Week 1 (Renal) Flashcards
Functions of the kidney
Maintain constant ECF volume and content: excrete metabolic waste, adjust urinary excretion of water and electrolytes
Endocrine organ: renin/angiotensin, prostaglandins, bradykinin, erythropoetin, 1,25-dihydroxy vitamin D
Determinants of GFR
Total GFR = single nephron GFR x nephron mass
snGFR = unit permeability of capillary wall x net pressure gradient (Starling forces) = Kf (ultrafiltration coefficient, which expresses intrinsic permeability of GBM to water) x Puf (mean ultrafiltration pressure across GBM)
snGFR = LpS x (Pgc - Pbs - OPgc)
snGFR = Kf x net filtration pressure
Lp = permeability; S = surface area
Autoregulation of GFR
Even when BP (and thus renal artery pressure) changes, GFR stays constant because it is autoregulated
However, angiotensin II is necessary for autoregulation so if you block ATII, GFR is not well autoregulated anymore
What is special about the glomerular capillary?
Very high hydraulic permeability
Very large surface area
Very high protein permselectivity
Causes of renal failure (loss of GFR)
Reduction in total number of glomeruli (normal or supernormal GFR): surgical removal of kidney or some kidney tissue (compensatory hypertrophy and remaining nephrons increase in size and snGFR increases; doesn’t happen after age 40 though), embolism or infarction of kidney tissue, drop out of individual glomeruli due to local glomerular disease (age), interstitial disease (tubular damage followed by glomerular dropout)
Reduction in snGFR (nephron number normal or decreased): reduced renal plasma flow (hemorrhagic/septic/anaphylactic shock), CHF, increased resistance of renal vasculature, impaired autoregulation, increased πgc (myeloma = high plasma protein, dehydration = hemoconcentration), decreased Pgc (ACEi = no constriction of eff art, BP decreased out of autoregulatory zone, NSAIDs inhibit prostaglandin = aff art constriction), increased Pbs (obstruction), decreased LpS (GBM thickened/not permeable due to disease, gentamicin decreases K, glomerular nephritis = inflammatory cells, fibrosis?)
Clinical estimation of GFR
GFR = UV/P
Ideal filtration marker should be: not protein bound in plasma, freely filtered at GBM, not secreted or reabsorbed, easy to measure, produced endogenously at steady state, not metabolized by any other organ in the body (only the kidney)
Inulin fits all of the above except is not created endogenously and need to infuse IV (not practical!)
Creatinine fits all of the above except 15% is secreted in proximal tubule, so tends to overestimate GFR (due to increased U); also levels depend on age, muscle mass, meat intake
Alternatives to using creatinine or inulin clearance to measure GFR
Cockroft Gault: uses age, weight, sex, FF
MDRD equation: uses sex, race, age, BUN, albumin, FF
Radiolabelled filtration markers: iothalamate, DTPA or EDTA
Cystatin-C
BUN
Blood urea nitrogen
BUN levels vary inversely with GFR (if BUN high, then GFR low)
Urea production not constant: increased with protein intake/bleeding; decreased by liver disease/malnutrition; increased in CHF (PCT Na and urease reabsorption increased due to low effective plasma volume)
Filtered and reabsorbed (with Na and H2O)
Urea reabosprtion is flow-dependent: more concentrated urine, the more urea is reabsorbed (if dehydrated, will reabsorb more = high BUN in dehydration)
How does the GBM determine which molecules can and cannot pass?
GBM behaves as size and charge discriminating membrane with pores of 4-4.5 nm radius
Water and small molecules (<1.8 nm) pass freely
Macromolecules (>5 nm) do not pass
Albumin (3.6 nm, polyanionic) passes in minute amounts due to negative charge
Barriers to protein passage across GBM: molecular size/shape, negative charge
Congenital nephrotic syndrome: Finnish type
Heavy proteinuria in utero
Death in first two years of life
Tx: kidney transplantation
Mutated gene responsible was isolated by positional cloning: NPHS1 (specifically expressed in kidney, mutations segregate with phenotype, encodes the protein nephrin)
Minimal change nephrotic syndrome (MCNS)
Commonest cause of nephrotic syndrome in children
May occur at any age
Relapsing and remitting course
Often responds dramatically to steroids
Minimal findings on light microscopy and IF
Fusion of podocytes on EM
Rarely causes CKD unless its pathology changes
Focal and segmental nephrosclerosis (FSGS)
May be specific or non-specific injury pattern
May be primary or secondary (obesity/HIV/drugs)
May be end-stage of MCNS
May cause massive proteinuria
May cause rapid kidney failure in young adults
May recur rapidly in kidney transplant
Putative role of circulating factor (suPAR)
Degrees of proteinuria
Normally <200 mg/day (mostly tubular)
Microalbuminuria (30-300 mg/day) is abnormal
Proteinuria >300 mg/day: transient (usually benign), orthostatic (often benign), fixed (marker of renal disease)
Heavy proteinuria (>3 g/day) “nephrotic range”
Nephrotic syndrome: edema, hypoalbuminemia, lipidemia, lipiduria, heavy proteinuria (>3g/day)
Some causes of nephrotic syndrome
Primary glomerulopathies: MCNS, FSGS, MN, MPGN, proliferative GN (IgA nephropathy)
Secondary glomerulopathies: diabetic nephropathy, SLE, plasma cell dyscrasias (myeloma, amyloid), virus infections (hepatitis, HIV), bacterial infections (strep, abscesses), other infections (malaria, amebiasis, syphilis), cancer (paraneoplastic syndrome)
What factors determine Puf (mean ultrafiltration pressure across GBM)?
Pgc: mean hydrostatic pressure in glomerular capillary (gc); 45mmHg, fairly constant along capillary; determined by balance of resistances of afferent arteriole and efferent arteriole
Pbs: mean hydrostatic pressure within tubule (Bowman’s space); constant at 10-12mmHg
πgc: mean oncotic pressure in glomerular capillary; rises along capillary as plasma is ultrafiltered and protein-free fluid is extracted (leaving more proteins and raising oncotic pressure!)
πbs: oncotic pressure within Bowman’s space; since GBM largely impremeable to protein, is close to 0 and can be ignored
When does creatinine clearance really badly overestimate GFR?
Chronic renal failure: GFR falls and secreted portion accounts for greater percent of urinary excretion
Heavy proteinuria: for unclear reasons, secretion increases and may lead to overestimation of GFR by 100%!
What happens to plasma creatinine when you remove a kidney and why?
1) When you remove a kidney, you cut the GFR in half
2) Creatinine filtration (GFR x Pcreat) and excretion (Ucreat x V) are cut in half too because GFR was cut in half
3) Production of creatinine remains the same (still same amount of muscle breakdown), so you’re in positive creatinine balance and plasma cretinine levels rise
4) As Pcreat rises, the creatinine filtration must also rise (since it’s GFR x Pcreat), and does so until creatinine excretion equals production
5) When Pcreat is doubled, the product of GFR x Pcreat is back to normal and new steady state is produced
Note: you’ll always be able to excrete 1500 mg/day because the plasma and thus urine concentration will just be higher!
How are GFR and serum creatinine related?
At near-normal levels of renal function, large changes in GFR produce only small changes in serum creatinine
When renal disease is advanced, small changes in GFR will produce large changes in serum creatinine
BUN:creatinine ratio
10 is normal BUN:creatinine ratio
Increased BUN ratio: increased urea production (excess dietary protein, GI bleeding, hemolytic anemia, steroid therapy = protein anabolism), increased urea reabsorption (CHF, dehydration), decreased creatinine production (muscle wasting)
Decreased BUN ratio (less used clinically): decreased urea production (low dietary protein, severe liver disease), increased urea excretion (overhydration), increased creatinine production (muscle breakdown = rhabdomyolysis)
Glomerular permselectivity
Size: 5.5 A is too big
Shape: linear, flexible molecules traverse GBM more easily than globular, rigid molecules
Charge: sialic acid is a mucoprotein in the basement membrane that has anionic residues (negative charge) to repel molecules with negative charge; albumin is 3.6 A but cannot pass due to negative charge
Podocin is anionic protein on sides of epithelial foot process and probably helps maintain separation of adjacent foot processes
Nephrin is located at slit diaphragm
In certain glomerular diseases, sialic acid content reduced so more negatively charged molecules can pass (some degree of size discrimination always remains though)
Consequences of loss of charge of GBM
1) Proteinuria
2) Fusion of epithelial foot processes
3) Retention of immunoglobulin aggregates (immune complexes) in the mesangium –> can lead to continuous stimulus for mesangial matrix production which could result in glomerular sclerosis and destruction
Blood flow into and around the nephron
Renal artery –> afferent arteriole –> glomerulus –> efferent arteriole –> capillary that supplies rest of nephron?!
Hydrostatic and oncotic pressures in that capillary that runs next to the nephron affects reabsorption from the tubule!
Low BP –> constrict efferent arteriole –> increased pressure in glomerular capillary but decreased pressure in efferent arteriole/capillary –> high oncotic pressure and low hydrostatic in capillary –> more fluid pulled out of PCT and into capillary –> reabsorb more water to increase BP (this shows that when BP down, you keep GFR up by constricting efferent arteriole AND you maintain body fluid by reabsorbing more water by the same mechanism!)
Three layers of glomerular capillary
Capillary lumen
1) Endothelial cells
2) Glomerular basement membrane (GBM)
3) Podocyte foot processes (part of visceral epithelial cells)
Filtrate in Bowman’s space?
Total body volume and distribution
Total body volume (TBV) = 60% of total body weight (TBW)
TBV = 60% intracellular and 40% extracellular (1/3 intravascular and 2/3 interstitial)
Of your total body weight, 60% is is total body volume, 40% is intracellular fluid and 20% is extracellular fluid (60-40-20 rule)
Ions and osmolality in different compartments
All compartments have same osmolality (because water follows solute to maintain osmotic equilibrium)
Intracellular: K+, PO4
Extracellular: Na+, Cl-
Effective plasma osmolality
Estimated to 2[Na+]
Posm = 280-290
Effective vs. ineffective solutes
Effective solutes contribute to osmolality and osmotic pressures; increase in number of solutes causes free water to move into their compartment; ex: Na+, K+, glucose
Ineffective solutes contribute to osmolality but not to osmotic pressures; can cross vascular walls and cell membranes so water never has to move to follow; ex: urea
Osmoregulation vs. volume regulation
Osmoregulation: maintains plasma osmolality (serum [Na+] and cell volume), uses osmoreceptors in hypothalamus to stimulate thirst and ADH, cause urine osmolality and water intake/excretion to change
Volume regulation: maintains effective circulating volume (effective tissue perfusion), uses sensors in carotid sinus (SNS, some ADH), afferent arteriole (RAAS, glomerular perfusion, GFR), and atria/ventricles when severe CHF (ANP when atria stretch/vol exapnds to get RID of water), cause urinary Na+ excretion and thirst
Remember, volume more important than osmolality!
Infusion of isotonic “normal saline”
Use volume regulation!
No osmolality change
Increased effective circulating volume (ECV)
Suppression of SNS, ADH, RAAS
Increased ANP to promote Na+ and water excretion
Free water ingestion
Use osmoregulation
Plasma osmolality decreased
Suppress ADH to excrete water
Urine osmolality decreases (more dilute)
Salt ingestion (potato chips with no water!)
Use both osmoregulation and volume regulation
Plasma osmolality increased so water shifts extracellularly (into blood vessels/plasma) to increase effective circulating volume (ECV)
Increased ADH, thirst to enhance free water reabsorption and intake which decreases water excretion and increases urine osmolality
Then, RAAS suppressed and ANP increases to cause water excretion
Sweating in a marathon runner
Uses both osmoregulation and volume regulation
Sweat is hypotonic so plasma osmolality increases and ECV decreases
Increased ADH, thirst, RAAS
Decreased ANP
Drink fluid equivalent to sweat composition so no electrolyte/volume disturbances! If drink water, will retain free water and become hyponatremic. If drink nothing, will continue to be hypernatremic.
Edema
Palpable swelling due to the expansion of interstitial fluid volume
Common clinical conditions associated with edema: CHF, cirrhosis, nephrotic syndrome
Why don’t you usually get edema?
Albumin in the blood maintains oncotic pressure
Lymphatics take away extra fluid
Edema formation
Alteration in more than one of Starling’s forces:
1) increased capillary hydraulic pressure
2) Increased capillary permeability
3) Increased interstitial oncotic pressure
4) Decreased plasma oncotic pressure
Lymphatic obstruction
Renal Na+ and water retention
Congestive heart failure causing edema
Poor CO –> decreased ECV –> decreased tissue perfusion
Increased RAAS, SNS, ADH –> Na+ and water retention –> increased plasma volume
Early in CHF, this enhances cardiac contractility and CO but as disease progresses, continuing accumulation of plasma volume reaches a point where cardiac contractility cannot be improved to improve CO so Na+ and water retention causes volume expansion and edema
Nephrotic syndrome
Edema, hypoalbuminemia, heavy proteinuria (>3g/day), hyperlipidemia/hyperlipiduria
Hypoalbuminemia due to urinary loss (and maybe altered albumin metabolism) –> decreased capillary oncotic pressure –> arterial underfilling
Also have renal Na+ retention due to underlying renal disease (independent of hypoalbuminemia)
Increased RAAS, SNS, ADH
Increased capillary permeability (Lp)
Altered reflection coefficient of proteins (s)
Administration of albumin improves renal Na+ excretion and edema (transiently since you’re still losing albumin due to renal disease!) because increases oncotic pressure of plasma so allows you to get rid of water!
Arguments against arterial underfilling due to hypoalbuminemia as sole cause of Na+ retention and edema formation in nephrosis
Gradual decrease in plasma albumin would mean gradual decrease in interstitial albumin (why…?) so oncotic pressure gradient would be minimal
People with no albumin don’t have edema!
Correction of renal disease improves Na+ excretion and corrects edema before hypoalbuminemia is corrected!
Ascites and hepatorenal syndrome
Happens in patients with cirrhosis
Portal hypertension (due to postsinusoidal obstruction from hepatic fibrosis) causes portosystemic shunt that reduces hepatic metabolism of vasoactive peptides (prostaglandins, substance P, VIP, glucagon all cause vasodilation!) which causes vasodilation of splanchnic bed and systemic circulation (also increased NO increased because reduced clearance of bacterial products and this also contributes)
Fall in systemic ECV and reduced systemic vascular resistance –> Increased RAAS, SNS, ADH to retain water –> heart decompensates and CO decreases –> ascites and edema
Also with SNS, overdo the vasoconstriction in kidneys, brain, liver, adrenals after water IS retained and this causes kidneys to shut down due to severe vasoconstriction (not disease of the kidney, it’s just that blood isn’t going there!) = decreased GFR = hepatorenal syndrome
Note: portal HTN causes splanchnic vasodilation but splanchnic vasodilation makes portal HTN worse because of blood pooling!
Definition of hepatorenal syndrome (HRS)
Clinical condition that occurs in patient with chronic liver disease, advanced hepatic failure, and portal HTN characterized by impaired renal function and marked abnormalities in arterial circulation and activity of endogenous vasoactive systems.
In kidney there is marked vasoconstriction that results in low GFR.
In extrarenal circulation there is predominance of arterial vasodilation that results in reduction of total systemic vascular resistance and arterial hypotension.
Diagnostic criteria for HRS
Cirrhosis with ascites
Serum creatinine >1.5 mg/dl
No improvement of serum Cr after > 2 days with diuretic withdrawal and volume expansion with albumin
Absence of shock
No current or recent nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria >500mg/day, microhematuria >50 RBC/hpf, and/or abnormal renal UTZ
Note: if patient improves with infusion of albumin, it is NOT HRS
Subtypes of HRS
Type I HRS: > doubling of initial serum creatinine to >2.5 mg/dl or 50% reduction in creatinine clearance to <20 ml/min within 2 weeks; may occur spontaneously but frequently has precipitating factor (severe bacterial infection (SBP), GI hemorrhage, major surgical procedure, or acute hepatitis imposed on cirrhosis); shorter survival of 2 weeks
Type II HRS: moderate and stable reduction in GFR; renal failure does not have rapidly progressive course; dominant clinical feature is severe ascites with poor or no response to diuretics; longer survival of 6 months
Management for HRS
Prevention: infuse albumin at dx of SBP; prophylaxis for SBP; use TNF inhibitor pentoxifylline in those with alcoholic hepatitis; avoid nephrotoxic agents/NSAIDs/ overdiuresis/large vol paracentesis
Use albumin to improve intravascular oncotic pressure and mobilize interstitial fluid into central blood volume
TIPS: divert portal blood flow to hepatic vein to systemic circulation; improve variceal bleed; improve renal perfusion; complications are bleeding, infection, hepatic encephalopathy and renal failure (due to dyes?)
Vasoconstrictors: analogues of vasopressin with decreased antidiuretic properties; terlipressin (not in US), octreotide (inhibits glucagon) + midodrine, NE + albumin; sometimes low dose vasopressin
Molecular adsorbent recycling system (MARS): combination of kidney and liver dialysis that has an albumin circuit so can remove albumin-bound toxins and water-soluble toxins (however not yet widely available or approved for tx of chronic liver disease)
Liver transplantation!!
Note: renal vasodilators do not work well!
Hyponatremia
[Na+] <136 mEq/L
Most common electrolyte disorder
Independent predictor of death amont ICU and geriatric patients, hear failure acute STEMI, cirrhosis (so need to pay attention to [Na] even though pt might not have symptoms!)
Pseudohyponatremia
Has nothing to do with total body water or salt imbalance
Falsely high volume: severe hyperlipidemia, hyperparaproteinemia (multiple myeloma, Waldenstrom’s macroglobulinemia)
Extracellular dilution due to extracellular free water shift: hyperglycemia (just give insulin to put glucose in cells!), hypertonic mannitol
Mis-measurement because lots of glucose/mannitol/sorbitol/glycine in blood brings water in but can’t measure those things so looks like hyponatremia
This doesn’t happen anymore!
True hyponatremia
Hypoosmolar state
Hypovolemic: sweat/renal/GI/pulmonary blood loss, third spacing (acute inflammatory state causes increased vascular permeability so intravascular vol shifts out into interstitial space), diuretics (HCTZ), mineralocorticoid insufficiency (cannot reabsorb Na+, cerebral salt wasting
Euvolemic: SIADH, hypothyroidism, cortisol insufficiency, psychogenic polydipsia, tea and toast/beer potomania, reset osmostat, pregnancy, nephrogenic SIAD
Hypervolemic: cirrhosis, nephrotic syndrome, CHF, renal failure
How do you get either hyper- or hypovolemic hyponatremia?
Initially you have low ECV (due to salt and water loss in hypovolemia or due to volume redistribution or vasodilation in hypervolemia), so increase ADH and thirst and drink a ton then get hyponatremic!
Must be able to secrete ADH and must have free water to drink in order to get hypovolemic hyponatremia
Note: looks like just the starting point that is different between hyper- and hypovolemic…mechanism is the same otherwise?
Causes of euvolemic hyponatremia
Hypothyroidism: not understood but maybe because CO down, renal plasma flow down so ADH upregulated to retain more water
Cortisol insufficiency: increased CRH which is co-expressed with ADH (just innocent bystander!)
Psychogenic polydipsia: dilution, kidneys can’t get rid of it quickly enough
SIADH: malignancies, drugs affecting CNS (antipsychotics, antidepressants, antiepileptics), CNS problems, pulmonary diseases, N/V, pain, hypoglycemia, NSAIDs, cyclophosphamide
Tea and toast syndrome/beer potomania: don’t eat enough so don’t have enough solute to make urine so can’t get rid of water (kidneys need solute in order to get rid of water)
Pregnancy: drink lots because higher thirst and threshold for ADH release is lower
Nephrogenic SIAD: gain of function mutation of ADH receptor so act like ADH always around!
Urine osmolality and urine Na+ findings in hyponatremia
Hypovolemia sweat/renal/GI/pulm/blood loss, third spacing: high urine osmolality, UNa <20
Hypovolemia mineralocorticoid insufficiency, cerebral salt wasting, diuretics: high urine osmolality, UNa >20
Euvolemia SIADH/SIAD, hypothyroid, cortisol insufficiency: high urine osmolality, UNa >40 (pts not retaining salt here!)
Euvolemia psychogenic polydipsia, tea and toast/beer potomania, reset osmostat, pregnancy: low urine osmolality, UNa varies
Hypervolemia cirrhosis, nephrotic syndrome, CHF: high urine osmolality, UNa <20 (trying to hold onto Na+)
Hypervolemia renal failure: urine osmolality similar to serum osmolality (cannot concentrate or dilute well), UNa >20 (cannot reabsorb Na+)
