Table Of ContentForeword
Mallucheetal. - ClinicalNephrology,DialysisandTransplantation -Foreword
Nephrology, Dialysis and
Transplantation
Isthereaneedforanothernephrologytext? edition,whichwasmadepossiblebythedili-
Certainlyanumberofexcellenttextbooksare gent and devoted input from the co-editors,
availablefornephrologiststolookupin-depth Drs.B.PeterSawaya,MohamedH.Sayegh,
informationonthevarioustopicsinthefield. andRaymondM.Hakim,withenormoushelp
The current treatise pursues a different pur- fromDr.NuhadIsmail.Theoverallqualityof
pose and incorporates a novel approach pio- thistreatisewasaccomplishedthroughexcel-
neeredbyDustri-Verlag.Theringbinderfor- lent contributions of the authors of the indi-
matallowsremovalofchapterstobecarried vidual chapters. The authors were recruited
toroundsorconferences,andreplacementof fromaroundtheworldandtheeditorswould
individualchaptersasthefieldprogressesin liketoextendtheirdeepestgratitudetothese
one,butnotnecessarily allothertopicscov- fineacademiciansfortheirgreatwork.Weare
ered by the book. This obviates the need to lookingforwardtoanongoingcollaboration
purchase every two to three years an entire inthecontinuedupdatingprocessofthetext.
newsetoftextbooksandallowsongoingand This lively process of continuous updating
timely updating of individual topics as re- willhopefullybeenhancedbyinputfromthe
quired.Itwasthegoaloftheeditorstocreate readers,which issolicitedand welcomedby
aclinicallyorientedtextprovidingthereader allsectioneditorsandthechiefeditor.Finally,
withconcise,up-to-dateinformationwithout wewouldberemissifwedidnotexpressour
lengthy historical perspectives and back- thanks to Jörg Feistle of Dustri-Verlag, who
ground information. The development of a hasbeenaconsistentandpleasantforceessen-
CD should later complement this treatise by tialtothecreationofthiswork.Lookingfor-
allowing more in-depth listings of detailed wardtoanenjoyableandsuccessfulongoing
references, presentation of charts, graphs, documentationoftheclinicalknowledgebase
photomicrographs, x-rays, etc. The current andprogressinthefieldofnephrology,dialy-
two volumes represent a well rounded first sisandtransplantation.
HartmutH.Malluche
Lexington,July1999
Mallucheetal. - ClinicalNephrology,Dialysisand Transplantation - Foreword V
Foreword
VI
Diagnostic Evaluations of the Kidney
1
I.
and the Urinary Tract
FrancisDumler,LeslieL.RocherandBeatriceL.Madrazo
Mallucheetal. - ClinicalNephrology,DialysisandTransplantation - I-1
Urinalysis labia and gently clean the periurethral area
using cotton balls prepacked in a soap solu-
tion. Suprapubic aspiration is most suitable
for infants and has almost no use in adult
Theurinalysisisthesinglemostusefuland practice.Urinalysisisbestperformedwithin
cost effective method of screening for renal 2hoursofcollection.Ifneeded,samplesmay
andurologicaldisease.Itissimple,inexpen- bemaintainedat4°Cforupto24hours.When
sive, widely available, and noninvasive. Al- delays are expected, adding a few drops of
though not specific as to cause, urinalysis acetic acid facilitates the preservation of
provides valuable information regarding the formedcastelements.
typeandseverityofrenalinvolvement.Until
Asampleofurineisplacedinacleartube
recently,itwascommonpracticetoperforma
fordipsticktesting.Asimilaraliquot,usually
urinalysisonallpatientsuponhospitaladmis-
10–12mL,iscentrifugedat3000rpmfor3
sion or for preoperative clearance regardless
–5minutes,thesupernatantpoured,andthe
ofclinicalpresentation.Thisisnotcosteffec-
sedimentresuspendedintheresidualvolume,
tive, and routine urinalysis is no longer rec-
usually 0.1 mL, for microscopic analysis. A
ommended asascreening testin thegeneral
completeurinalysisconsistsof3majorevalu-
population. However, it is indicated in all
ations: physical examination, overall chemi-
patientsatriskorsuspectedofhavingrenalor
calcomposition,andanalysisofformedele-
urological disease. In addition, pregnant
ments in the sediment. In many laboratories
women, diabetics, and the elderly should be
thelatterisperformedonlyifdipsticktesting
routinely screened. In patients with protein-
is abnormal or when specifically requested
uria, urinary sediment findingsare ageneral
regardlessofdipstickresults.
predictorofhistologyonrenalbiopsy.
Physical examination of the urine is done
Early morning concentratedurinaryspeci- byvisualinspectionofthesample,placedin
mens are preferred for urinalysis. Optimal a clear transparent container, under proper
samplesareobtainedafter14hoursofnofluid lighting,andagainstawhitebackground.The
intake.Specimenscanbeobtainedbysponta- coloroftheurineisdeterminedbyitschemi-
neousvoiding,catheterization,orsuprapubic calcomposition,concentrationofsolutes,and
aspiration. Clean-catch/midstream-voided pH.Hematuriaisthemostcommoncauseof
samplesarefirstchoice.Inmales,specimens abnormal color, ranging from red to black
shouldbeobtainedafterretractionofthefore- depending on amount, pH, and time. Red-
skin. Females should manually separate the tingedurinemayalsobeseenwithhemoglo-
Mallucheetal. - ClinicalNephrology,Dialysisand Transplantation - I-1 1
ChapterI - ClinicalNephrologyandHypertension
Table1. Routine UrinalysisTestingbyDipstick
Parameter Seconds Comment
Glucose 30 Nofalsepositives
Bilirubin 30 Noncharted colorsarepositive*
Ketone 40 Detectsacetoaceticacid only
SpecificGravity 45 Notaffectedbyglucoseor dye
Blood 60 Hemoglobinandmyoglobin*
pH 60
Protein 60 Albumin>globulin>light chains
Urobilinogen 60
Nitrite 60 Positivetestsuggests>105CFU/mL
Leukocytes 120 Fairlyspecific
*Falsenegativeresultsmayoccurduetohighascorbicacidcontent
binuriaandmyoglobinuria,aftereatingbeets, Glucose:Measuredusingaspecificglucose
andduringrifampintherapy.Yellowtobrown oxidase and peroxidase method. Glucose is
urine is due to bile pigments in jaundiced metabolized with glucose oxidase into glu-
patients.Urineofnormalcoloruponvoiding conic acid and hydrogen peroxide. The per-
that darkens with time suggests porphyria oxidasecatalyzestheoxidationofapotassium
(porphobilinogen), melanoma (melanogen), iodide chromogen by hydrogen peroxide re-
or alkaptonuria (homogentisic acid) in the sultinginashadeofcolorsrangingfromgreen
appropriateclinicalsetting.Manydrugsalso to brown. False negatives may occur in the
influencethecolorofurine.Theurinesample presenceoflargeamountsofascorbicacid.
may be immediately cloudy due to the pres- Bilirubin: Under normal circumstances
enceofformedelements,oritmaygetcloudy onlyconjugatedbilirubinisexcretedintothe
later because of precipitation of phosphates urine.Inpatientswithjaundiceduetoobstruc-
(alkaline or neutral pH) or urates (acid pH). tion or hepatocellular disease, bile pigments
Refrigeration accelerates precipitation. Pro- overflow into the urine. Bilirubin binds to
fuse white foam may suggest proteinuria. A diazotized dichloroaniline in a strong acid
pungent smell suggests bacteria, while a mediumandproducesvariousshadesoftan.
sweet fruity odor may be due to ketones. In Ketone: The nitroprusside reaction, which
addition, inborn errors of metabolism may detectsacetoacetate,ismostcommonlyused.
leadtoaparticularsmellintheurine:maple Betahydroxybutyricacid(whichaccountsfor
syrup (maple syrup urine disease), mousy 80%ofketonesinblood)andacetonearenot
(phenylketonuria), sweaty (isovaleric acid- detectedbythismethod.Withprolongedfast-
emia),orfishy(hypermethionemia)odor. ing or starvation, ketonuria may be detected
Overallchemicalcompositionismostcom- intheabsenceofketonemia.
monly evaluated using the dipstick method. Specificgravity:Assessestheabilitytocon-
Parametersusuallytestedarelistedbelowand centrate or dilute the urine. It correlates
inTable1bythetimerequiredtocompletethe closely with osmolality except when a high
reaction. concentration ofglucose or othersubstances
2
1 Dumler,RocherandMadrazo - Diagnostic Evaluations
presentintheurine(i.e.contrastagents,pro- a wide range of colors for measuring pH. A
teins) contribute more mass (an increase in consistently alkaline pH may be associated 1
I.
specificgravity)thanosmols.Theusualrange with a substantial vegetarian diet, the pres-
is1.001 – 1.035.Itcanbemeasuredusinga ence of urea-splitting bacteria, or metabolic
hygrometer,arefractometer,oradipstick;the alkalosis.AnacidpHiscommonduringlarge
latter is most commonly used. The dipstick meatconsumptionbutmaybeindicativeofa
detection method uses a polyionic polymer metabolicacidosis.Thedipsticktechniqueis
reagent that releases hydrogen ion (H+) as it adequateforscreeningonly.Whenacid-base
issaturatedwithcationspresentintheurine. disordersareclinicallysuspectedandknowl-
Theresultantchangeinacidityoftheindica- edgeoftheurinepHisessentialfordiagnosis
tor dye causes a color change from blue to andtreatment,accuratemeasurementrequires
yellow.Althoughnotinfluencedbyglucoseor use of an electrode pH meter and a urine
contrastagents,thismethodisusefulonlyas samplecollectedunderoil.
ascreeningtool.Ittendstooverestimatespe- Protein:Urinedipsticktechniquesforpro-
cificgravityatpH<6.0andunderestimateat teinprimarilydetectalbuminanddonotreact
pH>7.0.Whenclinicallyrelevant,itisessen- withimmunoglobulinlightchains.Sulfosali-
tial to measure urine osmolality. Osmolality cylicaciddetectsbothalbuminandimmuno-
providesthetruemeasureofsoluteconcentra- globulins. These techniques provide only a
tion in the urine. It is usually quantitated by qualitative assessment. As proteinuria is the
the freezing point technique. Normal values major abnormality observed in patients with
rangefrom50to1,200mosm/kg. renal disease, a positive dipstick test should
Blood: Detection is based on the pseudo- be followed by quantitation of protein in a
peroxidase capacity of hemoglobin or 24-hoururinesample,oratleastbyaprotein
myoglobin to catalyze a reaction between to creatinine ratio in a random sample. Dip-
diisopropylbenzene dihydroperioxide and stickmethodsuseapH-sensitivecolorimetric
3,3’,5,5’-tetramethylbenzidine. A spotted indicator, tetrabromophenol blue buffered at
patternindicatesintactredbloodcells,anda pH 3.0, that changes from yellow to dark
uniform pattern suggests free hemoglobin, green andturquoiseasproteinconcentration
myoglobinuria, or methemoglobinuria. This increases. The color shift is caused by the
methodisverysensitiveandcandetectaslittle bindingofnegativelychargedproteins.Neu-
as 3 red blood cells (RBC) per high power tral or positively charged proteins will not
field(HPF).Apositivetestintheabsenceof causecolorchange.Aslittleas20mg/dLof
RBCsintheurinarysedimentusuallyimplies albumincanbedetected.Itmaybedifficultto
lysisofRBCswithreleaseofhemoglobinbut differentiatenormalfromtrace.Ahighurine
may be due to the presence of free pigmen- pHmaygiveafalsenegativeresult.Detection
turia. Specific testing for hemoglobinuria or ofproteinuriaisthemostimportantreasonfor
myoglobinuria should be ordered for defini- orderingaurinalysiswhenscreeningthegen-
tiveidentificationwhenclinicallyindicated. eralpopulationforthepresenceofrenaldis-
pH:Althoughthenormalrangeisfrom4.5 ease.
to7.9,theusualurinarypHisbetween5.0and Urobilinogen: Based on the reaction be-
6.5.DuringwakinghoursurinarypHislower tween p-diethylaminobenzaldehyde and a
astheacidloadcontainedinthedietisexcreted. color enhancer that reacts with urobilinogen
The most common detection method uses inastrongacidmediumtoproduceapink-red
methylredandbromothymolblue,toprovide color.Avalue>2.0mg/dLmarksthetransi-
Mallucheetal. - ClinicalNephrology,Dialysisand Transplantation - I-1 3
ChapterI - ClinicalNephrologyandHypertension
Table2. UrinarySediment:NormalValuesandClinicalSignificance
RBC:<5/mm3or<3/HPF(0.3mmdiameter)*
WBC:<10/mm3or<5/HPF(0.3mmdiameter)**
Tubularepithelialcells: usuallydistaltubularcells(<1/HPF)
Squamousepithelialcells: lowerurinarytract
Casts:distaltubularlumenmoldsofTamm Horsfallmatrix:
hyaline: noclinicalsignificance
RBCs: glomerular hematuria
whitebloodcells: inflammation ofrenalparenchyma
epithelialcells: desquamationof tubularepithelium
granular: denaturedcells,precipitatedplasmaproteins
*If>80%ofRBCsaredysmorphic(withblebsorfragmented),thelikelihoodofglomerularhematuriaishigh
**Eosinophiluria(Hanselstainingtechnique)ishighlysuggestiveofallergicinterstitialnephritis,particularly
when infectionorothercausesof acutetubular necrosisareexcluded
tionfromnormaltoabnormal.Ahighurobil- Microscopic examination of the urinary
inogenconcentrationsuggeststhepresenceof sedimentisaveryusefulandsemiquantitative
a hemolytic process. As the base value is procedure. A drop of resuspended urine is
equivalent to 0.2 mg/dL,this test cannotde- placedonaglassslide,shieldedwithacover
terminetheabsenceofurobilinogen. slip,andexaminedatlow(100x–160x)and
Nitrate: Many urinary tract pathogens are high (400x) magnification under a bright-
capableofconvertingnitratestonitrites.Dip- field microscope. Although not essential,
stickmethodsallownitritestoreactwithp-ar- some recommend use of a counting (Fuchs-
sanilic acid to form a diazonium compound, Rosenthal) chamber. Timed collections (Ad-
which, after further reaction with 1,2,3,4- dis counts) are rarely used because they are
tetrahydrobenzo(h)-quinolin-3-ol,resultsina cumbersome, formed elements deteriorate,
pink end point. False negatives occur when and other diagnostic methods, such as renal
low dietary protein intake results in a low biopsy,aremorelikelytoprovideadefinitive
nitrate content in the urine, when prolonged diagnosis. Phase-contrast microscopy en-
storage in the bladder leads to nitrite break- hances cell morphology and allows the best
down,orwhenhighconcentrationsofascor- definitionofallformedurinarysedimentele-
bicacid(≥25mg/dL)arepresent.Inaddition, ments.Polarizedlightmaybeusedtolookfor
gram-positive organisms do not break down anisotropiccrystals(asisdonewithsynovial
nitrate.Thistestmaybenegativeinupto50% fluid in the assessment of crystal-induced
ofpatientswithbacteriuria. arthropathy).Ingeneral,thesampleshouldbe
Leukocytes: Lysed white blood cells examinedassoonaspossibletoavoidbacte-
(WBC)willreleaseesterases.Dipstickmeth- rial contamination and lysis of formed ele-
ods provide a substrate that liberates 3-hy- ments. Normal values for the urinary sedi-
droxy-5-phenylpyrroleafterhydrolysis.The mentareshowninTable2.
pyrrolesthenreactwithadiazoniumsaltcaus- Red blood cells (Figure 1a): The normal
ingachangeincolorfrompinktopurple. amount in a spun urinary sediment is < 3
4
1 Dumler,RocherandMadrazo - Diagnostic Evaluations
1
I.
Figure1a. Figure 1b.
Figure1c. Figure 1d.
Figure1. Urinarysedimentcells.a:numerousRBCsandoccasionalwhite(granular)cells;b:numerous
white cellsin cluster and occasional RBCs;c: tubular epithelialcells;d: transitionalcells(withpermissionof
Hoffmann-LaRocheInc.,copyright1973)
Mallucheetal. - ClinicalNephrology,Dialysisand Transplantation - I-1 5
ChapterI - ClinicalNephrologyandHypertension
RBCs/HPF. Because of varying amounts of the negative predictive value is high enough
RBCsedimentoncentrifugation,someprefer that nonglomerular bleeding cannot be ex-
to use a counting chamber and an aliquot of cludedbydysmorphichematuriaalone.
unspun urine. With this method the upper Perhapsthe mostimportantreason intest-
range of normal is 13,000 RBCs/mL. How- ingforhematuriaisthedetectionofurological
ever,therearenodatatosubstantiateasignifi- malignancies. The US Preventive Services
cant advantage relative to semiquantitative TaskForcerecommendsscreeningallpatients
techniques. On occasion, yeast and air bub- over age 60 for hematuria. In nonselected
blesmaybeconfusedwitherythrocytes.Add- populations, the prevalence of hematuria is
ing a drop of 25% acetic acid will dissolve about2–4%.Ofthosewithapositivetest,1%
RBCsbutnotyeastorbubbles. are bound to have urological malignancies,
It may be clinically relevant to ascertain themostcommonbeingbladdercarcinoma.
whether hematuria is glomerular, tubular, or Whitebloodcells(Figure1b):Thenormal
distal to the renal papillae in origin. RBCs amount in a spun urinary sediment is < 5
acquireddistaltotherenalpapillaetendtobe WBCs/HPF. Leukocytes are slightly larger
homogenous, while those originating from than erythrocytes and have a granular cyto-
theglomerulusortubuliarequitedysmorphic plasm. With the use of a counting chamber,
withvariousabnormalitiesinsize,shape,and theupperlimitofnormalis2,000WBCs/mL.
membrane appearance due to pH and osmo- Leukocytesmaybedifferentiatedfromrenal
lality changes in the distal segments of the tubularcellsbyspecificstainingtechniquesor
nephron. The latter may appear as crenated byadditionofglacialaceticacidthatenhances
forms,ghostcells,orbiconcavedisks,ormay the nuclei of white blood cells. Leukocytes
simulate budding yeast. Phase-contrast mi- canentertheurineatanypointintheurinary
croscopy allows for the best discrimination tract. The presence of white blood cell casts
between dysmorphic and homogenous (iso- and proteinuria suggests nephron involve-
morphic)RBCs.AllRBCsinnormalurineare ment. The most common causes of leuko-
dysmorphic.Nondysmorphichematuriaisal- cyturia are infection, inflammation, hemor-
waysabnormal.Hematuriaassociatedwith> rhage,and contamination.Pyuriamostcom-
80% dysmorphic cells is very suggestive of monly represents infection; its absence is
glomerular disease. Furthermore, the pres- helpful in excluding it. Polymorphonuclear
enceofRBCcastsorrenaltubularepithelial cells(PMNs)aretherule.However,inacute
cellscontainingphagocytizedRBCsisalmost allergic tubulointerstitial nephritis, a large
alwaysindicativeofglomerulonephritis. numberofurinaryleukocytesareeosinophils;
Althoughtheabovetechniquehaspotential thesearebestidentified using Hansel’sstain
fordiscriminatingbetweenglomerular(need (methyleneblueandeosinYinmethanol).A
forrenalbiopsy)andnonglomerular(needfor positive value is defined by >5% of white
urological workup) hematuria, patients with cells.Inadditiontoacuteinterstitialnephritis,
IgA nephropathy or postinfectious glomeru- eosinophiluriacanoccurinrapid(crescentic)
lonephritismayhaveapredominanceofnon- acuteglomerulonephritis(GN),acuteprosta-
dysmorphicerythrocytes.Inaddition,aggres- titis,andatheroembolicrenovasculardisease.
sive diuresis with furosemide may convert Renal tubular cells (Figure 1c): They are
hematuria from isomorphic to dysmorphic. rarely detected in normal urine (normal ≤ 1
Overall sensitivity and specificity values are cell/HPF).Theyderivefromthedistaltubule,
88% and 95%, respectively. Unfortunately, areslightlylargerthanleukocytes,andhavea
6
1 Dumler,RocherandMadrazo - Diagnostic Evaluations
singlelargeroundnucleusandgranularcyto- Granularcasts:Finelygranularcasts,like
plasm.Anincreasednumber,whenpresent,is hyalinecasts,maybeseeninnormalindividu- 1
I.
indicativeoftubulardamage.Theyarebetter als and provide little useful information.
differentiatedfromWBCsbystaining.When Coarsegranularcastswerethoughttobethe
containing phagocytized lipid droplets, they result of lysis of constituent granular cells.
are called oval-fat bodies. The identification However,recentstudiesindicatethatthegran-
ofrenaltubularcellscontainingphagocytized ules are composed of plasmaproteinsincor-
RBCshasthesameclinicalsignificanceasan poratedintotheTamm-Horsfallglycoprotein
RBCcast. matrix. Coarse granular casts are seen in a
variety of glomerular and tubular disorders
Squamous epithelial cells: They are the
andarethereforenotspecific.
most common cell types after white and red
bloodcellsandappearaslargeflatcellswhich Waxycasts:Theyarehighlyrefractileand,
arederivedfrombladder,urethra,orvagina. unlikehyalinecasts,resistanttoalkalinepH.
They are broad and convoluted, not disease
Transitional epithelial cells (Figure 1d):
specific, and suggestive of tubular hypertro-
They line the urinary epithelium from the
phy and chronic renal disease. They are be-
renalcalyxtotheproximalurethra.Theyare
lieved to be the consequence of cellular cast
rarelypresentinnormalurinebutmaybeseen
degenerationandareusuallyseenwithsevere
withinfectionsandneoplasiasoftheurinary
renalinsufficiency.
tract. When numerous, they are particularly
suggestiveofmalignancyandrequirefurther Fatty casts: Usually seen in nephrotic pa-
cytologicexamination. tients. Oval fat bodies are tubular epithelial
cellswithlipid-ladendropscommonlyasso-
Urinary casts are cylindrical elements
ciatedwithfattycasts.
formed in the distal tubule by aggregates of
Tamm-Horsfall glycoprotein gel. This proc- RBC casts (Figure 2b): They are charac-
essismorelikelytooccurinacidurineathigh teristic of glomerular bleeding (glomeru-
solute concentration. Acellular casts may be lonephritis),butonrareoccasionsmaybedue
hyaline,granular,waxy,orfatty.Cellularcasts to severe acute interstitial nephritis. If the
containerythrocytes,leukocytes,orrenaltu- erythrocytes degrade, the structure takes the
bularcells.Pigmentedcastsmaybeobserved appearanceof apigmentedcast.Truehemo-
inhemoglobinuriaandinhyperbilirubinemic globin casts are amorphous cylinders of an
states. Casts should be screened for at low orange to reddishcolor.In acid urine,eryth-
(10x)andidentifiedathigh(45x)powermag- rocytes lose their hemoglobin, and the cast
nification. Large bizarre casts in males are may look granular, but under phase-contrast
likely of prostatic origin. Triamterene can thedoublecontoursofthecellmembraneare
formcastsfromtrappedcrystalsatanacidpH. clearlydelineated.Disintegrationoferythro-
cytes may eventually result in brick-red
Hyalinecasts(Figure2a):Thesearecom-
granular cast. Strings of RBCs are not truly
posed of Tamm-Horsfall glycoprotein and
casts but have the same clinical significance
have a homogenous, clear, colorless appear-
asaRBCcast.
ance.Theymaybeseeninnormalindividuals
duringhighvolumediuresis,inthecourseof WBCcasts(Figure2c):Indicativeofinfec-
febrile illnesses, or in concentrated urine. tion(acutepyelonephritis),particularlywhen
Theirpresenceintheurinehasnopathologic associatedwithbacterialcasts.However,they
meaning. mayalsobeseeninacuteandchronicintersti-
Mallucheetal. - ClinicalNephrology,Dialysisand Transplantation - I-1 7
ChapterI - ClinicalNephrologyandHypertension
Figure2a. Figure 2b.
Figure2c. Figure 2d.
Figure2. Urinarysedimentcasts.a:hyalinecast;b:tubularepithelialcellcast;c:whitebloodcellcast;
d:RBCcast(with permissionofHoffmann-La Roche Inc., copyright 1973)
8
