineum (cycling, tractor-driving) may help
Notes
● Types
I → acute bacterial (culture evidence of infection)
II → chronic bacterial
III → chronic nonbacterial (no evidence of infection)
– inflammatory → WBC in semen, EPS, VB3
– non-inflammatory → no WBC in semen, EPS, VB3
IV → asymptomatic inflammatory prostatitis (histologic dx)
Benign Prostatic Hyperplasia
Lower UT symptoms:
● irritative: nocturia, urgency, incontinence, frequency
● obstructive: hesitancy, intermittancy, decrease force of
stream, postvoid dribbling, double voiding,
incomplete emptying
Physical Exam:
Prostate → enlargement, rubbery roundness, asymmetry
Blood tests: ↑ed PSA
BPH is caused by a proliferation of glands (25%) &/or fibromuscular stroma (75%) primarily in the transitional zone around the urethra; glands and stroma usually proliferate in a nodular configuration with hyperplastic nodules causing obstruction due to compression of the urethra and possibly leading to hydroureter, hydronephritis, and renal failure. BPH is androgen dependent, and incidence increases with age. It is unclear whether the hyperplasia results from increased growth or decreased apoptosis, but insulin-like growth factors and their receptors seem to play a role.
Prostate enlargement causes increased resistance to bladder emptying, and in response the detrusor muscle hypertrophies to overcome this resistance (there is also ↑ ECM deposition in the bladder wall) leading to ↓ed bladder compliance which manfests as urinary frequency & incomplete emptying – increased resistance to urination also causes intermittancy &/or a weaker stream.
Diagnosis is made histologically, although the clinical manifestations are lower urinary tract obstructive symptoms (LUTS).
Work-up includes H&P (including prostate exam looking for nodularity &/or tenderness) and urine culture to r/o prostatitis (can cause many of the same symptoms) and UA to assess for hematuria & check PSA level (to look for cancer). Optional tests include measuring the urine flow rate, bladder ultrasound to assess residual urine, and urodynamics (assesses the pressure in the bladder as it fills).
One-third of pts. with LUTS will spontaneously resolve, 1/3 will stay the same, and 1/3 will have progressively worsening symptoms; 10% of pts. will develop urinary retention, and at this time the bladder may be completely non-functional – rarely, a pt. will develop a stone in his bladder and in the worse case, renal failure due to back pressure from a bladder that will not empty.
LUTS may be exacerbated by diuretic therapy for HTN.
Treatment
● lifestyle changes: ↓ intake of EtOH & caffeine; ↓ fluid intake after dinner
● б-adrenergic antagonists to relax smooth muscle in the prostate and decrease overall resistance to urination.
– side effects: orthostatic dizziness, retrograde ejaculation
● 5-б-reductase inhibitors to inhibit conversion of testosterone to DHT (thereby lowering effective androgen activity in the prostate)
– takes up to 12mos to work, but may reduce size of prostate by as much as 30%
– may decrease PSA levels up to 50% after 6mos of tx, so PSA results for these pts. must be doubled for the purpose of prostate cancer screening.
– side effects: gynecomastia, ↓ libido, ED
● TURP
Notes
● Very common: 60yo man has 50% of having BPH.
● Most often found in the transitional zone.
● Urodynamics is considered the gold standard diagnostic test
for many urinary problems.
Nephrology / Urology 17 of 35
Urinary Tract Stones
Severe flank pain (referred to genitalia as stone passes)
Nausea/vomiting
Hematuria (often microscopic)
Physical Exam:
CVA tenderness
Lab Presentation
Urinalysis: usually urine pH < 5.0 (for uric acid stones), hematuria
Calcium oxalate stones comprise 85% of stones & can be seen radiographically; infection stones are associated with urea-splitting bacteria (such as Proteus); uric acid stones are radiolucent & seen in pts. with hyperuricemia/gout; cysteine stones are associated with hereditary cysteinuria & are rare but more common in childhood.
Struvite stones are associated with infection by urea-splitting organisms (e.g. Proteus, Psuedomonas, others); they are most often seen in pts. with recurrent UTI. All of the stone fragments must be removed because the stone contains bacteria. Pts. with + urine cultures for urea-splitting bacteria must be evaluated with renal imaging to r/o large asymptomatic stone in the renal pelvis.
Uric acid stones are associated with gout & will not be seen by X-ray but can be seen on ultrasound or CT.
Stones form in supersaturated urine (Ca & oxalate) with decreased amounts of natural inhibitors to stone formation (i.e. citrate). Most stones begin as a plaque in the collecting duct.
Obstruction causes renal dysfunction (obstructive nephropathy) and dilatation of the collecting system (hydronephrosis); it may cause atrophy of the effected kidney if unilateral & renal failure if bilateral.
Diagnosis includes history, UA, and CT.
Treatment
● Lithotripsy
● Drink water or lemonade (citrate) to decrease stone formation; low oxalate diet (don’t drink iced tea, which has high oxalate levels); moderate Ca-intake diet.
● Hyperuricosuric → allopurinol, alkalinize urine
● Ca-stone forming → low oxalate, low Na diet; give citrate
● Stone prevention:
● hydrate enough to produce 2L of urine per day
Notes
● Nephrolithiasis: stones in the collecting system of the kidney
Urolithiasis: stones elsewhere in the urinary tract
● Mucoprotein begins the crystalization process.
● Recurrence rate: 50% by 5yrs, 70% by 10yrs
– treatment → recurrence drops to 10%
● Risk factors: dehydration, family hx, diet, IBS, medical conditions causing aciduria or hypercalcuria.
● Ureteral stones cause the most pain; tx with tamsilosin (α–
blocker) to relax ureter & allow stone to pass; if it doesn’t
pass (> 7mm), must do a procedure to remove stone.
Cystitis (& UTIs)
Clinical Presentation
· Dysuria
· Urinary urgency & frequency
· Nocturia
Lab Presentation
UA: WBCs in urine (> 10/ hpf), +nitrates on dipstick test, +LE on dipstick test
Cystitis is inflammation of the urinary bladder; risk factors include include being female (short urethra), BPH in males, and instrumentation in the urinary tract (catheters, cytoscopy). Infectious causes include coliform bacteria & schistosomiasis; noninfectious
causes include radiation therapy & chemotherapy.
E.coli is the most common pathogen, and if untreated or treated inappropriately it may progress to and upper UTI (i.e. in kidney)
Risk factors include: use of spermicidal contraceptives/diaphragm, sexual intercourse, delayed post-coital micturition, fecal-vaginal contamination, & family history of UTIs.
Urinary culture is only necessary for recurrent UTI or symptoms of pyelonephritis (flank pain, fever).
Most cases of recurrent UTI are due to E.coli reinfection (not persistant infection & not always the same strain as the original infection).
Uncomplicated UTIs usually occur in sexually active young women, are community-acquired, and self-limited; communityacquired pyelonephritis, however, is most often seen in young to middle-aged healthy women presenting as a systemic illness often
accompanied by bacteremia.
Complicated UTIs are associated with functionally, metabolically, or anatomically abnormal urinary tracts and in pts. over 65yo.
The findings are usually localized, but bacteremia may develop in some cases. Risk-factors include: ↑ age, debility, male gender, hospitalization, long-term care, DM, & immunosuppression – pts. with pregnancy, in-dwelling catheters or stents, stones, recent antibiotic use, or symptoms > 7days are also said to have a complicated UTI. While the most common pathogen is still E.coli, Klebsiella, Enterobacter, Citrobacter, Proteus, Providencia, & Pseudomonas are more common in this setting & may show resistance to TMP/SMX (use 3rd-cephalosporin or flouroquinolone & check sensitivity).
Treatment
Simple UTI
● 3-day course of TMP/SMX or flouroquinolone
Recurrent UTI
●. 6-12mos low-dose prophylaxis w/ TMP/SMX, nitrofurantoin, or norfloxacin.
● post-intercourse low-dose prophylaxis
● self-treatment & diagnosis: 3 days of TMP/SMX or flouroquinolone
Complicated UTI:
● levofloxacin
Notes
● ↑er incidence in females (shorter urethra); BPH predisposes men to cystitis.
● Any diabetic with a UTI has a complicated UTI.
● Common organisms that cause UTIs: E.coli, Klebsiella, Proteus, Staph. saphrophyticus, & enterococcus.
● Diagnostic gold-standard is urine culture, but this is rarely necessary.
Acute Pyelonephritis
Clinical Presentation
· Fever/chills
· Flank pain
· Generalized muscle tenderness & malaise
· Dysuria
Lab Presentation
This a common UTI that accounts for 250,000 ER visits per year in the U.S. Most common pathogens are E.coli, Proteus, & Klebsiella.
Treatment
● Flouroquinolone IV plus Ampicillin (to cover enterococcus) for 2-3 days then pt. can be discharged from the hospital with 7-14days of oral antibiotics.
– may use aminoglycoside (but avoid this in pts. With chronic renal disease)
– keep pt. in the hospital if he/she has severe malaise, ausea/vomiting, &/or difficulty maintaining hydration
● If gram(+) organisms are identified, use amoxicillin &/or amoxicillin/clavulanate.
Erectile Dysfunction
Clinical Presentation
· Inadequate or absent erection, even with stimulation.
Lab Presentation
Causes of ED include: hormonal causes (hypogonadism, diabetes), drugs antihypertensives), vascular disease (HTN, dyslipidemia, diabetes), depression, neurologic disease, & structural problems – ED is also a marker for early-stage vascular disease. Nerves to the penis are crucial in initiating/maintaining erection and may be damaged in radical surgery or radiation in the pelvis.
Diagnosis is made by history, focused physical exam, and recommended tests include serum glucose, lipids, serum chemistries, testosterone (important to test in the morning because thats when concentration is highest), PSA, and CBC.
Treatment
● Type-5 phosphodiesterase inhibitors, to decrease degredation of cGMP.
● side effects: HA, flushing, dyspepsia, nasal congestion, blue vision
● may require up to 6 attempts for pts. to begin to have good results from these drugs.
● Contraindications:
· do not use in pts. who are taking nitroglycerine or other nitrate medications, as precipitous drops in BP may be fatal
· vardenafil is contraindicated is pts. who are also taking б-blockers (i.e. for BPH)
· tamulosin is the only б-blocker that can be used with tadalafil.
Notes
● occurs in up to 50% of men 40-70yrs old.
● Erection is normally mediated by NO/cGMP
– NO is produced by nonadrenergic, noncholinergic nerves
as well as by endothelial cells in the corpus cavernosum
● Smoking increases the risk for ED.
References:
1. J. G. Hardman & L. E. Limbird (Eds.), Goodman & Gilman’s The pharmacological basis of therapeutics, 10th ed., pp. 1171–1188. New York: McGraw-Hill.
2. Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
3. Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
