Assessment 12 Renal Professor Hints
1/25/11
Glomerular ds/mech of glomerular injury: distinguish between clinical presentations of nephritic and
nephrotic syndromes, mechanisms of immune-mediated and non-immune mediated glomerular injury
Nephrotic Syndrome
 Edema
 Proteinuria
 Hypoalbuminemia
 Hyperlipidemia
 Inactive Urinary Sediment
Abnormal filter without
inflammation
Podocyte Injury, subepithelial space
immune complex formation,
amyloidosis, etc.
Symptoms
Etiology
Mechanism
Nephritic Syndrome
 Dysmorphic RBC’s in
urine
 RBC Casts
 Active Urinary Sediment
Abnormal filter with inflammation
Subendothelial space or mesangial
immune complex deposition,
antibodies against GBM, ANCA,
etc.
Example
MCD, FSGS, Membranous , etc.
Post Streptococcal GN, Berger’s ds,
MPGN, etc.
Why subepithelial in nephrotic? Can’t access neutrophils, macrophages etc. in the blood for inflammation.
Note: The edema in nephrotic syndrome is due to enhanced salt water retention in the tubules, there has to be an
increase in TBW in order to have edema while maintaining BP. Yes decreased oncotic pressure helps out also but is
not the main cause, he says students miss this every year.
Clinical syndromes: distinguish amongst various causes of renal disease – nephritic, nephrotic, vascular, etc.
Disease
RPGN
(Nephritic)
PostStreptococcal
GN
(Nephritic)
Symptoms
Hematuria w/ RBC
casts, variable
oliguria, variable
proteinuria
Supepithelial
deposits,
hypercellularity
Associated with GAS
pharyngitis
Decreased C3 ,
elevated ASO titer or
Anti-DNaseB titer
Membranous
Nephropathy
(Nephrotic)
H&E Light Microscope
Immunoflourescence
EM
Granular deposition of C3
and IgG
Subepithelial deposits
Granular deposition of
IgG, C3
Subepithelial deposits
Hypercellularity,
proliferative pattern
Can be caused by
DISC (drugs,
infection, SLE,
cancer)
Assessment 12 Renal Professor Hints
MPGN I
1/25/11
Tram tracking
IgG, C3 deposits
Hypercellularity
Mixed
proliferative/membra
ne damage ds.
Can be associated
with HCV, HBV
MPGN II
Dense deposit ds.
Low C3 levels
“nephritic factor”
C3 but no IgG
deposition
IgA
Nephropathy
(Bergers ds.)
Can follow URI,
colds, etc.
Increased GBM
thickening and
cellularity
Granular deposition of C3
and IgG
Double contours, tram
tracking
Subendothelial deposits
Most common GN
worldwide
Mesangoproliferative
pattern of injury
Mesangial IgA deposits
Goodpastures
Can be associated
with henoch
schonlein purpura
(IgA complex
vasculitis), cirrhosis,
celiac ds. Etc.
Hempotysis,
Hematuria, etc.
Mesangial IgA and C3
deposits
Ab to α-3 chain of
Type IV collagen
Linear form on IF
Linear Linear Linear
Linear !
Assessment 12 Renal Professor Hints
Alport’s
1/25/11
Defect in α-5 chain of
Type IV collagen
Cataracts, hearing
problems, glomerulus
problems (defective
collagen type IV)
Compare
Thin BM with a
basket weave
appearance
Pauci –
Immune
PANinfarcts, RBC
cast, etc.
Small vessel
vasculitiscrescentic
GN
Negative
immunofluorescence
studies
C-ANCA: Wegener’s
P-ANCA:
Microscopic
polyangitis
Thrombotic
Microangiopa
thies
Wegeners: UR
symptoms,
hemoptysis, CANCA, etc.
HUS, TMA
HUS—E. Coli O157
TMA—could be due
to genetic defect (i.e.
vWF)
TMA
RPGN
Crescents
Very severe renal ds.
Many of the above
scenarios can
progress into this
Fibrin deposition
Note: Subepithelial immune complexes are smaller than subendothelial (size barrier of GBM)
Assessment 12 Renal Professor Hints
1/25/11
Tubulointerstitial nephritis: distinguish among clinical presentations – know causes, specific drugs involved
ATN
Chronic TIN
Drug-induced acute renal failure
allergic tubulointerstitial
nephritis
nephrotoxic tubular injury
Acute bacterial pyelonephritis
Metabolic disorders
hypercalcemia
hyperuricosuria
Environmental factors
Penicillins, Cephalosporinss,
Sulfonamides, Vancomycin all can lead
to ATN
Increased interstitial volume due to
mononuclear infiltrate, tubular injury
characterized by tubular basement
membrane necrosis and disruption
Interstitial fibrosis with less prominence of
cellular infiltrates
Analgesic Abuse
Nephropathy
Phenacetin, etc.
Decreased vascularity due to reduced
volume of capillaries
Tubular atrophy
Secondary glomerulosclerosis
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Renal glucosuria and amino
aciduria
Hypophosphatemia
Hyperchloremic acidosis
Hypokalemia
Hyperkalemia
Reduced urine concentrating
ability
Sodium wasting
Pyuria and urine epithelial cells
Clinical features:
Slow progressive
impairment of renal
function
Tubular dysfunction
characterized by the
development of
hyperkalemic,
hyperchloremic renal
tubular acidosis and
nephrogenic diabetes
insipidus
Impairment of sodium
reabsorption
Compare this to the acute biopsy (left)
•
•
May progress to the
development of papillary
necrosis
Clinical manifestations (when
induced by drugs): fever,
rash, eosinophilia, oliguric or
non-oliguric renal failure
Urinary findings: hematuria
(microscopic or gross),
pyuria, proteinuria,
eosinophiluria
Pyelonephritis: tubulointerstitial nephritis with pelvis and calyceal involvement
Acute - usually suppurative inflammation involving pelvi-calyceal system and parenchyma
Chronic - involvement of pelvi-calyceal system and parenchyma with prominent scarring
Assessment 12 Renal Professor Hints
1/25/11
Calcium and phosphate disturbances in renal failure: know effects on PTH, vit D metabolism, pathophys;
know clinical features of calciphylaxis; know tx of hyperphos
Remember: Serum calcium is regulated between 8.7-10.2mg/dL , Phosphate usually maintained from 2.5 – 4.5
mg/dL.
As the kidney fails there is a disproportionate increase in phosphate (since the proximal tubules are now
dysfunctional and can’t secrete as much P). As phosphate increases vitamin D decreases and PTH rises. (Recall the
primary objective of Vitamin D is phosphate and calcium reabsorption, whereas the primary action of PTH is to
increase serum calcium and decrease serum phosphate). Therefore, in chronic renal failure expect LOW vitamin D
levels and HIGH PTH levels.
Vitamin D cycle:
Sunlight converts 7-dehydrocholesterol to cholecalciferol (vitamin D3) which is hydroxylated by Cyp27 liver
enzymes (microsomes in mt.) to form calcidiol (25-hydroxy Vitamin D), this is then hydroxylated by 1-alpha
hydroxylase (CYP1-alpha) in the proximal tubules of the kidney.
25-OH Vitamin D is measured clinically to determine if someone is receiving appropriate amounts.
Recall Vitamin D is a steroid hormone Binds to VD-R which dimerizes w/ RXRpromotersynthesis of
immune stuff, calbindin 28k (intestine), etc.
REMEMBER ↑ PHOSPHORUS (AS IN RENAL FAILURE) CAUSES ↓ IN VITAMIN D AND ↑ IN PTH. P
inhibits 1-alpha hydroxylase and calcitriol inhibits synthesis of PTH (thus increase P decreases calcitriol and
decrease in calcitriol causes increase in PTH—see p.386 slide 2).
FGF23 is increased in renal disease also. FGF23 causes increased P excretion and decreased vitamin D. Why?
Too much phosphate in renal ds. Need to get rid of it, apparently FGF23 is involved in one of these pathways (PTH
also helps).
Due to the ↑↑↑ in PTH there is increased bone turnover (renal osteodystrophy), these leads to METASTATIC
calcificationvascular and nonvascular deposition of calcium ensues.
Calciphylaxis is basically a syndrome of vascular calcification, thrombosis, skin necrosis, etc. seen in renal failure.
The vascular calcification damages endothelial cells in the vasculature leading to atherosclerosis and CAD.
Therefore, patients with end stage renal disease (ESRD) have CARDIOVASCULAR PROBLEMS due to ↑↑↑ P
Assessment 12 Renal Professor Hints
1/25/11
(primary renal failure) decrease vitamin d (1-alpha hydroxylase) and increase PTH (due to high phosphate)
↑↑PTHbone turnover↑↑Serum CaMetastatic CalcificationCalcium deposits in the vasculature.
Treatment of ↑ P:
Diet (poor adherence) restrict soda, legumes, nuts (easier said than done). Phosphate binders acutely can be used.
Dialysis is a possibility.
Phosphate binding agents:
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Aluminum hydroxide, aluminum carbonate
Calcium carbonate (most common)effective binder and calcium supplement, associated w/
hypercalcemia and GI distrubances
Magnesium based (not used)
Aluminum and calcium free binding agent (sevelamer hydrochloride—the best but expensive).
Lanthanum carbonate acts in digestive tract to bind dietary phosphrous released from food -99.9999%
excreted and unabsorbed, someone forgot what significant digits are…
Practice Question: 58 y/o (70kg) white male presents with long standing hypertension and a serum creatinine of 6
mg/dl. He dies 1 month later of an acute anterior MI. What was his most likely cause of death?
Answer: Cardiovascular ds due to metastatic calcification. Since he is 58 years old (140-58) x 70kg / (6mg/dl x 72)
= estimate of GFR of about 13 ml/minThis is ESRD (stage V renal failure), his phosphorous is most likely very
high leading to what was prior discussed about cardiovascular problems and end stage renal failure.
Note: The formula used in class is [(140-age) / (Scr )] x .85 if female, I took into account the wt. variation in the
above problem, on the exam we probably would only have to use the formula w/o age.
REMEMBER CVD AND HIGH PHOSPHATE IN CHRONIC RENAL DS. ARE LINKED.
Chronic kidney disease: distinguish between acute and chronic; glomerular and tubular; inflammatory and
noninflam; know common causes; know clinical features of diabetic nephropathy; know effects of chronic
kidney disease on various organ systems
Acute Kidney Disease
History, etc.
Chronic Kidney Disease
Bone changes
Small Kidneys SHE SAID KNOW THIS FOR TEST
↑PTH
Waxy Casts KNOW FOR EXAM
Glomerular Disease
Heavy Proteinuria
RBC casts are pathognomonic SHE SAID KNOW
THIS FOR TEST
SG > 1.015 suggests glomerular ds.
Tubular Disease
Absence of Heavy Proteinuria
Can’t concentrate or dilute urineUrine is equal to
plasma osmolarity (1.01 SG~300mosm/kg)
Hyperkalemia and metabolic acidosis out of proportion
for the renal insufficiency
Inflammatory
WBC’s in urine (can also have proteinuria)
Eosinophils (allergic nephritis), KNOW THIS
Non-Inflammatory
Proteinuria w/o inflammatory signs (no WBC, etc.)
Assessment 12 Renal Professor Hints
1/25/11
Note: Diabetes is the #1 cause of ESRD in the USA.
Note: Protein restriction may reduce workload of glomeruli in ERSD.
Note: When nephrons are lost the normal ones work overtimedamage and further exacerbation of renal ds.
Hypertension in chronic renal ds. Is volume driven (p.407), essential HTN has normal volume status. Ace inhibitors
have been shown to have a selective advantage in proteinuric diseases.
Diabetic Nephropathy:
Early changes: hyperfiltration, resulting in glomerular capillary hypertension and glomerular hypertrophy. The
first clinical abnormality is microalbuminuria, which over time leads to overt proteinuria reduced GFR and HTN.
Think: There is preferential hyaline arteriosclerosis (non enzymatic glycosylation) of the efferent arteriole in
diabetic patients initially, this leads to an increase in GFR and more protein (albumin) filtered causing
microalbuminuria. This is why ACE-I’s and ARB’s are good in diabetics they relax the efferent arteriole (recall
this has the highest concentration of AT-1 receptors), basically helping to reverse the initial issue (does not reverse
ds. just symptoms).
Diabetes: Think in this order: MicroalbuminuriaProteinuriaIncrease Serum creatinineESRD
At any of these points the patient is more likely to die of CV events than renal events.
Know this Equation : GFR Estimate: (140-age)/ (Serum creatinine) x .85 (if female)
Effects of Renal Failure on Different Body Systems:
Nervous System
Vascular
Cardiac
Endocrine
Anemia
Gastrointestinal
Concentrating ability, encephalopathy (w/ asterixis)
↑urea, peripheral neuropathy
Hypertension (decreased GFR leads to less sodium
filtering, trade off hypothesis)
LV hypertrophy, CHF, Pericarditis (friction rub—etc.)
(uremic fibrinous Pericarditis)
Fasting hypoglycemia (decreased insulin degradation,
decreased GNG, impaired protein/calorie intake)
Due to decreased EPO production, can tx. w/ EPO
however this may increase BP due to anemic
vasodilatory effects being attenuated
Decreased appetite, gastroparesis leading to nausea,
malnutrition
BUN and Serum Cr Concentration
Drug Metabolism
Calcium / Phosphorous Metabolism
Potassium
Bicarbonate
Increase, usual 10:1 ratio is maintained (BUN:Cr), if
ratio> 20:1 think about pre-renal causes of renal failure
Altered due to decreased GFR and decreased excretion
Increased P, dec. Vit. D. increase PTHosteodystrophy,
metastatic calcification
Homeostasis is maintained until the very end stage of
renal ds. (last electrolyte to be disturbed)
Decreased acid secretion ability leads to metabolic
acidosis (think RTA Type I)
Assessment 12 Renal Professor Hints
1/25/11
Urinalysis: interpret urinalysis results
Urinary Concentration:
Specific gravity (number and wt. of solutes in solution determines this), not a marker of concentration when there
are heavy solutes in the urine (Glucose)
Osmolarity is determined by the number of solutes in urine. 1.002 SG = 50-100 mosm/kg, 1.010 SG = 300
mosm/kg, 1.030 = 1200 mosm/kg
Urinary pH:
Normal is 5-6.5, metabolic acidosis <5.3, pH > 7.5- suggests infection with urea splitting bacteria.
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Glycosuria in presence of normal blood glucose implies proximal tubular dysfunction.
Ketones present in DKA, AKA
Bilirubin urine excess tells us about hepatobiliary dysfunction.
Nitrite is absent in normal urine, positive nitrite suggest UTI w/ nitrate reducing gram negative bacteria.
Leukocyte esterase detects increased neutrophils in the urine.
Spot measurements of urine protein/ creatinine estimate a 24h protein collection. (ie. 200 mg protein/ 20
mg creatinine= 10g/day protein)
Remember that the urine protein dipstick is not positive for light chain proteinurea as seen in MM. (+
sulfosalicyclic acid though). Sulfosalicyclic acid test detects all protein in urine
𝑈𝑟𝑖𝑛𝑎𝑟𝑦 𝐴𝑛𝑖𝑜𝑛 𝐺𝑎𝑝 = (𝑁𝑎 + 𝐾)– 𝐶𝑙

Urinary Anion Gap
o Indirect estimate of NH4 in urine
o Clinical labs can’t measure NH4 easily in the urine, therefore labs measure the urinary anion gap
and estimate NH4 indirectly
o Sodium and potassium are the major urinary cations (we must consider potassium in urine, don’t
necessarily have to consider it with plasma anion gap since it has a small plasma concentration)
o Chloride is the major urinary anion
 Not bicarbonate
o Urinary anion gap is about 10 mEq/L normally
 Can vary widely depending on meal states, etc.
o This is useful when you are trying to evaluate normal anion gap metabolic acidosis (usually
hyperchloremic since it’s metabolic acidosis)
Renal Hematuria
Non Renal Hematuria
Dysmorphic RBC sediments
Normal shape RBC’s in sediments
RBC Casts****
No RBC casts
Absence of clots
Clots may be present
Assessment 12 Renal Professor Hints
Causes
WBC Casts
UTI,
pyelonephritis,
allergic interstitial
nephritis, intense
glomerulonephritis
RBC Casts
Nephritic Syndrome
Example
Causes
Example
1/25/11
Waxy Casts
Chronic Renal Failure
Cast KNOW THIS
KNOW THIS KNOW
THIS
Fatty Casts
Nephrotic Syndrome
Formed from tamm
horsfall protein (Cast of
dilated /atrophic tubules
in renal failure.)
Calcium Oxalate
Hypercalcuria,
very common
Cystine
Defects in COLA, etc.
causing cystine
formation and
hexagonal crystals in
urine
Triple Phosphate
Usually due to
bacterial infection
Hyaline Casts
Normal Cast
Do you see
anything?
Uric Acid
Gout, leukemia/
chemotherapy, etc.
Assessment 12 Renal Professor Hints
1/25/11
Acute renal failure: clinical presentation, distinguish between acute tubular necrosis, glomerular ds, acute
interstitial nephritis, obstruction; use FeNa and Urinary sodium and osm to distinguish between renal and
prerenal causes
Clinical Presentation: Usually asymptomatic and discovered on routine labs. Can be reversible if underlying ds. is
discovered.
Definition of ARF: Rapid deterioration in renal function (hours to days, not more than a month). Greater than
.5mg/dl increase in creatinine or increase of 50% of baseline value. Inability for kidney to regulate
electrolytes/water.
Cause
ATN
Ischemic Injury
Symptoms
Muddy Brown casts
Glomerular Ds.
See previous hints
AIN
See previous
hints
Obstruction
BPH, Carcinoma , etc.
Voiding complaints,
distended bladder
Urine Na>20
Other Findings
Fractional excretion
>1%
Tubular Necrosis w/
denuding of RTE’s,
mostly PT and thick
ascending loop (needs
more oxygen for ATP).
Muddy Brown Cast of
ATN
Etiology
Pre-Renal
Volume depletion, CHF,
Shock, Renal Artery
Stenosis, NSAID’s, etc.
Note: Renal artery stenosis
most likely due to
atherosclerosis in elderly,
more likely due to
fibromuscular dysplasia in
a young female.
FeNa
FeNa* = UNa *PCr/ PNa
Renal (Spefically ATN)
Glomerular: Post-strep
GN, Lupus, RPGN,
Hepatitis related, IgA
nephropathy,
Tubular: Acute Tubular
Necrosis (ATN)
(prolonged hypotension,
Medication toxicity,
toxins) , Acute Interstitial
Nephritis
Vascular: vasculitis
>1%
Post-Renal
BPH, Cancer, Stones, etc.
Assessment 12 Renal Professor Hints
1/25/11
*UCr
* < 1 % suggestive of
pre-renal
Urinary Sodium
Urinary Osmolarity
>20
300-500
<25
>500
So what is FeNa? IT is basically just the fraction of sodium excreted when compared to GFR. Think about how we
used clearance ratios before to see if something was secreted or not, basically just the same thing. We are just
comparing the clearance of sodium to the clearance of creatinine (GFR). If there are pre-renal problems going on
then there is going to be no change in the FeNa and it will resemble normal (which is <1%). If there is intrinsic
damage to the kidney tubules then the ratio will be >1% (damaged tubules can’t reabsorb sodium efficiently).
Derivation: Basically just clearance ratio’s, cancel the V since the urine flow rate is the same, denominator
collapsesFeNa
𝐹𝑒𝑁𝑎 =
𝐶𝑙𝑒𝑟𝑎𝑛𝑐𝑒 𝑆𝑜𝑑𝑖𝑢𝑚
𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝐺𝐹𝑅)
𝐹𝑒𝑁𝑎 =
𝑈𝑁𝑎 𝑉/𝑃𝑁𝑎
𝑈𝐶𝑟 𝑉/𝑃𝐶𝑟
𝐹𝑒𝑁𝑎 =
𝑈𝑁𝑎 /𝑃𝑁𝑎
𝑈𝐶𝑟 /𝑃𝐶𝑟
𝐹𝑒𝑁𝑎 =
𝑈𝑁𝑎 𝑃𝐶𝑟
𝑈𝐶𝑟 𝑃𝑁𝑎
Assessment 12 Renal Professor Hints
Test
Favors Prerenal
1/25/11
Favors A
BUN/Cr >20:1
10-15:1
U/A
Hyaline casts
Granular
casts
RTE’s
UNa+
<20 mEq/L
>25
mEq/L
FENa
<1%
>1%
Uosm >500 mOsm/kg
300350
Note : BUN is ↑↑ in Pre-Renal since there is less flow and more time for preferential reabsorbtion of BUN. Recall
that BUN is reabsorbed while Cr is freely filtered (slightly secreted), therefore if blood flow decreases BUN should
increase more than Cr due to reabsorption, also factors like vasopressin etc. could play a role. Just remember that
>20:1 BUN/Cr ratio means most likely pre-renal azotemia. KNOW THIS TABLE
Hypertension: understand pathophys of essential hypertension, factors involved in regulation of blood
pressure
Essential HTN: Multifactorial Etiology, usually idiopathic. As we age there is an increase in salt sensitivity leading
to more likelihood of developing essential HTN (can be managed by monitoring sodium intake initially). Most of
the consequences of HTN are due to compensatory mechanisms trying to compensate for the high blood pressure
(vascular/ventricular hypertrophy, atherosclerosis, nephrosclerosis).
Factors involved in regulation of BP: Baroreflexes and SNS, neurohumoral and endothelial factors (endothelin, NO,
prostacyclin, etc.), myogenic adjustments. RAAS system, ANP, etc.
Pathophys of Essential HTN: Hyperkinetic borderline HTNEssential HTN: Changes in CV function due to
increases in CO in younger years and switching this over to an increase in TPR to accommodate this change in CO
(Recall: MAP=CO x TPR). Baseline sympathetic level may be elevatedIncrease TPRdecrease β1 receptors
Assessment 12 Renal Professor Hints
1/25/11
(downregulation)Normal CO now but now there is a decrease wall lumen ratio due to the tonic high SNS and
structural changes that have occurredeven w/ downregulated SNS now we still have HTN.
High salt diet effects: Changes way PT handles sodiumincreases digitalis like factor (ouabain like) inhibits
Na/K pump causes Na accumulation in cellsalso increases intracellular calcium (just like digitalis)vascular
smooth muscle contraction and increased ECFVHTN
Practice Question: BP has dropped, are the carotid sinuses firing more or less to the brainstem?
Answer: Less. Their tonic inhibitory signals are decreased due to the dropped BP allowing more sympathetic
outflow.
This slide is taken directly from a slide titled “Factors Involved in Regulation of BP” (P.432), look at her stem for this
hint and take a hint.