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.
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 ↑
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
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.
●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,
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
Treatment
● 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
