Laboratory Diagnosis of Kidney Dysfunction
The Functional unit of the Kidney is the Nephron
(Learn Structure)
Renal Functions
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Regulation of ECF and composition
Conservation of water, electrolytes, aminoacids, sugars
Maintenance of acid-base balance in the body
Excretion of endogenous waste products
o Urea
o Uric acid
o Creatinine
o Phosphates
o Sulphates
 Endocrine activity
o Renin
o 1,25(OH) Vitamin D3
o Erythropoietin
Filtration And Reabsorption of Electrolytes and Water
 Sodium
 Chloride
 Bicarbonate
 Potassium
 Water
GFR = 125 mL/min= 180 L/24 hr
Susceptibility Of The Kidney To Injury
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Blood flow
Concentrating mechanisms
Filtration, absorption, secretion
Bioactivation
Renal Blood Flow
The two kidney comprise < 1% of total body weight but receive 20-25
% of cardiac output.
Filtration, Absorption, Excretion
 Glomerular filtration
 Absorption: lumen-to-cell-to-blood
 Excretion: blood-to-cell-to-lumen
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Aminoacids, glucose transporters
Organic anion transporters
Organic cation transporters
P-glycoprotein, MRP’s
When The Renal Function Should Be Assessed?
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Older age
Family history of Chronic Kidney Disease (CKD)
Decreased renal mass
Low birth weight
Diabetes mellitus
Hypertension
Autoimmune disease
Systemic infections
Urinary tract infections
Obstruction to the lower urinary tract
Drug toxicity
Renal Function Tests Are Divided Into Following Main Groups:
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Urine analysis
Blood examination
Glomerular function tests
Tubular function tests
In Vivo Assesment Of Renal Function
 Glomerular filtration rate (GFR)
 GFR= volume of blood completely removed of a substance per
unit time (mL/min)= 125 mL/min in humans
 Indirect markers of GFR:
o Blood urea nitrogen
o Serum Creatinine
Types of Clearance Tests:
Endogenous:
 Creatinine
 Urea
 Uric Acid
 Cystatin C
Exogenous:
 Inulin
 Para-amino hippuric acid (PAHA
 Diodrast (di-iodo pyridine acetic acid)
 Iodohexol
Clearance-Based Markers Of Kidney Function
Using the concepts of renal clearance, one may accurately estimate
the GFR using endogenous or exogenous substances. The renal
clearance of a specific substance is understood to be the volume of
plasma that can be completely cleared of that substance in a unit of
time.
This is expressed as:
(U x V) / P
U = concentration of the substance in the urine
V = volume excreted per minute
P = concentration of the substance in the plasma/serum
Substance Suitable For The Clearance-Based Estimation Of GFR
Homer Smith is widely credited with introducing renal clearance
methodologies and popularizing their utility in the noninvasive
measurement of GFR. In his seminal text The Kidney: Structure and
Function in Health and Disease, Homer Smith described properties of
a substance suitable for the clearance- based estimation of GFR, in
that it must:
 Be completely filterable at the glomerulus.
 Not be synthesized or destroyed by the tubules.
 Not be reabsorbed or excreted by the tubules.
 Be physiologically inert, so that its administration
 Does not have any disturbing effect upon the body.
 In addition to those specifications outlined by Smith, an ideal
substance should also be unbound to plasma proteins, not
undergo extra-renal elimination, and be easy and inexpensive to
measure.
Determination Of GFR
(Write EQUATION Below)
Creatinine:
 Non-enzymatic hydrolysis of creatine
 Released from skeletal muscle
 Generally constant way of production
 Completely filtered with limited secretion
Inulin:
 Exogenous compound
 Completely filtered with NO reabsorption and NO secretion
Inulin Is The Ideal Indicator For Determination Of GFR, Because Of The
Following Three Relations:
I.
Inulin is a poly-fructose without effect on GFR. Inulin has a
spherical configuration and a molecular weight of 5000. Inulin
filters freely through the glomerular barrier. Inulin is
uncharged and not bound to proteins in plasma. Inulin crosses
freely most capillaries and yet does not traverse the cell
membrane.
II.
All ultra filtered inulin molecules pass to the urine. In other
words, they are neither reabsorbed nor secreted in the tubules.
Inulin is an exogenous substance - not synthesized or broken
down in the body.
III.
Inulin is non-toxic and easy to measure.
But it’s still invasive method!
Inulin
Inulin clearance is still regarded as the gold standard for the
measurement of GFR, although it is rarely used clinically because of
the restricted availability of inulin and invasiveness of the procedure.
Currently, inulin measurement is not offered in most clinical
laboratories.
Urine Collection
Timed urine collections may be performed to estimate Creatinine
clearance, which is an approximation of GFR. Typically, a 24-h urine
collection is performed with a single blood draw shortly before or
after the collection to measure serum Creatinine. Shorter timed
collections may be appropriate for hospitalized individuals with
rapidly changing renal function. Although timed urine collection is
relatively easy to perform, there are a number of practical issues that
limit its use for Creatinine clearance measurement and
interpretation.
As described above, Creatinine clearance systematically
overestimates true GFR because of tubular secretion of Creatinine,
particularly when the GFR is decreased. Because urea is reabsorbed
but not secreted, whereas Creatinine is secreted but not reabsorbed,
the true GFR lies between the measured urea clearance and the
Creatinine clearance, suggesting a possible
assessment of Creatinine
and urea clearance. The major concern with 24-h urine collections
from outpatients is the possibility of over- or under-collections,
which substantially limits their reliability.
Plasma Clearance Methods
Plasma clearance methods may be employed in the assessment of
GFR. Testing typically involves the injection of an exogenous marker
in a single bolus dose and measuring the plasma disappearance of the
marker by using serial blood draws over a period of several hours.
These methods obviate the need for a urine collection and are
typically completed in a shorter period of time than conventional
timed urine Creatinine clearance measurement.
Markers currently in use include a number of:
 Radioactive:
o DTPA
o 51Cr-EDTA
o 125I-iothalamate
 Nonradioactive:
o Iohexol
o Iothalamate
Single-injection methods to measure plasma clearance of each of
these markers have been validated against urinary clearance of inulin
for the measurement of GFR. Radionuclide markers have the
advantage of ease of measurement, which must be balanced against
the disadvantage of radiation exposure and the requirement for
facilities to appropriately store and dispose of radioactive materials.
The use of unlabeled iothalamate and iohexol eliminate the issues
related to radiation. Single blood- sampling procedures and
abbreviated study periods have been evaluated for plasma clearance
markers, although bias and imprecision may be concerns in patients
with CKD
Novel Methods For GFR Estimation
An ideal functional marker in the setting of AKI is one that permits
real-time point-of-care measurement of GFR. Although no such
marker currently exists for clinical care, separate groups have
reported promising results using fluorescent markers in preclinical
models. Rabito et al. described a novel optical approach for GFR
determination using a fluorescent GFR marker, carbostyril124–
DTPA–europium, with the same clearance characteristics as 125Iiothalamate.
Following a single intravenous injection of marker into rats,
continuous real-time monitoring of clearance was possible by use of
transcutaneous fluorescence measurements.
More recently, Schock-Kusch et al. Investigated FITC-labeled
sinistrin, the active pharmaceutical ingredient of the commercially
available GFRmarker Inutest, as a marker of GFR. In freely moving
rats, real-time monitoring of FITC-sinistrin elimination kinetics was
performed by use of a portable transcutaneous device. Clearance
measurements that use this method were comparable to those
obtained by using a typical plasma clearance technique in healthy
rats and rats with kidney disease.
Wanget al. used fluorescent conjugates of inulin (filtered marker)
and dextran (non-filtered marker) and a portable optical ratiometric
fluorescence analyzer to estimate GFR in dogs and pigs. GFR
determination 60 min after a bolus infusion of the markers was
comparable to that performed by use of standard 6-h iohexol plasma
clearance methods. These developments have generated
considerable enthusiasm because they indicate that real-time
monitoring of GFR is attainable, and validation in the clinical setting
is highly anticipated.
Serum Creatinine – Based Equations
Several serum Creatinine – based equations have been developed to
estimate GFR, the most notable being the Cockcroft–Gault,
Modification of Diet in Renal Disease (MDRD), and CKD-EPI (Chronic
Kidney Disease Epidemiology Collaboration) equations for adults and
the Schwartz equation for children. Although these equations
generally increase the reliability of estimating the GFR, they all have
limitations.
Limitations
The Cockcroft–Gault and Schwartz equations have been shown to
overestimate the GFR, especially at lower Creatinine concentrations.
Lastly, the equations do not account for differences that may occur as
a result of unusually high or low muscle mass, extreme diets (vegan
or excessive meat consumption), or ethnic variation of groups not
included in their derivation.
The MDRD Formula For Calculation Of The GFR
The Modification of Diet in Renal Disease (MDRD) study was a
multicenter, controlled trial that evaluated the effect of dietary
protein restriction and strict blood pressure control on the
progression of renal disease. During the baseline period, serum
Creatinine and several variables were measured in 1,628 patients
with chronic renal disease. The objective was to develop an equation
that would predict GFR.
MDRD Study
From this study, it was determined that older age and female sex was
independent predictors of GFR, reflecting the well-known relation of
age and sex to muscle mass. GFR was further adjusted for body
surface area so that neither height nor weight was an independent
predictor of adjusted GFR. African American ethnicity was an
independent predictor of higher GFR as on average; black persons
have greater muscle mass than whites.
The Final MDRD Study Prediction Equation For GFR Is As Follows With PCR
Being Serum Or Plasma Creatinine In Mg/Dl:
GFR (mL/min/1.73 m2) = 186 x (Pcr)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if
African American)
The GFR is expressed in mL/min/1.73m2
There Are Some Limitations Of This Calculated GFR:
It may not be accurate if kidney function is fluctuating and not in a
steady state or in cases where muscle mass is abnormal. The GFR
estimate may be inaccurate in extremes of age and in patients with
severe malnutrition or obesity, paraplegia or quadriplegia, and in
pregnant women.
MDRD Limitations:
The MDRD equation is inaccurate for patients on drugs and with
conditions that interfere with Creatinine secretion (for example,
cimetidine or trimethoprim) or Creatinine assay (for example,
diabetic ketoacidosis or administration of certain cephalosporin). In
these cases, a 24-hour Creatinine clearance may be necessary to
accurately estimate kidney function.
Low Molecular Weight Proteins
Measured concentrations of several low molecular weight proteins,
including 2-microglobulin, cystatin C, and -trace protein (BTP), have
been evaluated as potential markers of GFR. In general, these
proteins are freely filtered by the glomerulus, reabsorbed and
catabolized, but not secreted by the renal tubules. As a result,
reductions in GFR are associated with increased plasma
concentrations.
Cystatin C
Free glomerular filtration, without tubular secretion.
Cystatin C, a 13,250 D, non-glycosylated protein does not bind to any
other plasma protein; the only elimination route for Cystatin C is
glomerular filtration.
Cystatin C is not influenced by an acute phase reaction.
No Re-Entrance Into The Blood Circulation
Cystatin C is reabsorbed by the tubules cells and thereby rapidly
degraded. In the case of tubules dysfunction, absorption is impaired
and Cystatin C is eliminated with the urine. Therefore, urinary
Cystatin C levels can be used as a marker of tubules dysfunction.
No Extra-Renal Elimination
Cystatin C is cleared only via glomerular filtration.
Cystatin C
CystatinC may be more reliable than serum Creatinine–based
methods in estimating GFR, particularly in those individuals with a
mild reduction in GFR, in whom changes in serum Creatinine are
typically not observed (the so-called Creatinine blind range of GFR).
Cystatin C may also be superior to Creatinine in estimation of
mortality and cardiovascular outcomes. Cystatin C has been reported
to rise faster than Creatinine after a fall in GFR, enabling earlier
identification of AKI. Several Cystatin C–based equations to estimate
GFR appear to be simpler and more accurate than Creatinine-based
equations.
Correlation Of Cystatin C With GFR Not Influenced By:
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Gender
Muscle mass
Age (children > 1 year of age show adult levels)
Protein intake
Metabolic factors influencing Creatinine tests;
o Bilirubin
o Ketones
o Elevated glucose
o Ascorbic acid
 Various drugs interfering with Creatinine tests:
o Cyclosporine A,
o Cephalosporins
o Aspirin
Cystatin C
The use of a Cystatin C and Creatinine combination equation for
estimating GFR in a multiethnic Asian population with CKD does not
require ethnicity coefficients because the derived coefficients are
very close to each other.
β2-Microglobulin
β2-Microglobulin is an 11.8-kDa protein that is the light chain of the
MHCI molecule expressed on the cell surface of all nucleated cells. It
dissociates from the heavy chain in the setting of cellular turnover
and enters the circulation as a monomer. 2-Microglobulin is filtered
at the glomerulus and almost entirely reabsorbed and catabolized by
proximal tubular cells. Unlike Creatinine, serum concentrations
appear to be largely independent of age and muscle mass; however,
there does not appear to be a clear advantage of β 2- microglobulin
over serum Creatinine in detecting small changes in GFR.
A major factor limiting the utility of β2- microglobulin as a marker of
renal function is its non-specificity, because serum β2- microglobulin
concentrations are known to increase in several malignancies and
inflammatory states.
BTP
BTP (also known as prostaglandin D2 synthase) is a low molecular
weight protein that is generated at a constant rate by glial cells in the
central nervous system. It is freely filtered by the glomerulus and
reabsorbed by the proximal tubule with minimal non-renal
elimination.
Recent studies suggest that serum BTP concentrations perform at a
similar level to Creatinine and Cystatin C not only in the estimation of
GFR, but also in the prediction of progressive renal dysfunction.
Equations to estimate GFR have been derived with the use of BTP,
although further validation is necessary in diverse populations. Like
Cystatin-C, corticosteroid administration appears to impact serum
concentrations of BTP
Kidney Injury Molecule-1 (KIM-1)
Kidney injury molecule-1 (KIM-1), a type 1 membrane protein, is
expressed in normal kidney tissue, but massively induced in
dedifferentiated proximal tubule epithelial cells in proteinuric, toxic
and ischemic kidney diseases.
 Is a sensitive and specific marker of proximal tubule injury.
Neutrophil Gelatinase- Associated Lipocalin (NGAL)
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protein
belonging to the so-called lipocalin superfamily, which is typically
debatable in three molecular forms, i.e., the 25-kDa monomer, a 45kDa homodimer and a 135-kDa heterodimer, where the monomer is
covalently linked to matrix metalloproteinase 9 (MMP-9)
NGAL is synthesized in tubular cells (prevalently in monomeric
form), but also in leukocytes neutrophils (prevalently in dimeric
form), as well as in a variety of other tissues, including heart, liver,
prostate, salivary glands, lung, trachea, uterus, stomach and colon.
Considering that the current commercial immunoassays are unable
to distinguish the different molecular forms, it is hence obvious that
the protein released by the kidney after AKI is virtually
indistinguishable from that potentially produced by other sources,
especially neutrophils
Marker of AKI and CKD, correlated with Creatinine concentration,
inversely associated with GFR
High concentration in uropathy and glomerular and cystic diseases
and in patients with IgA nephropathy.
„troponin of the kidney”? - Be careful
Enzymuria
Enzymes:
 N-acetyl-β-glucosoaminidase (NAG)
 Lysozyme (muramidase) β-galactosidase
 Alanine (leucine) aminopeptidase γ-glutamyltransferase
(GGT) Alkaline phosphatase
 GSH S-transferase-alpha (GSTα, GSTA) Cathepsin B
 GSTμ (GSTM)
 Tamm-Horsfall glycoprotein
 Lactate dehydrogenase
PT = Proximal tubule
DT = Distal tubule
CD = Collecting duct,
TAL = Thick ascending limb of Henle Loop
Urine Examination
Urine examination is an extremely valuable and most easily
performed test for the evaluation of kidney function.
It includes physical and macroscopic examination, chemical
examination and microscopic examination of the urine sediment.
Albuminuria
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The pathophysiologic
Correlates of albuminuria are variable: in those patients
With conditions such as Nephrotic syndrome, diffuse
Effacement of podocyte foot processes with loss of glomerular
Permselectivity is the cause of albuminuria.
Smaller amounts of albuminuria may accompany generalized
Endothelial dysfunction and serve as a window
Into systemic small vessel disease. In other patients,
albuminuria
 May be a consequence of proximal tubular
 Dysfunction and loss of tubular reabsorbing capacity.
Proteinuria
 High Molecular Weight:
o Albumin, IgG, Transferrin
o Generally indicates glomerular injury
 Low Molecular Weight:
o β2microglobulin, α1microglobulin, retinol binding
protein
o Generally indicates proximal tubular dysfunction
Albuminuria
Albuminuria is defined as the ratio of urinary albumin to Creatinine
(Cr) as recommended by the National Kidney Foundation K/DOQI
clinical practice guidelines for chronic kidney disease:
 Normoalbuminuria <30 mg/g Cr
 Microalbuminuria 30 to 300 mg/g Cr
 Macroalbuminuria ≥300 mg/g Cr
Albuminuria is an established risk factor for cardiovascular
morbidity and mortality in the general population and in individuals
with hypertension or diabetes mellitus. In renal transplant recipients,
albuminuria predicts graft loss and all-cause mortality. It may be the
result of glomerular injury, or it may also be a marker of systemic
inflammation and endothelial damage. Low levels of urine albumin
excretion well below the current albuminuria threshold
(normoalbuminuria) predict development of cardiovascular disease
in the general population
Increased urinary albumin excretion is an established risk for
mortality, cardiovascular disorder and adverse outcomes, both in the
general population and in patients with hypertension and diabetes.
Increased albumin in urine is also a marker of diffuse vascular
damage, systemic inflammation, renin- angiotensin system activation
and glomerular disorders or abnormal tubular function
Albuminuria is higher in those who go on to develop AKI and may
serve as an additional tool for renal risk stratification. In patients
with established proteinuric kidney disease, albuminuria reduction is
often used as a surrogate target in clinical practice, although
supporting data are lacking to make definitive clinical
recommendations or adopt albuminuria as an endpoint in clinical
trials.
Albuminuria Measurement Instead Protein?
Measurement of albuminuria instead of total protein may, however,
miss cases of kidney disease associated with multiple myeloma, in
which filtered light chains may be the dominant protein. Total
protein measurement is unlikely to be standardized, given the
diversity of proteins found in the urine.
Another Question Is How To Measure And Report Albuminuria Or
Proteinuria.
Twenty-four–hour urine collections are generally considered the
gold standard for albumin or protein quantification, but this
procedure has important limitations owing to frequent errors in
completeness of collection. As a result, many practitioners rely
largely on ratios of urinary albumin (or protein) to Creatinine on
random urine samples for assessment; when expressed as identical
units for both the numerator and denominator (such as mg/dL per
mg/dL), the ratio approximates the amount of albumin (or protein)
in grams excreted in 24 hours. First morning void specimens are
preferred, but may not be easily attained in clinical practice
Renal
Post hoc analyses of a subset of participants in the RENAAL
(Reduction of Endpoints in Non Insulin Dependent Diabetes Mellitus
with the Angiotensin II Antagonist Losartan) trial compared 24-h
urine protein, 24-h urine albumin, and Albumin:Creatinine ratios for
their association with renal function decline. The investigators found
that the Albumin:Creatinine ratio was the best measure to
predict renal events in patients with type 2 diabetes and
nephropathy. Likely reasons for the finding include variability in
completeness of 24- h urine collections and the prognostic
significance of urinary Creatinine excretion itself owing to its
association with biologically important variables such as muscle
mass and nutritional adequacy. In summary, albuminuria or
proteinuria adds importantly to risk stratification of individuals with
and at risk for CKD.
Albumin:creatinine ratio, preferably in first morning voids, is
the preferred test in patients with diabetes mellitus.
Protein:Creatinine ratio may be preferred in non-diabetic individuals.
Twenty-four hour samples are not generally necessary except in
select circumstances (e.g. The need for precise determination of
albumin or proteinexcretion rate in longitudinal care of patients with
glomerular disease and heavy proteinuria in whom clinical decisionmaking may be influenced)
Parameters Determined In Typical Urinalysis
(Purpose)
 (Overall Fluid Homeostasis) Urine osmolality of Specific Gravity
 (Acid-Base Balance) Urinary pH
 (Overall Fluid Homeostasis) Urinary volume
 (Extracellular Fluid Balance) Urinary electrolyte and solute
concentration: Na+, K+, Cl-, urea
 (Indication of Glomerular Filtration) Creatinine excretion
 (Proximal Tubular Function) Glucose, amino acids excretion
 (Proximal Tubular Function) Proteinuria: < 20kDa
 (Glomerular Function) Proteinuria: > 20 kDa
 (Specific Nephron Segment) Enzymuria
Urine Analysis- Physical Characteristics Volume
Normal range: 1-2.5 L/day
Polyuria: > 2.5 L/day
(diabetes mellitus, increased water intake)
Oliguria: < 400 mL/day
(acute glomerulonephritis, renal failure)
Anuria: < 100 mL/day (renal shut down)
Nocturia: The total volume of urine passed between the time the
individual goes to bed with the intention of sleeping and the time of
waking with the intention of rising.
Urine Analysis- Physical Characteristics Specific Gravity
Normal range: 1016-1025
(The ability of the kidney to concentrate or to dilute urine)
Increased:
 Excessive sweating,
 Nephrosis
 Diabetes mellitus
Decreased:  Excess water intake
 Chronic Nephritis
Urine Analysis - Chemical Characteristics
Glucose (fructose) test: Negative
Associated clinical conditions (+):
 Diabetes mellitus
 Gestational Diabetes
 Renal glycosuria
 Galactosemia
 Hereditary fructose intolerance
 Essential fructosuria
 Ketone bodies
 Diabetic ketoacidosis
 Starvation ketoacidosis
 Von Gierke’s disease (glycogen storage disease Ia)
 Proteins
 Glomerulonephritis
 Polyelonephritis
 Nephrotic syndrome
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Blood
Stones in ureter
Glomerulonephritis
Renal tuberculosis
Trauma to genito-urinary tract
Carcinoma urinary bladder
Urinary tract infection
Blood Examination
As markers of renal function creatinine, urea, uric acid and
electrolytes are done as a routine tests.
Creatinine
Derived from spontaneous conversion of muscle creatine (about 12% of total muscle mass per day)
Daily excretion is fairly constant and independent of urinary volume.
Thus, this measurement can be used to assess the relative
completeness of a 24-hour urine collection.
Average men excrete: 1.5 g/d into the urine
Women: less
Athletes: more
Patients with hepatic disease, muscular dystrophy, paraplegia and
poliomyelitis may excrete less Creatinine due to decreased
production. It should be noted that many laboratories use alkaline
picrate (Jaffe) method for measuring Creatinine.
Reference Range for serum Creatinine:
 Male: 0.6-1.3 mg/dL
 Female: 0.5-1.1 mg/dL
Note:
Creatinine production is based on weight and gender that is generally
related to muscle mass. Thus, be circumspect when treating
individuals with a high normal Creatinine when a low Creatinine is
appropriate due to small muscle mass. This would include children,
elderly, women, paralyzed patients, and amputees.
Creatinine- Increased Serum Concentration
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Impaired renal function
Very high protein diet
Anabolic steroids users
Very large muscle mass:
o Body builders
o Giants
o Acromegaly patients
 Rhabdomyolysis/crush injury
 Athletes taking oral creatine
 Drugs:
o Probenecid
o Cimetidine
o Triamterene
o Trimethoprim
o Amiloride
Urea
Urea is a major is a nitrogenous end product of protein and amino
acid catabolism, produced by liver and distributed throughout intra
and extracellular fluid.
Urea is freely filtered by the glomeruli.
Many renal diseases with various glomerular, tubular, interstitial or
vascular damage can cause an increase in plasma urea concentration
Plasma concentrations also tend to be slightly higher in males than in
females. High protein diet causes increases of plasma concentration
and urea excretion.
Measurement of plasma Creatinine provides a more accurate
assessment than urea because there are many non-renal factors that
affect urea level.
Nonrenal factors can affect the urea level (normal adults is level 1040mg/dl) like:
 Mild dehydration,
 High protein diet,
 Increased protein catabolism,
 Muscle wasting as in starvation,
 Reabsorption of blood proteins after a GIT hemorrhage,
 Treatment with cortisol or its synthetic analogous
States associated with elevated levels of urea in blood are referred to
as uremia or azotemia.
Causes of urea plasma elevations:
 Prerenal: Renal hypoperfusion
 Renal: Acute tubular necrosis
 Postrenal: Obstruction of urinary flow
Urea Nitrogen
Historically, urea was reported as blood urea nitrogen (BUN) and this
terminology has been incorrectly carried over to the present. Urea
nitrogen is now measured using serum and is reported as “serum
urea nitrogen” (SUN). Urea is synthesized mostly in the liver as a byproduct of the deamination of amino acids arising from protein
catabolism.
Increased concentrations of BUN may be observed in a number of
settings that are not directly related to alterations in GFR. For
example, urea is readily reabsorbed by the tubules, particularly
during volume depletion, resulting in increased plasma
concentrations while GFR is preserved.
Urea is filtered by the glomeruli; however, about 40-70% (amount
depends on urine flow) is reabsorbed by passive diffusion into blood
across the renal tubular epithelium. Thus, in conditions in which the
glomerular filtration rate is decreased, SUN will be increased. For this
reason, urea clearance tests are less informative than Creatinine
clearance tests and have been discontinued.
Reference Range for serum urea nitrogen: 8-18 mg/dL
Uric Acid
UA is formed from the breakdown of nucleonic acids and is an end
product of purine metabolism. The plasma from the liver to the
kidney, where it’s filtered and where about 70 % is excreted
transports UA.
Measurement of UA is used most commonly in the evaluation of renal
failure, gout and leukemia (production and destruction of cells).
In hospitalized patients, renal failure is the most common cause of
elevated UA levels, and gout is the least common cause.
Tubular Function Tests (Urine Concentration Test)
The ability of the kidney to concentrate urine is a test of tubular
function that can be carried out readily with only minor
inconvenience to the patient. This test requires a water deprivation
for 14 hours in healthy individuals. A specific gravity of > 1.02
indicates normal concentrating power. Specific gravity of 1.008 to
1.010 is isotonic with plasma and indicates no work done by kidneys.
The test should not be performed on a dehydrated patient.
Vasopressin Test
More patient friendly than water deprivation test. The subject has
nothing to drink after 6 p.m. At 8 p.m. five units of vasopressin
tannate is injected subcutaneously. All urine samples are collected
separately until 9 a.m. the next morning. Satisfactory concentration is
shown by at least one sample having a specific gravity above 1.020,
or an osmolality above 800 m osm /kg. The urine/plasma osmolality
ratio should reach 3 and values less than 2 are abnormal.
Urine Dilution (Water Load) Test
After an overnight fast the subject empties his bladder completely
and is given 1000 ml of water to drink. Urine specimens are collected
for the next 4 hours, the patient emptying bladder completely on
each occasion. Normally the patient will excrete at least 700 ml of
urine in the 4 hours, and at least one specimen will have a specific
gravity less than 1.004. Kidneys, which are severely damaged, cannot
excrete a urine of lower specific gravity than 1.010 or a volume above
400 ml in this time. The test should not be done if there is edema or
renal failure; water intoxication may result.
Classification Of Nephrotoxic Injury - Acute Renal Failure
The National Kidney Foundation Kidney Disease and Quality
Initiative has defined 2 proposals for the classification of acute
kidney injury (AKI), the Acute Kidney Injury Network (AKIN) and
RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria,
which are based on fall in GFR as inferred by changes in Creatinine or
urine output
Acute Renal Failure Definition:
Significant deterioration in renal function occurs over hours or days.
Reversible over days /weeks (injury to kidney is short term and
potentially reversible)- Clinically no symptom or sign but oliguria (<
400 ml/day) common.
No long-term complication seen in CKD, such as in:
 Renal anemia
 Renal bone disease
Acute Renal Failure
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Common clinical features:
Azotemia
Hypervolemia
Electrolytes abnormalities:
o Increased K+
o Increased Phosphate
o Decreased Na+
o Decreased Calcium
 Metabolic acidosis
 Hypertension
 Oliguria – Anuria
Classification Of Nephrotoxic Injury - Acute Renal Failure
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Hypoperfusion/Hypofiltration
Acute Tubular Necrosis
Obstruction
Tubulointerstial Fibrosis
Classification Of Nephrotoxic Injury - Chronic Renal Failure
Definition Of Chronic Renal Disease:
Structural or functional abnormalities of the kidneys for >3 months,
as manifested by either:
 Kidney damage, with or without decreased GFR, as defined by:
o Pathologic abnormalities
o Markers of kidney damage, including abnormalities in
the composition of the blood or urine or abnormalities in
imaging tests
 GFR < 60 ml/min/1.73 m2, with or without kidney damage
Classification Of Nephrotoxic Injury: Chronic Renal Failure
 Chronic Tubulointerstitial Fibrosis
 Papillary Necrosis
Definition Of ESRD Vs Kidney Failure
ESRD is a federal government defined term that indicates chronic
treatment by dialysis or transplantation
Kidney Failure: GFR < 15 ml/min/1.73 m2 or on dialysis.
Common Renal Diseases
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Glomerulopathies (GN)
Urinary tract infection
Urinary tract obstruction
Renal failure
Polycystic Kidney Disease
Others
Glomerulopathies
Glomerulopathies are the third most common cause of endstage
renal disease.
Glomerulopathy is a general term for a group of disorders in which:
 The kidneys are involved symmetrically.
 There is primarily an immunologically mediated injury to
glomeruli.
 May be part of a generalized disease eg: SLE(systemic lupus
erythematosus)
Classification of glomerulopathies:
 Nephrotic syndrome
 Nephritic syndrome.
Nephrotic Syndrome
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Proteinuria (>3.5 g/ day)
Hipoalbuminemaia (<30 g/L)
Edema
Hyperlipidemia (↑ LDL & cholesterol)
Etiology Of Nephrotic Syndrome
 Primary:
o Minimal change GN
o Membranous GN
o Focal segmental glomerulosclerosis - Ig A nephropathy
 Secondary:
o Infection; HBV, HIV, CMV,
o Malignancy; leukemia, lymphoma
o Drug/toxin; NSAID, mercury
o SLE
o Metabolic disease; DM
Nephritic Syndrome
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Hematuria
Hypertension
Oliguria
Uremia
Etiology Of Nephritic Syndrome
 Primary:
o lg A nephropathy
o Membranoproliferative GN
o Rapidly progressive GN2.
 Secondary
o Infection
o Multisystem disease:
 SLE,
 Henoch-Scholein purpura
 Goodpasture’s syndrome
Laboratory Presentations Of GN
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Hipoalbuminemaia
Proteinuria
Frothy urine/foamy
Hematuria
Microscopic or bloody urine
Reduced urine output (oliguria)
Uremia
Urinary Tract Infection (UTI)
 Presence of pure growth of >100 000 colony forming units/ml
in urine with pyuria.
 Haematuria
 Leukocytes
Pathogenesis Of Renal Stones
All urinary stones are composed of 98% crystalline material and 2%
mucoprotein
The crystalline component(s) may be found “pure” or in combination
with each other.
The common characteristic that all crystalline components share, is
that they have a very limited solubility in water or urine
A variety of animal models of stone disease as well as autopsy studies
in humans have shown that the collecting duct in the renal papilla
serves as the “uterus” for stone formation. It is here that urine has
achieved its maximum concentration and hence is most likely to be
supersaturated while it is still in a microscopic sized lumen. Clumps
of crystals become impacted in the opening of a collecting duct so
that some of the crystals are now exposed to the urine in that calyx
that comes from other collecting ducts.
99% of renal stones are composed of:
 Calcium oxalate 75% (mono or di hydrate)
 Calcium hydroxyl phosphate 15% (apatite)
 Magnesium ammonium phosphate 10% (struvite)
 Uric acid 5%
 Cysteine 1%
Investigations show that the formation of a stone is similar to the
development of a crystalline mass in vitro
Given that stone formation is an example of crystallization one could
predict:
 The necessity for a supersaturated state in urine
 The occurrence of spontaneous crystallization
 The need for the earliest polycrystalline state to be arrested in
the u.t. allowing time for growth
Risk Factors
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Occupation
Family history
Diet
Hydration
Small bowel disease (Irritable Bowl Disease) (Crohn’s disease) are
associated with an increased incidence of stone disease because of
the associated steattorhea. The fatty acids in the gut bind with
intraluminal calcium leaving the oxalate in a more easily absorbed
state. The net effect is hyperoxaluria. IBD may also result in
aciduria since there can be considerable amount of basic fluid lost
via the GI tract
 Medical conditions causing Hypercalciuria
 Medical conditions causing aciduria
Lab Tests
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Serum Ca, P, Uric Acid (repeat 2-3 times)
24 hours urine for Ca. P, Uric Acid
Serum PTH if serum Ca is high
Urine culture
Interesting Facts:
Increased HS-troponin concentrations not only in ACS:
 Non-ischemic cardiac diseases such as cardio-toxicity from
chemotherapy or poisoning, atrial fibrillation, hypertension,
left ventricular hypertrophy and systolic dysfunction
 Extra-cardiac disorders including pulmonary, renal and liver
disease
 Systemic or localized infections
 Head trauma
 Physiological conditions such as strenuous physical exercise
and aging
 Increased hs cTnI and cTnT concentrations
 Are common in outpatients with stable CKD
 Are influenced by both underlying cardiac and renal disease.