NEPHROLOGY
Dr. J. Bargman and Dr. M. Schreiber
Timothy Welke and Darren Yuen, chapter editors
Katherine Zukotynski, associate editor
NORMAL RENAL FUNCTION . . . . . . . . . . . . . . . 2
Renal Structure and Function
Renal Hemodynamics
Control of Renal Hemodynamics
Tubular Reabsorption and Secretion
Endocrine Function of the Kidney
Measurement of Renal Function
Measurement of Tubular Function
The Kidney In Pregnancy
URINE STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . 5
General
Urinalysis
Microscopy
Crystals
Urine Electrolytes
ABNORMAL RENAL FUNCTION . . . . . . . . . . . . 7
Proteinuria
Hematuria
ELECTROLYTE DISORDERS . . . . . . . . . . . . . . . . 9
Hyponatremia/Hypernatremia
Hyponatremia
Hypernatremia
Hypokalemia
Hyperkalemia
ACID-BASE DISORDERS . . . . . . . . . . . . . . . . . . .15
Renal Contribution to Acid-Base Balance
1˚ Metabolic Acidosis
1˚ Metabolic Alkalosis
1˚ Respiratory Acidosis
1˚ Respiratory Alkalosis
Mixed Disturbances
RENAL FAILURE . . . . . . . . . . . . . . . . . . . . . . . . . .18
ACUTE RENAL FAILURE (ARF) . . . . . . . . . . . . .18
Treatment
Indications for Dialysis in ARF
Prognosis
CHRONIC RENAL FAILURE (CRF) . . . . . . . . . . .20
Classification
Clinical Features of Uremia
Complications
Treatment
Indications for Dialysis in CRF
DIALYSIS AND RENAL . . . . . . . . . . . . . . . . . . . . .21
TRANSPLANTATION
Dialysis
Renal Transplantation
MCCQE 2002 Review Notes Nephrology – NP1
GLOMERULAR DISEASE . . . . . . . . . . . . . . . . . . .22
General Considerations
Classification of Glomerular Disease according to
Syndrome/Presentation
Classification of Glomerular Disease according to
Etiology
Primary Glomerular Disease
Secondary Glomerular Disease
TUBULOINTERSTITIAL NEPHRITIS . . . . . . . .27
Acute Tubulointerstitial Nephritis
Chronic Tubulointerstitial Nephritis
NSAID NEPHROPATHY . . . . . . . . . . . . . . . . . . .28
ACUTE TUBULAR NECROSIS (ATN) . . . . . . . . . 29
Ischemia
Toxins
VASCULAR DISEASES OF THE KIDNEY . . . . .29
DIABETES AND THE KIDNEY . . . . . . . . . . . . . .30
HYPERTENSION (HTN) . . . . . . . . . . . . . . . . . . .31
Renovascular Hypertension
Hypertension Caused by Renal Parenchymal Disease
PYELONEPHRITIS . . . . . . . . . . . . . . . . . . . . . . . .32
Acute Pyelonephritis
Chronic Pyelonephritis
CYSTIC DISEASES OF THE KIDNEY . . . . . . . . .33
Adult Polycystic Kidney Disease (PCKD)
Medullary Cystic Disease
Medullary Sponge Kidney
OTHER SYSTEMIC DISEASES . . . . . . . . . . . . . .34
AND THE KIDNEY
Hypertension Causing Renal Disease
Multiple Myeloma
Scleroderma
Vasculitides
Rheumatoid Arthritis (RA)
Cancer
Infections
HIV-Associated Renal Disease
DIURETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
NP2 – Nephrology MCCQE 2002 Review Notes
NORMAL RENAL FUNCTION
RENAL STRUCTURE AND FUNCTION
Nephron
❏ the individual renal tubule and its glomerulus
❏ glomerulus
• Bowman’s capsule - blind end of the renal tubule
• glomerular capillaries - filtering membrane which consists of
A) fenestrated endothelial cells
B) basement membrane
C) podocytes of visceral epithelial cells
• mesangium - consists of scattered cells with contractile and
phagocytic function which are capable of laying down both
matrix and collagen and of secreting biologically active
mediators
❏ proximal convoluted tubule (PCT)
• reabsorbs 65% of glomerular filtrate, including glucose,
amino acids, proteins, vitamins via active transport (water
follows passively)
• reabsorbs ~2/3 of filtered Na+ mostly via electroneutral
Na+ – H+ exchange
• important site of ammoniagenesis
❏ loop of Henle
• 25% of filtered Na+ is absorbed at the thick ascending limb
mostly via channel mediated (Na+-K+-2Cl–) reabsorption
of Na+, K+, and Cl–
• 15% of filtered water is removed in loop of Henle
❏ distal convoluted tubule (DCT)
• reabsorbs 5-10% filtered Na+ probably via directly coupled
NaCl pathway (without K+)
• relatively impermeable to water (5% of filtered water is removed in this segment)
• late distal segment is a site of ADH and aldosterone action
❏ juxtaglomerular (J-G) apparatus
• adjacent to glomerulus where afferent arteriole enters
• consists of
• myoepithelial cells - modified granulated smooth muscle cells in the media of the afferent
arteriole that contain renin
• macula densa - specialized region of the distal tubule which controls renin release
❏ collecting duct system
• final regulation of fluid and electrolyte balance
• along with late distal segment, responds to ADH and aldosterone
RENAL HEMODYNAMICS
❏ Renal Blood Flow (RBF) = 20~25% of cardiac output = 1200 mL/minute
❏ Renal Plasma Flow (RPF) = RBF x (1 - hematocrit) = 600 mL/minute
❏ Glomerular Filtration Rate (GFR)
• plasma volume filtered across glomeruli to Bowman’s capsule per unit time
• 20% of RPF = 120 mL/min
• maximal in young adulthood and decreases thereafter
❏ Filtration Fraction (FF)
• volume of plasma filtered across glomeruli, relative to the
volume of plasma flowing to the kidneys per unit time
• FF = GFR/RPF
• as RBF and RPF decrease, FF must increase to
preserve GFR; this is done by Angiotensin II (AII)
CONTROL OF RENAL HEMODYNAMICS
❏ goal is maintenance of GFR in the face of varying RBF
(autoregulation)
❏ mechanism
• decreased RBF ––> renin released from
juxtaglomerular apparatus
• renin activates angiotensinogen ––> Angiotensin I
• Angiotensin Converting Enzyme (ACE)
activates AI ––> AII
• AII constricts efferent renal arterioles, leading
to an increase in filtration fraction, maintaining
GFR in the face of decreased RBF
Figure 1. Nephron Structure
and Function
Illustrated by Heidi Maj
Figure 2. Renin-Angiotensin System and
the Control of Renal Hemodynamics
Illustrated by Heidi Maj
MCCQE 2002 Review Notes Nephrology – NP3
NORMAL RENAL FUNCTION . . . CONT.
TUBULAR REABSORPTION AND SECRETION
❏ the ultrafiltrate which crosses the glomerular capillaries into Bowman’s space starts its journey along
the tubular system
❏ in the tubule, it is further modified by reabsorption (tubular lumen to bloodstream) or secretion
(bloodstream to tubular lumen)
Table 1. Processes Occurring Along the Nephron
Site Absorption Secretion
PCT Na+, HCO3– Organic acids
glucose, amino acids,
phosphates, vitamins
Thick Ascending Na+, K+, C1–
Limb of Loop of Henle
DCT Na+, C1– H+, K+
ENDOCRINE FUNCTION OF THE KIDNEY
Erythropoietin
❏ hormone produced by kidneys (and liver to a lesser degree)
in response to hypoxia
❏ stimulates erythrocyte production and maturation
❏ produced in kidneys by fibroblast-like cells in cortical interstitium
❏ responds in 1.5 to 2 hours
❏ in renal disease anemia results from decreased renal capacity for
Epo production and release, as well as decreased red blood cell life
span (toxic hemolysis)
Vitamin D
❏ vitamin D is converted to the 25-hydroxy-vitamin D form in the liver
❏ the kidney converts 25-hydroxy-vitamin D to 1,25-dihydroxy-vitamin D
❏ in renal disease this capacity becomes impaired and contributes to the
tendency towards hypocalcemia and subsequent secondary
hyperparathyroidism (since 1,25-dihydroxy-Vitamin D is necessary
for intestinal calcium absorption)
MEASUREMENT OF RENAL FUNCTION
Serum Creatinine
❏ an indirect estimate of renal function using a product of creatinine
metabolism
❏ value is dependent on muscle mass as well as renal function (e.g. an
elderly woman with chronic renal failure may have the same
creatinine concentration as a 30 year old weightlifter)
❏ changes in creatinine concentration may reflect pathology better
than absolute values of creatinine (true GFR overestimated
since secreted by tubules)
❏ creatinine values may not be reflective of degree of renal disease as
creatinine concentration does not start to rise significantly until GFR
is quite diminished
Serum creatinine
concentration
0
0 GFR
Figure 4. Serum Creatinine Concentration as a Function of GFR
Creatinine Clearance
❏ estimate of GFR
❏ should be full 24 hour collection
Figure 3. Vitamin D Activation
Illustrated by Heidi Maj
NP4 – Nephrology MCCQE 2002 Review Notes
NORMAL RENAL FUNCTION . . . CONT.
❏ creatinine clearance as a reflection of GFR can be estimated by the
following formula
GFR = UCr x Vu
PCr
• UCr is urine creatinine concentration
• Vu is urine flow rate
• PCr is plasma creatinine concentration
❏ alternatively, GFR can be estimated using the formula:
(140 - age)(weight) x 1.2 (men) or 0.85 (women)
PCr
• age in years, weight in kg, PCr in umol/L
• normal value ranges from 75-120 ml/min
Clinical Pearl
❏ There is an inverse relationship between serum creatinine concentration
and creatinine clearance (e.g. if serum creatinine doubles in a given person,
creatinine clearance has been halved).
Blood Urea Nitrogen (BUN)
❏ less accurate and should not be used alone as a test of renal function
❏ modified by ECF volume, protein intake, catabolism, renal blood flow
❏ secreted and reabsorbed in nephron
MEASUREMENT OF TUBULAR FUNCTION
❏ urinary concentration
• a.m. urine osmolality or specific gravity (s.g.)
❏ acidification (i.e. appropriate urine pH given serum pH)
• if urinary pH is > 5.3 when patient is acidotic consider RTA (exceptions exist)
❏ potassium excretion
• can calculate the Trans-Tubular K+ Gradient (TTKG)
• the value assesses distal tubular K+ secretion and can be helpful in the setting of
hypokalemia or hyperkalemia (see below)
TTKG = UK/PK
Uosm/Posm
• UK is urinary K+ concentration
• PK is plasma K+ concentration
• Uosm is urinary osmolarity
• Posm is plasma osmolarity
❏ Fractional Excretion (FE) of various solutes (X)
FEX = UX/PX x 100%
Ucr/Pcr
THE KIDNEY IN PREGNANCY
❏ increased kidney size and dilatation of renal pelvis and ureters (increased UTI risk) due to increased
progesterone levels leading to increased smooth muscle relaxation of the collecting system
❏ 50% increase in GFR along with decreased creatinine and BUN
❏ 25-50% increase in renal blood flow
❏ blood pressure falls in 1st trimester (100/60), rises slowly toward normal in 2nd and 3rd trimesters
❏ glucosuria, slight proteinuria (< 200 mg/24 hours) often occur
Renal Risk Factors for Adverse Pregnancy Outcome
❏ pre-existing hypertension
❏ creatinine ≥ 180 umol/L
❏ nephrotic-range proteinuria
❏ active UTI
❏ collagen-vascular disease, especially if not in remission or if associated with antiphospholipid antibodies
MCCQE 2002 Review Notes Nephrology – NP5
URINE STUDIES
GENERAL
❏ freshly voided specimen
❏ use dipstick for urinalysis (specific gravity, pH, glucose, protein, hemoglobin, nitrites, leukocytes)
❏ centrifuge for 3-5 minutes
❏ resuspend sediment and perform microscopy to look for cells, casts, crystals, and bacteria
URINALYSIS
Specific Gravity
❏ the ratio of weights of equal volumes of urine and H2O (measures weight of solutes in urine)
❏ an estimate of urine osmolality (and if kidneys are working, of the patient’s state of hydration)
❏ values < 1.010 reflect dilute urine, values > 1.020 reflect concentrated urine
❏ may get falsely high values if losing glucose or proteins in urine
pH
❏ urine pH is normally between 4.5-7.0
❏ if persistently alkaline, consider:
• renal tubular acidosis
• UTI with urease producing bacteria (e.g. Proteus)
Glucose
❏ freely filtered at glomerulus and reabsorbed in proximal tubule
❏ may indicate hyperglycemia (once blood glucose levels exceed 9-11 mmol/L, renal tubular capacity for
reabsorption of glucose is overwhelmed)
❏ in the absence of hyperglycemia, may indicate proximal tubule dysfunction (e.g. Fanconi syndrome -
pan PCT transport dysfunction with glucosuria, aminoaciduria, phosphaturia, uricosuria, hypocalcemia,
hypomagnesemia and proximal RTA) or increased GFR (e.g. pregnancy)
Protein
❏ detection by dipstick only measures albumin levels in urine
❏ therefore, other protein such as Bence-Jones may be missed on dip but will be detected by other means
such as acid precipitation
❏ false +ve on dip: pH > 7, concentrated urine, blood contamination
❏ false -ve: dilute urine dipsticks are available to detect microalbuminuria (i.e. very small amounts of albumin)
in order to monitor the onset/progress of diabetic renal disease
❏ gold standard is the 24 hour urine collection for total protein (see Proteinuria section)
Clinical Pearl
❏ If a patient has clinically (dipstick) detectable proteinuria it is unnecessary to
send urine for microalbumin levels!
Nitrites
❏ nitrates in urine are converted by bacteria to nitrites
❏ positive result suggests but does not make the diagnosis of UTI
❏ false +ve: contamination
❏ false -ve: inadequate bladder retention time (takes 4 hrs to convert nitrates to nitrites), prolonged
storage of urine (leads to degradation of nitrites), certain pathogens (S. faecalis, other gram-positive
organisms, N. gonorrhea, and Mycobacterium tuberculosis) do not convert nitrates to nitrites
Ketones
❏ positive result can occur with: prolonged starvation, fasting, alcoholic or diabetic ketoacidosis
❏ false +ve: high urine ascorbic acid, very acidic urine of high specific gravity; abnormal-coloured urine;
urine containing levodopa metabolites
Hemoglobin/RBCs
❏ high urine ascorbic acid can give false -ve dipstick result
❏ if urine dip positive for blood but no RBC on microscopy, may indicate hemoglobinuria (e.g. hemolysis)
or myoglobinuria (e.g. rhabdomyolysis)
MICROSCOPY (see Hematuria section) (see Colour Atlas NP1-10)
Erythrocytes
❏ normal is up to 2-3 RBCs per high power field (HPF)
❏ spiculated, polymorphic RBCs suggest glomerular bleeding
❏ non-spiculated, uniform RBCs suggest extraglomerular bleeding
NP6 – Nephrology MCCQE 2002 Review Notes
URINE STUDIES . . . CONT.
Leukocytes
❏ up to 3 per HPF is acceptable
❏ detection of leukocytes by dipstick leukoesterase method indicates at least 4 per HPF
❏ indicates inflammatory process in the urinary system (e.g. UTI)
❏ if persistent sterile pyuria consider chronic urethritis, prostatitis, interstitial nephritis (especially if WBC casts),
renal TB, viral infections, calculi, papillary necrosis
❏ eosinophiluria suggests allergic interstitial nephritis, cholesterol emboli syndrome
Casts
❏ protein matrix formed by gelation of Tamm-Horsfall mucoprotein (glycoprotein excreted by renal tubule)
trapping cellular debris in tubular lumen and moulding it in the shape of the tubules
Table 2. Interpretation of Casts
Hyaline • Not indicative of disease
• Concentrated urine
• Fever
• Exercise
RBC • Glomerular bleeding
(e.g. glomerulonephritis)
= active sediment
Leukocyte • Pyelonephritis
• Interstitial nephritis
Heme-granular • ATN
• Proliferative GN
Fatty casts/oval fat bodies • Nephrotic syndrome
Crystals
❏ most have no pathologic significance, resulting from urinary concentration, acidification and cooling of urine
❏ calcium oxalate: double pyramids appearing as a square containing a cross; might indicate ethylene
glycol toxicity
❏ calcium phosphate: narrow rectangle needles, clumped in a radiating pattern
❏ uric acid: red/brown, rhomboid shaped
❏ calcium magnesium ammonium pyrophosphate (triple phosphate): coffin lids; associated with recurrent
UTI by urea-splitting organisms (Proteus, Klebsiella)
URINE ELECTROLYTES
❏ can be used to evaluate the source of an electrolyte abnormality or to grossly assess tubular function
❏ Na+, K+, Cl–, osmolality and pH are commonly measured
❏ there are no 'normal' values; output is based on intake in properly functioning kidneys and in disease states,
the values are interpreted in light of the pathology
Examples of Common Urine Electrolyte Abnormalities
Table 3. Distinguishing Pre-Renal from Intra-Renal
Disease in Acute Renal Failure
Index Pre-Renal Intra-Renal (e.g. ATN)
Urine Osmolality > 500 < 350
Urine Sodium (mmol/L) < 20 > 40
FENa+ < 1% > 3%
Plasma BUN/Cr (SI Units) > 80:1 < 40:1
❏ high urine Na+ in the setting of acute renal failure indicates intrarenal disease or the presence of
non-reabsorbable anions (e.g. ketones)
❏ high urine Na+ in the setting of hyponatremia: diuretics, tubular disease (eg. Bartter’s syndrome), SIADH
❏ a high FENa+ but low FEC1– is seen in metabolic alkalosis secondary to vomiting
❏ osmolality is useful to estimate the kidney’s concentrating ability
❏ the value for (Na+ + K+)-Cl–, also known as the urine net charge, is useful in discerning the cause of
metabolic acidosis:
• a negative value indicates the presence of unmeasured positive ions (i.e. ammonium) which is
seen in metabolic acidosis 2º to non-renal causes (e.g. diarrhea)
• a positive value suggests RTA, where ammonium excretion is not elevated and the urine net
negative charge is positive
❏ urine pH is useful to grossly assess renal acidification
• 'low' pH (< 5.5) in the presence of low serum pH is an appropriate renal response
• a high pH in this setting might indicate a renal acidification defect (RTA which is a collection of low
ammonium excretion diseases)
MCCQE 2002 Review Notes Nephrology – NP7
ABNORMAL RENAL FUNCTION
PROTEINURIA
Proteinuria
(determine using dipstick and/or 24 hour urine collection)
Physiological Pathological
young healthy persons (determine with urine protein electrophoresis and 24 hour urine collection)
Orthostatic Constant
• proteinuria • rule-out underlying
occurs with disease and follow-up
standing • may develop renal disease
• 5% of adolescents in the future
• generally resolves
spontaneously
Tubulointerstitial Glomerular Overflow
• usually < 2g/24 hour • usually > 2g/24 hour • < 2g/24 hour
• mixed LMW proteins • primarily albumin • primarily light chains
and LMW proteins
• occurs with
increased GFR,
increased plasma
light chain
concentration
Primary Secondary
Proliferative Nonproliferative Proliferative Nonproliferative
Figure 5. An Approach to Proteinuria
Table 4. Quantitative Proteinuria
Daily Protein Excretion Meaning
< 150 mg Normal
150 mg - 2 g Glomerular disease
Tubular disease
Orthostatic
Overflow
2 g - 3 g Usually glomerular
May be tubular
> 3 g Almost always glomerular
Unless light chains (multiple myeloma)
❏ normally < 150 mg protein/day is lost in the urine
• 40% albumin
• 40% Tamm-Horsfall mucoprotein (from cells of the ascending limb of the Loop of Henle
(i.e. does not arise from the plasma and forms the matrix for casts)
• 15% immunoglobulin
• 5% other plasma proteins
❏ filtration of plasma proteins at the glomerular capillary interface is based on
• size
• fenestration in the basement membrane excludes protein with a MW > albumin (60,000)
• proteins of MW less than albumin may filter through glomerular barrier but are normally
reabsorbed and catabolized by renal tubular cells
• charge
❏ glomerular dysfunction produces proteinuria, usually > 2 g/day consisting of higher MW proteins
(especially albumin) resulting in decreased oncotic pressure causing:
• hyperlipidemia due to hepatic lipoprotein synthesis stimulated by the decreased
plasma oncotic pressure
• tissue edema
NP8 – Nephrology MCCQE 2002 Review Notes
ABNORMAL RENAL FUNCTION . . . CONT.
❏ with tubular dysfunction there is no hyperlipidemia because albumin is not lost, although modest
excretion of LMW proteins (up to 2g/day) may occur (there may be associated edema but this is due to
decreased GFR and therefore salt and water retention, not to hypoalbuminemia)
❏ rarely, "overflow" proteinuria occurs where the filtered load of proteins (usually LMW) overwhelms tubular
capacity for reabsorption
• filtered load = GFR x plasma protein concentration
• "overflow" proteinuria occurs secondary to:
• increased GFR (e.g. in pregnancy)
• increased plasma protein concentration (e.g. immunoglobulin light chains - multiple myeloma)
HEMATURIA
❏ gross hematuria: pink, red, or tea-coloured urine
❏ microscopic hematuria: appears normal, may be detected by dipstick
❏ age-related causes:
• glomerular causes predominate in
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