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1
The Glomerulus
The Nephron (review)
1. Glomerular capillary network (capillary tuft) By the numbers: the kidney
625-700 mL/min plasma in to kidney
2. Bowman’s space
≥ 90 ml/min fluid filtered (GFR)
3. PCT (proximal convoluted tubule)
180 L of glomerular ultrafiltrate made /day
4. Loop of Henle
1-1.5 million nephrons / kidney
5. DCT (distal convoluted tubule)
25-30 minutes: time it takes for the whole
6. Collecting duct plasma volume to be filtered at the glomeruli
The Glomerulus
Basic Idea: blood comes in via afferent arterioles; fluid filters out of capillaries, across epithelial
cells & filtration barrier, into Bowman’s space, which is part of the proximal tubule, and flows
down the PCT
Filtrate just like plasma minus macromolecules
2
Equation: 𝐺𝐹𝑅 = 𝐾𝑓 Δ𝑃 − 𝑠Δ𝜋 = 𝐾𝑓 [ 𝑃𝑔𝑐 − 𝑃𝑏𝑠 − 𝑠 𝜋𝑔𝑐 − 𝜋𝑏𝑠 ]
where P is pressure, gc = glomerular capillary, bs = Bowman’s space.
Kf is a filtration constant
(reflects surface area & permeability for fluid movement)
s is a “reflection coefficient” of proteins across the capillary wall
(0=permeable, 1=impermeable)
Regulation of GFR
You can change either the driving force (Puf) or the filtration constant (Kf)
Changing glomerular hydrostatic pressure (Pgc) is most common way to alter GFR via Puf
Regulate by constricting or dilation of afferent / efferent renal arterioles
Kidney can maintain RBF and GFR pretty well over a range of BP MECHANISMS OF AUTOREGULATION
1. Renin – angiotensin – aldosterone system
I. RAAS system 2. Myogenic mechanism
1. BP falls (e.g. you’re bleeding out) 3. Tubuloglomerular feedback
2. Volume sensors activated ↑ renin release from juxtaglomerular
cells in macula densa
3. Renin cleaves angiotensingen → angiotensin I
4. AT I AT II via ACE (lung, vascular endothelial cells, glomerulus)
5. AT II:
a. ↑ systemic vasoconstriction
b. ↑ aldosterone (along with AT II itself) ↑ renal tubular Na reabsorption
i. Net effect: help restore extracellular fluid volume
c. KEY:ANGIOTENSIN II constricts EFFERENT > AFFERENT arteriole at glomerulus
i. increases Pgc to maintain GFR
Evaluating GFR
Need a substance: present in plasma, filtered freely at glomerulus, not reabsorbed / secreted / produced / metabolized by tubules
Inulin: polysaccharide, satisfies all above criteria: everything filtered shows up in urine
Filtered inulin = excreted inulin
𝑷inulin × 𝑮𝑭𝑹 = 𝑼inulin × 𝑽
4
o where P = plasma inulin, GFR = glomerular filtration rate, U = urine inulin, V = urine flow rate
𝑼
𝑮𝑭𝑹 = 𝑷inulin × 𝑽 = the ratio of urine to plasma inulin times the urine flow rate (mL / min)
inulin
𝑼
More generally, the clearance of any substance is 𝑷 × 𝑽
Can also calculate from age, lean body weight, and plasma creatinine (Cockcroft-Gault equation)
140−age × lean body weight (kg)
𝐶𝐶𝑟 = 𝑃𝐶𝑟 ×72
(don’t memorize this)
(multiply by 0.85 if woman (lower muscle mass as % body mass)
Note the factors at play: muscle mass decreases with age, bigger people have more muscle, etc.
This is different for different people: bigger / more muscle will have bigger creatinine clearances
More complicated ways to measure too (e.g. 4 variable MDRD formula – takes ethnicity, gender, age, serum Cr into account)
Electrical charge:
All 3 layers: glycoproteins with sialic acid moieties (negative charge)
Positively charged molecules filter more freely
Negatively charged molecules are blocked (e.g. albumin)
Minimal change disease: decrease in charge; see albuminuria
5
Size:
Big stuff doesn’t get through
Albumin: big (small % gets through) but so much albumin & so much plasma
that about 7g/day filtered
40 Å is about the cutoff
Proteinuria
Generally >2g/day suggests glomerular disease; tubular dz has less proteinuria
Glomerular proteinuria
Lose protein into urine (200mg >20g/day) via glomeruli
Tubular proteinuria
Disease of proximal tubules
Non-selective
(usually reabsorb small filtered proteins + some albumin)
Overproduction proteinuria
Making too much of a protein
(e.g. multiple myeloma light chains into urine)
6
The Tubules
What they do: reabsorb & secrete
180 L ultrafiltrate; >25K mEq sodium / day: and about 99% of ultrafiltrate reabsorbed
Most reabsorption: in EARLY PARTS of tubule (PROXIMAL TUBULE and Loop of Henle)
7
The Tubule
8
Aldosterone: By this point, Na
↑Na absorb/ K secretion in/out might be close
Reabsorbs: (↑Na/K ATPase activity, to 1: can’t use
Principal Cells
Sodium K+ channel opened too) concentration gradient
Water (if ADH) to bring in Na
ADH (antidiuretic hormone,
Excretes: a.k.a. vasopressin: 3Na/2K ATPase makes
Potassium ↑aquaporin insertion inside a little negative;
into membrane facing charge is driving force
urine side for Na absorption
H+ ATPase on urinary
COLLECTING side is predominant
DUCT way acid excreted
Secretes:
H+/K+ ATPase
Acid
Type A
Use Cl / HCO3
exchanger on apical
Type B
9
Remember the countercurrent exchange in the Loop of Henle (that it exists, not how it works)
Sets up a salt gradient (more concentrated at bottom)
Descending Limb of LH: permeable to H2O, not Na+ Ascending Limb of LH: permeable to NaCl, not H2O
Water flows out but not sodium Recover salt (flows from high salt concentration
(high salt concentration in interstitium) in lumen to lower in interstitium)
Urinary Dilution
High water load excrete by diluting urine!
Without ADH:
Sodium reabsorbed in ascending Loop
of Henle, distal tubule, leading to
dilute urine but…
Urinary Concentration
Water deprivation conserve by concentrating urine
Summary
Tubular Functions:
Reabsorption of most of ultrafiltrate
o >99% with bulk early, fine tuning later
Secretion of solutes
o K+, H+
Regulation of above processes (Angiotensin, aldosterone, ADH)
10
Sodium Balance
Distribution of total body water (60% weight)
1/3 extracellular fluid (ECF)
2/3 intracellular fluid (ICF)
Vascular space & ECF generally equilibrate with regard to electrolytes
Compartments
If you add isotonic sodium, it stays in extracellular space (vasculature, etc)
If you add sodium only, decrease ICF and increase ECF
(sodium stays outside of cells, draws water out)
If you add water only it distributes to ICF and ECF equally
11
Edema
Too much sodium too much ECF edema! (too little
sodium = low ECF = low intravascular volume too)
Note that when you have CHF, you’re starting at a higher ECF
level with reduced ability to get rid of sodium (hang on to all
that you can)
o Smaller increases in Na intake can push you over
the line to edema
The threshold for Na excretion is greater in edematous
states – e.g. start getting rid of Na at higher ECF volumes
Basic idea:
ECF reflects Na+
To maintain balance, just sense volume & adjust Na accordingly
(@ kidney since it’s the main way Na+ can leave)
2. Sensors
a. In both arterial & venous circulation
b. Sense stretch (direct relation to pressure)
c. Want ‘em close to brain (the important place; detect problems
before they arise)
d. Want redundancy (cause the brain is important)
12
3. Effectors: Two main mechanisms of regulation:
A. Systemic hemodynamics (cardiovascular) B. Renal Na+ excretion / retention
Sympathetics & angiotensin II: Sympathetics, angiotensin II, and
vasoconstrict & shunt blood towards brain aldosterone
o Clinically: cold extremities, etc. Also GFR & atrial natriuretic peptide, but these
aren’t as important
Tubuloglomerular Feedback
Happens at the single nephron level: another mechanism to control sodium balance
1. ↑ NaCl at macula densa (tubule cells - part of thick ascending limb) – there’s too much
NaCl getting through, so you need to slow down!
2. Macula densa feeds back on afferent arteriole by secreting adenosine (constrict: ↓GFR!)
13
Edema: When Sodium Balance Goes Bad
Cirrhosis
Portal hypertension (blood backs up in portal circulation)
Also shunted from arterial to venous circulation
↓ECV ↑ Na retention, etc.
↓ albumin
Ascites (backup to splanchnic ↓oncotic pressure
circ) & peripheral edema result
Venous pooling Cirrhosis
Nephrotic syndrome Nephrotic
CHF
Protein lost in urine Syndrome
↓albumin ↓oncotic pressure
Can’t keep blood in circulation
goes to interstitial space
↓ECV ↓Na retention, etc.
14
Osmolality & Disorders of Sodium Concentration
Osmoles & Osmolality
Osmole: # moles of a substance dissolved in solution: a quantity
(e.g. 1mmole glucose 1 mOsmole; 1mmol NaCl 2 mOsm)
Tonicity
Tonicity: measure of effective osmolality
Ineffective osmole: if the membrane is permeable, equilibrates & no gradient left
o Urea, glucose
Effective osmoles: restricted to one compartment
o Only effective osmoles contribute to tonicity
o Na is major extracellular osmole; largest determinant of tonicity in humans (2Na ~osmolality b/c NaCl)
BUN glucose
Estimated osmolality = 𝟐 × [Na] + + (KNOW THIS EQUATION)
𝟐.𝟖 𝟏𝟖
15
Regulation of Osmolality
Osmolality is primarily regulated by gain or loss of WATER
If you have too much Na or too little, the main mechanism is NOT gain / loss of Na
Plasma osmolality ~ 280 -285 mOsm / kg
o Sodium = 140 mOsm (2xNa ~280)
↑release of ADH ↓release of ADH
ADH is primary driver • 1% rise in tonicity • Fall in tonicity
(made in hypothalamus, stored in posterior pituitary & released)
• Pain • Ethanol
Increased osmolality from increased Na (relative lack of
• Nausea
water) triggers osmolality receptors
• ≥10% decrease in ECV
o Stimulates thirst (drink more)
ADH:
1) binds V2 receptors on basolateral surfaces of medullary
collecting duct cells ↑ cAMP ↑aquaporin-2
insertion into luminal side allows water reabsorption
OSMOREGULATION and
BLOOD PRESSURE / VOLUME REGULATION
are DIFFERENT!
Hyperosmolar hyponatremia
Addition of non-Na osmoles at concentration greater than plasma osmolality
Osmolality ↑ but Na ↓
o (volume added and/or water shifts from ICF to ECF due to ↑ extracellular osmolality, but no Na added)
Etiologies:
Hyperglycemia: e.g. diabetic ketoacidosis
o Normally, glucose put into ECF equilibrates with ICF (via insulin)
o Diabetes: ↓insulin, so glucose becomes effective osmole (more volume sucked out of cell)
o [Na] falls 1.6 mEq/L for every 100 mg/dL rise in glucose above 100
E.g. if you have a pt with Na = 130 and glc = 500, you can expect Na = 136.4 when you control glc to 100
Hypertonic infusions: e.g. give mannitol
18
Etiologies: Urine Na Why?
Renal Loss (diuretics, obstruction, RTA, etc.) > 20 mEq / L Can’t conserve Na via kidney mechanisms, so spill to urine
Non-renal Loss (GI: vomit/diarrhea, etc) < 10 mEq / L RAAS activated, so hang on to sodium
Treatment: give isotonic saline (replace Na & water, shut off non-osmotic ADH release)
Volume overloaded: ↑total volume sodium & water, but more water than sodium (hypoNa)
Gain of water > sodium
o Intense stimulation of RAAS: retain Na & H2O (CHF / cirrhosis)
CHF: AT II, ADH, impaired renal perfusion
(so can’t excrete excess Na & water) all contributing
o Can’t excrete Na/H2O (renal failure)
o Both lead to volume overload
DECREASED ECV (not effectively perfusing) non-osmotic ADH release (ongoing retention despite hypoNa)
Urine osm > plasma osm
(concentrating: using ADH to conserve water, so concentrated urine)
Treatment:
Fluid restriction
Treat underlying condition (CHF, etc.)
Sodium / water removal: diuretics / aquaretics (V2 blockers, antagonize ADH) /
dialysis
Note: in both hyper- and hypo-volemic disorders, urine osm > plasma; ADH increased in both
need to assess VOLUME status!
Treatment is very different! Isotonic saline for hypovolemic, fluid restriction for hypervolemic!
No clinical evidence of volume overload or hypovolemia (no edema, pulm edema, HF Sx, etc)
Fairly normal sodium balance but DO have EXCESS WATER
o Impaired free WATER EXCRETION but normal ECV
o ADH can be high, normal, low
Treatment of Hyponatremia
Remember: severe hyponatremia brain swells → seizures, other bad sx
If you give a more hypertonic solution (3% is max), you’ll raise Na levels very quickly
Routine therapy:
Raise slowly (no more than 8-12 mEq/L in 24h: 0.5 mEq/L/hr)
Once stable, can try aquaretic if too much ADH is problem (antagonize)
3% NaCl is for emergent therapy only!
Central Pontine Myelinolysis: what happens if you correct hypoNa too quickly?
ECF [Na] rises suddenly, water rushes out of cells & brain shrinks
Osmotic demyelination can occur (especially in pons)
Neuro sx: paraperesis, quadriparesis, dysarthria, dysphagia, coma, seizures
Dx: CT/ MRI, may take 2-4 wks for lesions to develop
o More risk if post-partum, malnourished, alcoholics
Managing SIADH
[Na]↓ with normal saline (0.9%)the Na will be excreted (RAAS working OK) but water will be retained (ectopic ADH).
Salt tablets don’t work either (same reasoning)
Aquaretics (conivaptan, tolvaptan): block V2 receptor for ADH in collecting duct (sodium excretion unchanged)
o Free water excretion (aquaresis, not diuresis)
o Don’t use if hypovolemic hypoosmolar hyponatremia: would lose volume!.
20
Hypernatremia
Lack of water relative to Na
Pts usually volume contracted; plasma osmolality always increased
Causes:
Loss / inadequate water intake (water loss > Na loss)
Hypernatremia makes you REALLY THIRSTY: have to ask “why wasn’t this person getting the water they need”?
o Sweating, diuretics, impaired thirst
o Lack of free access to fluid (elderly, nursing home, paralyzed)
o Urinary concentrating defect (DIABETES INSIPIDUS)
usually OK with just drinking a lot of water (but can become hypernatremic if access cut off)
Best way to expand plasma volume without inducing cerebral dehydration? Normal saline
o Minimal [Na] change so very little osmotic shift happens
o large proportion remains in vasculature so BP increases & perfusion better
Correct slowly (0.5 mEq/hr decrease in [Na], 8-12 mEq/L/day to avoid edema)
21
Diabetes Insipidus
ADH system is messed up: DI is the opposite of SIADH in a lot of ways!
Central DI Nephrogenic DI
not making enough ADH (hypothal / pituitary) kidneys not responding to ADH (ADH production OK)
Can be complete or partial (more common)
Pituitary tumors (do visual field tests),
Pituitary apoplexy (infarction post-partum) Drugs (lithium, others)
Infections, idiopathic too Electrolytes (hypercalcemia, hypokalemia)
Congenital mutations (e.g. V2 receptor)
Disease (SCD, amyloid, sjogren’s, renal lymphoma, others)
Treatment of DI:
Central Nephrogenic
DDx: pt with polyuria & drinking 5L fluid/ day: has ↑ plasma *Na+, ↑ Posm = 300, Uosm = 70, glc = nl
Primary polydipsia: [Na] & urine osm are low in polydipsia (large water ingestion so [Na] drops; shut off ADH so
dilute urine) – here plasma [Na] is high
Diuretics: not DM (glc normal), would think high Uosm (more salt excreted)
Renal concentrating defect is cause here: insufficient fluid intake to account for losses (so [Na] is high in plasma)
22
Disorders of Potassium Balance
Potassium:
Major intracellular cation (98% in cells)
3Na / 2K ATPase maintains gradients
Normal K+ homeostasis
Excess potassium needs to be dealt with (can’t have it hanging out in ECF – would disrupt potential):
1) Distribute excess K+ into cells (quick, right after ingestion – maintain ratio)
2) Excrete excess K+ into urine (need to eliminate what you “hid” in the cells)
PHYSIOLOGIC STUFF
Na out, K in. Catechols, insulin, thyroid hormone, state of K+ balance all regulate activity.
Na/K ATPase
Digitalis inhibits (can lead to fatal hyperkalemia)
23
Renal potassium excretion
KIDNEYS play major role in K+ balance
Small amounts lost in stool/sweat (can maybe see changes in fecal excretion with mineralocorticoid level shifts, K +
balance changes, rates of stool excretion)
REGULATION OF K+ SECRETION
Sodium Transepithelial
Aldosterone Plasma [K+] Distal flow rate
Reabsorption potential difference
↑ # Na channels in apical Wash away
membrane more negative secreted K+ (if
+
lumen more K secretion
+
↓flow, K builds up More Na+ If lots of poorly
in lumenless reabsorbed reabsorable anion
Enhances basolateral Na/K Same changes as
secretion) ↑Na/K ATPase (HCO3-), lumen more
ATPase (↑ *K+]in so bigger aldosterone
(independently!) activity more K+ negative
gradient) More flow more inside better
↑ # open K channels in apical
+ Na+ delivered gradient to secrete (so more K+ secreted)
membrane (↑ K+ permeability) see Sodium
Reabsorption
24
Hyperkalemia (serum K+> 5.5 mEq/L): Causes
1. Increased K+ Intake
a. Need accompanying defect in K+ excretion to be a problem
b. Body good at preventing K+ accumulation (taken into cells / excreted) MAJOR CATEGORIES
OF HYPERKALEMIA
2. Pseudohyperkalemia: lab artifact ↑ Intake
a. Take blood sample mechanical trauma during venipuncture Pseudohyperkalemia
b. RBCs damaged, release K+ in tube Shift from inout of cells
c. Can see ↑ K in serum samples (RBC removed from serum samples by ↓ renal excretion
clotting, release some K when they clot)
i. See even more if WBC > 100k or plt > 400k (more clotting)
ii. Can use green top tube (has heparin so no clotting) to measure K in plasma to avoid
c. Type I Diabetics: glucose load no insulin released glucose stays outside; water rushes out because glc
is osmole now K follows hyperkalemia
i. Treat with insulin: K+ goes back into cells (and glucose too – double effect)
ii. Total body K ↓ (high glucose osmotic diuresis, renal K+ loss)
Treatment
1) Stabilize membrane with calcium gluconate: short-acting – restores membrane potential / excitability
2) Shift K+ into cells by giving insulin & glucose: insulin drives K into cells (glc prevents hypoglycemia)
a. Sodium bicarbonate helps too (bicarb helps with acidosis)
3) Remove extra K+ (shifting is only temporary – need to get that potassium out of the body!)
a. Cation exchange resins (sodium polystyrene sulfonate = Kayexelate®) – takes up K in exchange for Na in gut
b. Dialysis if diabetic / available / etc (but invasive)
c. Diuretics to help excretion (with diuresis)
26
Decreased total body potassium, continued…
Potassium loss: hypokalemia usually from renal or GI loss
diarrhea (incl. laxative abuse)
GI loss
Symptoms
Impaired neuromuscular function (weakness paralysis, intestinal dilation, ileus)
Renal dysfunction
o poor response to ADH, polydipsia & polyuria
o Urinary acidification (K+ exchanged for H+ intracellular acidosis H+ loss by kidney)
o Chronic K+ depletion vacuolar lesions in PT/DT epithelial cells
can see interstitial fibrosis & tubular dilatation (can be irreversible!)
Treatment
K+ replacement
o Give as KCl oral or IV (oral is faster, can be dangerous IV)
o Prefer KCl to KHCO3 because Cl helps take care of metabolic acidosis that often comes with hypoK
Also, bicarb is non-reabsorbable (could promote more K loss!)
27
Acute Renal Failure
Routine lab panel (right): BUN & Cr are circled
Important & common (1-4% general med-surg admissions, 10-30% ICU admissions)
Prerenal ARF
Pathophysiology: need to get blood to glomerulus to form urine!
Autoregulation: hold RBF / GFR constant over perfusion pressure range
o ↓ perfusion dilate afferent (eicosanoids) & constrict efferent (angiotensin II) arterioles
If you ↓ renal perfusion below autoregulatory range, can get sudden GFR drop!
28
Picture to right has causes of prerenal failure
In general: not getting blood to kidney!
↓ intravascular volume
(ECF loss or sequestration)
↓ cardiac output
(myocardial dysfunction)
Pathogenesis: Causes
Calyces / pelvis of each kidney Children Anatomic abnormalities
generally only has 5-10 mL urine Young Adults Caliculi
Obstruction proximal dilatation Prostatic hypertrophy / cancer
of calyces / pelvis destroy Older adults Retroperitoneal / pelvic cancer
medulla & compress cortex Caliculi
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Clinically:
hydronephrosis (dilate urinary tract proximal to obstruction)
↑ UTI frequency
Treatment:
Address life-threatening issues first (sepsis, severe electrolyte abnormalities)
Try to preserve renal function (relieve obstruction!)
Direct therapy to cause of obstruction!
Renal ARF
Think renal after excluding prerenal & postrenal!
Categorization of renal ARF: ANATOMY
Vascular Intrarenal vascular
Thrombotic micoangiopathies: Glomerulonephritis
vascular thrombosis Interstitial
2° endothelial cell injury + platelet activation Tubular*
Etiologies: malignant hypertension, scleroderma, TTP, HUS,
pregnancy-related (Acute Tubular Necrosis is most common cause of ARF)
Glomerulonephritis
Rapidly Progressive Glomerulonephritis (RPGN): Glomerular injury + extensive crescent formation
Anti-GBM AB (e.g. Goodpasture’s)
Immune complex formation / deposition (lupus, post-strep, IgA nephropathy, endocarditis, mixed cryoglobulinemia)
Pauci-immune (“ANCA-associated GN”: Wegener’s & microscopic polyangitis)
RPGN: diagnosis
Renal insufficiency
U/A: glomerular hematuria, RBC casts, mild proteinuria
Systemic complaints: fatigue, edema, extrarenal involvement
o Multiorgan associations –
each has characteristic multi-system manifestations
o Each has its own diagnostic test too
o Don’t have to memorize for this lecture,
but maybe a good chart anyway
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Interstitial
Acute Interstitial Nephritis (AIN) CLINICAL PRESENTATION OF AIN
Inflammatory infiltrates in interstitium Renal Extrarenal
Rare but need to detect (treatable & reversible) ARF Hypersensitivity!
Drug rxn most commonly, but can be idiopathic or 2° Mild proteinuria
(<1g/day,↑ if 2° to NSAIDs) Low grade fever
to infection, dz, malignancy
Abnormal U/A: RBC, WBC, “Maculopapular” rash
o Methicillin & NSAIDs are big offenders, lots
WBC casts (see pic) Arthralgias
of Abx & common infections, leukemia,
Eosinophiluria Eosinophilia
lymphoma, SLE too
Flank pain
(2° to capsule distension)
Pathophysiology of AIN
Immunological hypersensitivity rxn to antigen
(usually extrarenal, e.g. drug)
Cell-mediated immunity key
(T-cell infiltrate, ± granulomas, Ab / immune complexes)
Treatment of AIN:
want to stop before it gets to fibrosis (can be irreversible)!
Stop agent
Ccontrol inflammation (corticosteroids, prednisone)
Tubular
Acute tubular necrosis: #1 CAUSE OF ARF in hospitalized patients (should always be #1 on DDx)
Injury to renal parenchyma following:
o Renal ischemia (sepsis, surgery, bleeding)
o Exposure to nephrotoxins (endogenous or exogenous)
ATN outcomes: high mortality rate (esp with dialysis), up to 80% with MOF in ICU
Ischemic ATN: from prolonged prerenal state (shock / sepsis)
ISCHEMIC ATN
Proximal tubule & medullary TALH are most susceptible to ischemic & toxic
injury (don’t get much O2)
o Avid Na+ retention by S3 segment of PT & TALH ↑O2 demand, ↓PO2
Poor oxygenation tubular injury (death or sloughing of normal cells into lumen)
o ↑ intracellular Ca, oxygen free radicals↑, ↓ ATP, apoptosis
Other factors: C’ activation (alternative pathway), intracellular adhesion molecules involved, inflammatory cells (T-cells),
inflammatory mediators, etc.
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Rhabdoymyolysis (endogenous nephrotoxin: myoglobin) Diagnosis of rhabdomyolysis
Important cause of ATN (10-15% hosp pts with ARF in US) Suggestive Hx
Causes: trauma, esp crush injury, cocaine, exercise, statins, many others Dipstick: heme + but no RBC
(tricking the dipstick: actually seeing Mb!)
Pathogenesis Serum creatine kinase ↑↑
Skeletal mm damage myoglobin released freely filtered @ Creatine ↑ disproportionate to BUN
glomerulus PT reabsorption overwhelmed delivered to DT, HyperK, hyperureicemia, HyperPO4
casts form (esp acid urine) Metabolic acidosis
HypoCa
(Ca/phos deposited in injured muscle)
Consequences:
Intrarenal vasoconstriction (second hit) – scavenging of nitric oxide Tx of rhabdomyolysis
o Third-spacing of fluid in damaged muscle hypovolemia more
Establish high urine flow rate
vasoconstriction
with saline infusion
Proximal tubule iron toxicity (from Mb) ± Supportive dialysis (but doesn’t
remove Mb, which is too big)
2. Exogenous nephrotoxins that cause ATN
Agent Effects
Gent: direct tubular toxin
Cationic: interacts with lipids in cell membranes
Aminoglycosides ARF 5-10 days after start of Rx (if right away, not AG’s fault!)
Antimicrobials Distal injury polyuria (nonoliguiric ARF)
Cr takes 3 wks to recover
Ampho B, vancomycin
Chemotherapy Cisplatin, 5-FU, others
Lithium
Radiocontrast for CT, cardiac cath, etc.
ATN via direct tubular toxicity
Other
Radioconstrast Prerenal ARF too! (intense intrarenal vasoconstriction)
Generally recover; avoid nephrotoxins while recovering
o No specific treatment
Presentation: ARF + heavy proteinuria + bland UA, U/S shows large kidneys
Path: FSGS with collapsed basement membrane
Treatment: antiretrovirals, prednisone, ACEi
32
Metabolic Acidosis
Acidemia: blood pH < 7.4 Alkalemia: blood pH > 7.4 Normal physiologic pH values*
Acidosis: processes that lower pH Alkalosis: processes that raise pH Extracellular fluids 7.37 – 7.43
3 HCO− Intracellular fluids 6.60 – 7.20
Henderson Hasselbach: 𝑝𝐻 = 6.10 + log(0.03 x PCO )
2 Range of extracellular pH 6.80 – 7.80
(Don’t memorize: (while still being alive)
just know you can calculate pH, bicarb, or PCO2 given the other two) * Biological processes run best at pH optima!
METABOLIC ACIDOSIS
Characteristics Etiology: REDUCTION OF HCO3-
Fall in plasma HCO3-
↑ acid production
Low arterial pH
↓ renal acid excretion
Compensatory hyperventilation Loss of HCO3- (stool or kidney)
(blow off CO2 ↓ PCO2)
In general, we produce acid overall (generates an acid load – how do we get rid of it?)
Extracellular buffer (HCO3-): 600k times higher than H+ concentration
Intracellular buffers (proteins, CHOs, phosphates in cells/bones)
o Cells/bones eventually buffer about 55-60% of acid loads
o H+ into cells, K+ out of cells
HCO3- Reclamation
Proximal tubule : 90% of bicarb reclaimed Collecting tubule: 10% bicarb reclaimed distally
Na/H antiport on apical surface, H combines with Same idea, just no sodium gradient available now (most
bicarb, CO2 in, bicarb reformed inside, Na/bicarb has been reabsorbed: have to use ATP to get the hydrogen
symport on BM side into lumen & Cl / bicarb antiport to get bicarb into blood)
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Acid Secretion
Collecting tubule: AMMONIUM BUFFERING Proximal tubule: another way to form ammonium
MAIN WAY that acid is excreted! From glutamine (protein products)
Ammonium can diffuse through to lumen, combine See diagram of ammonia recycling below
+
with H , gets trapped (only uncharged things move
through membranes) & excreted
Ammonia recycling:
Ammonia is freely permeable (NH3)
Ammonium gets trapped in collecting duct out in urine
(taking that extra hydrogen with it! acid secreted!)
34
In metabolic acidosis
↓ HCO3- is the primary problem
↓ PCO2 to compensate
o Tachypnea (try to “blow off CO2”)
o Try to maintain pH (but can’t quite)
AG Why? Examples
Unmeasured anions:
Normal AG value 5-11 Healthy people
(phosphates, sulfates, proteins)
High anion gap Exogenous acids, poisons
> 11 Extra anions present but not measured!
metabolic acidosis Endogenous ketoacids or lactates
Normal anion gap GI bicarb Loss
5-11 HCO3- out but replaced by Cl- in
metabolic acidosis Renal bicarb loss
Lactic acidosis
Lactic acid: chews up bicarb, leaves behind anion gap
↑ lactate production (seizure, shock, hypoxia, sepsis)
o altered redox state ↑ lactate production
↓ lactate utilization (hypoperfusion, liver dz – blocks
gluconeogenesis in liver & shunts pyruvate to lactic acid
formation)
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Ketoacidosis
Acetoacetate, β-hydroxybuturate chew up bicarb, leave
behind anion gap
Uncontrolled DM (usually type 1) is #1 cause
alcoholic ketoacidosis - #2 cause (↑ lipolysis, ↓
gluconeogenesis, ↓ calories with alcohol ↑ ketones)
fasting (using FA ketones for fuel)
GI losses
Diarrhea: gastroenteritis, E. coli, cholera, laxative abuse
Intestinal fluids have 50-70 mEq/L bicarb lose in diarrhea
Volume depletion ↑ NaCl reabsorption in kidney ↑ Cl
o For every bicarb lost, Cl- is gained normal anion gap
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Uretrosigmoidostomy
Implant ureters into sigmoid colon (old surgery for congenital bladder problems)
Hyperchloremic metabolic acidosis results
Urine: high Cl- and NH4+, colon:
o absorbs Cl- in exchange for HCO3-
o absorbs NH4+ with Cl- as anion
Other (rather predictable) problems: ↑ pyelonephritis, bowel incontinence (leak mixture of urine & stool at night on occasion)
Aldosterone deficiency
No response to aldosterone
(adrenal insufficiency, heparin,
diabetic nephropathy, HIV)
Type IV ↓ H+ & K+ secretion in distal tubules 15-17
↑
<5.3
(hypoaldosteronism) mild metabolic acidosis + hyperK ↑ Aldosterone resistance
+ (amiloride, triamterene,
↓ urinary NH4 excretion too
spironolactone, trimethoprim)
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Urine anion gap
UAG = (Na + K) - Cl
Different from serum AG!
Urine electrolytes: NaCl, KCl, NH4Cl
o So Na + K + NH4 should equal Cl
Urine AG therefore a measure of AMMONIUM: should be negative
o Negative UAG: ↑ ↑ NH4Cl
o + or near zero: ↓ ↓ NH4Cl
If pCO2 < expected: simultaneous respiratory alkalosis (overcompensating: breathing too fast?)
If pCO2 > expected: simultaneous respiratory acidosis (not compensating enough: breathing too slow?)
38
Nephrolithiasis
Common (13% males, 7% females) and more common (37% ↑ ’80-’94), and expensive ($2B in 2005)
Can be a phenotypic expression of an underlying metabolic disorder
Advances in technology: helical CT for Dx, minimally invasive interventions for Tx
Stone classification
INFECTION METABOLIC
Struvite Calcium (classic)
Carbonate apatite - calcium oxalate
- calcium phosphate
Cystine
Uric acid
Metabolic Stones
Metabolic stones: need abnormal urine physical chemistry as a consequence of renal pathophysiology
Metabolic Stones: Cystinuria
RARE: <1% all stone formers
KIDS: median age of onset 12 YEARS
o Aut recessive (hereditary)
High rate of recurrence but can ↓ recurrence with tx
Mechanism:
Impaired PT transporter
o reduces reabsorption of dibasic amino acids (cys, ornithine, lys, arg)
Results in increased urinary cystine excretion
Cystine insoluble @ physiologic urinary pH)
o Push urine pH ↑, can increase solubility of cysteine: can prevent
formation & eventually dissolve stones
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Metabolic Stones: Uric acid
5-10% all stones
o Gout = ↑ risk, but most pts don’t have gout (but do have “purine gluttony”- lots of steaks)
o Also associated with: chronic diarrheal states, diabetes + metabolic syndrome
RADIOLUCENT on PLAIN X-RAY (visible on CT)
o No calcium – so if a patient has pain & xray clear, could still have uric acid stones
Pathogenesis:
↑ urinary uric acid helpful but not mandatory
Acid urine pH required
o H+ + Urate- Uric Acid
o Drive soluble urate salt to insoluble uric acid (pKa 5.75)
Again: alkalinize urine make UA more soluble!
40
Metabolic Stones: Calcium Phosphate
Primary hyperparathyroidism
Bones, stones, abdominal moans, psychiatric overtones
Disease of middle age, W>M
All consequences from ↑ PTH
o Hypercalcemia (↑ gut absorption, ↑ load to kidney, hypercalciuria b/c of ↑ filtered load)
o ↑ calcium reabsorption by distal tubule (but overwhelmed by Ca load)
o ↑ bone resorption ( osteoporosis / osteopenia)
Treatment
Surgery (minimally invasive)
o 1 cm incision, stick mini vacuum cleaner into kidney collecting system, break up stone & suck it out
Uteroscopy: minimally invasive; grab it with a basket
Shock wave lithotripsy
o Hit kidney with shock wave to break stones up into tiny little pieces, wash out without symptoms
o Non-invasive!
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Metabolic Alkalosis
Compensation is part of metabolic acidosis
Has: generation phase (starts) and maintenance phase (persists)
For every 1 mEq/L rise in bicarb above 24, get a 0.7 mm Hg rise in PaCO2
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Proximal Tubule: Reclaim HCO3-
Net movement: dotted line (reclaim bicarb)
90% of filtered bicarb reclaimed here!
Secrete acid
H+ ATPase pump secretes H+ (↑ with aldosterone)
Same thing as before, the H+ just doesn’t combine with bicarb
o H+ buffered in lumen by / excreted as:
NH4Cl (most secreted this way)
H2PO4 (titratable acid), HCl
Note that Cl- still exchanges with bicarb on basolateral surface
o For every H+ secreted, a bicarb gets reabsorbed
In hypoK+
H+/K+ ATPase (exchanger): second way to secrete H+
o Activated when ↓ K+
Secrete base
43
Collecting duct: principal cells
Acid secretion
Generate a negative charge in lumen
44
Metabolic Alkalosis: Maintenance Phase
What keeps alkalosis going? Need impaired renal HCO3- excretion
↓ GFR: can’t get rid of extra bicarb
↑ tubular reabsorption
o Volume depletion, hyperaldosteronism, hypokalemia, chloride depletion
o All these keep kidney from getting rid of extra bicarb
Target maintenance for treatment!
Volume depletion
↓ ECV ↓ renal perfusion ↑ AT II ↑ aldosterone (see below)
↓ ECV Cl- depletion too (see below) Losing volume Losing volume
↑ aldosterone ↑ H+ secretion
↑ H+ ATPase ( type A cells)
↑ Na/K ATPase ↑ Na+ reabsorption (primary cells) more
Aldosterone negative lumen Losing volume Losing volume
↑ RAAS ↑ RAAS
Aldosterone: good for fixing ECV but bad for alkalosis! ↑ aldo ↑ aldo
Last thing you want to do is pee acid: H+ lost bicarb is retained!
Cl follows paracellularly
↓ Cl- in lumen by the time you get to collecting tubule
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Cl- “sensitive” (UCl < 25 mEq / L) Cl- “resistant” (UCl > 25 mEq / L)
Mineralocorticoid excess
GI loss Diuretics
Example 1° hyperaldosteronism
(vomiting, NG suction) (late-remote use)
Cushing’s syndrome
Syndromes of real & apparent mineralocorticoid excess (all of those listed above)
Normally: cortisol cortisone (inactive) by 11-β-OH-steroid-DH
o Cortisol can bind mineralocorticoid receptor just as well as aldosterone & provoke same effects
o Just normally inactivated in tissue where it would hit those MRs
Enzyme deficiency, inhibitors (licorice / chewing tobacco), or just a ton of cortisol (Cushing’s)
o Cortisol binds MR, aldosterone-like effects
Bartter’s Syndrome: acts like a loop diuretic Gitelman’s syndrome: acts like thiazide diuretic
Genetic defect of Na+ reabsorption in TALH Genetic defect of Na+ reabsorption in DCT
Both: ↑ distal Na delivery H+ & K+ wasting
+
Contraciton alkalosis
E.g. CHF pt treated with diuretic
Lose NaCl, KCl, HCl in ECF with diuretics
Don’t lose bicarb: same amt bicarb, less volume ↑ *HCO3-]
46
Chronic Kidney Disease
Measuring GFR
Inulin Clearance: gold standard, don’t really use clinically Definition of CKD
Serum Creatinine: 1st line (good or bad?) Kidney damage for ≥ 3 months
Creatinine Clearance: UV/P & match units o Structural or functional abnormalities of
o Hard to get urine, lots of problems, etc. kidney, ± ↓ GFR
↓ GFR for ≥ 3 months
Abbreviated MDRD study equation New staging for CKD: primarily based on kidney function
Better approximation, easier (no urine collection)
SCr, age, gender, race – but didn’t include older people in study (does it apply?)
Given to you on labs (hard to calculate – lab does it)
CKD: Epidemiology
20M with CKD in US, many more at risk
Staging: see picture (higher is worse: based on GFR)
Progression of CRD
Injury to a single nephron (glomerular, tubulessclerosis)
Initially ↓ GFR
Then ↑ GFR: residual nephrons start working harder!
o Can even take out a kidney and get GFR recovering
But ↑ snGFR ↑ injury to remaining nephrons!
o Downward spiral
Sodium in CRD
+
If GFR > 25 cc/min: can increase your FeNa to still get rid of salt (no symptoms!)
If GFR < 5-25 cc/min: start retaining sodium (edema, HTN, pulmonary congestion)
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Water
Normally: concentrate or dilute urine
Loop of Henle: generates medullary concentration gradient, reabsorb Na+ to dilute urine
Countercurrent mechanism is intact, adequate distal delivery of salt & water
CRD:
Scarring, not a lot of space to do the exchange: all of this messed up
Limits both concentration & dilution:
o Normal range for urine: 50-1200 mOsm/L
o CKD has an upper range of 600 mOsm/L
Potassium
If aldosterone production is normal: you can handle potassium until
GFR < 20 mL/min (then you start hyperK)
Deficient in aldosterone: develop hyperkalemia earlier(with higher GFRs!)
o ↓ aldo: primary adrenal problem, 2° adrenal problem to diabetes, HIV, or ACEi
Acid/Base Balance
Acid load: 1mEq/kg/day
Sulfuric acid: sulfur-containing amino acids
Excreted as H+ (titratible acids) & ammonium
In CKD:
GFR > 40 ml/min: ↑ ammonium excretion per nephron
o (can be 3-4x normal excretion per nephron because they’re
compensating)
Uremia
Multiple functions of kidney deteriorate in parallel complex symptoms
Kidney needs to eliminate poisons but we don’t know what they are!
Small water soluble molecules? Urea? But we used to give it as a diuretic! Not convincing
o Inhibits Na/K/2Cl cotransport
o Inhibits NO synth in Mϕ
o Precursor of guanidines: inhibits PMN superoxide production, may induce seizures, etc.
Protein bound compounds? if you eat less protein, less symptoms of CRD!
o P Cresol: multiple cell functions incl. oxygen uptake, drug protein binding, growth, permeability of cell membranes
Phenol is end product of protein metabolism
o Indoles: product of liver metabolism, ↑ levels ↓ endothelial cell prolif / repair
Middle molecules? (MW > 500 Da)
o These middle weight fractions of dialysis can inhibit various things – but we still don’t know
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Blood Pressure Regulation
Increased blood pressure:
Endocrine: Anemia
EPO deficiency is primary cause
↓ GFR ↓ EPO so ↑ anemia prevalence (see graph)
Secondary causes too:
Fe deficiency
Nutritional deficiencies
Occult GI bleeds
Anemia from any cause can happen in pts with CKD
need to do full evaluation first
Phosphorus:
Proximal tubule reabsorbs (2Na+ / H2PO4 cotransport)
o 15-20% gets through, excreted in urine
So phosphate would also be out of balance in kidney disease
49
Vitamin D:
Normal synthesis:
1. Make Vitamin D3 by exposure to sun
2. Precursor binds to D-binding protein
3. Hepatic: D3 25(OH)D3
(storage form)
50
Can’t rely on calcium or phosphate levels
o as calcium↓, PTH ↑, driving ↓ phosphate and ↓ Ca
o Maintains a pretty constant level of Ca and
phosphate
o but PTH itself is elevated (keeps increasing with ↓
GFR as each new drop in calcium happens)
Parathyroid hyperplasia
Need to crank up PTH so parathyroid grows
Eventually develops nodularity single nodule
Doesn’t respond to normal feedback
o Making PTH no matter what!
o Even if you correct Ca+2 levels, doesn’t help:
o e.g. transplant, might have to remove parathyroid
(↑↑ PTH persists!)
51
Pathogenesis of Hypertension
Definition: a persistent elevation of the systolic blood pressure and/or diastolic blood pressure in the systemic arteries
repeated measurements
Cutoff point is arbitrary: Classification of BP for adults 18yo or older
o Resting SBP ≥ 140 and/or BP classification SBP (mm Hg) DBP (mm Hg)
o Resting DBP ≥ 90 Normal <120 and <80
Prehypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Epidemiology: major public health problem Stage2 hypertension ≥160 or ≥100
High prevalence (24% all US adults, ↑ in Blacks)
↑ risk CVD (MI & stroke) & ESRD
Awareness is low (72% pts aware they have ↑ BP)
Treatment & control are lower (61% get Tx, 35% under control!)
Pathogenesis of Hypertension
BP = CO x PVR (need to keep them balanced)
HTN: ↑ CO and/or ↑ PVR
↑ CO: ↑ preload, ↑ contractility, ↑ HR
↑ PVR: ↑ arteriolar vasoconstriction, or structural alterations (remodeling)
↑ preload = ↑ECVF (extracellular fluid volume) ↑ contractility or ↑ HR ↑ PVR
↑ ECFV = Na, H2O retention
Arteriolar vasoconstriction
(alteration in kidney’s ability to regulate Na balance)
↑ sympathetics Vascular structural remodeling
↓ Na excretion & ↑total body Na
↑ catecholamines o ↓ elasticity, capacity of circulatory
↓ Na excretion: from ↓ GFR (CKD) and/or ↑
system to accommodate CO
tubular reabsorption (mineralocorticoids)
RAAS Many HTN pts have LOW RENIN & AT II levels (elderly, AAs)
See other lectures for full/better summary of RAAS
AT II effects via ATII type I receptor:
vasoconstriction ↑ tubular Na reabsorption (direct & via aldo) ↑ thirst
↑ aldo synthesis / release ↑ vascular cell hyperplasia & hypertrophy
Remember: non-circulating, local RAAS systems too (brain, heart, kidneys, arterial tree); regulate regional blood flow
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↑ SNS ↑ BP:
Heart: ↑ CO (↑ contractility & ↑HR)
Vasculature: ↑ PVR
Sympathetic Kidneys: ↑ fluid retention
Nervous
System
Contributes to development of HTN but not maintenance of HTN as much
Can induce vascular changes (smooth muscle hypertrophy) maintain
HTN although symp activity ↓
Potent vasodilator
Short-lived, highly permeable gas, released by endothelial cells in response to…
o BP changes, shear stress, pulsatile stretch
Nitric Oxide Also: ↓ platelet adhesion / aggregation, ↓ migration/proliferation of vascular smooth mm cells
53
Many factors: SALT INTAKE, obesity, occupation, alcohol intake, family size, crowding
Pheochromocytoma
See IVC displaced anteriorly on sagittal MRI (finding for adrenal tumors)
CATECHOLAMINE-SECRETING (unregulated & excessive)
o ↑ CO, ↑ PVR HTN
Primary hyperaldosteronism
Adrenal enlargement on T1-weighted MRI
Unregulated, excessive tumor production of aldosterone
o ↑ mineralocorticoid effect ↑ Na reabsorption in DT
o Na retention volume expansion HTN
o Renin: chronically suppressed
54
Risk factors for HTN
• Genetic predisposition or family history • Excessive alcohol intake
• Black race • Low socioeconomic status
• Diagnosis of prehypertension • Sleep apnea
• Increasing age • Use of certain illegal drugs or over the counter
• Obesity medications
• High sodium – low potassium intake
Resistant HTN
If you see a patient with HTN and can’t control despite multiple Rx’s (resistant), think of this list
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Non-pharmacologic Treatment of Hypertension
BP measurement history Benefits of “lifestyle” therapies
Harvey (1616): circulation ↓ BP
Hales (18th c): cannulated artery (horse) Non-hypertensives Prevent HTN
Prevent age-related rise in BP
Kortokoff: observed sounds made by constriction of artery at certain Always initial therapy
points in inflation / deflation of cuff that correspond to SBP & DBP Hypertensives Adjunct to drug therapy
Substitute for meds
Ascultory: listen to BP
Aneroid (dial measures pressure)
Less accurate than mercury
Mercury banned now though
Oscillometric (machine)
Less accurate
Measure amplitude of pulse waveform at
maximum, algorithm estimate SBP &
DBP
Underestimate higher BPs, overestimate lower BPs
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Blood pressure classification (JNC VII)
Treatment
Always encourage lifestyle: even if they’re normal; add drugs depending on stage (HTN stage 1 or 2)
LIFESTYLE THERAPIES TO ↓ BP
Weight loss (among those who are overweight or obese)
↓ salt (sodium chloride) intake
↑ potassium intake
Certain dietary patterns
o DASH diet
o Vegetarian diets
Increased physical activity
Moderation of alcohol intake (among those who drink)
Don’t see: smoking (doesn’t ↑ risk HTN on its own), trans-fats, saturated fat, cholesterol etc!
Hypertensives should still reduce these things (CVD/stroke risk!)
Calcium & Mg supplements, fish oil, fiber don’t seem to work in isolation
Studies in isolation: see table for ↓ SBP/DBP
57
1. fruits (bananas, oranges, orange juice)
2. vegetables (broccoli, tomatoes/tomato juice, potatoes)
3. others (beans, yogurt, dairy)
d. At least 4,700 mg per day (should be lower if impaired K excretion)
e. Impaired excretion:
1. Drugs: ACEi, ARB, K+-sparing diuretics
2. Medical conditions: diabetes with kidney damage, CKD, HF
b. What is it?
1. Emphasizes: fruits, vegetables, low-fat dairy products
2. Includes: whole grains, nuts, poultry, fish
3. Reduced: sat fat, total fat, cholesterol, red
meat, sweets, and sugar-containing beverages
5) Be physically active
a. As you exercise, ↑ BP; with training, less increase in BP with exercise (good!)
1. Sedentary lifestyle: ↑ BP, ↑ BMI, ↑ CVD risk
2. Moderate activity: can lower BP (brisk walking, swimming) - recommended
3. Vigorous activity: also lowers BP but ↑ risk orthopedic problems
b. Shoot for: 30 min most days in a week
Exercise advice:
43% pts reported getting advice to ↑ exercise; 75% of those reported exercising
42%: got advice to ↓ fatty foods, 88% reported trying
If you focus on sodium reduction, you can lower by 50% (confirmed by 24h urine!)
Great chance for success – be encouraging
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Management of End Stage Renal Disease
Stage Findings
GFR < 15 - need to start renal replacement therapy (dialysis or transplant)
Urinary abnormalities
I
GFR > 90 mL / min
Scope of the problem
II GFR 60-89
600K pts with ESRD, 100k/yr and growing, $28B/yr
III GFR 30-59
Minorities over-represented: AA, Hispanics, Native Americans
IV GFR 25-39
V (ERSD) GFR < 15
Leading causes: DM, HTN, chronic glomerulonephritis, HIV-associated
nephropathy (HIVAN), hereditary dz (polycystic kidney or alport's)
Hemodialysis
Dialysis = "to separate": separating crystalloid from colloid by a semi-permeable membrane
Dialyzer: biocompatible membrane with parallel hollow fibrils
o blood flows inside fibrils, rapid blood flow rate (450mL/min)
Dialysate: bathes blood with countercurrent flow
o solute drawn off by diffusion, fluid drawn off by convection
o Fast flow replenishes gradient
Inadequate dialysis:
Delay: pan-serositis can result (pericarditis especially common if severe fluid load, advanced uremia)
Inadequate: recurrent uremic symptoms & poor surival
Access failure is life-limiting problem (if you keep clotting, can run out of access sites)
60
Peritoneal dialysis
Uses peritoneal membrane as "dialyzer" membrane
Slower blood rate than hemodialysis, do it every day
Dialysate in via catheter with perforated tip in lower abd
CCPD: continuous cycling PD (4-6 exchanges at night)
CAPD: continuous ambulatory PD (4-6 exchanges in 24h)
Cath-related peritonitis: 0.5 episodes per pt/yr (fever, abd pain, nausea)
Signs: abd tenderness +/- rebound, cloudy dialysate, elevated peritoneal WBC with PMNs
50% gram + (coag - Staph, Staph aureus, VRE, Group B strep) - think skin organisms
15% gram - (pseudomonas), 5% polymicrobial, <2% fungal
PD vs hemodialysis
PD advantages PD disadvantages
Personal freedom Personal responsibility / time committment
Better BP control Protein wasting - big complication!
Higher Hgb/Hct (less blood loss) K wasting
No a/v access problems (clotting, infection) Potential for cath-related bacterial peritonitis
Smoother uremic control (avoid saw-tooth 4-6wk lead time (surgical visit, cath placement, cath maturation, education)
chemistries, big volume "cycler claustrophobia" - have to be hooked up toa machine at night
expansion/contraction) Need: space for supplies, visual acuity +/- helper
Transplantation
Dialysis is management, transplant is cure
Transplant: remember that kidney does more than fluid / electrolyte balance
o Mineral balance, EPO secretion, drug metabollism all taken care of with transplant but not dialysis
o Can reverse all signs & symptoms of uremia
Types :
Cadaveric: brain-dead donor
Living
o related donor
o unrelated donor
Cross-match negative (unrelated donor better than cadaveric as long as they're blood type compatible)
Cross-match positive (will do higher risk transplants in some exceptional situations)
Advantages Disadvantages
• Perioperative risks (morbidity & mortality)
• Freedom from dialysis • Lifelong need for immunosuppression
• Avoids accelerated CV syndrome with dialysis • Risk of rejection
• Better overall survival • Risk of allograft nephropathy
• Side effects of therapy
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Genetic Renal Disease
Glomerular disorders Tubular disorders
Salt wasting Tubular structure
Alport Syndrome (hereditary nephritis)
Bartters syndrome
Congenital Nephrotic Syndrome Autosomal dominant polycystic kidney disease
Liddle syndrome
Pathology
Bright-field: non-diagnostic (benign early sclerotic glomeruli later)
IF: loss of Goodpasture epitope in GBM (males/AR forms)
• (can see staining / non-staining alteration in females)
• Can be diagnostic
EM:
• Early: GBM thinning (non-diagnostic)
• Late: basket-weave pattern (pathognomonic) (areas of thinning and
thickening, breaks in GBM on close-up, looks moth-eaten, holey, patchy)
What’s Wrong?
Type IV Collagens
• α1-α6 subunits, 3 combine protamer
o 2 classes: (α1,3,5 | α2,4,6)
• α1-2 / α3-4 / α5-6 paired up on different
chromosomes (head-to-head)
• Goodpasture epitope is in globular domain of α3 subunit
• X-linked: α5 mutation, Autosomal: α3 + α4 mutation
Skin biopsy: can use for Dx
• α3,4,5 normally in GBM
• α5 is in skin too: see if it
stains! (near right)
• X-linked: no staining (males)
alternating stain (females)
IF of glomerulus:
• see all 3 (α3/4/5) are missing
• If you disrupt one, the whole collagen trimeric protamer can’t assemble
• Picture: far right
• This is why Goodpasture epitope (α3) lost in X-linked pt with α5 mutation
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Congenital Nephrotic Syndrome (NPHS1): a podocyte disorder
What’s wrong?
Mutation: Autosomal recessive (19q13.1,29) – NPHS1
Expressed in kidney (fetal & adult), encodes adhesive protein
Nephrin: the gene product, localized to slit diaphragm
o Slit diaphragm messed up, ↑ permeability proteinuria
Various mutations: in the end, affecting TALH NaCl transport (like loop diuretic – Na/K/2Cl cotransporter)
Why hypokalemia? ↑ distal flow to collecting duct ↑ Na reabsorption (aldosterone) ↑ negative lumen ↑ K secretion
Why metabolic alkalosis?
+ +
HypoK ↑ NH3 synth in PT; ↑ H /K ATPase in intercalated CD cells
Negative lumen effect like above
Why hypercalciuria? Less positive lumen, so less force driving paracellular reabsorption of Ca & Mg out of lumen
Why not hypomagnesemia? More salt wasting, hypoaldo ↑ Mg reabsorption in DCT
63
Liddle Syndrome: a salt-wasting tubular disorder
Genetics: PKD1 (85%) or PKD2 (15%), all probably membrane proteins / channels
Two hit model (cysts are focal) – a germline mutation, then a somatic one
64