Flashcards in Renal Deck (281):
What does the appearance of hazy, smoky, or foamy urine implicate?
Hazy: presence of cells or crystals
Smoky: acute glomerulonepritis
What is specific gravity and what is normal for urine?
Specific Gravity: ratio: weight of vol. of urine / weight of vol. of distilled water
number of solute particle dissolved in 1kg of water
What effect does protein have on urine pH?
high protein diet -> acidic urine (lower pH)
Vegetarian diet -> alkaline urine
What infection should be considered w/ very high (>8) urine pH?
Urea splitting microbes (ex. Proteus)
What is the cutoff size for protein filtration at the glomerulus?
Albumin: 69,000 - will not normally be filtered
How much protein is usually excreted in urine /day and what level will register as positive on a dipstick test?
250mg /day -> positive dipstick test
What is Tamm-Horsfall protein?
Glycoprotein Secreted by TALH
Constitutes the majority of protein excreted in urine
Can gel in lumen and produce urinary casts
4 sources of protein in urine
Tubular disorder: most filtered protein is taken up and degraded by proximal tubule. If damaged -> increased urine protein
Glomerular disease: increased filtration
Overflow state: excessive systemic production (ex. Ig light chain in multiple myeloma)
Contamination: semen, vaginal secretion, pus, blood, mucus
In a chemical test for blood in urine, what substances are detected?
RBC, Hb, Myoglobin
What is renal glycosuria? Causes?
glucose in urine due to reduction in reabsorption at PCT (normal blood glucose level)
-Fanconi's syndrome, interstitial nephritis, pregnancy
In urine, how many RBCs are normally visible /HPF?
What does the presence of dysmorphic RBCs on urinalysis indicate?
What are oval fat bodies seen in urinalysis?
tubular epithelial cells with fat droplets in cytoplasm
indication of NEPHROTIC syndrome
maltese-cross pattern of cholesterol / cholesterol ester
7 types of urinary casts
hyaline: may be normal w/ exercise or dehydration (Tamm-Horsfall)
WBC: inflammation of tubular interstitium (nephritis / pyelonephritis)
epithelial: tubular injury (acute tubular necrosis)
granular: fine - may be normal; coarse (muddy brown) - tubular necrosis
waxy: renal failure casts - advanced CKD
What is a renal lobule?
A group of nephrons draining into a common collecting duct
What type of collagen makes up the glomerular basement membrane?
What is a filtration slit?
space between foot processes of podocyte (visceral epithelium of glomerulus)
Nephrin: filtration protein: allows small things through
What is Heymann Nephritis?
Experimental model demonstrating possible mechanism behind in situ immune complex formation
Rats immunized with PCT brush border Ag develop Ab that is cross reactive w/ podocyte
Primary membranous glomerulonephropathy
In situ immune complex formation
Ab against unknown Ag in glomerular basement membrane
What determines the location of Ag or immune complex deposition in the glomerulus?
neutral: deposit in mesangium
anion: subendothelial (bet. endothelium and GBM
cation: subepithelial (bet. GBM and podocyte
What is focal segmental glomerulosclerosis?
damage to glomeruli increase stress on other glomeruli -> endothelial injury, podocyte injury, coagulatin, inflammation, messangial cell proliferation and increased ECM
What is tubulointerstitial fibrosis?
glomerulosclerosis -> proteinuria and tubular ischemia -> injury and activation of tubular cells -> cytokines and growth factors -> interstitial inflammation and fibrosis
global vs. segmental
level of the glomerulus
global: entire glomerulus
segmental: portion of glomerulus
What morphological feature is associated with rapidly progressive glomerulonephritis?
-form of hypercellularity. severe glomerular damage -> leakage of cytokines, procoagulant into bowman's space -> parieal epithelial proliferation and leukocyte infiltration
Calculation for plasma osmolality and normal values
Plasma osmolality = 2 * [Na+] + ([glucose]/18) + (BUN/2.8)
Normal = 288
Na = 140
glucose = 100
BUN = 10
Describe water distribution in terms of body weight, ECF and ICF
TBW = 0.6 * lean body weight
ECF = 1/3 TBW
ICF = 2/3 TBW
2 causes of pseudohyponatremia
1: lab artifact: elevated plasma protein expands plasma volume -> appearance of decreased [Na] (hyperlipidemia and hypergammaglobulinemia)
2: hyperosmolal hyponatremia: elevated glucose -> increased osm -> fluid shift from icf to ecf -> lowered [Na]
In the setting of elevated blood glucose, how is the post-correction [Na] estimated?
Post glucose correction [Na] = add 1.6 mM for every100 mg/dL blood glucose is over 200mg/dL to plasma [Na]
what effect does elevated BUN have on distribution of water?
None. Urea even distributes between ICF and ECF
Thirst regulator and 2 stimulators of thirst
Subfornical organ (hypothalamus)
increased plasma osmolality (2-3% increase)
decrease in blood volume or pressure (via Angiotensin II)
Process of ADH secretion
increased plasma osmolality (osmoreceptors) sensed (OVLT via TRPV1) -> ADH secretion from posterior pituitary
baroreceptors, chemoreceptors, nociceptors, ATII
Where is ADH synthesized and stored?
Synthesized in magnocellular neurons of supraoptic and paraventricular nuclei of hypothalamus
What nerves do baroreceptors send their signals along?
CN IX and X
Effect of ADH
TALH: stimulation of NaKCl transporter -> solute reabsorption
Collecting Duct: binds V2 receptor -> increased cAMP -> PKA -> insertion of AQP 2 in apical membrane
stimulates urea reabsorption at inner medullary CD
Components of countercurrent multiplier
Descending limb of Loop of Henley: high water permeability, low solute permeability
Ascending limb of Loop of Henley: water impermeable, active solute reabsorption
Medullary interstitium: solute from TALH -> high osmolality
From what tissue does renal cortical adenoma originate?
Found in cortex
How large are the lesions in renal papillary adenoma?
papillary / cortical adenoma
lesions are low grade, <5mm
Describe renal oncocytoma
Brown well-circumscribed tumors (large, up to 12cm) from intercalated cells of collecting ducts
eosinophilic cells have many mitochondria
Diseases with which Renal cell carcinoma may be associated with
Acquired Cystic Kidney Disease
Adult Polycystic Kidney Disease
Renal cell carcinoma cell types and associated genetic abnormalities
Clear cell: del(3p) (VHL gene: 3p25)
Papillary: trisomy 7, 17
Chromophobe: monosomy 1,2,6,10,13,17
Paraneoplastic syndromes associated w/ RCC
Describe staging of Renal Cell Carcinoma
T1a: kidney only, tumor < 4cm
T1b: kidney only, tumor 4-7cm
T2: kidney only, tumor >7cm
T3: invasion of perinephric fat, but not Gerota's fascia. Renal vein, not into ipsilateral adrenal gland
T4: invasion of Gerota's fascia, may include ipsilateral adrenal gland
Pathological description of Wilm's tumor
How frequent is recurrence of papillary uroepithelial tumors after resection?
Invasion of what muscle by papillary uroepithelial cancer is concerning?
Muscularis Propria of the bladder
20% of patients
Requires cystectomy (stage T2)
What is PUNLMT?
Papillary Urothelial Neoplasm of Low Malignant Potential
Papillary fronds w/ fairly normal epithelium - little atypia or disorganization
What are grades of papillary uroepithelial tumors?
Uroepithelial papilloma: fronds w/ normal epithelium
PUNLMP: fronds w/ minimal epithelial abnormality
Papillary urothelial carcinoma - low grade: mild-moderate nuclear atypia, mitotic figures basally
Papillary urothelial carcinoma - high grade: bizzare cells, loss of normal architecture
How is carcinoma in situ of the bladder often diagnosed?
Urine cytology: bladder epithelium is discohesive, so malignant cells are often found in urine.
What is the most common bladder cancer in North America?
Papillary carcinoma (90%)
With what other condition is squamous cell carcinoma of the bladder associated?
Schistosomiasis - transmitted by snails
What is the most common childhood bladder cancer?
What is the most common prostate cancer and its precursor?
Adenoma is most common
Prostatic Intraepithelial Neoplasia precursor
Where does prostatic adenocarcinoma tend to spread?
Where do most prostatic adenocarcinomas arise?
Peripheral zone (>80%)
What is the Gleason System?
Grading system for prostate cancer
Addition of 2 most prominent patterns (grades) observed in tumor
50% of tumors have multiple grades present
What is the most common sarcoma of the prostate?
Rhabdomyosarcoma - most often in children
2 functions that maintain normal plasma potassium concentration
distribution between ICF and ECF
excretion of potassium added to ECF via dietary intake
How do hyper- and hypokalemia affect resting membrane potential of cells?
hyperkalemia: hypopolarization -> suppression of Na channel activity (cardiac myocytes), shortened repolarization time
hypokalemia: hyperpolarization -> enhanced Na channel activity (cardiac myocytes), arrhythmia risk, prolonged repolarization
relationship of membrane potential to EC and IC [K+]
Em inversely proportional to -[K+]c/[K+]e
What is the effect of catecholamines on [K+]?
Catecholamines directly enhance Na/K ATPase activity -> hyperpolarization
B2 activation: increases cellular K+ uptake (esp. sk. muscle and liver) -> lower serum [K+]
**non-specific B-blockers (propanolol) impair K+ uptake -> increased serum [K+]
Alpha activation: impairs K+ cellular uptake and blocks insulin release
Effect of insulin in K+ balance
Reduces serum [K+]
Promotes skeletal muscle K+ uptake (via Na/K ATPase)
Liver: stimulation of Na/H exchanger -> elevated IC [Na+] -> increased activity of Na/K ATPase
**Insulin + glucose used to treat hyperkalemia**
How does aldosterone affect K+ levels?
Decreases serum [K+]
Principal cell of collecting duct: increased Na/K ATPase -> K+ excretion
aldosterone -> metabolic alkalosis -> cellular K+ uptake
What is the effect of exercise on serum [K+]?
Increases serum [K+]
increased ADP -> opening of ADP sensitive K+ channels -> local [K+] increase -> vasodilation and increased bf.
3 pathologic factors influencing K+ balance
pH: metabolic acidosis caused by mineral acids -> increased serum [K+]. organic and respiratory acidosis to a lesser extent
osmolality: hyperosmolality -> cellular water loss and increased IC [K+] -> passive effux. also, osmotic drag -> decreased IC [K+]
cell breakdown/ proliferation: BD -> increased EC [K+]; prolif -> decreased EC [K+]
How much K+ is filtered by the glomerulus daily? How much is excreted?
600-700mEq filtered daily
10% of that is excreted, the rest reabsorbed.
Renal Outer Medullary K+ channels
Found in TALH. Secrete K+ in exchange for NaCl reabsorption
Where is most K+ reabsorbed?
TALH by NaKCC
Describe K+ handling in the collecting duct
Principal cell: ROMK: K+ secretion if high tubular [Na]
Intercalated cell: K+/H+ ATPase: activity increased when interstitial (systemic) K+ is low -> reabsorption. activity decreased w/ elevated systemic K+
What is a WNK and how does it affect K+ levels?
With No Lysine (K) Kinase
-> internalization of ROMK in distal nephron -> decreased K+ secretion.
activated in low K+ state
What defines hypokalemia?
serum [K+] <3.5mEq/L
What defines hyperkalemia?
serum [K+] >5.1mEq/L
3 syndromes that can -> hypokalemia
Liddle: ENaC constitutively open
Barter: defective NKCC
Gitleman: defective NaCl cotransporter
How can antibiotics (penicillin) -> hypokalemia?
excreted as anions that increase K+ excretion
How can one differentiate between renal / extra renal K+ losses in a hypokalemic patient via 24 hr. urine collection?
25mEq/day K+ excreted = renal cause
What is psuedohyperkalemia?
apparent hyperkalemia due to K+ efflux from cells during / after blood draw. Lab artifact.
due to mechanical trauma, hemolysis
elevated WBC or platelet count.
How can penicillin -> hyperkalemia
anion paired w/ K+ as cation
EKG changes in hypokalemia
decreased T wave amplitude (serum [K+] <2, T may disappear)
increased U wave amplitude
P wave amplification
What EKG changes are seen w/ hyperkalemia?
elevated T wave
QRS widening (severe)
Vtach -> Vfib
Interventions for hyperkalemia
Calcium Gluconate: stabilizes cardiomyocyte membrane - rapid effect (1-2 min)
Insulin + glucose: rapid: 5-10 min w/ peak 30-60 min
NaHCO3: increased cellular K+ uptake
Albuterol (B2 agonist): ~30 min for onset
Kayexalate: remove K+ from body: 60 min onset
Dialysis: remove K+ rom body: 25-30 mEq/hour romoval, most efficient in 1st hr.
what characterizes nephrotic syndrome?
Proteinuria >3.5g / day
increased risk of infections and thromboembolic complications
3 causes of nephrotic syndrome
Minimal Change Disease
Focal Segmental Glomerulosclerosis
What is the difference between primary and secondary membranous glomerulonephropathy?
Primary: idiopathic autoimmune disorder - Ab against normal renal Ag (PLP A2 receptor on foot processes)
Secondary: meds (captopril, lithium), chronic infection (HepB+C, syph), malignancy (lung, breast, colon ca), autoimmune (SLE, autoimmune thyroiditis
Prognosis / treatment for primary / secondary membranous glomerulonephritis
Primary: usually unresponsive to corticosteroids - slowly progressive
Secondary: varies depending on inciting Ag
Characteristics of Minimal Change Disease
Nephrotic syndrome - selective proteinuria (albumin) - mostly children, may be post immunization or resp. infection.
Primary disease or secondary to NSAID, lymphoproliferation (Hodgkin's Lymphoma)
Poorly understood immunologic connection - assoc. w/ hx of allergic rxn
Podocyte foot process effacement seen on TEM (LM and DIF normal)
Minimal change disease prognosis
Good response to corticosteroids
What conditions is Focal Segmental Glomerulosclerosis associated with?
HIV (esp black males)
3 forms of FSGS
Primary: idopathic. extension of MCD?
Secondary: loss of functional renal tissue (w/ compensation by functional areas), IgA nephropathy. Assoc. w/ HIV and heroin
Inherited: usually mutation in gene coding for slit membrane related proteins (esp. podocin: anchors actin intracellularly)
What FSGS variant is especially associated w/ HIV?
collapsed glomeruli, enlarged visceral epithelial cells, dilated tubules
Endothelial cell Tubuloreticular inclusions (IFN-a modified ER)
azotemia (high BUN due to low GFR)
2 causes of nephritic syndrome
postinfectious glomerulonephritis (post strep)
acute proliferative glomerulonephritis (SLE assoc)
How do etiologies behind MPGN types I and II differ?
I: glomerular immune complex formation -> classical and alternative complement pathway activation
II: autoantibody (C3 nephritic factor - C3NeF) stabilizes C3bBb (alternative C3 convertase) and stabilizes -> constitutively active alternative pathway
What are some secondary causes of MPGN type I?
autoimmune disorders (SLE)
chronic infections (bacterial, viral, parasitic)
dysregulation of complement
What deposits are seen in types I and II MPGN?
Type I: IgG, C3,1q, 4 deposited in capillary loops and mesangium
TEM: subendothelial deposits w/ mesangial interposition
Type II: C3 in GBM and mesangium
TEM: Very electron dense material w/in lamina densa of GBM
Is kidney transplant a cure for MPGN?
high frequency of recurrence post-transplant
What does the GBM look like in RPGN (TEM)?
"wrinkled" convoluted with focal discontinuities
What are three groupings of RPGN?
Type I: anti-GBM (antibody to non-collagenous portion of type IV collagen) IgG deposits in GBM (linear staining by DIF)
Type II: immune complex mediated (postinfectious GN, SLE, IgA nephropathy) granular staining by DIF
Type II: pauci-immune. usually ANCA positive, may be associated w/ systemic vasculitis.
What is the difference in treatments for the 3 subtypes of RPGN?
Type I: plasmapheresis (remove IgG) and immunosuppression
Type II: treat underlying disease
Type III: immunosuppression
What is the most common glomerular disease worldwide?
IgA nephropathy (Berger Disease) - esp. SE Asia
persistent microhematuria, intermittent macrohematuria
Usually older children and young adults w/in days of mucosal infection
What is Berger Disease?
Disease of the mucosal immune system
Susceptible individuals produce excess IgA in setting of resp. infection or celiac, or decreased IgA clearance
Increased serum polymerization -> deposit in mesangium and activation of alternative complement.
What is Alport Syndrome?
X-linked hereditary nephritis
Defect in a-chain of type IV collagen -> defective assembly and dysfunction of GBM, cochlea, and ocular structures
2 diseases involving type IV collagen
Rapidly Progressive Glomerulonephritis (Type I): anti GBM Ab
Alport Syndrome: a-chain abnormality -> defective collagen assembly
What is Henoch-Schonlein Purpura?
Form of IgA nephropathy w/ systemic vasculitis
Most commonly in children post resp. infection
Purpuric rash, usually lower extremities, arthralgias, possible GI bleeding
good prognosis in children
Classes of renal disease seen in SLE
Class I: no changes
Class II: mesangial expansion
Class III: focal proliferative glomerulonephritis
Class IV: Most Common: diffuse proliferative glomerulonephritis - most gloms involved.
Class V: Nephrotic: membranous glomerulonephropathy
What are glomerular wire loops indicative of?
Glomerular capillary wall thickening seen in SLE glomerulonephritis (class V)
What deposits are present in SLE glomerulonephritis?
subepithelial: class V
subendothelial: class III and IV
Immune complexes also may be present in tubulointerstitium
What characterizes acute renal failure?
3 categories of ARF
Pre-renal: inadequate perfusion of kidney
Post-renal: obstruction of urine flow, usually bilateral
Renal: process affecting any kidney compartment
2 factors on which acute kidney injury is reliant
tubular injury: ischemia or drugs. ischemia -> low ATP, increased Ca2+, reactive O2, apoptotic enzyme activation (caspases), cytokine production
persistent, severe disturbance in blood flow: vasoconstriction -> reduced GFR
role of cell polarity in AKI
ischemia -> loss of brush border and cell polarity (reversible cellular injury)
redistrubution of Na/K ATPase to apical membrane -> increased Na transport to lumen, reased tubuloglomerular feedback and activation of Renin-Angiotensin-Aldosterone system
In the case of AKI (acute tubular necrosis) what determines potential for tubular regeneration?
Tubular basement membrane coherence
if membrane is intact, cells can regenerate
What is acute pyelonephritis?
Infection of renal parenchyma
Organisms most commonly assoc. w/ UTI
E. coli, enterobacter, enterococcus, Proteus, Klebsiella
Who is most susceptible to UTIs by age /sex?
50: men - BPH
3 factors that contribute to vesico-ureteral reflux
1. absence of intra-vesicular ureter (ureter enters perpendicular rather than at an angle -> decreased sphincter action w/ bladder contraction)
2. congenital para-ureteral diverticulum
3. inflammation of bladder wall
What are 2 non-bacterial causes of pyelonephritis and who is at risk
fungus, esp. Candida albicans: immunosuppressed and diabetic
CMV: transplant recipients
3 complications of acute pyelonephritis
Pyonephrosis: complete obstruction -> filling of renal pelvis, calyces and ureter with pus
Perinephric abscess: infection penetrates renal capsule
Necrotizing papillitis: renal papillae necrosis, may slough into pelvis -> additional obstruction. involves 1) infection 2) obstruction 3) compromised blood flow (DM, Sickle Cell)
What is acute tubulo-interstitial nephritis?
Inflammation of interstitium of kidney affecting tubules
May -> ARF
-patients have hx of hypersensitivity
-immune complexes present in tubular basement membrane
-anti-tubular basement Ab have been found
-Tcell damage has been implicated
What is the most common cause of Acute Tubulo-interstitial nephritis?
-Beta lactams (penicillin, methicillin, ampicillin)
What infections are associated with ATIN?
Not due to infectious organisms - deposition of Ag in interstitium -> response
What is normal GFR in adult men and women?
What is the Crockoft-Gault equation for estimation of creatinine clearance?
Creatinine clearance = [(140-age)(weight (kg))]/72* serum creatinine (mg/dL)
multiply by 0.85 if female
What criteria does the MDRD GFR equation include?
Age, sex, race, plasma creatinine, BUN, albumin
What is the advantage of the CKD-EPI compared to MDRD?
more accurate for GFR over 60 ml/min/1.73m2
Clinical picture of acute glomerulonephritis
Rapid course: worsening renal function over hours - days
RBCs, RBC casts, HTN, oliguria, edema, CHF
Causes: post infect, multisystem disease, primary
What tests should be ordered for a pt. with RPGN?
Hep C Ab
2 theories to explain edema in nephrotic syndrome
Underfill: hypoalbuminemia -> reduced oncotic pressure and fluid movement to interstitium (results in arterial underfilling)
Overfill: renal disease -> salt retention -> fluid retention (better explanation)
what is the underlying cause of hyperlipidemia in nephrotic syndrome?
Low oncotic pressure stimulates hepatic production of lipoproteins containing apolipoprotein B100 (VLDL, IDL, LDL) and cholesterol
Diminished catabolism: VLDL -> IDL -> LDL process impaired
4 substances readily reabsorbed in PCT
Na, PO4, HCO3, K
What are osmotic diuretics used for?
Acute renal failure
Dialysis Disequilibrium Syndrome
What effects do CA inhibitors have on urine and blood composition?
Urine: Alkaline: increased HCO3- excretion (25-30% increase)
Normal Anion gap metabolic acidosis
Increased K+ excretion
How do loop diuretics reach their site of action?
Secreted at prox tubule via organic acid pathway and transported to site of action
**potency dependent on urinary concentration of diuretic, not plasma conc.
What are the effects of loop diuretics on blood and urine compositions?
Increase excretion of : Na+, Cl-, K+, Ca++, Mg+
Decrease free H2O clearance
Uric acid: acute use, up; chronic use down
**impairment of concentration and dilution
Loop diuretics are the diuretics of choice for treating what?
Edema in renal failure
What is the mechanism of diuretic induced metabolic alkalosis?
Loop diuretics and Thiazides increase Na+ delivery to collecting duct -> increased ENaC activity (Na reabsorption) and resultant K+ secretion -> K+ deficit
K+ deficit in ICF -> increased activity of H+/K+ exchanger and increased H+ excretion and increased HCO3- absorption
What effect does acetazolamide have on urine pH?
Carbonic anhydrase inhibition -> increased HCO3- in tubular fluid and decreased CO2 liberation
Intracellularly: decreased AC activity -> decreased H+ production and inhibition of Na/H+ exchanger -> more Na stays in urine
What are the major uses of CA inhibitors?
Non-edematous states: Glaucoma
Urine alkalinization: cysteine and uric acid more soluble
Altitude sickness: correct respiratory alkalosis
What is the effect of loop diuretics on vascular tone?
Arterial: no effect
What diuretic class produces the highest peak urine flow?
What part of the nephron is most effected by mannitol?
TDLH: decreased H2O absorption
What is medullary washout?
Increased medullary blood flow (vasa recta) -> loss of concentration gradient -> impaired free water reabsorption
*key to diuresis w/ osmotic diuretics (mannitol)
Aldosterone antagonizing drugs and action
Spironolactone and Eplerenone
Competitive inhibition of aldosterone at collecting tubule, cytoplasmic receptor -> decreased ENaC insertion
**only effective in presence of Aldosterone!
Major side effects of Aldosterone antagonists
Gynecomastia (drugs also bind progesterone and androgen receptors)
What is the overall incidence and risk of death for prostate cancer?
How does smoking influence risk of prostate cancer
What are Hereditary and Familial prostate cancers?
Hereditary: 3 or more men in family or 2 brothers with prostate cancer (suspected dominant gene, but unidentified)
Familial: have a person in the family with prostate cancer
What degrees of relationship are considered in hereditary prostate cancer and what is the risk assoc. with incidence?
Paternal: Grandfather, Father, Uncle, Brother
Maternal: Grandfather, Brother
1 relative: 2.5x greater risk (familial)
2 relatives: 5x greater risk
What dietary components have been linked to prostate cancer?
Saturated fat, red meat, dairy
Dietary fat has been estimated to account for 10% of the difference in incidence between African American and Caucasian men
What are the most common symptoms of prostate cancer?
Weak urine stream
**Most prostate cancers are asymptomatic!!
What are the recommendations for prostate screening?
50 yrs if 10 yrs of life expectancy remaining
45 yrs if black or 1st degree relative w/ PCa
40 if relative w/ early diagnosis or PSA bet 1.0 - 2.5 ng/mL. >2.5, need biopsy
What is the risk of complications in prostate screening?
PSA blood test: 26/10,000 (0.26%): bruising, hematoma, dizziness, fainting
Diagnostics (biopsy): 68/10,000 (0.68%): bleeding, infection, clot formation, urinary difficulty
Treatment: no data
What is the PLCO trial?
US study evaluating Digital Rectal Exam vs. DRE + PSA in detection of prostate cancer. Used as basis for US Preventive Services Task Force recommendation against PSA as screening tool.
Showed no difference between groups
Major contamination!! 51% of DRE control group also received PSA. Also, premature reporting -> bad study
What is the PIVOT trial?
Prostate cancer Intervention Versus Observation Trial
Demonstrated 31% reduced risk of dying from prostate cancer w/ prostatectomy. at 13 years follow-up, expected 40% reduction.
Staging of prostate cancer
T1: small tumor, non-palpable
T2: palpable tumor
T3: local invasion (ex. seminal vessicle)
T4: invasion of bladder, bone, rectum, etc.
T1 and 2 are curable, T4 is not.
Indications for prostate biopsy
1. abnormal DRE
2. PSA >4.0 ng/mL
3. PSA change of >0.75ng/mL/year with baseline 4.0ng/mL
4. PSA >2.5 with multiple affected family members
What patients w/ diagnosis of prostate cancer should proceed with watchful waiting vs. treatment?
patients having <10 yrs life expectancy and low grade, low volume tumors.
What is active surveilance in prostate cancer care?
For pts with:
PSA <50% of any one core
PSA and DRE q 3mo x 2 yrs, then q 6mos. if no changes
10-12 core biopsy at 1 year then every 3-5 years until 80 yoa
What are the pathophysiological components of BPH?
1. increased prostate size (static)
2. increased smooth muscle tone (dynamic): primary cause of symptoms
What is the cause of BPH?
increased sensitivity to 5a-DHT
What is a pharmaceutical option in treatment of BPH?
Second line: Finasteride: inhibits formation of DHT
First line: a1-blockers (prazosin) -> inhibition of smooth muscle contraction
What is metabolic acidosis?
Results from a primary defect in [HCO3-] or [H+]
pH=6.1 + log ([HCO3-]/0.3pCO2)
How does the kidney maintain acid-base balance (2 things)
1. excrete the exact amount of nonvolatile acid produced (~70mmol/day) and replace consumed bicarb
2. reclaim filtered bicarb (~4500 mmol/day)
Total H+ secretion and Net H+ excretion
Total H+ secretion = HCO3 + NH4 + titratable acids
Net H+ excretion = [(U(NH4)x V + U(TA)x V) - (U(HCO3)x V)]
What is the job of a B-intercalated cell? Important protein?
Excretion of HCO3- in condition of metabolic alkalosis
Pendrin: apical transport protein: HCO3- out / Cl- in
V-ATPase: basal H+reabsorption
2 main urinary non-bicarb buffer systems
1. NH3 -> NH4+ (non-resorbable)
2. HPO4-- -> H2PO4-
What is the source of NH4+ in tubular fluid?
Proximal tubule: glutamine -> 2 NH4 (secreted) + 2 HCO3- (absorbed) + a-ketoglutarate
glutaminease and glutamine dehydrogenase
process stimulated by low pH
Outline the path of NH4 excretion
proximal tubule: glutamine -> 2 NH4 (stim by low pH)
TALH: NH4+ reabsorbed, transport to interstitium (via NKCC)
Collecting duct: NH4+ enters cells via basolateral K+ channel or NH3+ enters via basolateral Rhcg and leaves via apical Rhcg, protonated -> NH4+ which is trapped in urine
What is the effect of Aldosterone on urine H+ content?
In Collecting Duct:
a-intercalated cells: direct effect - stimulates H+ secretion via ATPase
Principal cells: indirect effect - enhanced Na+ reabsorption -> increased luminal (-) favors H+ secretion by intercalated cells
What is the difference between acidosis / -emia?
Acidemia / Alkalemia: deviation of pH above or below 7.4
-osis: process that can lead to -emia
How does the change in pCO2 relate to the change in [HCO3-] in metabolic acidosis?
fall in pCO2 = 1.0-1.3 x fall in [HCO3]
What is the cause of increased anion gap acidosis? what about normal anion gap acidosis?
Increased anion gap: production / addition of H+
Normal: addition of HCL or equivalent or primary loss of HCO3-
What is a normal anion gap?
140 - (105+25)
How does albumin level affect anion gap?
for 1 g/dL decrease in albumin add 2.5 to gap
What is urinary anion gap and what is it used for?
-NH4+ = U(Na) + U(K) - U(Cl)
should be 0 or very slightly positive
Normal plasma anion gap acidosis: elevated NH4+ excretion -> more negative urinary anion gap.
If 0 or (+), issue w/ urinary acidification -> Distal Renal Tubular Acidification (type I)
What are types I and II renal tubular acidosis?
Type I RTA: distal tubule H+ secretion defect (urinary pH > 5.5 w/ very low plasma [HCO3]
Type II RTA: proximal tubule H+ secretion defect and decrease in reclaiming filtered HCO3- (urinary pH <15)
What are some causes of Types I and II RTA?
I: ampho B, tonfovir, medullary sponge kidney, obstruction, H+ ATPase mutation
II: cystinosis, Fanconi, carbonic anhydrase inhibitors
4 causes of metabolic acidosis with increased anion gap
addition of ketoacids (DM, alcoholic ketosis (isopropyl), starvation)
renal failure (decreased net acid excretion)
ingestion (salicylate OD, MeOH, ethylene glycol, metformin)
What is the cause of metabolic alkalosis?
loss of H+
loss of Cl- in gradient greater than ECF
What is oliguria vs. anuria (volumes)
Oliguria < 50mL / 24hr
RIFLE criteria for ARF
Risk: GFR reduced 25%, SCr elevated 1.5x, urine output 4wks
esrd: complete loss of function >3mos
Is RIFLE criteria frequently used clinically?
No - complex urine calculations, baseline Creatinine needed
Signs of acute kidney injury
accumulation of nitrogenous waste (uremia)
increased serum creatinine
deranged ECF balance
electrolyte/ mineral disorders
What is the most prevalent etiology of Acute Kidney Injury (outpatient and in-hospital)?
Outpatient: Pre-renal (decreased renal perfusion)
In hospital: Acute Tubular Necrosis (renal)
What drugs can produce pre-renal AKI?
NSAID, ACEi, ARB, direct renin inhibitor, Cyclosporine, Tacrolimus
treatment of pre-renal AKI
Volume expansion (normal saline)
Address underlying issue: stop drugs, correct BP
Drugs associated with Acute interstitial necrosis
What is Hansel stain?
used for eosionophils in urine
What is hydronephrosis?
Dilation of the urinary tract
What is FENa?
Fraction of excreted Na
Urine Na x plasma Cr / Plasma Na x Urine Cr
If <1%: classic for pre-renal ATN, though not always the case
In a patient with pre-renal failure, what can produce an elevated FENa?
What are non-pre-renal causes of low FENa
radiocontrast injury and rhabdomyolysis
Define Acute kidney injury
Decline in kidney function over 48 hrs as reflected by:
Increase in serum Cr by more than 0.3 mg/dL
Increase in Cr by more than 50% from baseline
Development of Oliguria
What are the most common causes of death associated with acute renal failure?
Features of pre-renal kidney injury
Treat cause, return to normal function
Tubular function remains intact
may -> ATN
General causes of renal AKI
Tubular (Toxin, pigment, ischemic)
What is the difference between TTP and HUS and what kind of kidney injury do they contribute to?
TTP: caused by defect in ADAMTS13 -> vWF multimers -> excessive platelet agggregation
HUS: usually caused by E.coli O157:H7 (shiga-like toxin) -> endothelial injury and platelet aggregatin. Also caused by excessive complement activation
Both are renal causes of AKI
key indications of acute interstitial nephritis
often associated w/ antimicrobials
Allergic response (eosinophils in urine - hansel stain)
Often skin involvement
Signs of post-renal injury
hesitancy and frequency (including nocturnal) of urination
What volume of blood is typically filtered by the kidneys daily? How much of that is excreted as urine?
150-180 L/day (~100 mL/minute)
Urine: 1-2% of filtered volume (usually 1-2L / day)
3 drugs that alter tubular secretion of creatinine
All inhibit creatinine secretion -> falsely elevated GFR calculation
What is Cystatin C?
Protease inhibitor produced by all nucleated cells (constant rate of production)
Freely filtered and not reabsorbed, but metabolized by tubules
Serum test for GFR calculation - not yet widely used
What is normal GFR range?
varies by age, gender, race
What is the definition of Chronic Kidney Disease?
1. Kidney damage for >/= 3 mos (structural or functional abnormality of kidney) w/ or w/o decreased GFR manifest by either
-markers of kidney damage
2. GFR /= 3mos w/ or w/o kidney damage
In the staging of kidney disease, what marks kidney failure?
GFR <15 (G5)
At what point in kidney disease does all cause mortality and CV events begin to increase?
What are the greatest causes of CKD?
Diabetes and HTN
What is isothenuria?
Inability of kidney to concentrate and dilute urine (as in CKD)
How is salt and water overload managed in CKD?
Limit salt intake: <2g/day
Limit fluid intake: 1-1.5 L/day
Diuretics: Loop, high dose (40-120mg/day, dose 2-3x/day)
Add Metolazone (thiazide like)
How much acid is normally produced by the body / day? How much excreted?
12,000 mEq/day w/ ~60 mEq excreted
Carbs and fats -> CO2 and H2O -> lung
Protein -> SO4, PhO4, nitric acid
At what point in CKD is acidosis accompanied by increased anion gap?
Advanced CKD (G5)
due to retention of anions
What is the value of treating metabolic acidosis with oral bicarb in patients w/ CKD?
Slows progression of CKD (reduced NH4 production -> decreased inflammation)
Slows/ prevents bone disease
Prevents muscle breakdown (improved nutritional status and preserves lean mass)
At what point of CKD does K+ level become problematic?
Late stage - GFR HYPERKALEMIA
Are diabetics at risk for hyper or hypo kalemia?
Diabetics have reduced renin secretion -> reduced aldosterone and potential for inadequate excretion, esp. w/ CKD (may manifest in early CKD)
What drugs can produce hyperkalemia?
Aldosterone altering drugs: ACEi/ARB, spironolactone, heparin
Na+ channel altering drugs: triamterene, amiloride, pentamidine
drugs that directly alter K+ handling: Digoxin, non-selective B-blocker, NSAID
How is hyperkalemia treated in CKD patients?
Limit K+ intake
Stop K+ elevating drugs
Use Loop diuretics
Kayexalate (resin picks up K+ in exchange for Na+)
What is the effect of CKD on phosphorus, calcium, and PTH status?
CKD -> reduced GFR and increased PO4 levels and decreased Ca++ levels-> chronically elevated PTH to maintain balance
What is renal osteodystrophy?
Bone disease resulting from chronically elevated PTH seen in CKD
What is osteitis fibrosa cystica?
Disease of bone reabsorption due to excess PTH
May occur in CKD
What hormones are decreased in CKD?
EPO -> anemia
Vit D3 -> osteomalacia, OFC
Somatomedin -> decreased growth in children
What happens with insulin in CKD?
Filtered by glomerulus and absorbed / metabolized by PCT
In CKD this -> elevated insulin -> resistance
What hormones are elevated in CKD?
What drugs have been shown to slow progression of kidney disease in Types I and II diabetics?
Type I: ACEi and intensive BS control
Type II: ARB
When is dialysis a consideration in CKD?
Diabetic: GFR <10
What is the most common early manifestation of Diabetic Nephropathy?
Proteinuria: Microalbuminuria with progressive loss of protein over time
What is the pathogenesis of Diabetic Nephropathy?
AGEs -> disturbance of formation / degradation of ECM -> ECM excess -> mesangial expansion -> obliteration of capillary lumen surface area
TGF-B implicated: stimulates ECM formation and inhibits degradation
When is biopsy warranted in DN?
1. Early onset renal disease: w/in 10 years of becoming T1 Diabetic
2. Development of proteinuria absent significant retinal changes
3. Atypical features: hematuria, accelerated renal impairment
What are Kimmelstiel-Wilson nodules?
Nodular mesantial expansion seen in diabetic nephropathy
pink, hyaline, hypocellular
What is Bence-Jones proteinuria and what is it associated with?
Ig light chain (usually lambda) in urine
May be associated w/ Multiple Myeloma (plasma cell proliferation)
May deposit as amyloid (AL - primary amyloidosis)
What conditions are associated with secondary amyloidosis?
RA, connective tissue disease, TB, osteomyelitis
AA (improperly processed SAA (acute phase)) amyloid
Where does amyloid deposit w/in the kidney?
First (typically) in mesangium (looks like DN - distinguish by DIF)
Later on and w/in GBM -> dysfunction: protein loss, decreased filtration
What is myeloma cast nephropathy and what does it look like?
May occur in Multiple Myeloma
Ig light chains interact w/ Tamm-Horsfall protein -> occlusive casts w/in tubules
Pink, expanded tubule lumen w/ cracked appearance
What is involved in treatment of Myeloma Cast Nephropathy?
Treat underlying MM with chemo and steroids -> reduction in lt. chain production
Reduce lt. chain aggretation: increase free water intake, alkalinize urine, avoid additional nephrotoxic insult (radiocontrast)
What is the most common cause of acute renal failure in infants and young children?
Hemolytic Uremic Syndrome
What is the cause of TTP and how does it affect the kidney?
ADAMTS13 deficiency -> vWF multimer formation and platelet aggregation
Clot formation in renal vasculature -> hematuria, proteinuria, azotemia,
What is mesangiolysis and with what is it associated?
Apparent focal dissolution of the mesangial matrix
Associated with Thrombotic Microangiopathies
What genes are implicated in Adult Polycystic Kidney Disease?
What is the pathogenesis of ADPCKD?
Defect in PKD1 or 2 -> same manifestation (products probably linked)
Altered mechanosensation, Ca++ flux, cell-cell and cell-matrix interactions -> abnormal ECM, cell proliferation, fluid secretin -> cyst formation -> inflammation, fibrosis, insufficiency and failure
What gene is defective in autosomal recessive polycystic kidney disease?
PKHD1 on chromosome 6 (6p21.1)
How does the recessive form of PKD differ from the dominant?
In dominant, cysts develop from any portion of nephron
In recessive, from collecting duct only -> dilated tubules and compressed normal structures
Dominant presents at ~35 yoa while recessive presents early in life, usually by 1 year and necessitates renal transplant.
Recessive usually also presents w/ congenital hepatic fibrosis
What is Fanconi's syndrome?
Transport dysfunction in proximal tubule (defective energy metabolism?)
Presents with: hypophosphatemia, polyuria polydipsia dehydration, rickets (children, vitamin D resistant), osteomalacia (adults), growth failure, hypokalemia
May be congenital or acquired
What is hydronephrosis?
product of sustained urinary obstruction
-> dilation of renal pelvis and calyces with cortical atrophy
obstruction triggers interstitial inflammatory reaction -> fibrosis
4 types of renal calculi and associated factors
Calcium Oxalate: Hypercalcemia/uria, hyper PTH, sarcoidosis - radio opaque
Magnesium ammonium sulfate: Post infection w/ urea splitting bacteria (Proteus, some staph). Alkaline urine -> precipitation of staghorm calculi
Uric Acid: Gout, leukemia -> hyperuricemia. pH UA precip - radiolucent
Cystine: Genetic deficiency of AA reabsorption. stones at low pH
3 forms of Ca++ in the body and which is physiologically important
Ionized (50%) - physiologically important
Albumin bound (40%)
Complexed w/ anions (10%)
How does pH affect Ca++ balance?
Acidosis: excess H+ -> displacement of Ca++ from proteins and anions -> hypercalcemia
Alkalosis: H+ deficit -> increase in bound Ca++
3 hormones that regulate Calcium and net effect of each
PTH: increase serum Ca++, increase phosphate excretion
Calcitriol: increase Ca++ and phosphate
Calcitonin: decrease plasma Ca++, little effect on phosphate
How is calcium reabsorbed at different parts of the nephron?
PCT: 90% paracellular, passive. Increased Na+ reabsorption -> increased Ca++ reabsorption.
10% transcellularly: Ca++ permeable channels and basal transport by Ca ATPase and 3Na / Ca++ exchanger
TAL: 50% paracellular: secondary to activity of NaKCC. increased Na reabsorption -> increased K secretion -> drives Ca++ reabsorption
50% transcellularly: same as PCT
DCT/CT: 100% transcellularly: TRPV5 - regulated by PTH and VitD
What are claudin 16 and 19?
Tight junction proteins in TALH that allow paracellular reabsorption of Ca++
Mutation -> increased Ca++ excretion
Role of Ca++ sensing receptor in TALH
Increased serum Ca++ -> inhibition of apical K+ channel -> increased Ca++ excretion
What is TRPV5?
Ca++ channel in DCT / CT
Under control of PTH, and Vit D3
Saline (high salt) and loop diuretic
High salt inhibits PCT Na+ reabsorption and Ca++ reabsorption
Loop diuretic decreases K+ secretion and Ca++ reabsorption
Why might HCTZ be used to treat calcium stones?
Inhibition of Na++ reabsorption at DCT / CT -> stimulated Ca++ reabsorption, decreased Ca++ in urine
4 causes for increased Ca++ mobilization from bone
1. hyperparathyroidism: adenoma, hyperplasia, carcinoma (rare)
2. malignancy: a) local osteolytic hypercalcemia b) humoral hypercalcemia of malignancy (PTHrP)
4. Vitamin D intoxication
What is humoral hypercalcemia of malignancy?
Tumor secretes bone reabsorbing agent: PTHrP - not detected by PTH assay
Usually associated with sq. carcinoma of lung, head, neck, esophageal, renal, bladder, or ovary.
What is familial hypocalciuric hypercalcemia?
Defect in Ca++ sensing receptor -> failure of elevated Ca++ to suppress PTH
Elevated PTH -> enhanced Ca++ reabsorption by TALH and DT -> hypocalciuria
Acute management for hypercalcemia
Volume restoration: normal saline
loop (not thiazide) diuretics
chronic management: treat underlying cause
What is pseudohypoparathyroidism?
Bone does not respond to PTH -> decreased remodelling -> short stature, short metacarpals, hypocalcemia
Clinical signs of hypocalcemia
Neuromuscular irritability -> paraesthesias and tetany
Trousseau's sign: carpal spasm w/ BP cuff inflated above systolic BP for 3 min
Chovstek's sign: twitching of facial muscles when facial nerve tapped anterior to ear
Indicators of drug induced nephrotoxicity
1. SCr increase of 0.5 mg/dL if baseline 2
3. corellated with initiation of drug therapy
What is KIM-1?
Kidney Injury Molecule 1
Elevated with Proximal Tubular injury
3 symptoms of distal tubule injury
Polyuria: fail to maximally concentrate urine
Metabolic Acidosis: failure to acidify urine
Hyperkalemia: impaired K+ excretion
3 transporters involved in renal drug metabolism
OAT-1: Organic anion transporter
OCT-1: Organic cation transporter
Proximal tubule: active transport concentrates drugs in urine may lead to cytotoxicity.
By what mechanism can ACEi and ARB produced Drug Induced Nephrotoxicity and what patients are at risk?
blockade of Angiotensin II -> efferent arteriole dilation -> decreased GFR
Patients w/ bilateral renal artery stenosis, diabetic nephropathy, any condition producing low RBF
How can Hemodynamic Drug Induced Nephropathy be identified clinically?
following initiation of ACEi / ARB
SCr increase >30%
BUN/Scr ratio >20
proteinuria, hyaline casts
In a patient with HF and suspected Hemodynamic DIN, what is an appropriate replacement therapy?
Caused by ACEi / ARB
Replace w/ hydralazine and nitrate
How can NSAIDs -> hemodynamic DIN?
COX inhibition -> decreased prostaglandins -> inability to dilate afferent arteriole
What NSAID is less likely to produce in DIN in high risk patients?
Sulindac - possibly due to renal P450 metabolism
except in patients w/ hepatic disease
Risk factors for DIN w/ NSAID use
high plasma renin conditions: hepatic disease w/ ascites, SLE, volume depletion
diuretic use / hypoperfusion
What drugs are known for producing ATN?
What is the mechanism of amphotericin nephrotoxicity?
Related to cationic charge
Transported into lysosomes, inhibits function/ synthesis of cathepsin B and L (protolytic enzymes)
Inceased formation of superoxide and H2O2 -> oxidative stress
Proteinuria containing B2 microglobulin is a symptom of ATN caused by what drug?
What is the mechanism of Amphotericin B's nephrotoxicity?
Direct toxicity to Distal tubule
Increased permeability and necrosis
Reduced perfusion and ischemic injury
What can be done to prevent Amphotericin B nephrotoxicity?
Avoid other nephrotoxic drugs (cyclosporine)
High salt diet w/ 1L saline / day
What is the most common drug induced nephrotoxicity?
What drugs have been known to cause Acute Allergic Interstitial Nephritis?
B-lactams, rifampin, NSAIDs
What is the mechanism of Acute Allergic Interstitial Nephritis?
Drug binds to tubular basement membrane, acts as a hapten inducing antibody reaction
Antibody response in circulation, complex deposition in tubular interstitium
What drugs have been linked to chronic interstitial nephritis?
Analgesics: leading cause of papillary necrosis
Clinical presentation of lithium induced chronic interstitial nephritis
Insidious onset over the course of years. Mild reduction in CrCl (>50ml/min)
Proteinuria, RBC, WBC, and granular casts
What is the mechanism of Lithium nephrotoxicity?
decline in intracellular cAMP
defect in H2O transport in cortical CD
What preventive measures can be taken to prevent contrast induced nephrotoxicity?
Low osmolality ionic and non-ionic contrasts
Hydration w/ saline or NaHCO3 isotonic solution pre- and post-admin. (HCO3: alkaline environment -> decreased ROS formation)
Alt. procedure (MRI, US)