Nephrology/Urology Disorders 1. Nephrotic Syndrome Clinical Presentation

Transcription

Nephrology / Urology 1 of 35
Nephrology/Urology Disorders
1. Nephrotic Syndrome
Clinical Presentation
Lab Presentation
Symptoms:
UA: fixed proteinuria (> 3.5g / day / 1.73m2 body area),
lipiduria with oval fat bodies seen on microscopy
Signs:
Peripheral Edema
(Ascites & Pulmonary edema are possible.)
Blood tests: hypoalbuminemia, dyslipidemia (↑ LDL,
↑ VLDL, ↓ HDL), hypercholesterolemia
Complications:
Atherosclerosis
Venous Thrombosis
Bacterial Infection
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 ↑
h Treatment
Notes
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
t t
● The primary Na/water retention that occurs in NS (i.e. the
“overfill” mechanism) happens in the absence of a ↓ed
EABV and ↑ in the neural and hormonal factors that
respond to ↓ EABV; much of the Na/water retention occurs in
the more distal portions of the nephron.
● Work-up: 1) establish the degree & type of proteinuria (use urine
protein/Cr ratio): nephrotic vs subnephrotic; transient,
orthostatic, or fixed...
● verify that collection is adequate by checking
creatine excretion (20-25mg/kg/day for males &
15-20mg/kg/day in females).
2) look for secondary causes of NS: serologies, C3&C4
levels, SPEP, UPEP (to r/o MM), blood cultures,
renal ultrasound, screening for occult cancer; if no
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.
There are 4 histological variants: 1) perihilar FSGS is characterized by sclerotic lesions that have a predilection for glomerular
perihilar segments and usually are accompanied by hyalinosis & adhesions to Bowman’s capsule; there is no staining for Ig or
complement by immunoflourescence, and EM reveals foot-process effacement, 2) collapsing glomerulopathy may be seen HIV, IV
drug abuse, or as an idiopathic process and is characterized by focal segmental or global collapse of glomerular capillaries with
obliteration of capillary lumens; visceral epithelial cells that overlie collapsed segments usually are enlarged and contain
conspicuous resorption droplets, 3) glomerular tip lesion is characterized by consolidation of the glomerular segment that is adjacent
to the origin of and may project into the lumen of the proximal tubule; visceral epithelial cells adjacent to the consolidated segment
are enlarged & contain clear vacuoles & hyaline droplets, 4) cellular FSGS is characterized by endocapillary hypercellularity
involving at least 25% of the tuft and causing occlusion of the capillary lumens; the endocapillary cells typically include foam cells,
macrophages, and endothelial cells (this resembles the glomerular tip lesion but the hypercellular lesions are not limited to the origin
of the proximal tubule. 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 in nephron 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. The characteristic
histologic abnormality is diffuse global capillary wall thickening with subepithelial immune complex deposits in the absence of
significant hypercellularity; immunoflourescence shows diffuse global granular capillary wall staining for Ig & complement (C5-C9
deposition also forms the MAC and damages tubular epithelial cells). MG patients most often present with normal or slightly
decreased renal function, and if progressive renal insufficiency develops it is usually indolent (resulting in ESRD in 25% of pts.);
25% of pts. have a completely spontaneous remission of proteinuria within 5yrs. 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
Lab Presentation
Symptoms:
Blood tests: proteinuria, hyperglycemia
Signs:
HTN
Renal failure
Histology: thickened GBM, exudative lesions, mesangial
matrix expansion which when extreme produces
Kimmelstien-Wilson nodules; linear staining of
GBM for IgG (bound ionically due to abnormal
glycation)
Diabetic neuropathy progresses in 4 phases: Phase I → transient microalbuminuria with supranormal GFR & mild thickening of
the GBM with small ↑s in mesangial volume, Phase II → incipient nephropathy that develops 7-20y and is characterized by fixed
macroalbuminuria (15-200ug/min), near normal GFR, thick GBM, mesangial expansion, arteriolar sclerosis, tubular-intimal fibrosis,
Phase III → overt nephropathy that develops 7-10yrs and is characterized by overt proteinuria (>500mg/24h), + dipstick test,
decreased GFR (12ml/min/yr), same pathology as phase II but more advanced, Phase IV → ESRD that develops within 7-10yrs and
is characterized by GFR < 20ml/min with a + dipstick test. Microalbuminuria is a strong predictor of the subsequent development of
overt DMN (predictive value as high as 80%) and HTN in DM type I; microalbuminuria predicts overt proteinuria (over 10yrs of
follow-up) far less consistently in DM type II (20% vs. 80%).
The first pathologic change in DMN is thickening of the GBM, TBM, and Bowman’s capsule (seen in first 1-2yrs of disease).
Within a few years, afferent & efferent arteriolar hyalinosis can be noted, leading ultimately to the replacement of the vessel wall by
a homogenous, waxy & translucent material (containing Igs, albumin, complement, fibrinogen, and other plasma proteins) – these
“exudative” lesions are also seen in the glomerular subendothelial space & parietal aspect of Bowman’s capsule (IgG binds ionically
& not by normal Ag/Ab-binding to the GBM secondary to abnormal glycation). Increases in the relative area of the mesangium
develops later (begins as early as 5-7 years), with 2/3 of the mesangial expansion from ECM expansion and 1/3 due to increased cell
size & number. The mesangial & GBM changes are characterized by an expansion of all intrinsic components of the mesangium:
type IV & VI collagen, laminin, and fibronectin – true fibrosis appears later in the disease as it progresses to ESRD & more
glomeruli become completely sclerosed with total capillary obliteration. Two major structural glomerular lesions (GBM thickening
& mesangial expansion) develop only after several years of diabetes, with their incidence & progression determined by degree of
glycemic control as well as genetic & environmental factors. Genetic factors include: 1) familial – ↑er incidence of DMN in
siblings of pts. with DM & DMN than in sibs. of pts. with DM alone, 2) ethnic – incidence of ESRD is 4x higher in AAs than
whites, 3) phenotypic – diabetics with frank HTN develop DMN & ESRD more rapidly, 3) DNA markers – ACE-gene deletion or
insertion, gene that maps to 18q22.3.
In DMN, loss of renal autoregulation and increased sensitivity to angII, NE, and vasopressin lead to afferent arteriolar dilation &
efferent arteriolar constricition, respectively, which result in ↑ed intraglomerular capillary hydrostatic pressure that then causes
stretch-receptor mediated cytokine release and subsequent structural changes. Non-hemodynamic mechanisms of disease
development include: angiotensin and the high-glucose medium acting as growth-factors for mesangial & smooth-muscle cells &
stimulating mesangial cell synthesis of fibronectin, collagen I & IV, TGF-β expression and inhibition of tubular cell proteases
(leading to ↓ protein turnover & favoring cell growth). Hyperglycemia results in tissue injury via the production of reactive oxygen
species and activation of multiple metabolic pathways: 1) polyol pathway – ↑ aldose reductase → ↑ conversion of glucose to sorbitol
→ sorbitol accumulates intracellularly, is converted into myoinositol, and ↓s the Na/K-ATPase activity of the cell, 2) protein kinase
C pathway – ↑ activity of PKC in vascular smooth muscle & endothelial cells → ↑ secretion of TGF-β & PDGF, and 3) advanced
glycosylation endproducts pathway – AGEs are irreversibly cross-linked products of non-enzymatic glycosylation of protein
followed by slow chemical changes; AGEs of long-lived proteins (e.g. collagen) may accumulate, esp. in cases of renal
insufficiency, and cellular damage results from intracellular accumulation of insoluble AGEs → ↑ed rigidity of tissues with vascular
Treatment
Notes
1) Glycemic control
- definately helps in type I, may not help in type II
Epidemiology of Diabetic Nephropathy:
● 40% of pts. with Type I; 30-50% of pts. with Type II
● leading cause of ESRD in North America
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)
● 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
Lab Presentation
Symptoms:
UA: proteinuria, hematuria (> 3 RBCs per high-power field)
with dysmophic RBCs, RBC casts, oliguria/anuria.
tea-colored urine.
Signs:
Peripheral Edema
(excess Na/water retention)
Complications:
HTN
Uremia
CHF &/or Pulmonary Edema
Loss of GFR
Blood tests: azotemia, uremia (if renal failure is severe).
(fluid retention)
(↓ filtration)
(fluid retention)
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.
Crescentic glomerulonephritis is structurally the most severe form of glomerulonephritis usually presenting as rapidly
progressive nephritis – it is the most common finding on renal biopsy in patients with new onset renal ds with a nephritic sediment
(RBC casts) & serum creatinine > 3g/24hrs. Crescents are proliferations of cells within the Bowman’ s capsule that include
mononuclear phagocytes & glomerular epithelial cells, and crescent formation occurs in response to glomerular rupture (a marker of
severe glomerular injury); crescents do not indicate the cause of injury, however, and within a specific pathologic category of
glomerulonephritis a higher percentage of crescents indicates a worse prognosis; among pathogenetically different
glomerulonephritides (anti-GBM, lupus nephritis, IgA nephropathy, post-streptococcal glomerulonephritis), the pathogenetic
category may be more important prognostically than the % crescents (ex. a patient with post-streptococcal glomerulonephritis with
50% crescents has a better prognosis for renal survival than a patient with anti-GBM or ANCA disease with 25% crescents). Moral:
Both the structural severity (morphologic stage) and immunopathologic category of disease (such as IgA nephropathy, lupus
nephritis, anti-GBM or ANCA disease) are important in prognosis. Immune-complex glomerulonephritis shows glomerular
immune-complex localization with granular staining of the GBM on immunoflourescence – it may be caused by the immune
response to an antecedant or concurrent infection (ex. acute poststreptococcal glomerulonephritis, or HCV causing
membranoproliferative glomerulonephritis); Anti-GBM glomerulonephritis shows linear IgG immunoflourescence staining of the
GBM and anti-GBM antibodies by serology – along with ANCA pauci-immune glomerulonephritis, anti-GBM disease is one of the
most aggressive forms of glomerulonephritis; early diagnosis and treatment is important to prevent extensive sclerosis of glomeruli
& advanced tubulointestinal injury (after which response to treatment is unlikely); Pauci-immune glomerulonephritis includes most
patients with greater than 50% crescents on renal biopsy and is characterized by little or no immunohistologic evidence of immune
complex or anti-GBM deposition within glomeruli – over 80% of pts. with pauci-immune crescentic glomerulonephritis have
circulating ANCAs. Sub-types of pauci-immune glomerulonephritis include microscopic polyangiitis, Wegener’s granulomatosis,
and Churg-Strauss syndrome (eosinophilia, asthma, & granulomas).
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. Qualitative & quantitative characteristics of the pathogenic immune
complexes that result in localization predominantly in subendothelial zones where they are not in contact with the cellular
inflammatory mediator systems in the blood usually causes nephrotic sydrome rather than nephritis (membranous lupus
glomerulonephritis). Over time, a lupus patients immune response and disease characteristics may change.
Glomerulonephritis may also be a manifestation of systemic small vessel vasculitides: Henoch-Schonlein purpura is caused by
vascular localization of IgA-dominant immune complexes leading to IgA-nephropathy in the glomeruli (& is most common
vasculitis in kids); Cryoglobulinic vasculitis is caused by cryoglobin deposition in vessels and is often associated with HCV and
causes membranoproliferative glomerulonephritis (other types of glomerulonephritis may develop as well). Pauci-immune
glomerulonephritis may also be a result of a systemic vasculitis, which often present with clinical manifestations in multiple organs:
skin purpura, hemoptysis (alveolar hemorrhage), abdominal pain (gut infarcts), & mononeuritis (vasculitis in epineural and
perineural vessels of peripheral nerves). ANCA small-vessel vasculitis often causes pulmonary-renal vasculitic syndrome, usually
characterized by rapidly progressive glomerulonephritis combined with pulmonary hemorrhage.
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. Thin basement membrane nephropathy (26% of asymptomatic hematuria) is diagnosed on biopsy by seeing thinning of the
GBM lamina densa. IgA nephropathy (28% of asymptomatic hematuria) shows IgApredominant mesangial immune deposits. Alport’s
syndrome (hereditary nephritis) is a less common cause of asymptomatic hematuria that on biopsy shows marked lamination of the lamina
densa with the kidney & skin having + immunohistochemical staining for α-chains of type IV collagen – Alport’s syndrome is a genetic ds
caused by a defect in the type IV collagen genes; in males it initially manifests as asymptomatic hematuria (sometimes with episodes of gross
hematuria) beginning in the first year of life with progressively worsening proteinuria & renal insufficiency (rate of progression is highly
variable); females (who are almost all heterozygous) show only intermittent asymptomatic hematuria.
● Immunoflourescence characterization of Disease
Linear GBM staining → anti-GBM disease
Granular GBM staining → immune complex disease
↓↓ staining along with ANCA+ serology → pauci-immune disease
● Asymptomatic Proteinuria
FSGS
Mesangioproliferative GN
● Neprotic Syndrome
MCG
Membranous glomerulopathy
idiopathic (primary)
secondary (e.g. lupus)
FSGS
● Acute Nephritis
Acute Diffuse Proliferative GN
Post-streptococcal GN
Post-staphylococcal GN
Focal or Diffuse Proliferative GN
IgA Nephropathy
Membranoproliferative GN
type I
type II
Fibrillary GN
Membranoproliferative GN
type I
type II
Fibrillary GN
Diabetic Glomerulosclerosis
Amyloidosis
● Rapidly Progressive Nephritis
Crescentic GN
Anti-GBM GN
Immune Complex GN
ANCA GN
Light-chain Deposition Disease
● Pulmonary-Renal Vasculitic Syndrome
Goodpasteur’s (anti-GBM)
● Asymptomatic Microscopic Hematuria
Thin Basement Membrane Nephropathy
IgA Nephropathy
Alport Syndrome
Immune complex vasculitis
Lupus
ANCA Vasculitis
Microscopic polyangiitis
Wegener’s
Churg-Strauss
● Recurrent Gross Hematuria
Thin Basement Membrane Nephropathy
IgA Nephropathy
Alport Syndrome
● Chronic Renal Failure
Chronic Sclerosing GN
● Nephrotic-dominant diseases: MCG, membranous glomerulopathy, diabetic glomerulosclerosis, amyloidosis
Nephritic-dominant diseases: crescentic GN, acute diffuse proliferative GN,
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.
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
UA: 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.
Renal ultrasound should be done in all pts. with ARF; it is 93-98% sensitive for obstruction and may show a hypertrophic kidney
(associated with chronic ds). CT may be helpful in some pts. to reveal a cause of obstruction (esp. ureteral obstruction at the level of
the bony pelvis). MRI may be used with gadolinium contrast (not the nephrotoxic iodine contrast used in intravenous pyelography).
The general diagnostic strategy is to rule out pre-renal and post-renal causes before considering an intra-renal cause of disease; this
is done by doing a good H&P – an attempt to percuss the bladder should be made (+ means at least 500mL of urine in the bladder),
the prostate exam should be done in men & the pelvic exam done in women. Lab evaluation of the serum & urine should be done,
with a creatinine kinase level obtained if rhabdomyolysis is suspected.
Treatment
Notes
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.
.● Prerenal ARF is made worse by ACE-inhibitors, since they
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.
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.
● Treat infections aggressively.
● Treat severe metabolic acidosis, but correct slowly to
prevent hypocalcemic complications (e.g. tetany).
● Dietary Interventions
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, β-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,
5. Chronic Kidney Disease
Lab Presentation
Symptoms:
Nocturia & polyuria (↑ urine volume due to ↓ed
concentration)
Signs:
UA: broad casts, proteinuria, isosthenuria (urine osmolarity
similar to plasma osmolarity)
Renal US: Small echogenic kidneys (↑ fibrosis)
Complications:
Osteitis Fibrosa Cystica (↓ serum [Ca], ↑ PTH, ↓ vit.D)
Anemia (normochromic & normocytic)
Uremia
early signs: LOA, altered taste, fatigue, pruritis, pericarditis, GI
bleeding
later signs: coma, vomiting, parasthesias
Impaired growth in kids
Blood tests: anemia, hyperphosphatemia, hypocalcemia,
↑ BUN & ↑ creatinine (stable levels)
Histology: dilated tubules, fibrosis in the kidney interstisium
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 in nephron 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
Treatment
Notes
● Dialysis at GFR < 15
.● Renal ultrasound is the best test for distinguishing chronic
kidney disease; it will show a small (fibrotic) kidney.
Medical Therapy Heirarchy:
● Leading causes: DM, HTN
1. ACE-inhibitors to ↓ intra-glomerular BP and inhibit
PAI-1 (a pro-fibrotic signalling molecule)
2. β-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
● 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.
6. Hyponatremia
Lab Presentation
General S&S:
Moderate or Gradual-onset → confusion, muscle cramps,
lethargy, anorexia, nausea
Hypervolemic: ↑ urine osmolality (> 100), ↓ urine [Na]
Severe or Rapid-onset → seizures &/or coma
Hypovolemic:
Specific S&S
intrarenal losses → ↑ urine Osm, ↑ urine [Na] (> 40mEq/L)
Hypervolemic → edema
extrerenal losses → ↑ urine Osm, ↓ urine [Na]
Hypovolemic → dry mucous membranes, ↓ skin turgor,
Isovolemic (SIADH): ↑ urine Osm, ↑ urine [Na],
l
h
l lit
Hyponatremia is defined as plasma [Na] < 135mEq/L. Since sodium is the major determinant of the osmolarity of the ECF,
↓ed [Na] → ↓ed osmolarity of the plasma relative to the ICF → water enters cells down its osmotic gradient → cells swell until
osmotic equilibrium is re-established between the ECF & ICF. Swelling of neurons is responsible for the potentially life-threatening
complications of hyponatremia: seizures & coma. Hyponatremia may occur in setting where ECFV is normal, increased. or
decreased, and though the vast majority of cases of hyponatremia occur when the serum osmolarity less than normal, hyponatremia
may also occur when serum osmolarity is normal or increased.
Hypervolemic hyponatremia occurs in pts. with syndromes that cause Na-retention by the kidneys (CHF, nephrotic syndrome,
liver cirrhosis). Thirst is stimulated and water is retained in excess of sodium due to non-osmotic release of ADH (in opposition to
the osmotic effect which would be to suppress ADH because as plasma [Na] is ↓ed, plasma osmolality is also ↓ed). This happens
because “effective circulating arterial volume” (i.e. level of kidney perfusion) is decreased (due to ↓ed CO in CHF, portal pooling in
cirrhosis, unclear mechanism in nephrotic syndrome) even though total body water is increased, and the ↓ed EACV is sensed by the
kidney leading to non-osmotic ADH release.
Hypovolemic hyponatremia happens when the body loses both Na & water but loses Na in excess of water, as in diarrhea or
prolonged sweating. Water loss in excess of Na-loss (initial disturbance in diarrhea/sweating) → ↓ ECFV with hypernatremia
(hyperosmolality of plasma) → osmotic release of ADH & ↑ thirst → normonatremia with ↓ed ECFV (osmolarity returned to normal
in the setting of ↓ed total amount of plasma sodium) → if sodium and water losses continue, continued ↓ing ECFV eventually leads
to non-osmotic release of ADH → ↑ thirst → hyponatremia & continued progressive dilution of body fluids (in most cases the ADHmediated retention of water does not compensate fully for Na loss and the pt. has a ↓ed ECFV).
Isovolemic hyponatremia is the most common form of hyponatremia, resulting from the a reduction in the kidney’s capacity to
dilute urine further than 100mOsm/kg H2O (if dilution is severely impaired, water intake need not be severe to cause hyponatremia).
Patients do not develop clinical evidence of ECFV expansion because most of the retained water moves into the ICF, and the slight
↑ in ECFV is offset by transient loss of Na/water by the kidney. The most common cause for impaired urinary dilution is SIADH,
which → renal water retention (assuming pts. drinks enough water) → ↑ ECFV & body water dilution → ↑ Na/water excretion (nonosmotic: baroreceptor-mediated) → hyponatremia & swollen cells → steady-state develops as ECFV tends towards normal &
collecting duct becomes resistant to ADH. If their Na intake is normal, SIADH pts. secrete lots of Na in the urine, since their ECFV
is increased.
In hypertonic hyponatremia, the serum osmolarity is increased due to hyperglycemia or hypertonic infusions (i.e. mannitol,
glucose) even though the [Na] is low; this is the only hyponatremia not caused by retention of ingested water in the presence of a
defect in dilution/excretion of urine – it is also the only hyponatremia associated with water movement out of cells into the ECF
Treatment
Notes
1) Hypervolemic hyponatremia → water restriction
● Hyponatremia is most often associated with impaired excretion
of water.
2) Hypovolemic hyponatremia → IV isotonic NaCl to
expand the ECFV, which inhibits further non-osmotic
release of ADH & reverses other abnormalities that
impair urinary dilution.
3) Isovolemic hyponatremia → water restriction
- if hyponatremia is severe (cerebral edema), give
concentrated NaCl to induce osmotic diuresis
(Na is excreted & water follows).
4) Hyperglycemic (hypertonic) hyponatremia → give
l
l
l
[ l
] d IV fl d/ l
l
● Never correct sodium faster than 1mEq/hr – central pontine
myelinolysis, seizures, and coma may occur; correct serum
sodium only halfway to normal range in the first 24hrs.
● Etiologies of SIADH: oat cell CA of lung, CHS ds, lung ds,
chlorperamide use.
- hypothyroidism, hypoadrenalism
7. Hypokalemia
Lab Presentation
GI: impaired motility, nausea & vomiting
Blood tests: [K+] < 3.3 mEq/L
MSK: weakness, paralysis possible, rhabdomyolysis
CV: atrial & ventricular dysrhythmias
Renal K-loss → urine K > 30mEq/day, FEK > 10%
- pts. who stopped their diuretic 2 half-lives before
evaluation may have low urine potassium due to total
body depletion & absence of current diuresis.
GI K-loss → urine K < 20 mEq/day, FEK < 6%
Etiology and Pathogenesis
Hypokalemia may be seen with increased K-uptake by cells (catecholamine excess, exogenous insulin administration, or
metabolic alkalosis), ↓ intake &/or ↑ GI loss (diarrhea), or ↑ urinary excretion (usually due to diuretic therapy → ↑ volume & Nadelivery to CCD as well as ↓ ECFV leading to ↑ RAAS & K-excretion).
In renal artery stenosis, ↓ renal perfusion → ↑ activity of RAAS → hypokalemia. If aldosterone is infused under experimental
conditions, initial rise in ECFV diminishes (after about 12-18 days) due to a diuresis known as “aldosterone escape” (likely involves
down-regulation of the thiazide-sensitive Na/Cl co-transporter in the DT.
Prolonged vomiting may cause hypokalemia as follows: vomiting → ↑ H+ loss → ↑ bicarb. in plasma → ↑ K+ excretion due to
tubular delivery of bicarb. (urine is alkaline here) – as volume depletion develops, Na is initially absorbed with Cl though some Na
stays in the tubule with bicarb.; later in more severe volume depletion → Na is absorbed with bicarb. too → acidic urine again along
with low urinary Na & Cl (as well as metabolic alkalosis – see # 9).
Treatment
Notes
● Replace K (PO or IV depending on severity)
- a 20mEq infusion will raise serum [K] by 0.25mEq/L
- do not exceed 20mEq/hour IV-infusion
.
8. Hyperkalemia
Lab Presentation
GI: nausea, vomiting, diarrhea
Blood tests: [K+] > 5.5 mEq/L
Neuro: muscle cramps, weakness, parasthesias, paralysis,
areflexia, tetany, focal neurologic deficits, confusion
ECG:
6.5 – 7.5 mEq/L → tall peaked T-waves, short QT interval,
prolonged PR
Respiratory insufficiency
Cardiac arrest
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
Notes
● If no ECG changes, no need for emergent treatment.
● 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.
● If ECG changes are seen:
1. IV Ca2+ to stabilize membrane potential
2. Insulin, β2-agonist, IV bicarb → ↑ K-uptake into cells
3. loop diuretic, cation exchange resin → urinary & GI
K-excretion
4. (maybe dialysis if hyperkalemia is severe)
● 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.
9. Metabolic Alkalosis
Lab Presentation
Irritability
Neuromuscular hyperexcitability
UA:
H+ loss by vomiting:
Generation phase: pH > 5.5, Na > 15
Maintenance phase: pH > 5.5, Na >15, Cl < 15
Late phase: pH < 5.5, Na < 15, Cl < 15
Hypokalemia (weakness, cramping, ileus)
H+ loss by diuretic overdose: hypochloremia with chloruria
Metabolic alkalosis is a primary increase in plasma bicarb. concentration due to gain of bicarb. or loss of H+. There are two basic
types of metabolic alkalosis: those that develop in the context of volume contraction (vomiting, NG drainage, diuretics), and those
that develop in volume expansion & HTN (hyperaldosteronism).
In metabolic alkalosis due to vomiting, pathogenesis proceeds as follows: in the generation phase, loss of H+ from the stomach (at
gastric pH = 1, 100mEq/L) → dissasociation of plasma H2CO3 (to make more H+ to secrete into the stomach) → ↑ HCO3- in plasma
that is initially delivered to the urine along with Na & K (at this time, the presence of bicarb. in the urine makes urine pH > 5.5);
during the maintenance phase, volume contraction develops from loss of Na in the urine (Na becomes the cation associated with the
excess urine bicarb.) → ↑ Na reabsorbtion in the tubule along with Cl (so at this time urine Cl decreases while urine Na is still
elevated) → diagnostic dissasociation of Na from Cl in the urine – as volume depletion worsens and filtered load of Cl decreases, Na
becomes reabsorbed along with Cl as well as HCO3-, and urine pH decreases as less bicarb. is excreted. Also, as a consequence of
volume depletion, aldosterone secretion is ↑ed → ↑ Na reabsorbtion → ↑ K & H excretion → H combines with bicarb. in urine,
preventing bicarb. reabsorbtion → paradoxical worsening of the alkalosis (paradoxical aciduria in the setting of plasma alkalosis).
Even if the primary disturbance is stopped, ECFV must be restored.
In metabolic alkalosis from diuretic use, Na & Cl are lost together from tubular blockade in the loop of Henle (furosemide) or
DCT (thiazides) → volume contraction with ↑ K excretion (hypokalemia possible) → stimulation of aldosterone secretion → further
↑ in K excretion & H+ excretion → bicarb. retention in plasma & H+s combine with NH3 to make NH4+ which is excreted with Cl →
hypochloremia develops that matches the level of ↑ in [HCO3-].
Metabolic alkalosis with volume expansion & HTN occurs in hyperaldosteronism (adrenal hyperplasia or adenoma), and it is also
accompanied by hypochloremia.
Metabolic alkalosis often develops when the physical exam suggests hypovolemia & chronic GI volume loss.
Treatment
Notes
● Correct the underlying defect
● Expected compensation: for every 1 mEq/L rise in plasma
HCO3-, pCO2 should increase by 0.6-0.7mmHg.
● Hydration, & in pts. prone to volume overload (CHF),
give KCl solution instead of normal saline.
● Bartter’s syndrome: defect in Na/K/2Cl co-transporter in the
LoH → similar to furosemide overdose.
● Gitelman’s syndrome: defect in NaCl transported in the DCT
→ similar to thiazide overdose.
10. Metabolic Acidosis
Lab Presentation
Blood tests: ↓ pH, ↓ PaCO2, ↓ HCO3UA:
Ketonuria → ketoacidosis, paraldehyde poisoning, starvation,
isopropyl alcohol intoxication
No Ketonuria → uremia (renal failure), lactic acidosis,
methanol, ethylene glycol, or salicylate poisoning
Metabolic Acidosis results from production of excess acid or loss of HCO3-. Causes of metabolic acidosis with an increased
anion gap ( > 12) include: methanol poisoning, uremia, diabetic ketoacidosis, paraldehyde, ischemia / lactic acidosis, ethylene
glycol, & salicylate toxicity. In diabetic ketoacidosis & lactic acidosis, there is endogenous production of strong acids that
disassociate at plasma pH → H+ depletes HCO3- and the dissociated anion of the strong acid replaces bicarbonate in the ECF.
Aspirin overdose can produce a respiratory alkalosis (depression of CNS function) as well as the metabolic acidosis.
Metabolic acidosis with a normal anion gap may be caused by diarrhea (loss of HCO3- in the stool) or renal tubular acidosis (↓ed
secretion of H+ in the tubule). The metabolic acidosis of advanced renal faliure has elements of normal anion-gap acidosis (↓ed
NH4+ and titratable acid secretion) and increased anion-gap acidosis (retention of sulfates, phosphates, & urates) – serum bicarb.
usually stabilizes at 15-20mEq/L and anion-gap at 15-20mEq/L.
Treatment
Notes
● When acidosis is severe or plasma bicarb. is dropping
rapidly, give IV bicarb. to raise plasma pH to 7.2
- effective distribution is 40% of body weight:
28L in a 70kg male
- do not correct beyond pH 7.25 because:
i. Hb dissasociation curve shifts to the left
ii. may cause volume overload
iii. may precipitate or worsen hypercarbia
● Expected compensation: for every 1mEq/L ↓ in [HCO3-],
pCO2 should fall by 1.2 mmHg.
● Winter’s Formula for expected compensation:
pCO2 = 1.5 x [HCO3-] + 8 (+/- 2)
● Anion Gap = Na+ - (Cl- + HCO3-)
- normal anion gap is 12 mEq/L
● pH 7.2 = [H+] of 60mEq/L
10. Prostatitis
Lab Presentation
ABP → fever/chills, pelvic &/or perineal pain, dysuria
suprapubic tenderness; “boggy” prostate,
post-ejaculatory pain, urinary retention
Blood tests: ↑ed PSA
UA: WBCs in urine
CBP → frequency, urgency, dysuria, pelvic/testicular ache,
post-ejaculatory pain
NBP → pain anywhere in the pelvis, nocturia, dysuria,
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 (see below) 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
Notes
ABP → flouroquinolone antibiotic (penetrates prostate
well) for at least 4 weeks; hospitalization may be
necessary
● Types
CBP → flouroquinolone or sulfa antibiotic for 4-6 weeks;
anti-inflammatories for symptoms
NBP → anti-inflammatories, trial of antibiotics,
● α-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
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)
● Diagnosis: Four Glass Test
VB1 → initial voided urine; finds urethritis
VB2 → midstream urine; finds cystitis
EPS → fluid obtained w/ prostatic massage; finds prostatitis
VB3 → fluid obtained after prostatic massage; finds prostatitis
11. Benign Prostatic Hyperplasia
Lab Presentation
Lower UT symptoms:
Blood tests: ↑ed PSA
● 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
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
Notes
● lifestyle changes: ↓ intake of EtOH & caffeine; ↓ fluid
intake after dinner
● Very common: 60yo man has 50% of having BPH.
● α-adrenergic antagonists to relax smooth muscle in the
prostate and decrease overall resistance to urination.
- side effects: orthostatic dizziness, retrograde ejaculation
● 5-α-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
● Most often found in the transitional zone.
● Urodynamics is considered the gold standard diagnostic test
for many urinary problems.
12. Prostate Cancer
Lab Presentation
Symptoms:
LUTS
Blood tests: ↑ed PSA (> 4.0ng/mL)
Physical Exam:
Histology: small, compact glands; lack of basal-cell layer;
PSA+ & PAP+, prominent nucleoli
Prostate→ nodular, induration, obliteration of the median sulcus
fixation of the prostate to the pelvic wall,
UA: hematuria
Prostate cancers develop 80% of the time in the peripheral zone of the prostate. The most likely precursor lesion is prostatic
intraepithelial neoplasia, an intraductal lesion characterized by cytologic atypia (nuclear enlargement with presence of nucleoli)
within pre-existing ducts.
Prostate cancer has a propensity for invasion through the prostatic capsule, often by perineural invasion; common sites of
metastases are regional lymph nodes & bone – immunostaining with PSA/PAP is useful to confirm the prostatic origin of mets
(usually in lymph nodes & bone).
The challenge of diagnosing prostate CA is that when it is localized, pts. overwhelmingly show no symptoms, but once it spreads
beyond the prostate, there is no cure. Most prostate cancers (80%) are not clinically important, however, in that pts. will not develop
symptoms or potential mortality from the disease.
Treatment
● Watchful waiting (with serial PSA & prostate waiting) if
cancer is confined to the prostate; for younger pts.,
surgery & radiation are options.
● Surgery & radiation are considered the standard of care.
- surgery: 10yrDFS = cure
radiation: 10yrDFS does not necessarily mean cure
● For widely metastatic disease:
- docetaxel increases survival for a few months
- castration operation or drugs to shut-down the
testosterone axis; this works for ~ 2 years, after
which the cancer becomes testosterone-independent
Notes
● Epidemiology:
● 200,000 new cases per year - #1 in men
● 1 in 6 men will develop prostate CA in their lifetime
● most common CA & 2nd most common cancer death in
American men.
● hereditary forms (~ 10%) tend to occur in younger men
(i.e. those below age 55)
● Risk Factors: age (exponential ↑ after 50y), ethnicity, family
hx (dx made before 60y), geographic variation,
high-fat diet, ↑ testosterone, viral infection,
environmental factors: agent orange, pesticides
● Prostate: luminal cells → PSA & PAP +
basal cells → HMW cytokeratin +, PSA & PAP –
● Prostate CA is most often found in the peripheral zone;
testosterone is converted into DHT by prostatic epithelial
5-α-reductase, & DHT is required fof prostatic CA
(its also required for prostatic hypertrophy).
13. Renal Dysplasia
Lab Presentation
Histology: undifferentiated tubules & ducts, surrounded by
mantles of undifferentiated mesenchyme.
y
Renal dysplasia is caused by an abnormality in metanephric differentiation, almost always (90%) associated with other urinary
tract abnormalities that cause obstruction to urinary flow. Dysplasia is distinguished pathologically by undifferentiated tubules &
ducts surrounded by mantles of undifferentiated mesenchyme that may contain muscle or cartilage.
Multicystic renal dysplasia is usually unilateral & presents as a flank mass in an infant; this is the most common cause of an
abdominal mass in newborns.
Treatment
Notes
● Most common cause of abdominal mass in newborns.
14. Renal Cystic Diseases
Lab Presentation
Adult polycystic disease is an autosomal dominant condition that presents as bilateral flank masses & renal failure in midlife.
Gross pathology shows markedly enlarged & distorted kidneys; histology shows cysts with normal kidney in between.
Infantile polycystic disease is an autosomal recessive condition that is present at birth; 75% of infants die in the perinatal period.
Gross pathology shows enlarged but smooth kidneys; histology shows cysts that are dilations of the collecting system.
Simple renal cysts are common (seen in 50% of adults > 50yrs) and usually incidentally found by radiology or on autopsy; they may
be single or multiple and usually are found in the renal cortex. Histology shows cysts lined by a single layer of flattened epithelium.
Acquired cystic kidney disease is found in 75% of pts. with ESRD who undergo long-term dialysis. Cysts are initially lined by
flattened epithelium but may undergo hyperplastic &/or neoplastic epithelial proliferations (renal cell CA).
Treatment
Notes
.
15. Urinary Tract Stones
Lab Presentation
Severe flank pain (referred to genitalia as stone passes)
Nausea/vomiting
Hematuria (often microscopic)
UA: usually urine pH < 5.0 (for uric acid stones),
hematuria
Physical Exam:
CVA tenderness
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
Notes
● Lithotripsy
● Nephrolithiasis: stones in the collecting system of the kidney
Urolithiasis: stones elsewhere in the urinary tract
● 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, HCTZ
● Stone prevention:
● hydrate enough to produce 2L of urine per day
● 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 (αblocker) to relax ureter & allow stone to pass; if it doesn’t
pass (> 7mm), must do a procedure to remove stone.
16. Renal Cell Carcinoma
Lab Presentation
Symptoms:
Hematuria
Flank Pain
Gross path: large, yellow/orange mass that may be cystic or
solid; hemorrhage & necrosis are common
Histology: different patterns – clear cell is the most common.
Signs:
Abdominal Mass
Complications:
Ectopic hormone production
Renal cell CA arises from the tubular epithelial cells; 90% are adenocarcinomas and may have a variety of histologic patterns
(clear cell, papillary, ect.). The majority (95%) are sporadic, rare, & familial – abnormalities of chromosome 3 have been associated
with clear cell RCC & abnormalities of chromosomes 7 and 17 have been associated with papillary RCC.
Classic clinical features are hematuria, flank pain, and abdominal mass, but all 3 occur in only 10% of patients. RCC may present
with ectopic hormone production, as metastatic disease, or as an asymptomatic renal mass incidentially found radiographically –
it may also grow into the renal vein, IVC, & heart.
Most are asymptomatic & are discovered incidentially; these cancers have a high cure rate, but those that produce symptoms have
a much poorer prognosis Currently the best test to diagnose kidney cancer is abdominal CT with contrast. The only curative
therapy involves surgical removal of the tumor – radical nephrectomy is done for stage T1-T3, and partial nephrectomy can be done
for peripheral exophytic tumors < 4cm. Standard therapy for advanced/metastatic disease is immunotherapy (IL-2 & IFN), which
rarely provides a chance for cure but slows disease progression in 1/3 of pts.
Treatment
Notes
(see above)
● Epidemiology
● more common in men (2:1)
● usually found in pts. between 50-70yrs.
● associations: smoking, family hx, polycystic kidney ds,
chronic renal failure, dialysis, VHL ds, tuberous sclerosis
● Renal cell CA is the most common malignant tumor of the
kidney.
● The survival of pts. is excellent at early stages of disease but
limited at more advanced stages.
● Masses other than renal cell carcinomas that may be found in
the kidney include: angiomyolipoma, oncocytoma, renal
pelvic transitional cell carcinoma, and benign complex
renal cysts.
17. Cystitis (& UTIs)
Lab Presentation
Dysuria
Urinary urgency & frequency
Nocturia
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
Notes
Simple UTI
● 3-day course of TMP/SMX or flouroquinolone
● ↑er incidence in females (shorter urethra); BPH predisposes
men to cystitis.
Recurrent UTI
● Any diabetic with a UTI has a complicated 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
● Common organisms that cause UTIs: E.coli, Klebsiella,
Proteus, Staph. saphrophyticus, & enterococcus.
● Diagnostic gold-standard is urine culture, but this is rarely
necessary.
.
18. Bladder Carcinoma
Lab Presentation
Hematuria (may be intermittant)
Dysuria, frequency, urgency
Transitional cell carcinoma represents 90% of bladder tumors; they may arise anywhere in the urinary tract (renal pelvis, ureter,
bladder, or urethra) though about 90% arise in the bladder. Any transitional cell carcinoma anywhere in the urinary tract is a marker
for unstable urothelium: the pt. is at risk for further urinary tract cancers. Risk factors include exposure to carcinogens (arylamines),
tobacco use (major factor accounting for 60% of bladder cancers in the US), cyclophosphamide. Diagnosis is usually made by urine
cytology (usually done for hematuria or dysuria) &/or cytoscopy & biopsy – All pts. with hematuria should have cytoscopy, urinary
cytology, or upper urinary tract imaging to r/o bladder carcinoma. If a tumor is found, the initial diagnostic & theraputic procedure
is the TURBT – a majority of pts. with superficial tumors (Ta or T1) can be effectively treated with transurethral resection alone. In
certain cases of high-grade superficial tumors, additional therapy may include intravescical injection of BCG, mitomycin, or
thiotepa. Bladder cancers have a high rate of recurrence & so pts. must be followed with frequent cytoscopies. Patients whose
cancer invades the bladder muscle wall (T2 & T3) require radical cystectomy, which has a 10yrDFS of ~ 66% - after surgery the
urine is diverted into either a urostomy or an orthoptic neobladder (made from pts. small intestine). When the cancer has spread
outside the bladder, platinum-based chemotx is used and surgery is reserved for when the pts. bladder symptoms are so severe the
procedure is palliative.
Squamous cell CA of the bladder is rare in the US but is assoicated with schistosomiasis & is common worldwide.
Adenocarcinoma is an unusual tumor that may be associated with congenital anomalies or metaplasias (extensive cystitis
glandularis). Mesenchymal tumors are rare in adults but more common in kids (esp. rhabdomyosarcoma).
Treatment
Notes
(see above)
● Epidemiology:
● incidence ↑es with age and peaks at 70-80yrs.
● more common in men (3:1)
● more common in caucaisans in the US and in areas where
schistosomiasis is prevalent.
● Order urine cytology to r/o bladder CA in the work-up of
hematuria/dysuria.
19. Cryptorchidism
Lab Presentation
Cryptorchidism is the failure of the testes to descend into the scrotum; they may end up as intrabdominal or inguinal structures.
Histologic changes include reduced #s of seminiferous tubules & germ cells with infertility if cryptorchidism is uncorrected – there
is also an increased risk of germ-cell neoplasms even if the cryptorchidism is surgically corrected.
Treatment
Notes
● Surgery.
.
20. Orchitis
Lab Presentation
Orchitis is acute, chronic, or granulomatous inflammation of the testes &/or epididymis. Common etiologies include gramnegative bacteria, syphillus, & mumps.
Treatment
Notes
.
21. Testicular Torsion
Lab Presentation
Pain
Nausea/vomiting
SNS activation (↑ HR, ↑ BP, sweating)
Erythematous, edematous testicle with loss of cremasteric reflex.
- not all older children have a cremasteric reflex, however.
Torsion is twisting of the spermatic cord distal to the tunica vaginalis, producing infarction of the testis within a few hours. It
may be associated with vigorous exercise &/or abnormalities of testicular attachment in the scrotum. Men with testicles that lie
horizontally (rather than vertically) or with the epididymus anterior are at increased risk. It most often occurs in males < 20yrs old.
Therapy must be done within 6hrs to be sure to save the involved testicle.
Obtain an ultrasound to r/o torsion if you don’t think the pt. has it, but if the H&P indicates torsion, send the pt. to surgery
immediately. A nuclear scan may be done (& is positive if radioactive isotope is concentrated in the testes), but will show a false
negative if increased erythema in the scrotal wall hides low flow in the testes; some infants are too small to have an accurate test as
well.
Treatment
Notes
● Surgery
● Salvage Rates:
0 – 6 hrs → 85-90%
6 – 12hrs → 50%
> 24hrs → < 5%
(likely intermittant torsion)
22. Germ Cell Neoplasms
Lab Presentation
Solid Testicular Mass
Blood tests:
Virilization
Gynecomastia
Non-seminomas → ↑ AFP &/or ↑ BHCG
Seminomas → no AFP, only 10% show ↑ BHCG
Most primary testicular germ cell tumors present as painless, solid masses within the testis. Seminoma is the most common pure
germ cell tumor (40-50%) with an incidence peak in the 4th decade of life; gross pathology shows a solid gray-white mass with no
necrosis or hemorrhage, and histology shows a uniform pattern with large tumor cells & lymphocytes where cells are usually AFPand BHCG-. Embryonal carcinoma peaks in the 3rd decade of life; gross pathology is a gray-white solid mass often with necrosis &
hemorrhage – gross pathology is a solid grey-white mass without necrosis or hemorrhage, and histology shows a variable pattern
with markedly anaplastic pleomorphic cells that are usually BHCG- and may be AFP+. Yolk sac tumors present most often in the 1st
decade of life but may be a component of adult mixed germ-cell tumors – gross pathology shows a cystic to solid mass, often with
hemorrhage & necrosis, and histology shows a variable pattern (cystic, papillary, glandular, ect.) with cells characteristically AFP+
& BHCG-. Choriocarcinoma is usually found as a component of mixed germ-cell tumors; grossly they are extremely hemorrhagic
&/or necrotic, and diagnosis is made histologically by seeing both neoplastic syncytiotrophoblasts & cytotrophoblasts – cells are
usually AFP- & strongly BHCG+. Teratomas are characterized by tissues from all 3 germ layers; pure tumors are more common in
children, but in adults the tumors are more aggressive. Mixed germ cell tumors are more common than any individual pure type –
the most common form in mixed teratoma & embryonal carcinoma (teratocarcinoma).
Germ cell tumors of the testes are rapidly growing tumors that also tend to metastasize early to retroperitoneal & eventually
mediastinal lymph nodes. The most common presentation is a painless solid testicular mass – all intratesticular masses should be
considered a malignancy until proven otherwise. Patients with intratesticular masses consistant with testicular neoplasm should
undergo radical orchiectomy though an inguinal approach (do not do needle biopsy or transscrotal resection because this may
involve the lymphatics & spread the cancer.
Seminomas are very sensitive to radiation & effective doses can be delivered with minimal mortality. Non-seminomas are less
sensitive to radiation but respond well to platinum-based chemotherapy (made cure of testicular cancer possible even in advanced
cases of metastatic disease) – in both seminomas & non-seminomatous tumors, cure rates typically exceed 95%.
Treatment
Notes
(see above)
● Testicular CA is the most common solid tumor among men
age 20-40.
● Non-germ cell testicular tumors include: sertoli-cell tumors &
Leydig-cell tumors; the majority of these are benign, though
Leydig cell tumors may present with sequelae of ↑↑ androgen
producition in boys.
23. Renal Pelvic / Ureteral Cancer
Flank pain
Hematuria
Lab Presentation
(obstruction)
Upper tract transitional cell cancers are rare but can occur in the renal pelvis or ureter; they can be seen as primary tumors in pts.
with a history of lower tract (bladder) cancer. Diagnosis is made with IV-pyelogram, urinary cytology, & hematuria. These cancers
are aggressive and usually require radical nephroureterectomy (removal of kidney, renal pelvis, & entire ureter to the level of the
bladder on the side of the tumor). In certain cases of low-grade, low-stage ds partial ureterectomy can be performed. Patients
require constant surveillance via cytoscopy because 50% of pts. will develop bladder cancer.
Treatment
Notes
.
25. Penile Cancer
Lab Presentation
Penile mass &/or ulceration.
Penile cancer accounts for < 1% of malignancies among males in the US but may constitute up to 10% of male malignancies in
some African & South American countries – incidence increases with age & most cases happen in men > 60yo. Circumcision is a
prophylactic measure that virtually eliminates the occurence of penile cancer; the development of penile tumors has been attributed
to chronic irritative effects & may be extenuated by phimosis (inability to retract the foreskin) that occurs in 50% of pts. with penile
cancer.
Tumors are usually squamous cell carcinomas; they occur as invasive lesions presenting as penile mass or ulcer on the glans,
foreskin, or shaft, often coexisting with secondary infection – it may also be obscured on physical exam by phimosis.
Penile cancer may occur in an early stage as carcinoma in situ, and when this occurs as a red velvety emarginated lesion on the
glans, it is referred to as erythroplasia of Queyrat – if it involves the penile shaft or base it is referred to as Bowen’s disease.
In the case of carcinoma in situ, 5-FU cream can be used as a primary treatment modality.
Excisional biopsy is often performed to confirm the diagnosis and stage the disease. The 5yrDFS of localized disease is 80%, but
if the cancer has spread to the inguinal lymph nodes, 5yrDFS (cure rate) drops to 30% - pts. with distant mets have cure rates of
< 5%.
Treatment
Notes
Carcinoma in situ → 5-FU topical cream,
laser ablative therapy
.
Invasive carcinoma → total penectomy +/- inguinal
lymphadenectomy
CA with distant mets → palliative chemotx &/or radiation
26. Acute Pyelonephritis
Lab Presentation
Fever/chills
Flank pain
Generalized muscle tenderness & malaise
Dysuria
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.
Notes
27. Erectile Dysfunction
Lab Presentation
Inadequate or absent erection, even with stimulation.
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
Notes
● Type-5 phosphodiesterase inhibitors, to decrease
degredation of cGMP.
● occurs in up to 50% of men 40-70yrs old.
● 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:
i. do not use in pts. who are taking nitroglycerine or
other nitrate medications, as precipitous drops in
BP may be fatal
ii. vardenafil is contraindicated is pts. who are also
taking α-blockers (i.e. for BPH)
iii. tamulosin is the only α-blocker that can be used
with tadalafil.
● 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.
● Diabetes is the most common endocrine cause of ED.
28. Vescicouretural Reflux
Lab Presentation
↓ed renal function
Renal insufficiency/ ESRD
DMSA scan: may show renal scarring of pyelonephritis
↓ed somatic growth
Renin-mediated HTN
Retrograde flow of urine from the bladder into the kidney due to an acquired birth defect. If the urine carries infection, lifethreatening pyelonephritis may develop associated with renal scarring.
Natural resolution is dependent upon age at diagnosis, grade of reflux, and whether ds is bilateral or unilateral; infants will likely
outgrow reflux if they are put on antibiotic prophylaxis to prevent infection..
Treatment
Notes
● Antibiotics for prophylaxis
- sterile reflux is non-pathogenic
● Pyelonephritis is 2.5x more likely with medical management
than with surgery, though outcomes with regards to cystitis,
HTN, renal scarring, & renal growth are similar.
- late scars may develop with medical management.
● Surgery may be necessary if reflux is not resolved by
medical therapy or if the immediate presentation is
severe.
- procedure restores the function of the ureter/bladder
valve by decreasing its diameter (via a collagen
injection).
- cystoscopic surgery is less invasive but not as
effective.
29. Ureteropelvic & Ureterovesciculojunctional Obstructions
Lab Presentation
Hydronephrosis
Pyelonephritis
Obstruction at the proximal aspect of the ureter causes trapping of urine in the kidney and renal dilation (hydronephrosis).
Obstruction at the junction of the ureter/bladder causes trapping of urine in the ureter & kidney.
Diagnosis may be made by lasix scan (inject contrast material into the blood then see if renal excretion is delayed due to
obstruction).
Treatment
Notes
● Surgery: remove stenotic area then reconnect normal
portion of the ureter.
.
30. Posterior Urethral Valves
Lab Presentation
Hydronephrosis
Pyelonephritis
PUVs cause obstruction of urinary flow that results in massive reflux of urine into the kidney. Life-threatening pyelonephritis
may develop, and increased renal backpressure also interferes with proper development of the kidneys (causing renal dysplasia).
Treatment
Notes
● Placement of Foley catheter.
● Type I: more common
Type II: less common
31. Ureterocele
Lab Presentation
Hydronephrosis
Pyelonephritis
A ureterocele is a dilation of the tip of the ureter when it enters the bladder; they often develop in the context of duplication of the
collecting system (2 ureters on one side). Ureteroceles cause obstruction of the urinary flow and lead to hydronephrosis &
pyelonephritis (as do other causes of urinary flow obstruction).
The ureteral dilation that characterize ureteroceles may involve just the tip of the ureter as it enters the bladder or the entire ureter
up to the kidney.
Treatment
Notes
● Surgery
.

Nephrology/Urology Disorders 1. Nephrotic Syndrome Clinical Presentation

Transcription

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