Renal Flashcards
Approach to patient with kidney issue
Laboratory testing: • Serum Creatinine & Urea Nitrogen • Creatinine clearance (Estimated GFR) • Urinalysis with microscopic examination • Urine Electrolytes and Osmolality • Spot Urine Protein and Creatinine ratio • 24 hours Urine Collection • Assessing Urine Output -Oliguria (400cc/day)
History and Physical examination
Imaging:
• Kidney Imaging (U/S, Doppler, Nuclear scan, MRI, Angiogram)
Invasive testing:
• Kidney Biopsy
Indication for renal biopsy
- Acute kidney injury
- Nephrotic or nephritic syndrome
- Hematuria
- Systemic Disease
- Transplant Allograft
ONLY perform biopsy if:
- Cannot determine with less invasive procedure
- Suggestion of parenchymal disease
- Differential diagnosis includes diseases that have different treatments and courses
Serum creatinine as measurement of GFR
Non-protein waste product of skeletal muscle metabolism
15-25 mg/kg/day= proportional to muscle mass; Serum concentration dependent on:
- Excretion (glomerular filtration)
- Secretion into lumen
Changes in creatinine excretion have hyperbolic relationship with GFR:
- jump from 1 to 2 mg/dL–> 50% loss of nephrons
Conditions changing creatinine excretion:
Decreased creatinine: less muscle mass
- Hepatic cirrhosis
- Limb amputation
- Spinal cord injury
- Morbid obesity
Increased creatinine: more muscle mass or drugs:
• Influence of muscle mass
• Blocking proximal secretion
- cimetidine, trimethoprim, probenecid
• Interference with Jaffe rxn e.g. ketones, methanol, cephalosporins, isopropanol
(mass spectroscopy, HPLC et al)
Urinalysis
Blood: strip detects peroxidase
- blood, myoglobin, free hemoglobin
Leukocyte alkaline esterase detects polys.
Nitrate: detected by a reaction with an azo dye
- presence suggests bacteria
Protein: depends on urine concentration.
- 1+ as significant as 3+
Specific gravity closely approximates osmolality
- If specific gravity is high then concentrating ability likely intact
Urinary sediment types
Casts
RBCs
Crystals
Indications for Renal Ultrasound
To quantify kidney size
To evaluate for hydronephrosis
To evaluate the perirenal space for abscess or hematoma
To screen for ADPKD (polycystic kidney disease)
To localize the kidney for invasive procedures
To evaluate for kidney vein thrombosis (doppler US)
To assess kidney blood flow (doppler US)
Indications for IV pyelography
IV contrast dye given- monitor kidney excretion
To assess renal size and contour
To investigate recurrent urinary tract infection
To detect and locate calculi
To evaluate suspected urinary tract obstruction
To evaluate the cause of hematuria
Indication for radionuclide studies
To quantify total kidney function and the contribution of each kidney
To evaluate kidney parenchymal integrity
To evaluate kidney infection or scar
To evaluate renovascular hypertension
Little benefit when the single kidney GFR is below 15 ml/min
Glomerular filtration agent (renal scan)
- Freely filtered by the glomerulus and is not reabsorbed
- To estimate GFR
- Technetium diethylenetriamine pentaacetic acid (99mTc-DPTA)
Tubular secretion agents (renal scan)
- Evaluate renal blood flow and function
- Plasma clearance
- Technetinum mercaptoaceyltriglycine (99mTc-MAG3)
Tubular fixation agents (renal scan)
- Bound to the tubules and delineates the contuor of functional renal tissue
- To assess cortical scarring from pyelonephritis and/or vesicoureteral reflux
- Technetium dimercaptosuccinate [99mTc-DMSA]
Indication for renal CT
To further evaluate a renal mass
To display calcification pattern in a mass
To delineate the extent of renal trauma
To guide percutaneous needle aspiration or biopsy
To diagnose adrenal causes for hypertension (50% of HTN is genetic, other causes linked to renal function)
Indication for renal MRI/MRA
- Diagnosing renovascular lesions
- To assess renal vein thrombosis
- Evaluation of potential living kidney donors and transplanted kidneys
- To evaluate suspected pheochromocytoma
- Delineating complex mass where CT is not definitive
- Staging kidney neoplasms, particularly in evaluating for renal vein or inferior venal caval extension of tumor
Indication for renal angiography
- Suspected artery lesions: atherosclerotic or fibrodysplatic stenoic lesions of the renal arteries, aneursysms, arteriovenous fistulae.
- Large vessel vasculitis
- Unexplained hematuria
- Kidney transplantation
- Diagnoses for renal vein thrombosis
- Complex or highly unusual renal masses or trauma etc
“Can be used for diagnostic or for therapeutic purposes”
Definition of Acute renal failure (ARF)
Acute loss of kidney function
- Typically connotes acute drop in GFR
Multiple definitions of this, typically based on changes in:
- Serum Creatinine
- Urine output
Other definitions of ARF:
- Oliguria: <50cc UOP/day
- Azotemia: elevated blood urea nitrogen (BUN ) without symptoms of uremia
- Uremia: buildup of toxins that are cleared by the kidney. Most of these toxins are unknown.
* * An elevated Urea level alone is NOT sufficient to diagnose uremia
Differential diagnosis of ARF
- Prerenal causes
- Intrinsic causes:
- Tubular necrosis
- Interstitial nephritis
- Acute glomerulonephritis - Postrenal causes
Pre-renal azotemia
Elevated nitrogen levels in blood NOT due to kidney damage
- Renal blood flow decreased–> decreased GFR–> decreased clearance of metabolites
- Kidney is intact and cells are not damaged
- Kidney avidly reabsorbs salt and water to try and preserve intravascular blood volume and renal blood flow.
Features:
- History of volume depletion
- Exam consistent with volume depletion
- Fractional Excretion of Na (FENa) < 1 %
- Urine Na < 20 mEq/L (low if kidney is Na avid, tubules intact)
- Urine Osm > 500 mOsm/L
- Increased BUN/Creatinine Ratio
- Bland urinalysis
- Ultimate Test: Give Fluid
- If immediate improvement, then it’s pre-renal
Hepato-renal syndrome
Advanced liver failure- toxins usually cleared by liver cause:
- Splanchnic vasodilatation
- Renal vasoconstriction
- Urine Looks Like Pre-Renal Azotemia
- Urine Na < 20mEq/L
- Bland UA
- Does not get better with saline
Post-renal obstruction
In patients with two functioning kidneys, both need to be effected to produce significant renal failure Causes: - Urethral obstruction – most common - Obstruction of a solitary kidney - Bilateral ureteral obstruction
Causes:
- Urethral obstruction
- Bladder neck obstruction (prostatic hypertrophy, bladder carcinoma, bladder infecion)
- Bilateral ureter obstruction:
1. Intraureteral: - Sulfonamide, uric acid crystals, blood clots/stones
2. Extraureteral: - tumor (cervix, prostate, endometriosis)
- Retroperitoneal fibrosis
- Ureteral ligation/edema due to pelvic operation
Diagnosis of post-renal obstruction
• Historic predisposition:
Benign Prostatic Hypertrophy
Abdominal malignancy
Nephrolithiasis
• Symptoms of obstruction:
Urinary frequency/urgency (suggesting urethral obstruction)
Patients with post-renal ARF do NOT need to be anuric. A partial obstruction may still lead to enough back-pressure to decreased kidney function
Urinalysis: bland sediment
Urine lytes: not helpful
Evidence of obstruction: renal U/S, abdominal CT
Acute tubular necrosis/ injury (ATN/ATI): types
Defined as sudden death of tubular cells (NOT glomerular cells)
There are two sub-categories of ATN:
- Ischemic ATN: results from severe renal hypoperfusion. Ischemia results in death of susceptible tubular cells
- Nephrotoxic ATN: injury secondary to substances that directly damage renal tubules, leading to cell death
Acute tubular necrosis: causes
Ischemic:
- Septic shock
- Extensive trauma
- Massive hemorrhage
- Post-operative
- Pancreatitis
- Pregnancy- post-partum hemorrhage
- Transfusion reactions
Toxic:
- Radiocontrast media
- Antibiotics (aminoglycosides, amphotericin)
- Myoglobin (rhabdomyolysis)
- Hemoglobin
- Heavy metals (mercury, arsenic, lead, bismuth, uranium, etc.)
- Insecticides
- Chemotherapy
- Uric acid, calcium
- Need to hydrate patients when exposed to nephrotoxic substances to dilute toxicity
Acute tubular necrosis: Diagnosis
- History: prolonged hypotension, muscle crush, toxin exposure, drugs, coma, seizures
Urine sediment:
- granular casts on urinalysis
- Casts= mucoprotein secreted by renal tubule cells
- -> decreased GFR–> increased accumulation of casts
Urine lytes:
- Na > 20 mEq/L or FENa> 1%
Pathology finding (rare to biopsy):
- Normal glomeruli
- Tubular epithelial cells flattened with pyknotic nuclei, swelling and necrosis of cells with sloughing into tubules
- Interstitium – edema with minimal cellular infiltrate
Acute interstitial nephritis: casues
Allergic reaction in kidney
Typically due to medications:
- NSAIDs
- PPI
Acute interstitial nephritis: diagnosis
History:
- Drug hypersensitivity
- Eosinophil > 10% in periphery
Urine WBCs with negative culture (no infection)
- Casts with no pyelonephritis
- No urinary obstruction/inflammation of kidneys on imaging
Gold standard diagnosis: kidney biopsy
Acute glomerulonephritis
Inflammation of glomeruli, typically auto-immune
Urine sediment:
- Dysmorphic RBCs
- RBC casts, WBC casts
- Proteinuria
Causes: Acute post-infectious glomerulonephritis Autoimmune diseases: - SLE - Polyarteritis nodosa - Henoch-Schonlein purpura - Goodpastures syndrome ANCA vasculitis (most common cause in hospital)
Renal athero-emboli
Small atheromatous crystals flecking off arterial wall–> kidney
- After manipulation of arteries (post-embolization)
- Loss of kidney function after 1-2 weeks
- Urine bland, maybe eosinophilia
- PE may show emboli (fingertips)
- No specific treatment
Management of ARF
- Pre-renal:
- replace fluid
- CHF: treat arrhythmias, inotropes, reduce load - Post-renal:
- Remove cause/bypass obstruction (EMERGENCY when creatinine begins to elevate) - Acute tubular necrosis:
- No interventions will improve renal function after onset of acute tubular necrosis
Supportive care of Acute Renal Failure
- Intravascular volume (overloaded):
- low salt diet, water restriction
- diuretic use - Hyponatremia:
- restrict free water, avoid D5W in IVF???? - Hyperkalemia:
- Renal diet, eliminate K/K-sparing diuretics
- K-binding ion exchange resin in colon
- Glucose/insulin, 50-100 mEq NaHCO3, albuterol, Ca-gluconate - Metabolic acidosis:
- Sodium bicarb to maintain HCO3 > 15 - Hyperphosphatemia, hypermagnesemia, hypocalcemia
- Phosphate-binding agents
- Avoid milk
- Discontinue Mg-containing antacids (malox, mylanta)
- Ca-gluconate, Ca-carbonate
Long-term outcomes of ARF
- Pre-renal: recovery complete if perfusion restored
- Post-renal: almost complete recovery with fast resolution of obstruction (within 1 week)
- ATN:
- Mild injury: complete recovery
- Prolonged oliguria: decreased recovery
- > 50% mortality in ICU patients with ATN and HD support (Hemodialysis) - AIN: complete recovery after agent withdraw
- Renal arteroemboli: rare recovery
Cockroft-Gault estimation of Creatinine Clearance
(24 x age x ideal weight(kg))/ (72x (serum creatinine))
Stages of Chronic kidney disease
Based on creatinine clearance: Stage 1: normal GFR with signs of kidney disease Stage 2: GFR 60-99 (mild impairment) Stage 3: GFR 30-59 (moderate impairment) Stage 4: GFR 15-29 (severe impairment) Stage 5: GFR <15 Stage 6: renal replacement therapy
Symptoms of real failure
Mild: minimal fatigue, salt and H2O retention (edema, HTN)
Moderate dysfunction: more fatigue and edema, mildly impaired cognition, appetite preserved
Severe dysfunction: fatigue, loss of appetite (nausea, vomiting)
- Symptoms= UREMIC
Signs of severe uremia
Asterixis
Seizures
Pericardial friction rub: serosanguinous pericardial fluid
Lab abnormalities:
- prolonged bleeding time (platelet dysfunction)
- profound anemia
- low calcium and high phosphate- sometimes with subperiostial bone resorbtion on x-ray
- high alkaline phosphotase (secondary hyperparathyroidism)
- low bicarbonate (metabolic acidosis)
- high potassium
Complications and therapy of uremia:
Treated with medical management:
- Anemia (Hg 9-10: avoid transfusion)
- Pulmonary edema
- Vascular calcification (bone disease)
- Severe acidosis
- Bone disease
Treated with renal dialysis/replacement:
- Peripheral nervous system dysfunction
- Pericarditis
- Malnutrition
Preservation of GFR
Renal disease tends to be progressive, even if an insult is recognized and eliminated
Concept of progressive glomerular damage
Hyperfiltration injury
Efferent vs. afferent vasoconstriction
Physician uses anti-hypertensives to preserve renal function (ACE-I, ARB) by lowering GFR
- See slight elevations in creatinine (demonstrative benefit)
Diabetes: progression to nephropathy
Type 1 diabetics:
First 20 years: diabetes result in overt proteinuria in 15-20% of cases (if no proteinuria by 30 years, home free)
- All who develop proteinuria also have retinopathy and/or neuropathy
- Nephrotic range proteinuria (3+ g/day)
- Followed by end-stage renal disease in 5 years
Type 2 diabetics:
- Less predictable (onset unknown)
- May or may not include retinopathy/neuropathy
- Same pathology
Albuminuria in diabetes
- Microalbuminuria = >30 mg albumin daily
- Overt nephropathy > 300mg/day (nephrotic syndrome approximately 3,000 mg/day
- Routine urinalysis can’t detect microalbuminuria
- Microalbunuria portends nephropathy
Control/prevention of Diabetic nephropathy
- Controlling BP to less than 130/80
- Utilizing ACE inhibitors and ARB’s
- Diuretics
- Disrupt RAAS
- Very tight blood sugar control
- Type 2 outcome less predictable because of comorbidities like hypertensive renal disease, atherosclerosis, obesity
- Now overt proteinuria =5%, ESRD= 0.8%
Anemia due to nephropathy
Begins with GFR < 60 ml/min
- Progressive hemoglobin decline as GFR falls further
- Major cause = erythropoeitin deficiency
Treatment:
- Recombinant erythropoeitin injections
- Iron supplementation
- Target Hgb 9-10 grams- NOT TO NORMAL
Why correct anemia?
- Increased feeling of well being
- Reversal of LVH
- Improved cognition
- Improved cognition
- Improved life expectancy
- Forestall dialysis ?
Correction of Platelet deficiency in nephropathy
- Desmopressin – increased multimeric form of factor VIII vonWillebrand factor (increases platelet “stickiness”)
- Tachyphylaxis after 2nd dose
- Cryoprecipitate
- Conjugated estrogen – delayed onset, longer effect
- PRCB to hct > 30%
Metabolic acidosis
Cause= fall in serum bicarbonate
Symptoms:
- Normal anion gap, then high anion gap
- Bicarb < 16 is symptomatic
Treatment:
- Oral bicarbonate or citrate: 30-40 meq daily usually does the trick
Renal bone diseases
Renal osteodystrophy–> elevated PTH–> Osteitis fibrosa (cystica)
Low bone turn over disease (osteoporosis)
Osteomalacia
Osteitis fibrosa
- High PTH due to: hypocalcemia, hyperphosphetemia, low calcitriol level,
- Low calcium due to low calcitriol level
- High phosphate due to decreased GFR
- Result of increased PTH: too rapid bone turnover, abnormal bone (woven vs. trabecular)
Management:
- Maintain PTH at 2-3 times normal value (uremic bone resistance to PTH)-target varies with GFR (keep endogenous PTH low- Cinacalcet)
- Begin measuring PTH in stage 3 kidney disease
- Raise calcium to normal (vitD analogs, calcium carbonate, calcium acetate, calcitriol)
- Keep phosphate below 5 (phosphate binder= calcium acetate, calcium carbonate, sevelamer,or lanthanum carbonate with meals)
- Keep C X P < 55
- Kidney transplantation
Low bone turnover (adynamic) bone disease
High calcium X phosphate product; Low PTH
- May result from overzealous management of PTH with phosphate binders containing calcium
Result: vascular calcification, valvular calcification
** Most ESRD patients develop coronary calcifications
Osteomalacia
Historically iatrogenic
Heavy metal (aluminum) deposits at calcification front in bone
Don’t use aluminum hydroxide as a phosphate binder
Dietary consideration in ESRD
Protein restriction: malnutrition vs. minimal renal preservation effect
Potassium: 2 gram restriction. Usually clearance less than 25 ml/min
Low phosphate with stage 3-4 CKD
Sodium restriction: from day one
Fluid – variable
Renal replacement therapy (hemodialysis)
Hemodialysis: thrice weekly for 4 hours per treatment in center
- Short daily hemodialysis-home?
- Nocturnal hemodialysis-home?
- Peritoneal dialysis: at home, often at night
- Dialytic mortality: 24% annually
Renal transplantation
Deceased donor: - 95% one year patient survival - 90% one year graft survival - half-life 8-10 years - 4-6 year wait Live donor: - 98% one year pt - 94% one year graft survival - half-life 17 years
Donor issues: cadaver and live organ “quality”
Recipient issues: age and comorbidity
Renal transplant risks
- Surgical-bleed/hematoma/lymphocoele/MI
- Immunosuppression risk = meds
- Induction meds: IL2 receptor bockers, antithymocyte globulin
- Calcineurin inhibitors-cyclosporine, tacrolymus
- Antimetabolite = sirolimus, mycophenolic acid
- Corticosteroids
Osmolality calculation
2 x {Na+} + Glu/18 + Urea/2.8
- Can be directly measured by lab
Tonicity
“Effective osmoles”= Tonically active osmoles are confined to one side of cell membrane or the other
- Water moves across ICF and ECF to maintain equal tonicity between compartments (since Na and K cannot move)
Effective= Na, K, Cl, Mannitol
Ineffective= urea, ethanol
* Glucose can be effective or ineffective (depending on insulin)
- Can NOT be directly measured by lab
Physiology of response to changes in effective vascular volume, tonicity
RAAS responds to effective vascular volume (total body Na)
Hypothalamus responds to tonicity (amount of water in spaces= concentration of Na)
- Secretes ADH and stimulates sensation of thirst
- 10% reduction in effective vascular volume overrides tonicity and stimulates hypothalamic secretion of ADH + thirst
ECF volume
Na is major osmole of ECF
- Total body Na determines ECF volume
- Stable hemodynamics is dependent on stable ECF volume (maintained by Na balance)
Na Intake (dietary) = Na Output (renal and extrarenal)
- Renal excretion of Na is the major way of regulate Na content in body
- Extrarenal Na loss can outpace Na intake under certain conditions (diarrhea, burns, blood loss) leading to total body Na loss and abnormally low ECF volume (hypovolemia)
ECF volume disorder
Abnormalities in total body sodium content
- Normal total body sodium=euvolemia
- Too little sodium=volume depletion/ hypotension
- Too much sodium=volume overload/ edema
Osmolar disorders
Abnormalities in sodium concentration= abnormalities of water balance
- Too much water (relative to sodium) =hyponatremia
- Too little water (relative to sodium) =hypernatremia
IV fluid administration to correct water balance
IVF used to give NaCl–> Isotonic Saline
- Often called “normal saline”
- Tonicity is comparable to the aqueous portion of blood
IVF used to give water–> 5mg/dl dextrose
- Often called “D5W”
- Giving pure water IV would lyse red cells
5mg/dl dextrose is close to iso-osmolar initially, but the dextrose gets metabolized
- This leaves behind water
Renal handling of Na
Glomerulus: Na is freely filtered
- Daily Na filtered=
GFRxPna=180Lx140meq/L=25,200meq
- Kidneys have an enormous capacity for Na excretion
Tubules: >99% of filtered Na is reabsorbed
- Daily Na intake 80 to 250 meq
- Changes in daily Na intake only require very small adjustments in the rate of Na reabsorption
- Increased renin/AngII/aldo activity leads to increased Na reabsorption
Action of diuretics on various parts of kidney
CAI (acetazolamide)= proximal tubule
Furosemide= loop of henle
Thiazide= Distal tubule
Amiloride= Collecting duct
Effect of sodium depletion/hypovolemia on kidneys
Decreased venous return to heart--> decreased CO--> decreased BP--> increased baroreceptor stimulation--> increased sympathetic tone--> increased renin secretion--> 1. Angiotensin II formation--> vascular constriction and Na reabsorption 2. Angiotensin II--> aldosterone--> Na reabsorption
ADH: MOA
insert water channels into collecting duct luminal surface to increase water reabsorption
Medullary collecting tubule= water impermeable (without ADH)
- Need high osmotic gradient between medullary lumen and interstitium
- Allows for water to exit out of lumen down concentration gradient–> reabsorption
Maximal urinary concentration= determined by osmotic gradient in medulla and ADH secretion (max 1200 osmol)
Osmole intake and urine volume
Osmole intake = 600-1000 mOsmol per day
- Na, K, and protein (majority of osmol intake in western diet–> converted to urea)
Osm intake must = osmol output
- If ADH level fixed, Osm intake determines Urine volume
(ex: Urine osm= 300 msosm/L, Osm intake= 600 mosm; urine volume= 2 liters (600/300))
Stimuli for thirst
- Hypertonicity
- Habit (For normal people, drinking “8 glasses of water daily” has no proven health benefit!)
- Dry mouth
- Social conventions
- True volume depletion
- Effective volume depletion
Disorders of thirst
Psychogenic polydipsia or compulsive water drinking
- Normal individuals can excrete 12-15 liters/day of free water
- Psychiatric illness or drugs for its treatment can interfere with water excretion
Decreased water intake
- Physical disability limiting access to fluids
- Primary hypodipsia from lesions of the thirst center (rare)
- Geriatric hypodipsia (common)
Polyuria
> 3 L of urine daily
- Water diuresis: inability to concentrate urine: Uosm300
- “Mixed” diuresis: Uosm 150-300
Hyponatremia measurement
High serum osmol: hyperglycemia Normal serum osmol: hyperlipid, protein Low serum osmol: everything else - Hypo-osmolar hyponatremia: to develop patient must have: 1. Fluid intake (IV/PO) 2. [Osm] of fluid in< [Osm] fluid out
Hypo-osmolar hyponatremia
- Is kidney doing right thing?
- tonicity too low
- ADH should be absent (test for ADH with urine osmolality–> urine should be < 100 mosmol)
- A low urine osmol that is NOT < 100 (ie there is still ADH or urine is not maximally diluted) when the plasma osmol is low means there is:
- inappropriate ADH secretion OR
- > 10% effective intra-vascular volume depletion (blood loss)
- kidney damage (v. common)
Urine Osm < 100 mosmol:
- RARE conditions: psychogenic polydipsia, beer potomania (tea and toast diet), osmostat reset, or “you fixed it” hyponatremia
Determine causes of inappropriate ADH secretion
- Evaluate volume states (hypo-, hyper-, eu-volemic)
- History
- Orthostatic vitals (HR)- change of > 10% when sitting–> standing
- Urine [Na] < 20 mEq/L (volume depleted)
- Rule out diuretcs, kidney disease, etc.
Hypervolemia states
Determined by Extra-cellular fluid volume
CHF
Cirhosis Nephrosis
Hypovolemia states
GI losses Sweating Thiazides Cerebral Na wasting Aldosterone deficiency
Euvolemic states
SIADH
Glucocorticoid deficiency (glucocorticoids prevent fluid overload)
Hypothyroidism
Reset Osmostat (hypothalamus damaged–> fluid balance reset at new level causing fluid overload)
Causes of SIADH
Idiopathic Drugs (ADH release enhanced): - TCA, amitrptyline, haldol, morphine, vincristine, cyclophosphamide Drugs promoting ADH action: - ASA, NSAIDs Cancers: SCLC (paraneoplastic syndrome Brain damage Meningitis Infections Hypothyroidism
Treatment of Hypovolemic hyponatremia
Normal saline
Indications:
1. Dangerous hypovolemia (organ dysfunction, unstable vitals) –> bolus regardless of effect on hyponatremia
2. Mild-moderate hyponatremia and:
- Clearly due to volume depletion
- SIADH with urine electrolyte content < Saline (Electrolyte content = 2 x (U[Na] + U[K]), Can lower urine electrolyte content by giving Lasix)
- Benefit: Less risk of over-correction, Easier to fix volume status (since you can give more)
- Risks:
1. Can worsen hyponatremia in SIADH
2. If urine electrolyte content > saline electrolyte content, then water from saline will be retained in body
3. Over-correction still possible especially in hypovemic hyponatremia:
- Volume status restored before resolution of hyponatremia –> ADH drops to zero. Brisk water diuresis ensues–> rapid over-correction.
- Important example of “You fixed it” hyponatremia
Hypertonic saline
- only used in severe cases (CNS symptoms; Na < 120 mEq/L; unsure if SIADH vs volume depletion, but don’t want drop in [Na])
- Benefit: Increases Na regardless of cause of hyponatremia
- Risk: Can over-correct, and delays restoration of volume status in patient with undetected volume depletion
Treatment of Euvolemic hyponatremia
Fluid restriction:
+/- Hypertonic Saline (+/- Lasix)
+/- Vaptan (largely experimental- blocks ADH effect)
+/- NaCl or Urea tablets (chronic management)
+/- Demeclocycline (chronic management)
Treatment of Hypervolemic hyponatremia
Fluid restriction
Lasix
+/- Vaptan (largely experimental)
Risks of hyponatremia
If [Na] > 120, probably not an emergency
If [Na] < 120, then need to guess how well-compensated patient is:
- How quickly did this happen? (prior serum [Na]?)
- The faster the change, the more dangerous
- Is patient symptomatic?
Mild: Nausea, Headache
Moderate: Mental Status Change (can be subtle)
Severe: Seizure, Coma, Death
- Reversing disorder needs to be done gradually (over a couple of days) to avoid other complications of disrupting homeostasis
- Order FREQUENT LABS for serum [Na] and admit to ICU for close monitoring
Overcorrection of hyponatremia
Osmotic demyelination: Signs/Symptoms: - Dysarthria/Dysphagia - Weakness/paresis - Seizures - Lethargy/confusion/obtundation/coma - Often irreversible Occurs 2-6 days after over-correction
- Incidence: Unknown (Probably not that frequent)
High risk groups:
- Overcorrection: >12 mEq [Na] over 24 hours
- Females who have not had menopause
- Alcoholism
- Malnutrition, liver disease, hypokalemia
Treatment of hypernatremia
Water!
- Give isotonic solution as bolus to avoid tonicity disorder
Do NOT bring serum [Na] down by more than 12 mEq/day
Central vs Nephrogenic Diabetes insipidus
- Cannot reach urine osmol of 600 or more
Central: no ADH secretion
- Should be corrected by dDAVP
- Treatment: dDAVP (or excess water intake)
Nephrogenic: kidneys don’t respond to ADH
- Will not correct with dDAVP
- Treatment: discontinue offending meds, administer thiazide diuretics (paradoxical), NSAIDs, Na-restriction
Renal Dysplasia
Congenital anomalies of the kidney and urinary tract (CAKUT) due to:
- Malformation of renal parenchyma resulting in failure of normal nephron development–> renal dysplasia, renal agenesis, renal tubular dysgenesis, and polycystic renal diseases.
- Abnormalities of embryonic migration of the kidneys as seen in renal ectopy (eg, pelvic kidney) and fusion anomalies, such as horseshoe kidney.
- Abnormalities of the developing urinary collecting system as seen in duplicate collecting systems, posterior urethral valves, and UPJ obstruction
Kidneys are variable in size but most are smaller
- Discovered during routine antenatal screening.(increased echogenicity as a result of abnormal renal parenchymal tissue, poor corticomedullary differentiation, and parenchymal cysts.)
- By 20 weeks gestation, fetal urine accounts for 90 percent of the amniotic volume. Oligohydramnios is a clue .
- Associated urological findings- abnormalities of the renal pelvis and calyces (congenital hydronephrosis) and ureters (duplicating collecting system), megaureter, ureteral stenosis, and vesicoureteral reflux (VUR).
- Symptomatic presentation due to urinary tract infection, hematuria, fever, and abdominal pain
Clinical:
Important Contributor to ESRD in children (Especially in bilateral disease)
- In past, thought was that progressive loss of renal function was due to associated collecting system abnormality leading repeated bouts of pyleonephritis
- Modern belief is that parenchymal abnormalities are the cause of progressive decline in renal function
Management:
- Medical prophylaxis of UTI versus surgical correction of collecting system abnormalities
- No convincing evidence that surgery is superior
- Severe reflux with very frequent and/or severe UTI’s is
nevertheless often managed surgically.
- The rate of spontaneous resolution is dependent upon age, grade of reflux, and whether the reflux is unilateral or bilateral.
Cystic kidney disease
Types:
- Autosomal dominant polycystic kidney disease
- Autosomal recessive polycystic kidney disease
- Medullary sponge
- Mdullary cystic disease/nephronophthisis
- Simple renal cysts- few, no disease
- Acquired cystic disease of renal failure
Autosomal dominant polycystic kidney disease (ADPKD)
AKA—Adult Polycystic Kidney Disease - Common congenital disease—1/1000 births
- Accounts for 5% of all adult renal failure
- Initial symptoms occur between 30 & 50 yrs
- Back pain is most common complaint
- Half of all ADPKD pts will require transplantation or dialysis
Symptoms:
- Typically asymptomatic until the fourth decade of life
- loin “fullness”
- Palpable flank masses in adults
- Hematuria (gross clots)
- Azotemia
- Uremia
Pathogenesis:
- 85% of cases show mutation in PKD 1 gene on chromosome 16 (40s-50s, worse outcome)
» Protein = polycystin-1
– 15% of cases show mutation in PKD 2 gene on chromosome 4 (70s-80s, better prognosis)
» Protein = polycystin-2 – Both proteins reside in tubular cell cilia
» Defects affect calcium signaling
» Mutations result in abnormal renal tubular growth
Gross pathology:
- Bilateral Enlargement
- Up to 4500 g
- Distorted shape
- Multiple cysts of varying sizes filled with clear, straw-colored fluid
Histo:
- Simple cysts lined by flattened cuboidal and columnar epithelium
- Arise from proximal and distal tubules as well as from the collecting ducts
- Normal renal parenchyma can be present between the cysts
Associated path:
- Hepatic Cysts—33% of cases
- Splenic Cysts—10% of cases
- Pancreatic Cysts—5% of cases
- Cerebral Aneurysms—No Family history- 6 % prevalence, family history -21% prevalence.
- Diverticular Disease of the colon often seen
Clinical Management of PKD
Supportive Care – Monitor Creatinine – Aggressive blood pressure control » ACEI, especially if there is evidence of proteinuria. » Avoid caffeine, DASH diet
Future therapies:
– Vaptans (ADH antagonists) have been effective
in animal studies in preventing progression – Human Studies are ongoing
Antibiotics:
- Some drugs do not penetrate cysts well. - Fluoroquinolones, TMP- sulfa,
chloramphenicol best for cyst penetration.
- Do not adjust dose for UTI in renal insufficiency.
Autosomal recessive polycystic kidney disease
AKA—Infantile Polycystic Kidney Disease
- Rare—1/10,000 to 1/50,000 births
- 75% of affected infants die perinatally
- Rare cases can manifest in older children
Clinical correlates:
- Results in Oligohydramnios (decreased amniotic fluid as fetal kidneys can’t properly filter blood, produce urine)
- Causes Pulmonary Hypoplasia due to mass effects
- See Associated Hepatic and Pancreatic Cysts
- Infants often have biliary dysgenesis and hepatic fibrosis
Pathogenesis:
Mutations in the PKHD1 gene
- Protein = fibrocystin
- Fibrocystin is involved in cell proliferation and adhesion
- Fibrocystin is found in the kidneys, liver, and pancreas
Pathology:
- Disease is Bilateral
- Enlarged Kidneys (often impede delivery)
- Fusiform Cysts of Collecting Ducts – Affects cortical and medullary ducts
- Cysts Arranged Radially, Perpendicular to renal capusule
- Accompanying interstitial fibrosis and tubular atrophy (due to compression)
Nephrocalcinosis: differential
Nephrocalcinosis with hypercalemia and hypercalciuria: associated with systemic problems: - Primary hyperparathyroidism – Sarcoidosis - Vitamin D therapy - Milk alkali syndrome
Nephrocalcinosis without hypercalcemia but presence of hypercalciuria- not systemic problem
– Distal RTA
- Medullary sponge kidney
- Premature infant with lasix usage
Medullary sponge kidney
Unknown pathogenesis:
Epidemiology:
- Sex predilection-slight male predominance
- Symptomatic cases usually emerge at 30-60 yrs
- Nonhereditary
Symptoms:
- flank pain, dysuria, hematuria, gravel sized stones.
- Hypercalciuria in 50% of symptomatic pts
Clinical course:
- Increased risk of kidney stones and urinary tract infection
- Excellent long-term prognosis – progressive disease very rare
Pathology:
- May be associated with hemihypertrophy
- bilateral in 75% of patients
- Cysts involve the branches of collecting ducts and papillae
- Glomeruli are normal if secondarily affected by distal obstruction
- Kidneys are not enlarged and are symetrical
- Discovered in work-ups of nephrolithiasis
Microscopic
– Flattened cuboidal or transitional epithelium
– Intracystic calcifications
– Associated intersitial inflammation
Acute renal failure: differential
- Acute tubular injury due to hypotension/ sepsis
- Staphylococcal pyelonephritis with abcess formation.
- Obstructive uropathy
- Prerenal from volume depletion (febrile)
Acute tubular injury
Etiology:
- Ischemic
- Toxic
- Inflammatory
- Immunologic
- Atrophy
- Viral
Management:
- Keep Mean arterial pressure>65
- No nephrotoxins
- Adjust Antibiotics dosage
- Once euvolemic, cautiously give IVF based on insensible losses and urine output
- Assess need for renal replacement therapy based on daily labs and clinical picture.
Sterile pyuria: differential infectious or non-infectious causes
Infectious causes
- A recently (within last 2 weeks) treated UTI
- Chlamydial urethritis
- Prostatitis
- Appendicitis – if appendix lies close to ureter or bladder
- Renal tract tuberculosis
- Adenovirus, BK,rejection – in immunocompromised patients
Non infection related
- Recent cystoscopy and urinary tract surgery
- Urinary tract stones
- Urinary tract neoplasm
- Interstitial nephritis
- Polycystic kidneys
- Interstitial cystitis-( cystoscopy shows inflammation with ulceration)
- SLE and other systemic inflammatory diseases, Kawasaki disease
Interstitial nephritis
Causes:
- DRUGS: NSAIDS, PCN, cephalosporins, rafampin, cimetidine, ciprofloxacin, allopurinol
- Infections: legionella, mycobacteria, streptococcus, CMV, BK polyoma etc
- Idiopathic- 8% Autoimmune disorders-SLE, sarcoidosis, Sjögren’s
syndrome.
- TINU (tubulo-interstital nephritis and uveitis) syndrome- flank pain, sterile pyuria, hematuria, proteinuria (usually subnephrotic range) and uveitis.
Histo:
- Key is eosinophilic infiltrate in interstitium - Variable amount of interstitial edema
- Can see “spill-over” effects on glomerulus
- Interstitial fibrosis is dependent on duration of disease.
Acute pyelonephritis
Path:
- Acute inflammation of tubules
- Secondary tubular damage
- Spill-over into interstitium
- Neutrophilic casts in tubular lumens
- Casts may be seen in urine
Symptoms:
- Cystitis- dysuria,frequency,urgency, suprapubic pain, and/or hematuria.
- Pyelonephritis consist of the above symptoms (symptoms of cystitis may or may not be present) plus fever (>38oC), chills, flank pain, costovertebral angle tenderness, and nausea/vomiting
Management:
- Untreated cases can lead to chronic pyelonephritis
1. Complicated Cystitis: - oral fluoroquinolone such as ciprofloxacin (500 mg orally twice daily or 1000 mg extended release once daily)
- levofloxacin (750 mg orally once daily) for 7 to 14 days.
- Avoid moxifloxacin..
2. Complicated Pyelonephritis — should be managed initially as inpatients. Use broad spectrum antibiotics while awaiting susceptible testing
3. Underlying urinary tract anatomic or functional abnormalities (such as obstruction or neurogenic bladder) should be addressed in consultation with an urologist.
Complications requiring hospitalization:
Diabetes
- Pregnancy
- History of acute pyelonephritis in the past year
- Symptoms for seven or more days before seeking care
- Broad-spectrum antimicrobial resistant uropathogen
- Renal failure
- Urinary tract obstruction
- Presence of an indwelling urethral catheter, stent, nephrostomy tube or urinary diversion
- Recent urinary tract instrumentation, Renal transplantation, Immunosuppression
Chronic Interstitial disease
Histo
- tubular atrophy
- interstitial fibrosis
- tubular protein casts
- Lymphocytes and plasma cells in interstitium
- Pathology is dependent on chronicity of inflammation
- Secondary Glomerular changes occur
- Uncommon cause of interstitial disease
Normal blood gas levels
Bicarb= 25 mmol/L pCO2= 40 mmHg pH= 7.42= 6.1 + log[25/(0.03x40)]= 6.1 + log(20.8)
Acid-base buffers in human blood
Monobasic-dibasic phosphate HPO42-/H2PO4- = pK 6.8 Ammonium-ammonia NH4+/NH3= pK 9.2 Lactic acid-lactate = pK 3.9 Deoxygenated hemoglobin= pK 7.9 Oxygenated hemoglobin= pK 6.7 Serum proteins (albumin, immunoglobulins)
Causes of metabolic acidosis
- Addition of H+ ions to the body from endogenous (e.g., lactic acid) or exogenous (e.g., salicylic acid) sources.
- Loss of HCO3- from body fluids via GI tract (diarrhea) or the kidneys (renal tubular acidosis).
- Decrease in the ability of the kidneys to excrete acid (acute or chronic renal failure).
- Rapid dilution of the extracellular fluid with a non- HCO3- solution (so-called dilutional acidosis).
- In simple metabolic acidosis, serum HCO3 is ALWAYS lower than 25 (normal value)
Anion Gap
Anion Gap (AG)= Na+ - (Cl- + HCO3-) Normal AG= 10-12
- Adding any acid to blood (besides HCl)–> anion gap > 10
Causes:
- Lactic acidosis
- Ketoacidosis
- Toxins (salicylate, methanol, ethylene glycol)
- Renal failure
- Rhabdomyolysis
- Toxic shock
Non-Anion Gap Acidosis
Hyperchloremic non-Anion Gap Acidosis:
- Add HCl to blood- buffer 10 meq of H+ with 10 mEq HCO3-
- Simultaneously, 10 mEq Cl- is added (part of anion gap equation)
- Anion gap does not change, but acid was added to blood
Causes:
- GI losses of bicarb due to: diarrhea, panreatic drainage, anion exchange resins
- Expansion acidosis (inappropriate fluid replacement with large volumes of isotonic saline—> dilutes HCO3, raises Cl-)
- Proximal Renal Tubular Acidosis: kidney can’t resorb bicarb (also seen withcarbonic anhydrase inhibitors)
- Distal Renal Tubular Acidosis: Impaired H+ ion secretion (renal insufficiency, distal RTA)
- Hypoaldosteronism (hyperkalemia–> decreased kidney production–> decreased NH4Cl excretion)
- Parenteral hyperalimentation, addition of HCl, recovery from ketoacidosis
Overshoot alkalosis
Administration of too much bicarb–> imbalance between bicarb and pCO2
- patient attempts to increase pCO2:
- Stops breathing to increase pCO2
- NO benefit in giving NaHCO3 to patients in severe DKA, regardless of pH
- Unsure about giving bicarb for shock-induced severe lactic acidosis
Clinical manifestations of metabolic acidosis
Respiratory: Kussmaul’s breathing (blowing off CO2)
Cardiac: decreased contractility, hypotension.
Increased ionized Ca2+:
- H+ and Ca+2 compete for binding to albumin.
- Increased H+ (acidosis)–> unbound Ca+2
- If a patient is already hypocalcemic (low ionized Ca2+) while he is suffering from metabolic acidosis, correction of metabolic acidosis (without first or concomitantly correcting hypocalcemia) will worsen hypocalcemia and precipitate tetany.
Systemic arterial vasodilatation: hypotension.
Demineralization of skeleton (chronic metabolic acidosis);
- H+ is buffered by bone.
- In distal renal tubular acidosis, filtered PO42- and SO42- require cations for excretion since H+ excretion is not adequate–> Ca2+ and Mg2+ are lost in urine.
Treatment of metabolic acidosis
- Always try to treat underlying cause: fluids, vasopressors, antibiotics for septic shock; IABP, inotropes, etc., for cardiogenic shock; fluids and insulin for diabetic ketoacidosis.
- Calculate HCO3- deficit: if you decide to give NaHCO3, then calculate HCO3- deficit as follows:
- Total Body Water = Body Weight x 0.6 Liters
- HCO3- deficit = (25 – [HCO3-]) x TBW
- e.g., 70 Kg man, serum [HCO3-] = 10 meq/L
- HCO3- deficit = (25 –10)meq/L x 42L = 630 meq. - Replace ½ of HCO3- deficit in 1st 24 hours, and the remaining ½ in next 48 hours.
- e.g., in above case, want to give 315 meq HCO3- in 1st 24 hours.
- Put 3 amps (150 meq total) NaHCO3 in 1L of D5W. 2L of this fluid will give 300 meq of NaHCO3. Rate of IV infusion = 2000ml/24 hr = 83 ml/hr. - Don’t forget to correct hypocalcemia if present.
HCO3- reabsorption, H+ secretion in kidney
Proximal tubule:
- Carbonic anhydrase present in lumen (nowhere else)
- H+ secreted by Na+/H+ exchanger in apical membrane
- H+ combines with HCO3- to form H2CO3
- Carbonic anhydrase: H2CO3–> H2O and CO2
- Carbonic anhydrase: CO2–> proximal tubular cell–> HCO3–> reabsorbed (80-90%)
Distal tubule/collecting duct (intercalated cells):
- H+ secreted by H-ATPase–> forms H2C)# in lumen–> dissociates to H2O and CO2 (slowly reabsorbed)
- 5% in loop of Henle, 3% in distal tubule, 1-2% in collecting duct
Disorders associated with hypokalemia
Loop, thiazide diuretics
Inadequate intake
GI losses, sweating
Diabetic ketoacidosis
Hypomagnesemia
Alkalosis
Hyperaldosteronism
Congenital:
- Bartter’s syndrome
- Gitelman’s syndrome
- Liddle’s syndrome
Factors increasing H+ secretion, HCO3 reabsorption
- Increased Na+ reabsorption : Proximal tubular H+ secretion is linked to Na+ entry. In the distal tubule, enhanced Na+ reabsorption increases lumen electronegativity.
- Mineralocorticoids: Increased Na+ reabsorption in the distal nephron (increased ENaC channels), increased H+-ATPase activity.
- Increased pCO2: Increased intracellular acidosis.
- Hypokalemia: increased ammoniagenesis.
- With volume contratction, renal blood flow decreases–>
1. Decrease GFR : decrease filtered NaCl, NaHCO3 and H2O.
2. Increase Proximal Reabsorption of both Na+ and HCO3-.
3. Increase renin/angiotensin II/aldosterone: enhance distal Na+ reabsorption and H+-ATPase, leading to increased HCO3- reabsorption.
- With volume contratction, renal blood flow decreases–>
Sustained metabolic alkalosis
Due to:
- Volume contratction (decreased effective circulatory volume)
- Persistant Hypokalemia
- Both
Causes:
- Vomiting/gastric drainag
- Diuretic therapy inhibiting NaCl reabsorption (Furosemide, ethacrynic acid, metolzone, bumetanide, thiazides)
- Sudden relief of chronic hypercapnia
- Congenital chloridorrhea (diarrhea)
- Administration of alkali
- Resistance to chloride (excess mineralocorticoids, Bartter’s syndrome, Severe K+ depletion)
Clinical manifestations of metabolic alkalosis
- decreased ionized Ca2+: paresthesias, carpopedal spasm.
- decreasedrespiratory drive: decreased pO2, increased pCO2. Important if you are trying to wean your patient from the ventilator.
- decreased K+: polyuria, polydipsia, muscle weakness
Causes of Respiratory Acidosis
Acute:
- Airway obstruction (aspiration, laryngospasm, bronchospasm)
- Circulatory catastrophes
- CNS depression
- NM impairment
- Ventilatory restriction
Chronic:
- COPD
- NM diseases
- Ventilatory restriction
- CNS disorders
Causes of Respiratory alkalosis
- Hypoxia (high altitude, V/Q mismatch, hypotension)
- CNS
- Drugs/hormones (salicylates, nicotine, dinitrophenol, xanthines, pressor hormones, progesterone)
- Pulmonary diseases (interstitial fibrosis, pneumonia, pulmonary edema, embolism)
- Other (pregnancy, hepatic failure, gram-neg septicemia, heat)
- Mechanical overventilation
Estimation of metabolic compensation for respiratory acid-base disorders
- Respiratory acidosis:
Acute: ^HCO3= 0.1^(pCO2)
- or 1 mEq increase in HCO3 for 10 mm Hg increase in PCO2
Chronic: ^HCO3= 0.3^(pCO2)
- or 3.5 mEq increase in HCO3 for 10 mm Hg increase in PCO2 - Respiratory alkalosis
Acute: ^HCO3 = 0.2 ^pCO2
- or 2 mEq drop in HCO3 for 10 mm Hg drop in pCO2
Chronic: ^HCO3= 0.4 ^pCO2
- or 5 mEq drop in HCO3 for 10 mm Hg drop in PCO2
^= delta (change in value)
Estimation of respiratory compensation of metabolic acid/base disorders
- pCO2= 1.5 x HCO3- +8 +/- 2 (Winter’s formula)
- pCO2= 15 + HCO3-
- pCO2= last 2 digits of pH
Urine dipstick stats
Specific gravity of water= 1.000
Specific gravity of urine= 1.0XX (higher= more dehydrated)
pH of urine= 5-6.5
Contents of blood: Protein in blood: - Red blood cells (heme) - Myoglobin Heme Nitrites (Nitrate breakdown from UTI) Ketones (low sugar diet--> ketogenesis) Glucose (diabetes)
Renal embryology and dysmorphogenesis
Kidneys develop in utero; issues with development can be clinically important
- Single kidney (can survive without awareness of absent kidney)
- Kidney malrotation and duplication
- Collecting system faces laterally, passes over anatomic structures
- Can develop uro-pelvic junction obstruction (painful, UTIs, hydronephrosis) - Horseshoe kidney:
- Common malformation in Turner’s (45X) - Polycystic kidneys
- Potter syndrome:
- Congenital absence of kidneys
- Oligohydramnios–> less fluid in sac–> abnormal limb development
- Dies from lung failure due to inadequate fluid in amniotic sac - Multiple ureters, can be attached to various structures
- Uretocele: obstructs ureters from emptying into bladder
- Vesicoureteral reflux: on urination, moves back up toward kidney
- Scale of 1-5 (5= worst, more UTIs, hydronephrosis) - “Prune belly syndrome”- no abdominal musculature, organ malformation
Clinical presentation of renal dysmorphology
Asymptomatic UTIs Hematuria Renal insufficiency/hypertension Obstruction Wilm's tumor
Kidney changes in children
GFR: Increases with age- comparable to adult levels at 2-3 years
Osmolarity: increased ability to concentrate urine
Capacity: increases with age
- 2 ounces at birth
- 1 ounce per year until adulthood
Decreased ability to reabsorb bicarbonate
- Lower serum bicarb in children than adults (19 vs 24)
- Children compensate with higher respiratory rate
Yellow/orange urine color
Concentrated urine
Bile
Medications (rifampin, coumadin, flagyl)
Urate
Red/Brown/Black urine color
Blood (RBCs, hemoglobin)
Myoglobin
Medications (phenothiazines, dilantin)
Food (beets, blackberries, red dye)
Blue/Green urine color
Medications (amitryiptyline, methylene blue, indomethacin)
Pseudomonas infection
Bloody urine
Hemoglobinuria
Hematuria (renal, extrarenal)
Glomerular: casts, red cell morphology, concurrent proteinuria, cola colored, concurrent hypertension and edema
- Vasculitis (Henoch Schonlein purpura, HUS)
- Glomerulonephritis
- Recurrent hematuria syndrome
Non-glomerular:
- UTI
- Trauma
- Nephrolithiasis, hypercaciuria
- Hemoglobinopathies
- Renal malformations
- Medications
- Tumors
Body content of potassium
Normal 70 Kg man= 3500 mEq of K
- 98% distributed in intracellular compartment
- 75% in muscle
- 2% in extracellular fluids
Body distribution of K: RBC (250 mEq) Muscle (2635 mEq) Liver (250 mEq) Bone (300 mEq)
Body fluid K:
- Normal serum K = 3.5 to 5 meq/L
- Extracellular K is freely filterable.
- Normal intracellular K = 120 to 150 meq/L
Excretion:
- Urine< 20-25 mEq/day
- Stool= 5-10 mEq/day
Principle Cell
Location: collecting duct
Main job= moving potassium out of kidney (Pee K out)
Tubular lumen:
- Na channel (move Na in)
- K channel (move K out)
Capillary side:
- ATPase (Na out of cell into blood, K into cell)
- Aldosterone Receptor: opens Na channel on luminal side)–> electronegative gradient set up in lumen–> K moves out
Intercalated cell
Absorbs potassium (keep K In)
Tubular lumen:
- H+ ATPase: pumps H+ out
- K/H+ ATPase: K+ in, H+ out
Capillary side:
- Cl- moves into cell, HCO3- moves out (into blood)
Nernst equation
Resting membrane potential (Em) is greatly influenced by shifts in extracellular potassium (Ke)
- Will lead to dramatic changes in cardiac rhythm, NM function
Factors influencing internal distribution of K
Decrease:
- Insulin
- Beta-2 stimulation
- Alkalosis
- Anabolism
Increase:
- Mineral acidosis (H shifts into cells, K out)
- increased tonicity
- Beta-blockade
- alpha-stimulation
Insulin effects on K
Promotes entry of K into skeletal and hepatic cells by increasing Na-K ATPase
- Also causes hyperpolarization–> passive entry
- Remember that patients with severe hyperglycemia are already K-deprived–> treating with insulin can worsen this
Catecholamine effects on K
Beta-agonists–> increased aldosterone (hypokalemia)
Alpha-agonists/ beta-blockers–> decreased aldosterone (hyperkalemia)
MOA:
- Beta-2-adrenergic agonists activates Na-K-ATPase –> increased K uptake in liver and muscle.
- Beta-adrenergic receptors in muscle also activates Na-K-2Cl cotransporter, (1/3 of K uptake response to catecholamines)
- Beta-adrenergic agonists impair the ability to buffer increases in K due to IV loading or exercise. The cellular mechanism is unknown.
- Propranolol (Beta blocker, non selective)–> decreased aldosterone–> can cause hyperkalemia
- Chronic digitalis use can increase risk of hypokalemia
- atenolol (beta 1 blocker, selective)= will not effect K levels
Acidosis effects on K
Acute acidemia shifts H into cells and K out of cells.
- Acute acidemia also inhibits distal tubular secretion of K.
- In general, a 0.1 unit decrease in pH will increase serum K by 0.5 to 0.6 meq/L
- Metabolic acidosis causes a more pronounced increase in serum K than respiratory acidosis.
- More commonly caused by mineral acidosis
Hypertonicity effects on K
Hyperglycemia is clinically the most common cause of hypertonicity.
- Other causes: hypertonic mannitol, hypernatremia
- Hypertonicity shifts K and water out of cells.
- Important cause of hyperkalemia in diabetic patients, especially in hyperosmolar nonketotic coma.
- In diabetic ketoacidosis, hyperkalemia is not as marked because of associated severe K deficiency.
Body potassium balance
Small increases in plasma K stimulates aldosterone release–> distal K excretion
- Elevated plasma K–> increased aldosterone
- Aldosterone–> Na absorption via EnaC channel–> electronegative lumen
- Increase transport of Na out, K in via Na K ATPase pump on capillary side–> increased intracellular K conc.
- Increased intracellular K–> Opens up ROMK channels for K excretion.
Distal Na Delivery and K balance
Na enters the cell via amiloride-sensitive ENaC, resulting in the generation of lumen-negative potential in the cortical collecting duct.
- This negative lumen potential drives K exit via ROMK (small K) and Ca-activated K (maxi-K) channels.
- Increases in distal Na delivery, increase in K secretion.
- When luminal Na is < 8 meq/L, K secretion ceases
Mineralocorticoids and K balance
Aldosterone increases ENaC activity:
- re-distributes ENaC from cell interior to plasma membrane
- Decreases ENaC ubiquitination and degradation (aldosterone activates serum glucocorticoid-induced kinase 1 (SGK-1) which phosphorylates Nedd4-2. Phosphorylated Nedd4-2 cannot bind to the PPxY motif of ENaC, resulting in failure to ubiquitinate ENaC).
- Increases open probability of ENaC (channel activating protease 1 or CAP-1).
- Increases ENaC activity results in increased apical Na entry, making the lumen more negative, favoring K secretion via ROMK and Maxi-K channels.
- Aldosterone also increases expression of Na-K-ATPase in CCD
Luminal flow rate and K balance
- Increase in distal flow rate, increased K secretion.
- This is because lower tubular fluid K concentration due to K free fluid from more proximal segments and therefore high concentration gradient maintained.
- Most likely mediated by Ca-activated K channel (Maxi-K) channels.
Acid-base balance and K balance
Acute metabolic/repsiratory acidosis: decrease K secretion by decreasing apical Na/K channel conductances in CCD
Chronic metabolic acidosis: increases K secretion by inhibiting proximal tubule Na and fluid reabsorption, thereby increasing distal Na delivery.
Acute metabolic or respiratory alkalosis: increases K secretion by increasing channel open probability.
Decreased effective arterial blood volume and K levels
Increased filtration fraction (due to low blood levels):
- Increased proximal Na reabsorption–> Decreased distal Na delivery–>
- RAAS activation–> increased aldosterone–>
* BUT, no Na to be reabsorbed in distal tubule–> K is not dumped
- Hypokalemia will not ensue
Increased effective arterial blood volume
Decreased filtration fraction:
- Decreased proximal Na reabsorption–> Increased distal Na delivery
- decreased JG activity–> decreased renin–> decreased aldosterone
* Aldosterone decreases (decreasing Na reabsorption–> potential hyperkalemia) BUT Na reabsorbed in distal tubule–> more K dumped
- No hyperkalemia
Hyperkalemia due to cell shifts
- Cell injury (rhabdo, tumor lysis, massive hemolysis, ischemia)
- toxins, drugs (digoxin, succinylcholine)
- DKA (hypertonicity–> solvent drag moves K out with water), non-ketotic hyperosmolar states
- Hyperkalemic periodic paralysis
Metabolic acidosis and hyperkalemia
Inorganic (mineral acids like HCl): causes K shifts
- H moves in (without Cl)–> K must move out
Organic acidosis examples:
- DKA (insulin deficiency, hypertonicity)
- Lactic acidosis (cell ischemia)
- Epsilon aminocaproic acid, IV lysine/arginine
Impaired renal K excretion and hyperkalemia
- Decrease in mineralocorticoid activity (no Na channel activation, K does not go out)
- Decreased distal sodium delivery: oliguric ARF, glomerulonephritis, CHF, hepatorenal
- Abnormal cortical collecting duct (drugs, tubulo-interstitial disease, urinary obstruction–> backward pressure in collecting ducts–> electronegative charge in lumen disrupted–> impeded secretion)
Hyperkalemia and drugs
Diabetics: microvascular disease of JG cells; hyperrenin, hyperaldosterone
NSAIDs: inhibits renin release (due to decreased prostaglandin synthesis)
Beta blockers: propanolol predisposes to hyperkalemia, block adrenergic system–> hyporeninism hypoaldosteronism
Cyclosporin: suppress renin release
ACE-I: prevent Angiotensin-I going to angiotensin II
ARBs: Angiotensin II can’t produce aldosterone
Heparin: inhibit aldosterone biosynthesis in adrenal gland
Azole antifungals: inhibit aldosterone synthesis (ketoconazole> diflucan)
Spironolactone/eplerinone: prevent aldosterone from binding
Drugs inhibitng ENaC channel (amiloride, triamterine, rifampin, amiloride
Risks of hyperkalemia: EKG abnormalities
TdP, arrhythmias
Management of hyperkalemia
Ca gluconate: prevent arrhythmias
Glucose-insulin: move K back into cells (with glucose to prevent hypoglycemia, except in diabetics
Beta-agonists (higher concentrations): stimulate Na/K ATPase
NaHCO3: temporary measure
Kayexalate: dump K from body
- Oral (4 hours- binds more K in intestine) or rectal (2 hours)
Dialysis: physically remove K from blood
- Diffusion of K out of body
Chronic management of Hyperkalemia
Stop offending meds
Low K diet (70 mEq/day)
Assess volume, BP status
- Can use florinef (mineralocorticoid–> stimulate aldosterone receptors)
- Loop diuretics (dump K)
- NaHCO3
Kayexalate: can cause GI ulceration (don’t give in post-op ileus, bowel obstruction)
Hypokalemia
Caused by:
- Cellular shifts: insulin, -adrenergic agonists, anabolism
- Inadequate dietary intake: alcoholism or anorexia nervosa
- GI losses: NG suction, vomiting, diarrhea (villous adenoma of colon), laxative use
- LOWER GI losses cause hypokalemia; upper GI losses (NG suction)–> alkalosis–> hypokalemia
- Hypokalemic periodic paralysis: mutated L-type Ca channel.
- Renal K wasting.
- Ureterosigmoidostomy: secretion of K and HCO3 in exchange for Na and Cl in colon.
Pseudohypokalemia
AML: metabolically active cells take up K with marked leukocytosis (test tube phenomenon)
- Prevent by storing blood at 4 degrees C
Cell shifts causing hypokalemia
- Anabolism: Rx of pernicious anemia, TPN, rapidly growing leukemia and lymphomas.
- Hypothermia (K moves intracellularly- don’t aggressively correct K as it will move back out as they warm up)
- QRS prolonged, PR prolonged, brady, amplitude decreases, giant osbrone wave or j wave
- Barium and chloroquine intoxication (RARE- poisons Na/K pump)
- Hypokalemic periodic paralysis
Hypokalemic periodic paralysis
Intermittent acute attacks of muscle weakness with low K and often low phos and low Mg.
Triggered by large CHO meals, rest post exercise; two forms:
- AD, mutation in alpha 1 subunit of DHP sensitive Ca channel
- Thyrotoxicosis: Asians and Mexicans
- Only K replacement for acute attack and then stop (episodic)
- Long term management: B2 blockade (propanolol- moves K extracellularly, prevents thyrotoxicosis (T3-T4 conversion), acetazolamide, low carb diet, Rx hyperthyroidism
GI losses causing hypokalemia (lower GI)
Most common finding: Urinary K renal K loss due to alkalosis from loss of stomach HCl
- Clay ingestion: (binds K in GI tract, also see low Fe); but red clay associated with hyperkalemia (contains K).
- Chloridorrhea, villous adenoma, chronic laxative abuse (colon effect)
- High volume profuse diarrhea involving small bowel.
Chronic laxative abuse
Laxative effect on colon—>
K depletion–>
1. Intracellular acidosis–> Increased renal NH3 production (to deplete H overload)–>Increased urinary excretion of NH4Cl
2. Increased intercalated cell H+/K ATPase activity
** Generates metabolic alkalosis
Renal potassium wasting
Urinary K > 20 mEq/day with no history of diarrhea
- Coupling of increased distal sodium delivery, increased mineralocorticoid activity
Increased EABV–> decreased Na reabsorption (Na dumping) + high K in urine
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Primary mineralocorticoid release
Primary hyperrrenism:
- Elevated renin, aldosterone
- Saline suppression test
- Differential diagnosis: malignant HTN (50% hypokalemic due to pressure natriuresis), RAS (15% hypokalemic)
Primary Hyperaldosteronism:
- Elevated aldo, depressed renin
- Differential: Conn’s syndrome, bilateral adrenal cortical hyperplasia
Increase in non-aldo mineralocorticoid: - Depressed renin and aldosterone Differential: - Cushing's - Congenital adrenal hyperplasia (11-beta hydroxylase deficiency= virilization, 17-alpha hydroxylase deficiency= decreased sex hormones) - Liddle syndrome
Liddle’s syndrome
Non-responsiveness to aldosterone:
Mutation causing Na channel to be open all the time (not responsive to aldosterone)
- Leads to Na retention, K loss
Symptoms:
- Hypertension
- Hypokalemia
- Metabolic alkalosis-like hyperaldosteronism, decreased renin, aldosterone
Treatment:
- Na restriction
- Drugs blocking Na channel: triamterene, amiloride
Primary increase in distal Na delivery–> hypokalemia
Diuretics (acting on proximal collecting duct)
- Causes volume depletion–> high aldosterone–> hypokalemia
Magnesium deficiency
- Mg deficiency inhibits thick ascending limb Na absorption
- important cofactor for ATP production; TAL uses ATP–> depletion–> less Na reabsorption (more K dumping)
- Similar to 10 mg lasix dose
Non-reabsorbable anions:
- Sodium dragged distally due to nonreabsorbable anion
- Aldosterone+ sodium coupled–> K wasting
- DKA, carbenicillin, ticarcillin can also drag Na distally
Bartter’s syndrome:
- Like being on Lasix: Cl-channel mutation (type 3- only type that survives to adulthood- Also seen in inner ear (deafness))
- Treat with K replacement, K-sparing diuretics
- Ca-wasting seen–> hypercalciuria, Mg wasting
- Increased secretion of prostaglandins prevents HTN
Gitelman’s syndrome
- Similar to thiazide diuretics: NaCl co-transporter inactivating mutation
- Hypokalemia, hypomagnesemia, hypocalciuria (retaining Ca in blood)
- Asymptomatic- see symptoms in adolescence (cramps, muscle weakness)
Clinical manifestations of hypokalemia
Cardiac:
- decreases excitability, increases conduction.
- Arrhythmias (atrial fibrillation).
- Potentiates digitalis toxicity (K and digoxin competes for binding sites in the Na-K-ATPase).
- U-wave after T-wave with increased amplitude
Neuromuscular:
- ascending muscle weakness,
- respiratory failure,
- rhabdomyolysis,
- paralytic ileus.
Renal:
- Impaired concentrating ability(decreases aquaporin 2 expression in collecting duct)
- Increased renal ammoniagenesis
- Increased bicarbonate and Na reabsorption( increased exporession of Na-H exchanger in proximal tubule (increased Na and HCO3 reabsorption)
- Hypokalemic nephropathy
- Elevation in blood pressure
Treatment of hypokalemia
Replace KCl IV or PO
- drop from 4-3 meq/L–> loss of 200-400 mEq of K
- KCl used to replete Cl as well
- IV repletion should be non-dextrose
Body content of Calcium
70 kg man= 1.3 kg calcium
99% in bone, teeth
1% soft tissues
0.15% in extracellular fluid
Body fluid calcium:
- Concentration= 8.5 to 10.5 mg/dl
- 50%= ionized form (BIOLOGICALLY ACTIVE form). Normal ionized calcium is 4.5 to 5.1 mg/dl
- 40%= bound to serum proteins (albumin, globulins) and not ultrafiltrable
- At pH 7.4, 1 g/dl of albumin binds 0.8 mg/dl of calcium
- 10% is complexed to organic anions (citrate, phosphate, acetate, bicarbonate) and ultrafiltrable
Body balance of calcium (input/output)
Normal intake= 1 gm per day.
- 20 to 30% is absorbed in the duodenum and jejunum and ileum= 300 mg absorbed and 150 mg gets secreted.
- Net uptake= approximately 150 -200 mg
- No net gain or loss of calcium from the skeleton.
- To maintain calcium balance, the kidneys must excrete 150 – 200 mg of calcium per day
PTH regulation of serum calcium
PTH: secreted from parathyroid gland
- Synthesized as 115 aa polypeptide (pre-pro PTH)–> 90 aa (pro-PTH)–> 81 aa (cleaved based on body needs)
- decreased plasma Ca2+ –> PTH–>
1. Bone: resorption–> Ca release
2. Kidneys: increased phosphate excretion (decreased phosphate), increase calcium reabsorption, increased calcitriol (Vit D) formation to increase intestinal CaHPO4 absorption
Vitamin D metabolism
Cholecalciferol converted to calcitriol in Kidneys (after PTH stimulation due to low serum Ca)
Causes:
- Ca and Phosphate uptake by small intestines
- Mobilizes Ca from bone by increasing bone resorption
- Decreases Calcium and phosphate excretion at the level of the kidney.
Calcitonin regulation of serum calcium
- Secretion stimulated by Ca.
- Inhibits osteoclastic bone resorption
- Promotes renal excretion of Ca
*Neither athyroid patients (calcitonin-deficient) nor patients with medullary thyroid cancer (excess calcitonin production) have alterations in Ca homeostasis.
Role of phosphorous in calcium metabolism
Calcium + Phosphate hydroxyapatite
Therefore, decrease in phosphate–> increased calcium (won’t form hydroxyapatite)
Renal resorption of calcium
Parallels Na reabsorption:
- PCT: 60%
- Descending limb: 10%
- TAL: 20-25%
- DCT: 5-10%
- Collecting duct: 0.5%
Factors stimulating renal calcium resorption
- Extracellular volume depletion: increased Na reabsorption, increased Ca reabsorption.
- PTH: increased Ca reabsorption in cortical thick ascending limb, distal convoluted tubules and connecting tubules, independent of Na reabsorption.
- Thiazide diuretics: volume contraction, increased proximal Ca reabsorption. Also direct effect on distal tubule reabsorption.
- Metabolic alkalosis: increased Ca reabsorption in distal tubule.
Factors inhibiting renal calcium reabsorption
- Extracellular volume expansion: decreased Na reabsorption, decreased Ca reabsorption.
- Hypercalcemia: increased Ca excretion in proximal tubule, decreased Ca reabsorption in coritical and medullary thick ascending limb.
- Loop diuretics: decreased Na reabsorption in loop, decreased Ca reabsorption.
- Metabolic acidosis: H displaces Ca from bound albumin, increases ionized Ca, increased filtered Ca load. H inhibits distal tubular Ca reabsorption.
Hypercalcemia due to increased bone resorption:
- Primary hyperparathyroidism
- Ambulatory patients: MEN-1, MEN-2;
- can be seen in 1 gland (85%) or all 4 glands (15%)) - Malignancies (hospitalized patients)
- osteolytic hypercalcemia= cytokine production (breast, myeloma, NSCLC, lymphoma)
- humoral hypercalcemia= PTHrP; (squamous cell lung, head/neck, renal, ovarian)
- tumoral calcitriol (Hodgkin’s/non-Hodgkin’s) - Dissolution of bones:
- post-renal transplant (autonomous PTH)
- Immobilization
- Thyrotoxicosis (osteoclast activity inc.)
- Familial hypocalciuric hypercalcemia= mutation in CaSR
Hypercalcemia due to Increased intestinal absorption
- Milk-alkali syndrome: hypercalcemia, alkalemia, nephrocalcinosis, renal failure
- Hypervitaminosis D: alpha-hydroxylase in macrophages autonomously converts Vit D
- Granulomatous diseases (sarcoidosis, TB, leprosy)
Hypercalcemia due to Decreased renal clearance
Thiazide diuretics lower urinary calcium excretion, an effect that is useful in the treatment of patients with hypercalciuria and recurrent calcium nephrolithiasis.
Miscellaneous causes of hypercalcemia
Li Rx- mild hypercalcemia, most likely due to increased secretion of PTH due to an increase in set point at which calcium suppresses PTH release.
Pheo: It can be due to concurrent hyperparathyroidism (in MEN, type II) or to the pheochromocytoma itself due to tumoral production of PTH-related protein.
Rhabdo: during the diuretic phase of acute renal failure, most often in patients with rhabdomyolysis due to the mobilization of calcium that had been deposited in the injured muscle.
Clinical manifestations of hypercalcemia
“Groans, bones, moans, and stones”
CNS: psychiatric (irritability, depression, psychosis), confusion, lethargy, proximal muscle weakness, cranial nerve abnormalities, obtundation, coma.
Cardiac: hypertension, arrhythmias, heart block, shortened QT on EKG.
GI: anorexia, nausea, vomiting, pancreatitis, peptic ulcer disease (Ca stimulates gastrin secretion).
GU: polyuria (nephrogenic diabetes insipidus), nephrocalcinosis, nephrolithiasis, acute renal failure.
Neuromuscular: hyporeflexia, myalgia, arthralgia.
Skeletal: bone pain
Metastatic calcification
Diagnosis of hypercalcemia
History: medications, family history, malignancies, anemia.
Blood tests:
- iPTH (high in hyperparathyroidism, low in malignancies);
- PTHrP (malignancies);
- phosphate (low in hyperpara);
- 1,25-(OH)2-Vitamin D3 (increased in sarcoidosis, granulomatous diseases);
- 25-(OH)-Vitamin D3 (increased in hypervitaminosis D);
- ionized Ca;
- serum protein immunoelectrophoresis (multiple myeloma);
- thyroid function tests.
24h urine Ca excretion (highest in malignancy, high in hyperpara, normal to low in familial hypocalciuric hypercalcemia).
X-rays: metastases, osteitis fibrosa cystica, chondrocalcinosis, nephrolithiasis
Sestamibi scanning: detects solitary parathyroid adenoma in >90% of patients.
Treatment of hypercalcemia
- Discontinue Ca supplements and Vitamin D.
2 Volume expansion with saline - Loop diuretics (only after volume expansion)
- Bisphosphonates.(with normal renal function- prevent Ca leeching from bones)
- Calcitonin (works in the short term)
- Dialysis in patients with renal failure.
- Avoid IV phosphate as it can cause metastatic calcification.
Hypocalcemia due to hypoparathyroidism
- Surgical ablation or post-irradiation
- Infiltrative diseases: tumor, amyloid, Wilson’s diseases, hemochromatosis.
- Hypomagnesemia: impaired PTH secretion.
- Idiopathic hypoparathyroidism
- Polyglandular autoimmune syndrome Type 1: hypoparathyroidism, primary adrenal insufficiency, chronic mucocutaneous candidiasis
Hypocalcemia due to pseudohypoparathyroidism
end-organ resistance to PTH, circulating PTH is elevated. Classic phenotype is short stature, obesity, bradydactyly, mental retardation (Albright’s hereditary osteodystrophy) .
Albright’s hereditary osteodystrophy= absent third knuckle
Hypocalcemia due to Vit D deficiency
- Dietary: elderly, malnourished alcoholics(Mg def)
- Malabsorption(small bowel disease)
- Impaired bile salt formation: cholestyramine
- Anti-convulsant drugs: phenobarbital, phenytoin(impaired 25 hydroxylation in liver)
- Chronic renal insufficiency
- Vitamin D dependent rickets
Other causes of hypocalcemia
- Hyperphosphatemia
- Nephrotic syndrome (loss of Vit. D binding protein)
- Drugs: bisphosphonates, loop diuretics, amphotericin B, aminoglycosides, cis-platinum, phenobarbital, phenytoin
- Acute pancreatitis (deposition of Ca)
- Hungry bone syndrome (total parathyroidectomy–> no bone resorption–> bones eat all ECF calcium)
- Rhabdomyolysis: deposition of calcium in injury phase (released during degradation phase)
- Massive blood transfusion: citrated blood
- Use of MRI contrast (Gadolinum)- spurious hypocalcemia- no Rx.
Clinical manifestations of hypocalcemia
Acute: NM irritability: - Paresthesias - Muscle twitching - Carpopedal spasm - Trousseau's sign (inflate BP cuff--> hand spasm) - Chvostek's sign (tap facial nerve--> twitch) - Seizures - Laryngospasm - Bronchospasm
Cardiac:
- Prolonged QT interval
- Hypotension
- Heart failure
- Arrhythmia
Papilledema
Chronic:
- Ectopic calcification
- Extrapyramidal signs
- Parkinsonism
- Dementia
- Subcapsular cataracts
- Abnormal dentition
- Dry skin
Test for hypocalcemia
Blood tests:
- ionized Ca (pseudohypocalcemia:hypoalbuminemia )
- Mg (hypomagnesemia)
- iPTH
- 1,25-(OH)2-Vitamin D3
- 25-(OH) -Vitamin D3
Most hypocalcemia patients with hyperphosphatemia and normal renal function will have hypoparathyroidism (idiopathic, acquired or pseudohypoparathyroidism)
Treatment of hypocalcemia
- Acute: 10-20 ml of Ca gluconate (90 mg elemental Ca/ 10 ml) in 50 – 100 ml of D5W IV over 10 minutes. Needs cardiac monitoring because serious cardiac arrhythmias may occur.
- Intermediate (for recurrent and symptomatic hypocalcemia): Ca gluconate (10 – 15 mg/Kg) over 6 – 8 hours.
- Chronic: Ca supplements (1-2 g elemental Ca per day), thiazide diuretics, rocaltrol (0.5 to 1.5 g/day).
- Mg deficiency: empirical Rx. estimate 1-2 meq/Kg deficit. Replace 1x deficit over 1st day, and 1x deficit over remaining 2-4 days.
- 4 ml of 50% MgSO4 (16 meq) IM q4-6h
- 12 ml of 50% MgSO4 (49 meq) in 1L D5W IV over 3h
- 4 ml of 50% MgSO4 in 100 ml D5W IV over 10 min in generalized seizures
Nephrotic glomerular disease (nephrotic syndrome) urinalysis
Heavy proteniuria Free fat droplets Oval fat bodies Fatty casts Variable hematuria
Nephritic glomerular disease (Glomerulonephritis) urinanalysis
Red cells
Red cell casts
Variable proteinuria
Frequent white cell and white cell casts
Scale of clinical manifestations of glomerular injury
Nephrotic syndrome—> Nephritic syndrome:
- Minimal change glomerulopathy
- Membranous glomerulopathy
- Focal segmental glomerulosclerosis
- Mesangioproliferative glomerulopathy
- Membranoproliferative glomerulonephritis
- Proliferative glomerulonephritis
- Acute diffuse proliferative glomerulonephritis
- Crescentic glomerulonephritis
Diagnostic characteristics of nephrotic syndrome
Present with:
- Edema
- Dyspnea
- Hypertension
- Proteinuria > 3 grams/24 hours:
- Patient can have nephrotic proteinuria WITHOUT nephrotic syndrome - Hypoalbuminemia ( edema
- ANP
- Increased activity in Na/K ATPase in basolateral membrane - Hyperlipidemia/Thromboembolism:
- High cholesterol and triglycerides
- Increased hepatic lipoprotein synthesis
- Impaired catabolism of triglycerides
- Impaired clearance from circulation
- Increased risk of atherosclerosis
Other complications of nephrotic syndrome:
- Arterial/venous thromboembolism: renal vein thrombosis
- Protein malnutrition
- Acute renal failure due to hypovolemia- (esp. with very low serum albumin level)
- Infection
- Iron deficiency, Vit D deficiency, altered pharmacokinetics of protein bound drugs
Etiologies of nephrotic syndrome
Primary diseases of kidney:
- Minimal change disease: common in kids, steroid responsive
- Membranous nephropathy: associated with malignancy, thrombosis
- Focal segmental glomerulosclerosis: most common cause of idiopathic nephrotic syndrome in adults, particularly blacks; treated with prolonged high dose steroids
- Membranoproliferative glomerulonephritis
Systemic diseases:
- Diabetes
- Plasma cell dyscrasias
- SLE
Treatment of Nephrotic syndrome
ALL patients recieve:
- ACE/ARB: decrease protein excretion, improve blood pressure (lower GFR)
- Lipid lowering therapy: statins
- Diuretics: manage symptoms
Immunofluorescent studies of the kidney
Pattern of Glomerular Tuft Involvement - Peripheral (basement membranes vs. Mesangial Character of Deposits - Granular vs. Linear (Goodpasture's) Type of Deposits - Ig species (IgG and IgA) and Complement Components Intensity of Deposits Blood Vessel and Tubular Deposits
Electron microscopy studies of kidney
- Epithelial cell foot process fusion
- Subepithelial electron dense deposits
- Endothelial cell swelling or proliferation
- Subendothelial electron dense deposits
- Character of capillary basement membranes
- Mesangial cellularity and/or dense deposits
- Fibril deposition
- Tubular basement membranes or cellular inclusions
Minimal change disease (glomerular disease)
“Nil” disease= Proteinuria with epithelial cell foot processes fusion
Most common cause of nephrotic syndrome in children
Prognosis:
- Progression to renal failure v. rare
- Responsive to steroids
- 50-65% of adults relapse (have steroid dependence)
- Good prognosis in children
Pathogenesis:
- Probably immunologic basis
- More prevalent in certain HLA haplotypes
- Proposed Immune dysfunction: Circulating cytokine (IL-13) that damages epithelial cells; innate T cell dysregulation (cmyb pathway)
Treatment: directed at T cells
- Prednisone (first-line)
- Cyclophosphamide or cyclosporine (relapsing or steroid resistant)
- Mycophenolate mofetil (relapsing or steroid-resistant), rituximab, tacrolimus
Membranous glomerulonephropathy: clinical course and treatment
Clinical course:
- 1/3 with spontaneous complete remission
- 1/3 with persistent proteinuria
- 1/3 with progression to ESRD
Treatment:
- ACE/ARB for tight BP control
- Immune-suppression for those at high risk of ESRD:
1. elevated creatinine at presentation
2. proteinuria > 8g/dL for 6 months after conservative treatment (ACE/ARB)
3. worsening kidney function
4. Refractory manifestations of nephrosis
Immune suppression:
- Cyclophosphamide or calcineurin inhibitor + Corticosteroids
- Alternate Agents- Rituximab (NIH clinical trials)
Primary Membranous glomerulonephropathy: pathogenesis
- Autoimmune Disease – IgG4 linked to certain MHC loci
- Production of autoantibody to M-type phospholipase A2 receptor
- Immune complexes are formed in situ: C5b-C9 attack complex that injures epithelial cells
Secondary membranous glomerulonephropathy: pathogenesis
- Chronic circulating immune complexes of a specific size are trapped (IgG mediated)
- Antigen-antibody complex activate complement attack complex, causing epithelial and BM injury
Causes:
- Systemic lupus erythematosus (WHO Class V)
- Drugs:
- Penicillamine
- Bucillamine
- Gold salts
- Anti-TNF therapy
- Tiopronin
- NSAIDs - Hepatitis B virus/ Hepatitis C virus
- Malignancy
- Hematopoietic cell transplant / GVHD Status post renal transplantation
- Sarcoidosis
- Treponema,
- Thyroglobulin
Membranous glomerulonephropathy: histo
Electron-dense subepithelial deposits
Granular deposition of IgG deposits
Granular characteristic of basement membrane on silver stain
Focal segmental glomerulosclerosis (FSGS)
AKA: Focal Sclerosis
Two Major Clinical Forms:
- Primary or Idiopathic (includes familial/genetic forms)
- Secondary
- Virus (HIV, Parvovirus B19)
- Drugs (Heroin, Interferon, Lithium)
- Adaptive functional response (obesity, loss of one kidney)
Multiple Histologic Subtypes:
- Classic
- Perihilar
- Cellular
- Tip Variant
- Collapsing (Associated with HIV)
FSGS: histologic changes
Light microscopy:
- Mesangial cell proliferation
- Focal process: not all glomeruli involved
- Segmental process: only tufts involved
- Trichrome stain: expansion of mesangium
Immunofluorescence:
- Trapping of IgM within mesangium
Electron microscopy: Epithelial Cell Injury - Foot process fusion - Detachment from underlying basement membrane Mesangial Changes - Fibrosis - Mesangial Matrix Increase - Insudative deposition of IgM and C3 - Lipid vacuoles
FSGS: Pathogenesis
- Primary event is Epithelial Cell injury induced by circulating factor (SuPAR)
- Can see return of proteinuria within 24 hr’s after transplant
- Candidate circulating factor has been tentatively identified - Subsequent loss of GBM integrity
- Glomerular structure becomes hyper permeable
- See secondary extracellular matrix depositions and insudative trapping of IgM in the mesangium
Genetic predisposition:
- Polymorphisms/mutations in: Nephrin gene, Podocin gene
Injury:
Angio-poietin-like-e–> alters slit diaphragm between podocyte processes–> loss of GBM integrity–> proteinuria
FSGS: clinical presentation
35-40% cases of nephrotic syndrome in adults
- 50% of cases of NS in blacks
- only 20% of nephrotic syndrome cases in children
Clinical course/prognosis:
- Immunosuppressive therapy only for primary FSGS
- 50% will have partial or complete remission with treatment
- Poor prognostic factors- proteinuria >10 grams/day; histology (collapsing), renal failure at presentation, poor response to therapy, black race
Treatment:
- Immunosuppression if nephrotic at preserved GFR
- Prolonged/high dose steroids - 1 mg/kg for at least 6 months
- If unable to tolerate steroids – cyclosporine
- If GFR may recur immediately post-kidney transplant
Clinical features of nephritic syndrome
- Hematuria with varying proteinuria
- Decreased renal function
- Hypertension
- Edema
Urinalysis:
- Red cells
- Red cell casts
- Variable proteinuria
- Frequent white cell/white cell casts
Etiology of nephritic syndrome
Primary renal disorders:
- IgA nephropathy
- Post-strep glomerulonephritis
- Membranoproliferative glomerulonephritis (MPGN)
IgA nephropathy: pathogenesis
Immune complex glomerulonephritis involving intense deposition of dimeric and polymeric forms of IgA1 within the mesangium of the glomerulus
- There is a defect in IgA metabolism
- The O-glycosylation pattern of serum IgA1 is abnormal
- The precise mechanism responsible for this aberrant glycosylation is not established.
- Genetic deficiency in the enzymatic machinery mediating O-glycosylation of IgA1 (galactosyltransferase)
Begins with infection–> excess IgA–> kidney can’t clear IgA from blood–> deposition
IgA nephropathy: histology
Light microscopy:
Capillary lumens open
Proteinuria generally swells epithelium (not a lot of swelling here)
Too many cells in section of mesangium= mesangial hypercellularity and increase in matrix
= mesangial proliferation
RBCs in mesangial space
Immunofluorescence:
IgA deposition
Electron microscopy:
- Mesangial Expansion and increased mesangial cellularity
- Finely granular electron dense deposits are present along mesangial reflections
IgA nephropathy: Epidemiology, clinical course/prognosis
Most common cause of GN worldwide**
- Young age (15-30 years of age)
- Asian**
Variable clinical presentation:
- 40%-”Synpharyngitic” gross hematuria (pharyngitis with hematuria)
- 40%-Microscopic hematuria with mild proteinuria (asymptomatic
- 10%-Nephrotic proteinuria
- 10%-RPGN (rapid progressive glomerulonephritis)
Prognosis:
- Good prognosis if minimal proteinuria (<500mg/day)
- Worse outcome if elevated Cr, HTN or moderate/nephrotic proteinuria
IgA nephropathy: treatment
- Observation if mild disease
- If proteinuria >500mg/day – ACEI/ARBs + fish oil
- Nephrotic or RPGN – Steroids +/- cyclophosphamide
- Severe disease may require maintenance rx with azathioprine or mycophenolate
Post-streptococcal glomerulonephritis: Pathogenesis
Immune complex mediated disease
- *Follow group A beta-Hemolytic Strep infection**
- See elevated antibody titers to strep Ag’s
- Antigenic component not well characterized
- ? endostreptosin or cationic protein related to streptokinase
- Complexes lodge in glomerulus
Post-streptococcal glomerulonephritis: histology
Light microscopy:
- Glomerular tuft enlarged, small urinary space
- Capillary lumens congested
- Segmented neutrophils
- Peripheral inflammatory glomerulonephritis
Immunofluorescence:
- Coarse Granular Pattern
- Capillary wall mainly but some mesangial
IgG and C3
Electron microscopy:
- Coarse Electron Dense Deposits (cross-react with streptococcal antigens)
- Subepithelial and Mesangial Location
- Epithelial and Mesangial Cell Proliferation
- Some Foot Process Fusion
Post-streptococcal glomerulonephritis: Clinical course, prognosis
Diagnosis:
- Often a clinical diagnosis
- Latent period of 10-21 days from infection to nephritis
- Low Complement (C3) levels
- Elevated titers of antistreptolysin O, antihyaluronidase and Anti-DNAase B antibodies
Clinical course:
- Due to: Nephritogenic group A streptococcipharyngitis or impetigo
- More common in children
- Usually self-limited, renal function normalizes in 3-4 weeks
Post-streptococcal glomerulonephritis: treatment
Treatment is supportive only
Dietary sodium restriction
Loop diuretics for edema
Membranoproliferative Glomerulonephritis Type 1: Pathogenesis
Primary and Secondary forms
- Both involve activation of classic and alternative complement pathways
- Stimulating Antigen in Primary form is not known (truly idiopathic)
- Secondary Type I MPGN associated with antigens from:
- SLE, Hep B, Hep C, HIV, Endocarditis, CLL,
- Alpha 1-antitrypsin deficiency
Membranoproliferative Glomerulonephritis Type 1: histology
Light microscopy:
- Small urinary space, enlarged glomerulus
- Lobular proliferation of tuft (vs diffuse in post-strep)
- NO neutrophils (not actively inflammatory)
- PAS stain (glycoproteins): see basement membrane duplication/splitting
Immunofluorescence:
- IgG, C3 (low in serum–> ends up in glomerulus), C1q located in subendothelium (vs epithelial)
Electron microscopy:
- Focal foot process fusion
- Capillary Basement membrane duplication
- Subendothelial electron dense deposits
- Mesangial electron dense deposits
Membranoproliferative Glomerulonephritis Type 2: Pathogenesis
- Uncontrolled activation of alternative complement pathway
- Loss of control secondary to an inherited deficiency of factor H (Factor H normally inactivates the C3bBb complex)
- Without inactivation, continuous cleavage of C3 leading to the formation of abundant C3bC3bBb (the C5 convertase)
- -> C3b dimer deposition along the GBM
Membranoproliferative Glomerulonephritis Type 2: histology
Light microscopy (same as Type 1):
- Small urinary space, enlarged glomerulus
- Lobular proliferation of tuft (vs diffuse in post-strep)
- NO neutrophils (not actively inflammatory)
- PAS stain (glycoproteins): see basement membrane duplication/splitting
Immunofluorescence (same as type 1):
- IgG, C3 (low in serum–> ends up in glomerulus), C1q located in Basement membrane (vs subendothelium)
Electron microscopy:
- band-like dense deposits in basement membrane
Membranoproliferative Glomerulonephritis: clinical course/diagnosis/prognosis
Underlying pathology= Hypocomplementemia
Two major types:
- Type I – most common form, idiopathic. Clinical features=
- Infections – HCV (circulating cryoglobulins/systemic vasculitis), HBV, IE, malaria, endocarditis
- Autoimmune - Lupus, Sjogren’s, RA
- Other: Cryoglobulinemia (without HCV), Sickle Cell, Lymphoma - Type II – dense deposit disease, children. Clinical features:
- Partial lipodystrophy
- Retinal drusen
* Recurs in > 90% of kidney transplants
Membranoproliferative Glomerulonephritis Type 1: treatment
Treat underlying condition (e.g. HCV)
Idiopathic, nephrotic - Corticosteroids
Antiplatelets? Cyclosporine?
*Relapse is common
Membranoproliferative Glomerulonephritis Type 2: treatment
- Angiotensin blockade
- Lipid-lowering rx
- If elevated C3 nephritic factor – plasma exchange
- Eculizumab may be an interesting option
Diabetic Nephropathy: pathophysiology
Most common cause of end stage renal disease in the U.S.
Occurs in both Type I and Type II DM
Hyperglycemia results in:
- Activated protein kinase C pathway
- Polyol pathway
- Oxygen radical production
- Increase in system wide glycation of proteins
Events due to hyperglycemia cause:
- General accumulation of hyperglycosylated proteins
- Glomerular hypertrophy
- Mesangial expansion
- Basement membrane thickening
- Hyperfiltration injury (related to obesity)
Diabetic nephropathy: histology
- Nodular and diffuse forms
- PAS positive mesangial expansion
- Basement membrane thickening
- Hilar vessel sclerosis
- Histology is the same for types I & II
Histo:
Light microscopy:
- Nodular diffuse nephropathy:
- Acellular, PAS, glycosylated proteins deposited in glomerular tuft
- Start in mesangium and spread to rest of glomerulus, compress capillaries
Immunofluorescence:
- Pseudo-linear peripheral IgG and Albumin
- Nodular mesangial deposition of IgM and C3
- Insudative Vascular deposition of IgM and C3, especially in hilar vessels
Electron microscopy:
- Thickened GBM and TBM, >600nm
- Fused epithelial foot processes
- Mesangial expansion, nodular, by the deposition of amorphous ground substance
- Insudative electron dense deposits in mesangium and blood vessels
Diabetic nephropathy: clinical course and treatment
Early:
- Increased GFR
- Glomerular hypertrophy
- Increased kidney size
- Microalbuminuria
Late:
- GFR decreases
- Macroalbuminuria–> proteinuria
Treatment:
- Blood sugar control (HbA1c~7%)
- Screen for microalbuminuria - if present treat with ACEI or ARBs
- Tight control of blood pressure (500-1000 mg/g creatinine)
Amyloidosis: Pathophysiology
A collection of diseases sharing a common feature:
- common feature = Extracellular deposition of pathologic insoluble fibrillar proteins
- Protein deposition impairs normal function
Multiple organs and tissues can be involved
Virchow coined the term amyloid, meaning starch like
Renal dialysis–> alpha-2-beta globulin deposition
Amyloidosis: Histology
Light microscope:
- Amorphous deposition of pink material around glomeruli, afferent, efferent arterioles
- Congo red positive, Not PAS positive
Immunofluorescence:
- Non-specific staining with Ig reagents
Characteristics of protein:
- Many precursor proteins
- Abnormal folding
- Beta pleated sheet configuration
- Appear as fibrils by EM, 8-10nm in diameter, indefinite length
- Appears “apple green” with Congo red stain under polarized light
Primary amyloidosis
Plasma cell dyscrasia with fragment of light chains forming amyloid fibrils
Treatment: chemo +/- bone marrow transplant
Secondary amyloidosis
chronic inflammatory states (e.g. RA, IBD, CF, psoriasis) with acute phase reactant serum amyloid A forming fibrils
Causes:
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriatic arthritis
- Chronic infections (e.g. bronchiectasis, TB, osteomyelitis)
- Inflammatory bowel disease
- Cystic Fibrosis
- Malignancy (e.g. RCC, NHL)
- Familial Mediterranean Fever
Treatment: treat underlying inflammatory disorder
Lupus Nephritis: pathogenesis
- Immune Complex Mediated Glomerulonephritis
- Secondary to a Variety of Autoantigens
- Associated with Systemic Lupus Erythematosus
Lupus nephritis: classification
- Class I and II: Mesangial
electron-dense deposits - Class III and IV –Mesangial and subendothelial deposits with endocapillary proliferation
- Class V – Subepithelial deposits
- resembles idiopathic membranous glomerular nephritis
Activity index:
- Leukocyte infiltration
- Hyaline deposition
- Necrosis
- Cellular crescents
- Interstitial inflammation
Chronicity index: predictive of rapid renal decline
- Glomerular sclerosis
- Fibrous crescents (epithelial cell proliferation compressing tuft)
- Tubular atrophy
- Interstitial fibrosis
Lupus nephritis: histology
Lupus nephritis ressembles many diseases–> plastic disease (nothing specific!)
Light microscopy:
- Mesangial cell proliferation
Immunofluorescence:
- See deposition of all immunoglobulins, complement proteins
- Peripheral and mesangial deposition, granular
- IgM, IgG, IgA, C3, C1q
Electron microscopy:
- Presence of Ig detected
Lupus nephritis: treatment
Many factors play a role when deciding treatment:
- Pathology (activity and chronicity indexes)
- Symptoms (asymptomatic or full blown nephrotic syndrome)
- Risk factors for worse prognosis (AA race, males, low socioeconomic status, higher creatinine at presentation, high grade proteinuria)
- Compliance
Meds:
- ACEI/ARB Rx
- Immunosuppressive Rx for Classes III-V
- III and IV: Steroids + Cyclophosphamide or MMF
- IV and V: FK+MMF+steroids
- V alone (similar to membranous): Steroids+CYA or CsA - No immunosuppression for Stage VI
- Rarely recurs after kidney transplant
Rapidly progressive glomerulonephritis:
RPGN
Rapid loss of kidney function over 3 months
- Anti-Glomerular basement membrane (GBM) antibody:
- Goodpasture’s - Immune complex
- SLE
- Post-infectious
- etc. - Pauci-immune (+ANCA):
- Wegener’s
- Microscopic polyarteritis
** Nephrology emergency
Pauci-immune RPGN: pathophysiology
ANCA-positive=
Antineutrophil cytoplasmic autoantibody (ANCA)-mediated glomerulonephritis
Pauci-immune RPGN: histology
Light microscopy:
- Proliferation of crescent-shaped cells compressing glomerular capillaries–> decreased GFR
- Lose nuclei with fibrinous material (necrosis)
Immunofluorescence:
- Negative for all reagents (Pauci-immune)
- NOT mixed connective tissue disease
- Must be vasculitis (Wegener’s, microscopic polyarteritis, etc.)
Electron microscopy:
- No electron dense deposits, fibril deposits
- No specific cellular injury
Microscopic polyarteritis
- Spare of the upper respiratory tract (vs Wegener’s granulomatosis)
- Pulmonary infiltrates/hemorrhage
- RPGN
- Crescentic GN with no immune deposits/negative immunostaining (Pauci immune)
- Positive P-ANCA (vs C-ANCA in Wegener’s)
Rx: immunosuppression (Cytoxins and steroids) + plasmapheresis in severe renal dysfunction.
Wegener’s granulomatosis
- Upper/lower respiratory tract disease (sinusitis) including pulmonary hemorrhage
- RPGN
- Crescentic GN with no immune deposits/negative immunostaining (Pauci immune)
- Positive C-ANCA (vs P-ANCA in polyarteritis)
Rx: Immunosuppression (CTX and steroids) + plasmapheresis in severe renal dysfunction.
Goodpasture’s syndrome
- Can develop at any age
- Pulmonary hemorrhage/glomerulonephritis
- Circulating anti-GBM antibody
- Antigen-alpha-3 chain type IV collagen
Rx: plasmapharesis/immunosuppression
Distal Renal Tubular Acidosis
Type 1 Renal Tubular Acidosis:
Failure of distal alpha intercalated cells to excrete H+
Leads to: - Elevated blood H+ - Inability to acidify urine (pH > 5.3) - Elevated Chloride - Elevated K Hyperchloremic non-anion gap acidosis
Proximal Renal Tubular Acidosis
Type 2 Renal Tubular Acidosis
Failure of proximal tubular cells to reabsorb bicarb
Leads to:
- Elevated blood H+
- CAN acidify urine (excrete H+)- ph < 5.3
Seen in Fanconi’s anemia
