dr.sajadiyeh
TRANSCRIPT
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DR.Sh.Sajjadieh
nephrologist
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Abnormal quantity of protein excretion in theurine is called proteinuria.
95% of normal adults excrete less than 150mg/d. Children and adolescent can excrete up to 250
mg/d.
Higher rates of protein excretion that persistbeyond a single measurement should beevaluated.
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Proteinuria is defined as urinary proteinexcretion exceeding 2 SD from the mean.
Normal values depend upon the age Premature neonates 140 mg/m2/d
full term neonates 70 mg/m2/dChildren
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30 to 150 mg/day Usually only small proteins (
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Disruption of glomerular capillary barriers
(high m. wt. proteinuria)
Tubular damage, inability of prox. tubule to
reabsorb normally filtered proteins (low m.wt. proteinuria)
Increased production of normal and abnormal
plasma proteins which are filtered and
inadequately reabsorbed
Increased tubular production of protein
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PH indicators change color with protein Sensitive for albumin but not
immunoglobulins
Strongly pigmented urine interferes withcolor reaction (hyperbilirubinemia,pyridium)
False positives in very alkaline urine Sensitivity, 32-46% using 25 mg/dL
proteinuria
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Cold precipitation of proteins with a strong acid -
urine will become turbid, measured byphotometry
Poor precision - coefficient of variation is 20% Gamma globulins and albumin detected, more
sensitive to the latter
Substituting trichloracetic acid results in more
sensitivity for gamma globulins
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Turbidity of urine from anothercause
Radiographic contrast dye (high SGon urinometer but normal dipstick)
Penicillin, cephalosporin,
sulfonamides, tolbutamide, tolectin False negative in alkaline urine
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If SSA is positive while dipstick reagent isnegative
- non albumin proteinuria is suspected(e.g., gamma globulin paraproteins)-Pancreatic transplant patients,
nonalbumin pancreatic enzymes in urine
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Radioimmunoassay double antibody
technique Immunoturbidometric technique - albumin +
antibody create a turbid mixture measured byspectrophotometry
Albumin - antibody complexes measured by
laser nephelometer
ELISA
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70-80% of excreted protein is in upright
position.
The urine dipstick for protein primarilydetects albumin.
Urinanalysis
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In normal urine, 60% of the proteins
originate from the plasma and other 40%from the kidney and urogenital tract.
Normal protein composition is
approximately 40%albumin, 40% Tomm-Horsfal protein, 15% immunoglobulins,
5% other plasma proteins.
Urinanalysis
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Dipstick is simplest and least expensivemethod.
It detects protein concentration > 20 mg%
and depends on urine concentration and isinsensitive to globulin.
False positive in highly alkaline urine,
presence of bacteria, blood, ammoniumcompounds, or chlorhexidine.
Urinanalysis
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Sulfosalicylic acid is more sensitive (down
to 5 mg%) and react equally with albuminand globulin.
Urinanalysis
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False positive results can occur if the urine
contains tolbutamide, radiocontrastagents, or high level of cephalosporin,
penicillin, or sulfonamides.
Urinanalysis
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Quantitatively method is urine
electrophoresis.
At times, it is necessary to quantifyprotein excretion; determining the24-hour protein collection, or protein
to creatinine ratio.
Urinanalysis
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Microalbuminuria refers to elevatedurine albumin excretion that is below
the level of detection (30-300 mg/d or20-200 mg/min) by routine urine
protein dipstick test.
Urinanalysis
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There are three basic types of proteinuria :glomerular, tubular, and overflow.
Only glomerular proteinuria (ie, albuminuria)is identified on a urine dipstick.
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the proteinuria in glomerular diseaseis due to increased filtration of
macromolecules (such as albumin)across the glomerular capillary wall.
Glomerular proteinuria :
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Low molecular weight proteins ( such asmicroglobulin, immunoglobulin light
chains, retinol-binding protein, and aminoacids) have a molecular weight that isgenerally under 25,000 in comparison tothe 69,000 molecular weight of albumin.
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These smaller proteins can be filteredacross the glomerular and are then almost
completely reabsorbed in the proximaltubule.
Tubular Proteinuria
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Interference with proximal tubularreabsorption, due to a variety of
tubulointerstitial diseases or even someprimary glomerular diseases, can lead toincreased excretion of these smaller proteins.
Tubular Proteinuria
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Tubular proteinuria is not diagnosed clinicallysince the dipstick for protein does not detect
low molecular weight proteins and thequantity excreted is relatively small.
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Characteristic Tubular Glomerular
Sp. Gravity Isosthenuric High (conc.)
Protein 1+ on dipstick 3+
Hematuria Usually absent Often present
Casts Tubular cells/none
Variable (RBC,granular
UPEP Broad bandmultiple globulin
Albumin peak
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Increased excretion of low molecular weightproteins can occur with marked overproductionof a particular protein
(almost always immunoglobulin light chains inmultiple myeloma)
In this setting, the filtered load is increased to a
level that exceeds the normal proximalreabsorptive capacity.
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Abnormal protein excretion due to tissue ortumor necrosis.
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Proteinuria without hematuria or an elevatedserum creatinine concentration
asymptomatic and the presence ofproteinuria is discovered incidentally.
This is different from that in patients withmore prominent renal disease who have one
or more of the following: heavy proteinuria(>3 g/day), lipiduria, edema, and/or an activeurine sediment containing red cells (whichare often dysmorphic) and red cell casts.
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Annual screening for proteinuria is not cost-effective in the general population of healthyindividuals under age 60.
Routine urinalysis is recommended for highrisk patients :diabetes or hypertension
Early detection of proteinuria in high risk
patients is important because theadministration of an ACE inhibitor or ARBslow the progression of proteinuric chronickidney disease.
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Almost all cases ofpersistent proteinuria aredue to glomerular proteinuria.
Increased filtration of macromolecules (suchas albumin) across the glomerular capillarywall :
diabetic nephropathy and other glomerular
diseasesorthostatic or exercise-induced proteinuria Most patients with benign causes of isolated
proteinuria excrete less than 1 to 2 g/day
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Low molecular weight proteins :2-microglobulin,immunoglobulin light chains,, and amino acids havea molecular weight that is generally under 25,000 can
be filtered across the glomerulus and are then almostcompletely reabsorbed in the proximal tubule. The increased excretion of immunoglobulin light chains
(or Bence Jones proteins) in tubular proteinuria is mild,polyclonal (both kappa and lambda), and not injurious to
the kidney. This is in contrast to the monoclonal andpotentially nephrotoxic nature of the light chains in theoverflow proteinuria seen in multiple myeloma.
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Increased excretion of low molecular weightproteins can occur with marked
overproduction of a particular protein,leading to increased glomerular filtration andexcretion. This is almost always due toimmunoglobulin light chains in multiplemyeloma, but may also be due to lysozyme(AML), myoglobin (in rhabdomyolysis), orhemoglobin (in intravascular hemolysis) .
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Some patients have mixed forms of proteinuria: Patients with myeloma kidney also may develop
a component of tubular proteinuria, since theexcreted light chains may be toxic to thetubules, leading to diminished reabsorption.
Glomerular diseases such as focal segmental
glomerulosclerosis can be associated withproximal tubular injury, leading to tubularproteinuria.
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Standard urine dipstick Detection of albumin via a colorimetric reaction
between albumin and tetrabromophenol blueproducing different shades of green according to the
concentration of albumin in the sample. The dipstick is insensitive to the presence of non-
albumin proteins. positive dipstick usually reflects glomerular
proteinuria. Pure tubular or overflow proteinuria will not be
diagnosed unless a 24-hour urine is collected for someother reason, or the urine is tested with sulfosalicylicacid which detects all proteins.
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Both the dipstick and sulfosalicylic acid testwill detect urinary lysozyme (AML). Thus,lysozyme excretion should be measured in
this setting, particularly if other signs of thenephrotic syndrome (such as edema andhyperlipidemia) are absent.
The results with the dipstick and SSA serve asonly a rough guide of the degree of proteinexcretion since urine concentration will affectthe measurement.
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Determination of the degree of proteinexcretion is a central part of the evaluation ofpatients with acute and chronic kidney diseases
The degree of proteinuria is prognosticallyimportant in patients with a primary glomerulardisease.
Most patients with the benign forms of isolated proteinuriaexcrete less than 1 to 2 g/day.
The degree of proteinuria is used to monitor theresponse to therapy.
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Most patients with persistent proteinuriashould undergo a quantitative measurement ofprotein excretion.
24-hour urine measurement; however, collectingthese specimens is cumbersome in ambulatorycare settings.
Random urine specimen to estimate the degreeof proteinuria .This test calculates the total
protein-to-creatinine ratio (mg/g). This ratiocorrelates with daily protein excretion expressedin terms of g per 1.73m2 of body surface area .
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It is important to note the units ofmeasurement in your laboratory. If the
urinary creatinine concentration is measuredin mmol/L, the formula must be amended asfollows, since 1 mg/dL equals 0.088 mmol/L:
Protein excretion = (Urine
[protein] x 0.088) Urine [creatinine]
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Microalbuminuria is defined as persistent albuminexcretion between 30 and 300 mg/day (20 to 200 g/min).
The normal rate of albumin excretion is less than 20mg/day (15 g/min).
The standard urine dipstick is an insensitive method todetect microalbuminuria, which is the earliest clinicalmanifestation of diabetic nephropathy and, in patientswithout diabetes, is a marker of increased cardiovascularrisk.
Dipsticks are available that detect the urine albuminconcentration in this range, but the preferred test fordiagnosis and monitoring is the urine albumin-to-creatinine ratio.
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The urine sediment should be examined for othersigns of glomerular disease such as hematuria, redcell casts, or lipiduria and Red cell casts.
If the sediment is unremarkable, the differentialdiagnosis includes transient proteinuria, orthostaticproteinuria, and persistent proteinuria.
The urine dipstick should be repeated on at least
one other visit. If these subsequent tests arenegative for protein, the likely diagnosis is transientproteinuria.
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Transient proteinuria is common:(fever and exercise)
With marked exercise, the excretion of bothalbumin and low molecular weight proteins isincreased, suggesting both an increase inglomerular permeability (to allow the filtration
of albumin) and a reduction in proximalreabsorption.
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If the patient is younger than age 30 and has documentedproteinuria on more than one occasion. This test detectsorthostatic proteinuria, a relatively common finding inadolescents (occurring in 2 to 5 percent), but an
uncommon disorder in those over the age of 30 . Orthostatic proteinuria is characterized by increased
protein excretion in the upright position, but normalprotein excretion when the patient is supine?neurohumoral activation and altered glomerular
hemodynamics Total protein excretion is generally less than 1 g/day inorthostatic proteinuria, but may exceed 3 g/day inselected patients.
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Orthostatic proteinuria is a benign conditionrequiring no further evaluation or specifictherapy .In many patients, the condition
resolves over time. Many patients with glomerular disease will havea modest reduction in protein excretion whensupine. However, the diagnosis of orthostaticproteinuria requires that protein excretion be
normal when supine (less than 50 mg per 8hours), not merely less than when in the uprightposition
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Split urines are collected according to the followingprotocol .
o A 16-hour upright collection is obtained between 7 AMand 11 PM, with the patient performing normalactivities and finishing the collection by voiding just
before 11 PM. (The times can be adjusted according tothe normal times at which the patient awakens andgoes to sleep.)
o The patient should assume the recumbent position 2hours before the daytime collection is finished toavoid contamination of the supine collection withurine formed when in the upright position.
o A separate overnight 8 hour collection is obtainedbetween 11 PM and 7 AM.
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Instead of the cumbersome 24-hour urinecollection, the protein-to-creatinine (Pr/Cr)
ratio may be used on a first morning spoturine specimen and on a specimen collectedwhile upright. For this, the patient isinstructed to void before going to bed and to
remain recumbent until the first morningsample is obtained.
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A thorough evaluation Underlying renal or systemic disorder .
Renal function tests :BUN and Cr,quantitative measurement of urine protein,ultrasound examination
All patients with persistent proteinuria
should be referred to a nephrologist fordecisions regarding further management(eg, renal biopsy).
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A renal biopsy is performed if there is some signof severe or progressive disease, such asnephrotic syndrome, increasing protein
excretion, or an elevation in the plasmacreatinine concentration. Biopsies are often not performed among
patients with stable non-nephrotic proteinuria,providing renal function is stable and hematuria
is not present, since knowledge of histologyobtained by the biopsy is unlikely to altertherapy.
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The level of non-nephrotic proteinuria thatshould be evaluated by biopsy is not clear.
Perform a biopsy in patients with non-nephrotic
proteinuria of 2 to 3 g/day but not for proteinuirathat is less than 1 g/day .If a patient withproteinuria greater than 1 g/day is reluctant toundergo biopsy, absolute indications include
increasing proteinuria or plasma creatinineconcentration, or a significant elevation in bloodpressure over baseline values.
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The prognosis of patients with glomerularproteinuria is related to the quantity of proteinexcreted. Non-nephrotic proteinuria (less than 3
g/day) is associated with a much lower risk ofprogressive chronic kidney disease thannephrotic range proteinuria.
These observations indicate the need for
persistent monitoring of patients withapparently benign, nonorthostatic, andpersistent isolated proteinuria.
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Is not a disease but a group of signs andsymptoms seen in patients with heavy
proteinuria
Presents with edemaproteinuria usually > 3.5g / 24hrs (>0.05g / kg /
24hrs in children)
serum albumin < 30g/L
other features:hyperlipidaemia, and hypercoaguable state
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Proteinuria > 3.5 grams/day Hypoalbuminemia Edema Lipiduria Hyperlipidemia
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Proteinuria: due to an increase in glomerularpermeability
Hypoalbuminemia: occurs when liver synthesis cannot
keep up with urine losses
Edema mechanism is complex and still in dispute: primary saltand water retention associated with reduced renal function aswell as reduced plasma oncotic pressure are primary factors(overfill and underfill)
Minimal change disease fits the underfill theory bestHyperlipidemia: increased liver synthesis
Hypercoagulation: increased fibrinogen and loss of
antithrombin III
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PrimaryMembranous Glomerulopathy
Focal Segmental GlomerulosclerosisMinimal Change DiseaseMembranoproliferative GN
Secondary
Diabetic glomerulosclerosisParaproteinemia /AmyloidosisLupus Nephritis
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Systemic diseasesdiabetes mellitus
amyloidosis
SLE and other connective tissue diseases
HIV/Aids
nephrotoxinsnsaids
mercury poisoning
penicillaminegold salts
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Allergiesbee sting
pollens
poison ivy
Circulatory effectscongestive cardiac failure
constrictive pericarditis
renal vein thrombosis (cause or result?)
Neoplasticleukemia
solid tumors
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Nephrotic syndrome
Nephrotic range proteinuriaadults >3.0-3.5 grams/d
children >40 mg/h
Defining Clinical featuresProteinuria causes Hypoalbuminemia
Edema - altered Starling forces
Hyperlipidemia - increased liver production of
beta lipoprotein, decreased lipoprotein lipase,decreased conversion of Free fatty acid to
triglycerides
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Nephrotic syndrome
Hypercoagulableurinary loss of anti-thrombin III and plasminogenhemoconcentration
Risk of Infections-urinary loss of gamma globulin
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History and Physical Exam
Urine Analysis
Lab Studies
Renal Biopsy
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Urine Sediment Types
Nephritic urine Nephrotic urine Chronic GN
red cells (hematuria) heavy proteinuria proteinuria
variable proteinuria free fat droplets variable
hematuria
granular casts fatty casts broad waxy casts
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24 urine collection Serum electrolytes, BUN, creatinine, lipid profile,
serum albumin Serological work up - depends upon the clinical
presentation - common serological tests done are:ANA; Anti-ds DNA Complement levels (C3, C4)Hepatitis B and C serologies SPEP; UPEP, ANCA,anti GBM Abs
Renal Ultrasound Renal Biopsy
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Na+< 60 mmol/24 hrs water restriction diuretics (if not volume depleted) reduced protein diet (controversial) treat infections prophylaxis for thrombosis specific therapy
corticosteroids
immunosuppression
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Edema - salt restriction, diuretics Hyperlipidemia - lipid lowering agents ACE/ARB -
decrease Pgc and decrease proteinuria
Renal protective
Hypercoagulable - ASA
Specific treatment based on biopsy
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Minimal change diseaseprednisone for 16 weeks (p)
prednisone and cyclophosphamide ( p+c)
FSGSp, p+c, p+cyclosporine(cs)
Membranous
Ponticelli Regimenp+c
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Most common in children Etiology:
Idiopathic
Drugs
NSAIDToxins Mercury, LeadInfections HIV, MononucleosisTumors Hodgkin disease
Patient usually normotensive, nephrotic sediment,normal renal function.
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Pathogenesis - unknown, most likelyautoimmune
Treatment
85% respond to steroids
If resistant to steroid may require
cyclophosphamide
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Most common primary renal disease inAfrican-Americans
Etiology:
IdiopathicDrugs Intravenous heroinInfections HIVOthers reflux nephropathy, obesity
Patient usually hypertensive. Usuallyprogresses to ESRD over 5-20 years.
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Pathogenesis
Primary - immunologic?
Secondary - common end point of manyrenal diseases
Treatment
Steroids
Immunomodulators - cyclosporine,Tacrolimus, mycophenolic acid
ACE/ARB and anti-lipid agents
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Most common cause of idiopathic nephroticsyndrome in Caucasian adults.
Heavy proteinuria is common. Hypertension
and azotemia develops as disease progresses. Increased incidence of renal vein thrombosis.
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Primary Autoantibody to glomerular antigen
Secondary Circulating antigen deposits
Antibody to antigen attaches causingimmune reaction
In both Complement activated and cell damage due
to C5-9 attack complex
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Rule of 1/31/3 Spontaneous remission1/3 Partial remission / slow deterioration
1/3
Progress to ESRD Steroids alone are not very effective Methylprednisolone alternating with chlorambucil,
Methylprednisolone alternating with
cyclophosphamide. Cyclosporin
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1-Declining renal function 2- Persistent proteinuria 3-Amount of proteinuria at the time of presentation 4-male sex 5-Advanced age (>50) 6-Poorly controlled HTN 7-Crescents on renal biopsy 8-The presence of frequent mononuclear cells in the
interstitium 9-FSGS superimposed on membranous glomerulopathy
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Most common cause of nephrotic syndrome inadults.
Leading cause of ESRD in USA
30% of patients with Type I and 20% of patientswith Type II DM develop diabetic nephropathy.
Initially microalbuminuria followed by heavy
proteinuria and decline in renal function. Diagnosis usually made on clinical grounds and
biopsy not needed.
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Glomerular Hyperfiltration
Efferent arteriolar vasoconstriction
Afferent arteriolar vasodilation
Hyperglycemia
Advanced glycation endproducts
Glycation of proteins
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Blood glucose control Control of hypertension
Use of ACE inhibitors/ARBs Control of hyperlipidemia Smoking cessation
Protein Restriction
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Myeloma Cast Nephropathy Disease of older adults
Usually presents with Bone pain
Hypercalcemia
Pathologic fractures
anemia
Proteinuria - consists of monoclonal immunoglobulins
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Myeloma Cast Nephropathy Path. shows multiple intraluminal
proteinaceous casts
Pathogenesis Disorder of plasma cells with overproduction of
the antibody light chain
Treatment Hydration, plasmapheresis to remove the
abnormal protein and chemotherapy to suppressplasma cells
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Primary Amyloid Amyloid deposition in heart, GI Tract, Skin, nerves and
tongue
No bone lesions or excess marrow plasma cells
Secondary amyloid Chronic Inflammatory conditions
Tuberculosis, Chronic osteomyelitis, Rheumatoid arthritis,ulcerative colitis, Hodgkins Disease
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Amyloid protein produced in plasma celldyscrasias is preferentially lamda light chains
Kappa chain can occur and termed light chain
deposition disease Kappa chain deposits tend to deposit in
tubules and glomeruli, spare vessels Kappa more aggressive than lambda
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Hematuria that is not explained by anobvious underlying condition is fairlycommon. In many such patients, particularly
young adult patients, the hematuria istransient and of no consequence .On theother hand, there is an appreciable risk ofmalignancy in older patients (eg, over age 40)with hematuria, even if transient .However,even among older patients, a urologic causefor the hematuria can often not be identified .
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Gross hematuria is suspected because of thepresence of red or brown urine. The colorchange does not necessarily reflect thedegree of blood loss, since as little as 1 mL ofblood per liter of urine can induce a visiblecolor change.
Gross hematuria with passage of clots almostalways indicates a lower urinary tract source.
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As contamination with blood is a possibility inmenstruating and post-partum women, urinefor analysis is best obtained when the othercause of bleeding has ceased. If this is notpossible a tampon can be inserted, andurinalysis obtained after the perineum is
thoroughly cleansed.
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The initial step in the evaluation of patients withred urine is centrifugation of the specimen to seeif the red or brown color is in the urine sediment
or the supernatant. Hematuria is responsible if the red to brown
color is seen only in the urine sediment, with thesupernatant being clear.
If it is the supernatant that is red to brown, thenthe supernatant should be tested for heme(hemoglobin or myoglobin) with a urine dipstick.
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A red to brown supernatant that is negativefor heme (hemoglobin or myoglobin) is a rarefinding that can be seen in several conditions,including porphyria ,the use of the bladderanalgesic phenazopyridine, and the ingestionof beets in susceptible subjects.
http://www.uptodate.com/contents/phenazopyridine-drug-information?source=see_linkhttp://www.uptodate.com/contents/phenazopyridine-drug-information?source=see_link -
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Medications: Doxorubicin, ChloroquineDeferoxamine, Ibuprofen ,Iron, sorbitol,Nitrofurantoin ,Phenazopyridine,
Phenolphthalein, Rifampin. Food dyes :Beets (in selected patients),
Blackberries, Food coloring. Metabolities: Bile pigments, Homogentisic
acid, Melanin, Methemoglobin, Porphyrin ,Tyrosinosis, Urates.
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Microscopic hematuria may be discovered byaccident when blood (either red blood cells orhemoglobin) is found on a urinalysis ordipstick done for other purposes.
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Although abnormal hematuria is commonly definedas the presence of more than 2 RBCs per high powerfield in a spun urine sediment, there is no "safe" lowerlimit below which significant disease can be excluded .
Some experienced clinicians prefer to definehematuria by quantitative counting of RBCs in ahemocytometer chamber. A count of more than 8000per mL in centrifuged urine (with back calculation to
the original volume of the urine sample) or 13,000 permL in uncentrifuged urine is considered abnormal .
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The urine sediment (or direct counting of RBC per mL ofuncentrifuged urine) is the gold standard for the detectionof microscopic hematuria. Dipsticks for heme detect 1 to 2RBCs per high power field and are therefore at least assensitive as urine sediment examination, but result inmore false positive tests due to the following:
Semen is present in the urine after ejaculation and maycause a positive heme reaction on the dipstick .
An alkaline urine with a pH greater than 9 orcontamination with oxidizing agents used to clean the
perineum. The presence of myoglobinuria. positive dipstick test must always be confirmed with
microscopic examination of the urine
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The identification of the glomeruli as the source ofbleeding is important both prognostically and tooptimize the subsequent evaluation. In particular,patients with clear evidence of glomerular hematuriado not need to be evaluated for potentially seriousurologic disease .
Glomerular hematuria may result from immune-mediated injury to the glomerular capillary wall, or in
noninflammatory glomerulopathies such as thinbasement membrane nephropathy from localizedgaps in the glomerular capillary wall.
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signs of glomerular bleeding (best identified by anephrologist or other experienced examiner)include red cell casts (considered by most to bepathognomonic for glomerular disease,although rarely described in acute interstitialnephritis), protein excretion exceeding 500mg/day at a time when there is no grossbleeding, a dysmorphic appearance of some red
cells (particularly acanthocytes, which are bestseen by phase contrast microscopy), and brown,cola-colored urine with gross hematuria.
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An additional important abnormality thatmay be seen in patients with hematuria isblood clots. Clots virtually never occur inglomerular disease, perhaps due to thepresence of urokinase and tissue-typeplasminogen activators in the glomeruli and
the renal tubules.
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As a general principle, hematuria itself is notdangerous unless extraglomerular bleeding is sobrisk that it causes clots that obstruct theureter(s).
The evaluation should address the followingthree questions:
Are there any clues from the history or physicalexamination that suggest a particular diagnosis?
Does the hematuria represent glomerular orextraglomerular bleeding? Is the hematuria transient or persistent?
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Concurrent pyuria and dysuria, which are usuallyindicative of a urinary tract infection, but may alsooccur with bladder malignancy.
A recent upper respiratory infection raises the
possibility of postinfectious glomerulonephritis or IgAnephropathy. A positive family history of renal disease, as in
hereditary nephritis, polycystic kidney disease, orsickle cell disease.
Unilateral flank pain, which may radiate to the groin,suggests ureteral obstruction due to a calculus orblood clot, but can occasionally be seen withmalignancy.
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Symptoms of prostatic obstruction in older mensuch as hesitancy and dribbling. there is generalagreement that the presence of BPH should not
dissuade the clinician from pursuing furtherevaluation of hematuria, particularly since oldermen are more likely to have more seriousdisorders such as cancer of the prostate or
bladder. Among those with gross hematuria inwhom no other cause can be identified,finasteride usually suppresses the hematuria.
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Recent vigorous exercise or trauma. History of a bleeding disorder or bleeding from
multiple sites due to excessive anticoagulanttherapy.
Cyclic hematuria in women that is most prominentduring and shortly after menstruation, suggestingendometriosis of the urinary tract .
Contamination with menstrual blood is always a
possibility, and should be ruled out by repeatingthe urinalysis when menstruation has ceased.
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Medications that might cause nephritis (usuallywith other findings, typically with renalinsufficiency).
Black patients should be screened for sickle cell
trait or disease, which can lead to papillarynecrosis and hematuria.
Travel or residence in areas endemic forSchistosoma haematobium or tuberculosis.
Sterile pyuria with hematuria, which may occurwith renal tuberculosis, analgesic nephropathyand other interstitial diseases.
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The main indication for performing a renal biopsy inpatients with isolated glomerular hematuria isevidence ofprogressive disease as manifested byincreasing protein excretion and/or an elevation in the
serum creatinine concentration Renal biopsy is not usually performed for isolated
glomerular hematuria (ie, no proteinuria and noelevation in serum creatinine), since there is no
specific therapy for these conditions and the renalprognosis is excellent as long as there is no proteinuriaor elevation in serum creatinine.
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There is no cause oflow-level hematuria that, in the absence ofother signs and symptoms, requires immediate diagnosis. As aresult, it is reasonable to repeat an abnormal urinalysis in a fewdays to determine if hematuria is transient or persistent.
Transient microscopic hematuria is a common problem in adults.
No obvious etiology can be identified in most patients withtransient hematuria. Fever, infection, trauma, and exercise are potential causes of
transient hematuria. Transient hematuria can also occur withurinary tract infection
An important exception to the typically benign nature of transient
hematuria occurs in patients over age 40 in whom even transienthematuria carries an increased risk of malignancy
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All patients should have a urine culture toexclude infection prior to evaluation ofhematuria. The urinalysis should be
rechecked in six weeks to determine whetherhematuria has resolved. Patients who haveresolution of hematuria do not require further
evaluation.
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A voided urine specimen should be sent for cytology inpatients at increased risk for urothelial cancers.
The sensitivity of urine cytology is greatest for carcinomaof the bladder (approximately 90 percent). By comparison,sensitivity for upper tract transitional cell carcinoma islimited.Urine cytology is frequently obtained duringcystoscopy, which is usually performed in patients at riskfor malignancy.
Among patients at low risk for genitourinary cancer, someinvestigators recommend that either urine cytology or
cystoscopy be performed .Cystoscopy is subsequentlydone if malignant and/or atypical/suspicious cells areidentified.
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Once glomerular bleeding has been excludedin a patient with otherwise unexplainedhematuria, the diagnostic work-up shouldinclude a search for lesions in the kidney,collecting system, ureters, and bladder.
The diagnostic yield in adults increases withage and may be higher for gross hematuriathan for microscopic hematuria.
The optimal radiologic evaluation for isolatedhematuria is uncertain
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A number of modalities are available to evaluatethe genitourinary tract among patients withunexplained hematuria. These includeconventional radiography, IVP, retrograde
pyelography, ultrasonography,MRI,MRU,conventional CT scanning, and multidetector CTurography.
Patients with malignancy in the bladder or
kidneys are at increased risk for malignancy atthe other site and should undergo furtherevaluation.
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Screening for hematuria in patients whohave no symptoms suggestive of urinary tractdisease is not recommended.
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Polyuria has generally been defined as aurine output exceeding 3 L/day in adults. Itmust be differentiated from the more
common complaints of frequency or nocturia,which are not associated with an increase inthe total urine output.
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In the absence of a glucose-induced osmoticdiuresis in uncontrolled diabetes mellitus,there are three major causes of polyuria in
the outpatient setting, each of which is dueto a defect in water balance leading to theexcretion of large volumes of dilute urine(urine osmolality usually below 250
mosmol/kg): primary polydipsia, which isprimarily seen in adults and adolescents;central DI; and nephrogenic DI .
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Primary polydipsia also called psychogenicpolydipsia :a primary increase in water intake.This disorder is most often seen in anxious,
middle-aged women and in patients withpsychiatric illnesses, including those taking aphenothiazine which can lead to the sensationof a dry mouth. Primary polydipsia can also be
induced by hypothalamic lesions that directlyaffect the thirst center, as may occur with aninfiltrative disease such as sarcoidosis.
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Central DI also called neurohypophyseal orneurogenic DI is associated with deficientsecretion of ADH. This condition is most oftenidiopathic (possibly due to autoimmuneinjury to the ADH-producing cells), or can beinduced by trauma, pituitary surgery, or
hypoxic or ischemic encephalopathy. Rarefamilial cases have been described.
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Nephrogenic DI is characterized by normalADH secretion but varying degrees of renalresistance to its water-retaining effect. This
problem, in its mild form, is relatively common,since most patients who are elderly or who haveunderlying renal disease have a reduction in
maximum concentrating ability. This defect,however, is not severe enough to produce asymptomatic increase in urine output.
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Symptomatic polyuria due to ADH-resistanceis seen primarily in 2 settings :
Nephrogenic DI presenting in childhood is
almost always due to inherited defects.Nephrogenic DI presenting in adults is almost
always acquired with chronic lithium use andhypercalcemia being the most common
causes of a defect severe enough to producepolyuria.
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The cause of polyuria is often suggested from
the history (eg, age of onset and eliciting the
possible presence of the different causes ofDI), and rarely by the plasma sodiumconcentration. Specific testing is thenperformed to establish the diagnosis.
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Onset of polyuria : In the majority of cases ofhereditarynephrogenic
DI, severe polyuria manifests during the first week oflife.
In familial central DI (usually an autosomal dominantdisease), polyuria may present after the first year oflife, sometimes in young adulthood, due topreservation of function of the normal allele.
In adults, the onset is usually abrupt in central DI ("Isuddenly began urinating too much a few days ago"),and almost always gradual in acquired nephrogenicDI or primary polydipsia.
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The new onset of nocturia in the absence ofother causes of nocturia is often a first clue toDI. The urine is normally most concentrated
in the morning due to lack of fluid ingestionovernight; as a result, the first manifestationof a loss of concentrating ability is often
nocturia.
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Family history : There are familial forms ofboth central and nephrogenic DI.
A family history of polyuria is helpful both for
diagnosis and to identify asymptomaticmembers of affected families who harbor thesuspect allele. Thus, all families withhereditary DI should have their molecular
defect identified.
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Plasma sodium and urine osmolality: Each ofthe three causes of polyuria is associated withan increase in water output and the excretion
of a relatively dilute urine. With primarypolydipsia, the polyuria is an appropriateresponse to enhanced water intake; in
comparison, the water loss is inappropriatewith either form of DI.
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Measurement of the plasma sodium concentration andthe urine osmolality may be helpful in distinguishingbetween these disorders:
A low plasma sodium concentration (less than 137 meq/L)with a low urine osmolality (eg, less than one-half the
plasma osmolality) is usually indicative of water overloaddue to primary polydipsia.
A high-normal plasma sodium concentration (greater than142 meq/L, due to water loss) points toward DI,particularly if the urine osmolality is less than the plasma
osmolality . A normal plasma sodium concentration is not helpful in
diagnosis but, if associated with a urine osmolality morethan 600 mosmol/kg, excludes a diagnosis of DI.
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Measurement of urine output : Potentialproblems include an incomplete collectionand the necessity for multiple containers if
the patient has severe polyuria, which can beminimized by obtaining an eight hour ratherthan a 24 hour collection. Measurement of
urinary creatinine excretion can helpdetermine if the collection is complete.
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Water restriction test : Even if the historyand/or plasma sodium concentration andurine osmolality appear to be helpful, the
diagnosis should be confirmed by raising theplasma osmolality either by water restriction.Water restriction is important to
differentiate central DI from primarypolydipsia; simply giving exogenous ADH.
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Plasma and urine ADH measurementUnless the history and water restriction testprovide unequivocal results
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