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resulting in hemolytic anemia, platelet consumption, and intracapillary thrombi, with associated
endothelial cell injury. Differentiatingamongthevariouscauses ofthis entitycanallow forbetter
targetedtherapy.Hemolyticuremicsyndrome (HUS) resultsfrom diarrheal bacterialtoxins(e.g.,
Shiga and Shiga-like toxin) that cause direct injury to the endothelial cells. Thrombotic
thrombocytopenic purpura (TTP) can result from a reduced activity of ADAMTS13 (due to
deficiencyorinhibitoryantibodies)leadingtovonWillebrandfactor–richmicrothrombisecondarily
affecting arterioles and capillaries of a variety of organs. Atypical HUS has been described in
patientswithmutationsorinhibitorsinproteinsthatregulatethecomplementcascade,suchasfactor
HandfactorI,responsivetotreatmentwitheculizumab,aC5inhibitor.10Malignanthypertensionand
a varietyofmedications (e.g., mitomycinC,clopidogrel, gemcitabine,tacrolimus) havealsobeen
associatedwithTMA.Classification,diagnosis,andtherapyarediscussedinChapter20,Disorders
ofHemostasisandThrombosis.
Atheroembolic disease can be seen in patients with diffuse atherosclerosis after undergoing an
invasive aortic or other large artery manipulation, including cardiac catheterization, coronary
arterial bypass grafting, aortic aneurysm repair, and placement of an intra-aortic balloon pump.
Physical findings may include retinal arteriolar plaques, lower extremity livedo reticularis, and
areas of digital necrosis. Peripheral eosinophilia and hypocomplementemia may be present, and
WBC casts may be found in the urine sediment. However, in many cases, the only laboratory
abnormality is a rising Cr that follows a stepwise progression. Renal biopsy shows cholesterol
cleftsinthesmall arteries. Anticoagulationmayworsenembolicdisease andshouldbeavoided if
possible.Nospecifictreatmentisavailable.ManypatientsprogresstoCKDandeventoend-stage
renaldisease(ESRD).
Interstitial
Acute interstitial nephritis (AIN) involves an acute inflammation of the renal parenchyma. The
causes of AIN are broad and include medications (in >70% of cases), infectious agents, and
systemicdiseases.β-Lactamantibioticsarethemostfrequentlycitedcausativeagents,butnearlyall
antibiotics can be implicated. Other medications, such as proton pump inhibitors, 5aminosalicylates,andallopurinol,havebeenassociatedwith AIN.NSAIDscanproduceachronic
interstitial nephritis with nephrotic range proteinuria. Streptococcal infections, leptospirosis, and
sarcoidosishavealsobeenimplicatedinAIN.Theclassictriadoffever,rash,andeosinophiliais
seeninless thanone-third ofpatients,anditsabsencedoesnotexcludethediagnosis. Pyuriaand
WBC casts on urine microscopy are also suggestive of AIN. The time course typically requires
exposureforatleast5–10daysbeforerenalimpairmentoccurs.
Treatment isprincipallywithdrawalof the offending agent. Renal recovery typically ensues,
althoughthetimecourseisvariable,andtemporarydialyticsupportmaybenecessaryinsevere
cases.Ashortcourseofprednisoneat1mg/kg/dmayhastenrecovery.
11
Parenchymal infections with pyelonephritis or renal abscesses are uncommon causes of AKI.
BilateralinvolvementisusuallynecessarytoinduceariseinCr.Urinefindingsincludepyuriaand
WBCcasts,andantibiotictherapyisguidedbycultureresults.
DIAGNOSIS
Uncoveringthe causeofAKI requires careful attentionto the eventspreceding the rise inCr.In the
hospitalizedpatient,bloodpressurepatterns,irregularcardiacrhythms,hydrationstatus,medications,
and iodinated contrast use must be investigated. Antibiotic dose and duration as well as PRN
medicationsshouldnotbeoverlooked.
Evidenceofongoing hypovolemia or hypoperfusion is suggestive ofprerenal disease but mayhave
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progressed to an acute tubular injury pattern. Most causes of postrenal disease are identified on
ultrasoundbydilationofthecollectingsystemorbymassiveurineoutputuponplacementofabladder
catheter. However, obstruction cannot be completely ruled out even if not identified on imaging,
especially in the setting of early obstruction or volume depletion. Patients may need volume
resuscitationandanultrasoundrepeatedinseveraldaysifrenalfunctiondoesnotimprove.
UrinarycastspointtowardanintrinsiccauseofAKI.Granularcasts(“muddybrown”)suggestATN,
WBCcastssuggestaninflammatoryorinfectiousinterstitialprocess, andRBCcastsstronglysuggest
glomerulardisease.Identificationofcrystalsintheurinesedimentmaybesupportiveofkidneydisease
relatedto intoxicationof ethyleneglycol, uric acid excretion,tumor lysis syndrome, or medications
suchasacyclovirandindinavir.Thisunderscorestheimportanceofexaminingurinarysedimentinthe
evaluationofAKI.
VariouslaboratoryparameterscanbeusedtodifferentiateprerenalstatesfromATNinoliguricpatients
andaresummarizedinTable13-2. Thebasis forthese testsis toevaluatetubular integrity, which is
preserved in prerenaldisease butlostinATN.Instates ofhypoperfusion,the kidneys should avidly
reabsorbsodium,resultinginalowFENa:FENa=([UNa×PCr]/[PNa×UCr])×100,whereUisurineand
Pisplasma.
TABLE13-2
LABORATORYFINDINGSINOLIGURICACUTEKIDNEYINJURY
Diagnosis BUN:Cr FE
Na
(%)
UrineOsmolality
(mOsm/kg)
Urine
Na
Urine
SG
Sediment
Prerenal
azotemia
>20:1 <1 >500 <20 >1.020 Bland
OliguricATN <20:1 >1 <350 >40 Variable Granular
casts
ATN,acutetubularnecrosis;BUN,bloodureanitrogen;Cr,creatinine;FENa,fractionalexcretionofsodium;SG,specificgravity.
A value <1% suggests renal hypoperfusion with intact tubular function. Loop diuretics and
metabolic alkalosis can induce natriuresis, increase the FENa, and mask the presence of renal
hypoperfusion.TheFE
Urea
caninsteadbecalculatedinthesesettings,whereavalueof<35%suggestsa
prerenalprocess.
Contrast and pigment nephropathy can result in a low FENa because of early vasoconstriction
(“prerenal” drop in glomerular perfusion), as can glomerular diseases because of intact tubular
function.TheFENaalsohaslimitedutilitywhenAKIissuperimposedonCKDbecausetheunderlying
tubulardysfunctionmakesthetestdifficulttointerpret.
Withhypoperfusion,theurineistypicallyconcentrated,containinganosmolality>500mOsm/kganda
highspecificgravity(>1.020).InATN,concentratingabilityislostandtheurineisusuallyisosmolar
totheserum(isosthenuria).Intheblood,theratioofBUNtoCrisnormally<20:1,andanelevationis
consistentwithhypovolemia.
TheFENashouldnotbeusedalonetodeterminethecauseofAKI,butinsteadinterpretedinthecontext
ofthepatientandclinicalscenario.
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TREATMENT
Disease-specific therapies are covered in their respective sections. In general, treatment of AKI is
primarily supportive in nature. Volume status should be evaluated to correct for hypovolemia or
hypervolemia. Volume deficits, if present, should be corrected, after which the goal of fluid
managementshouldbetokeepinputequaltooutput.Intheoliguricvolume-overloadedsetting,atrial
of diuretics (usually high-dose loop diuretics in a bolus or as a continuous drip) may simplify
management,althoughithasnotbeenshowntohastenrecovery.
Electrolyte imbalances should be corrected in the setting of AKI. Hyperkalemia, when mild (<6
mEq/L),maybetreatedwithdietarypotassiumrestrictionandpotassium-bindingresins(e.g.,sodium
polystyrenesulfonate,sodiumzirconiumcyclosilicate).WhenfurtherelevatedoraccompaniedbyECG
abnormalities, immediate medical therapy is indicated with calcium gluconate, insulin and glucose,
inhaled β-agonists, and possibly bicarbonate (see Chapter 12, Fluid and Electrolyte Management).
Severehyperkalemiathatisrefractorytomedicalmanagementisanindicationforurgentdialysis.
Mildmetabolicacidosiscanbetreatedwithoralsodiumbicarbonate,650–1300mgthreetimesdaily.
Severeacidosis(pH<7.2)canbetemporizedwithIVsodiumbicarbonatebutrequiresmonitoringfor
volume overload, rebound alkalosis, and hypocalcemia. Acidosis that is refractory to medical
managementisanindicationforurgentdialysis.
SPECIALCONSIDERATIONS
PatientswithAKIrequiredailyassessmenttodeterminetheneedforrenalreplacementtherapy.Severe
acidosis,hyperkalemia,orvolumeoverloadrefractorytomedicalmanagementmandatestheinitiation
ofdialysis.Certaindrugandalcoholintoxications(methanol,ethyleneglycol,orsalicylates)shouldbe
treatedwithhemodialysis.Uremicpericarditis(withafrictionrub)or encephalopathyshouldalsobe
treated promptlywith renal replacementtherapy. Patients sufferingfrom acute oliguric renal failure
whoarenotexpectedtorecoverpromptlymaybenefitfromearlierinitiationofdialysis.
Intheabsenceofoneoftheseacuteindications,thetimingofinitiatingdialytictherapyislesscertain.
Two studies analyzedthissubjectinICUpatientsinarandomizedcontrolled fashionwithsomewhat
contradictoryresults.StartingdialyticsupportinpatientswithathreefoldelevationinCroraCrof4
mg/dLorgreaterdidnotshowimprovedoutcomesascomparedtodelayingdialysisuntilatraditional
indicationdeveloped.12Asmallerstudy,however,didshowasurvivaladvantageforpatientsbeginning
dialysiswithatwo-tothreefoldincreaseinCr,ascomparedtopatientswithmoresevereelevations.
13
Glomerulopathies
GENERALPRINCIPLES
Glomerulardiseasestraditionallyhavebeenclassifiedbasedontheclinicalpresentationasexistingon
a spectrum with the nephrotic syndrome on one end (characterized by proteinuria >3.5 g/d and
accompanied by hypoalbuminemia, hyperlipidemia, and edema), and the nephritic syndrome on the
other end (characterizedbyhematuria, hypertension, edema, and renal insufficiency). Althoughmost
haveoverlappingfeatures,specificdiseasesdohaveatendencytofeatureonesyndromeovertheother,
relatedtothepredominanthistologicsiteofglomerularinjury.Inmostcases,akidneybiopsywillbe
necessarytodeterminethemostspecificdiagnosis,astepthatiscrucialfortreatment.
Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous
nephropathy (MN) typically present with nephrotic features. IgA nephropathy, postinfectious
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glomerulonephritis, anti-GBM antibody disease, and antineutrophil cytoplasmic antibody (ANCA)associated vasculitis typically present with nephritic features. Membranoproliferative
glomerulonephropathy(MPGN)canpresentwithoverlappingfeaturesofbothnephrotic andnephritic
disease.
Nephroticdiseasestypicallyshowinjuryalongthefiltrationbarrier,withthickeningoftheglomerular
basement membrane (GBM) or fusion of the podocyte foot processes. By comparison, nephritic
diseases generally show varying degrees of mesangial cell proliferation and mesangial deposition.
Withmoreaggressivedisease,cellularorfibrouscrescentsmaybeseenwithinBowmancapsule.
When a nephrotic process is suspected, it may be useful to check antinuclear antibodies (ANA),
complementlevels(C3,C4),cryoglobulins,andviralserologies(HIV,hepatitisBandC,parvovirus,
cytomegalovirus[CMV],Epstein–Barrvirus[EBV]).Itis importanttoreviewthemedicationprofile
and rule out malignancy or other systemic infectious or inflammatory conditions. A serum protein
electrophoresis(SPEP)andurineimmunofixationcanbeperformedinproteinuricpatientstoevaluate
foramonoclonalgammopathyandshouldbesuspectedwhenalargeprotein–albumingapispresent.
Whenanephriticprocessissuspected,testingforanti-GBMantibodies,ANCA,andanti-streptolysinO(ASO)titers maybe helpful innarrowingthe differential diagnosis. As withnephrotic processes,
testingforANA,C3,C4,cryoglobulins,andviralserologiescanalsoprovideusefulinformation.
Complement levels may be decreased in certain nephritic disorders, such as postinfectious
glomerulonephritis, lupusnephritis, MPGN, C3 glomerulopathy, and subacute bacterial endocarditis.
Others, such as IgAnephropathy, ANCA vasculitis, and anti-GBM antibody disease, typically have
normalcomplementlevels.
TREATMENT
Manydisorderssharesimilarfeatures,andgeneraltherapeuticmaneuverscanbeaddressedasagroup.
Specifictherapiesforindividualglomerulardiseasesarediscussedlaterinthechapter.
Glomerular disease presenting with proteinuria should be treated withACE inhibitors orARBs to
reduceintraglomerularpressureiftherearenoconcernsforhyperkalemiaandiftheserumcreatinineis
stable. Efficacycanbe monitored byserial urineproteintoCr ratios. Electrolytes andCr shouldbe
checked within 1 week of treatment initiation or an increase in dose to document stability of renal
functionandpotassium.ACrincreasewithintherangeof0.1–0.3mg/dL(orupto30%ofbaseline)is
acceptable and if greater, then renal artery stenosis should be ruled out. Modest dietary protein
restrictionto0.8g/kg/dmayslowprogression,butthisremainscontroversial.
Edemaandvolumeoverloadcanusuallybeeffectivelymanagedwithdiureticscombinedwithsodium
restriction.Aggressivetreatmentofhypertensioncanalsoslowtheprogressionofrenaldisease.
Hyperlipidemiaassociatedwithnephrotic syndromerespondstodietarymodificationandstatins (3-
hydroxy-3-methylglutaryl–coenzymeA[HMG-CoA]reductaseinhibitors).
Nephrotic syndrome is associated with a hypercoagulable state and can predispose patients to
thromboemboliccomplications.Deepvenousthrombiandrenalveinthrombosismayoccurandshould
betreatedwithheparinfollowedbylong-termoralanticoagulation.
Anticoagulation is absolutely indicated in the setting of deep venous thrombosis or pulmonary
embolism. Prophylactic anticoagulation should be considered in severely nephrotic patients with a
serum albumin<2.0–2.5g/dL andadditional riskfactorsthatcouldpredispose them to clotting (e.g.,
family historyof clots,immobilization).14 Exactmechanisms of thrombosis remain controversial but
likelyincludeurinarylossofantithromboticproteinsandincreasedsynthesisofclottingfactors.
When immunosuppression is considered, the risk of therapy should always be weighed against the
potentialbenefit.Renalsalvageabilityshouldbeaddressed,andpatientswithadvancedkidneydisease
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onpresentationwhoareunlikelytobenefitfromsuchtreatmentmaybebetterservedbyavoidingthe
risks of high-dose immunosuppression. Cytotoxic agents (e.g., cyclophosphamide) require close
monitoringofWBCcounts,checkedatleastweeklyattheinitiationoftherapy.Doseadjustmentsmay
be needed to maintain the WBC count >3500 cells/μL. Rituximab, a monoclonal antibody directed
againstCD20,hasshownpromiseinavarietyofimmune-mediateddisorders,including severelupus
nephritis,MN,andANCA-associatedvasculitis.15Otherimmunosuppressiveagentsincludecalcineurin
inhibitors (e.g., tacrolimus, cyclosporine) and mycophenolate mofetil. Therapeutic plasma exchange
hasaroleinonlyspecificcircumstancesasdescribedinmoredetailbelow.
MinimalChangeDisease
GENERALPRINCIPLES
Epidemiology
MCDisthemostcommoncauseofnephroticsyndromeinchildrenbuthasasecondpeakinadultsaged
50–60years.Typically,thereissuddenonsetofproteinuriawithhypertensionandedema,althoughrenal
insufficiencyisunusual.
AssociatedConditions
SecondaryformsofMCDmayaccompanycertainmalignancies(Hodgkindiseaseandsolidtumorsbeing
themostcommon)andtherefore,patientsintheappropriateagegroupshouldundergofurthercancer
screening.AformofinterstitialnephritisassociatedwithNSAIDusemayalsobeassociatedwithMCD.
DIAGNOSIS
Thekidneybiopsyrevealsnormalglomerulionlightmicroscopyandnegativeimmunofluorescence.
Electronmicroscopyshowscompletefootprocesseffacement.Thismayhaveasimilarappearanceto
earlyonsetFSGSandthusbedifficulttodifferentiate.
TREATMENT
Inadults,treatmentwithhigh-doseoralprednisoneat1mg/kgdaily(notexceeding80mg/d)or2mg/kg
on alternate days (not exceeding 120 mg,every other day) may induce remission (i.e., decrease in
proteinuria) after a minimumof4 weeks,butcanrequire upto16weeks oftherapy.Prednisonecan
thenbetaperedoffovera6-monthperiod.
Relapsemayoccurinupto75%ofadults.Reinstitutionofprednisoneisofteneffective.Ifthepatientis
steroid dependent or steroid resistant, cytotoxic agents may be needed, with cyclophosphamide 2
mg/kg/d or chlorambucil0.2 mg/kg/d. Cyclosporine3–5mg/kg/dor mycophenolatemofetil 1000 mg
twice a dayfor2yearscanbeconsidered as alternative therapies.16Rituximabmaybe beneficialin
frequentlyrelapsingorglucocorticoid-dependentMCD.
17
FocalSegmentalGlomerulosclerosis
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GENERALPRINCIPLES
FSGS is not a single disease but rather a pattern of glomerular injurywith various mechanisms. It
typicallypresentswithnephroticsyndrome,hypertension,andsometimesrenalinsufficiency.
FSGScanbeclassifiedintoprimary(idiopathic)andsecondaryforms.18SecondaryformsofFSGSare
associated with obesity, vesicoureteral reflux, sickle cell disease, medications (pamidronate, αinterferon,tyrosinekinaseinhibitors),andinfections(HIV,parvovirus,CMV,EBV).
DIAGNOSIS
Thekidneybiopsyrevealssegmentalsclerosisofsomeglomeruliunderlightmicroscopy.Thedegreeof
interstitialfibrosisandtubularatrophy(ratherthanglomerularscarring)correlateswithprognosis.
ImmunofluorescenceshowsdepositionofIgMandC3inareasofsclerosis,representingareasoftrapped
immunedeposits.Electronmicroscopyshowseffacementofthepodocytefootprocessessimilartothat
seeninMCD.Lesionscanbeclassifiedintodistincthistomorphologicvariants,thoughtheirclinical
significanceisuncertain.Thetipvarianttendstohavethemostfavorableprognosiswhilethecollapsing
variantisassociatedwiththepoorestoutcomes.
TREATMENT
ManagementissimilartoMCD.Forpatientswithnephroticrangeproteinuria,atrialofhigh-doseoral
prednisoneat1mg/kgdaily(notexceeding80mgdaily)or2mg/kgonalternatedays(notexceeding120
mg,everyotherday)mayinduceremissionandthenbetaperedoffovera6-monthperiod.Patientswho
relapseafteraperiodofapparentresponsivenessmaybenefitfromarepeatcourseofsteroids.
Nonrespondersandrelapsersmayrespondtotreatmentwithcyclosporine5mg/kg/d.Cyclophosphamide
andmycophenolatemofetilcanalsobeused.Inductionofacompleteremission(<0.3g/dofproteinuria)
orapartialremission(50%reductioninproteinuriaand<3.5g/d)isassociatedwithsignificantlyslower
lossofrenalfunction.
MembranousNephropathy
GENERALPRINCIPLES
MNusuallypresentswithheavyproteinuriaandnephroticsyndrome.Diseaseprogressionisvariable,
with one-third remitting spontaneously, one-third progressing to ESRD, and one-third with an
intermediatecourse.
Secondary etiologies of MN include autoimmune or collagen vascular diseases (systemic lupus
erythematosus [SLE] class V, Sjögren syndrome, rheumatoid arthritis), infection (viral hepatitis,
syphilis),andmedications(penicillamine,NSAIDs,mercury,gold).Malignancymayalsoplayarole;
patientswithMNshouldundergoage-appropriatecancerscreening.
DIAGNOSIS
KidneybiopsyshowsthickeningoftheGBMwithoutsignificanthypercellularityonlightmicroscopy.
Alsoseenare“spikes”alongtheGBMonsilverstain,representingareasofnormalbasementmembrane
interposedbetweensubepithelialdeposits.Onimmunofluorescence,thereisgranularstainingalongthe
GBMwithIgGandC3.Onelectronmicroscopy,subepithelialdepositsareseen.Antibodiestothe
podocyteantigenphospholipaseA2receptorhavebeenimplicatedin70%ofadultidiopathicMN.
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Antibodiesagainstthrombospondintype-1domain-containing7A(THSD7A)areseenin10%ofpatients
withMNandhavebeenlinkedtomalignancy.19Additionalpodocyteantigensarecurrentlybeing
investigated.
TREATMENT
Up to30%ofpatientswithMNwill gointospontaneousremission.20KDIGOguidelinesrecommend
conservativetherapyas aninitial approachwithACEinhibitors or ARBsforproteinuria and blood
pressure control, diuretics for volume management, with or without anticoagulation.Because of the
generally favorable prognosis, specific therapy should be reserved for patients at higher risk for
progression(e.g.,heavyproteinuria,reducedGFR,malegender,age>50years,hypertension).
Whenimmunosuppressionisconsidered,avarietyofregimenshavebeenstudied.Oneoptionistouse
alternating monthsofacorticosteroidanda cytotoxicagentfor6 months(prednisone0.5 mg/kg/dfor
months1,3,and5,andcyclophosphamide2.5mg/kg/dformonths2,4,and6).
21
Rituximabhasbeenshowntoprovideamoredurableremissionwhencomparedtocyclosporineat24
monthsoftreatment.
22
DiabeticNephropathy
GENERALPRINCIPLES
Diabeticnephropathy(DN)isthemostcommoncauseofESRDintheUnitedStates.Riskfactorsinclude
smoking,familyhistoryofESRD,hypertension,andpoorglycemiccontrol.Thedegreeofalbuminuria
alsocorrelateswiththeriskofprogressiontoESRD.Earlydiseaseischaracterizedbyglomerular
hyperfiltrationwithanelevatedGFR,followedbyalineardeclinethatmayprogresstoESRD.
DIAGNOSIS
DiagnosticTesting
KidneybiopsyisnotusuallyperformedinpatientswhopresentwithclassicDNunlesstherateofrenal
declineismorerapidthanwouldbeanticipated,ortoruleoutothercausesofnephroticsyndrome.
HistologyforDNshowsglomerularsclerosiswithnodularmesangialexpansion(Kimmelstiel–Wilson
nodules)onlightmicroscopy.Immunofluorescencedoesnotrevealimmunedeposition.Electron
microscopymayshowGBMthickening.
TREATMENT
Tightglycemiccontrolwasassociatedwithbetteroutcomesinpatientswithtype1diabetesmellitus;the
benefitwasnotasprofoundinpatientswithtype2diabetesmellitus.23Specifichyperglycemictherapyis
discussedfurtherinChapter23,DiabetesMellitusandRelatedDisorders.AnACEinhibitororARBis
consideredthefirst-lineagentinthetreatmentofhypertensionindiabeticpatientsandcanimprove
proteinuria.StudiescombiningACEinhibitorswithanARBorthedirectrenininhibitoraliskirenhave
shownworserenalandcardiovascularoutcomes.24Metforminshouldnotbestartedinpatientswitha
GFR<45mL/min/1.73m2duetoariskoflacticacidosis.Sodium–glucosecotransporter-2(SGLT2)
inhibitors(empaglifozin,canaglifozin,dapaglifozin)havebeenstudiedextensivelyamongpatientswith
diabetesmellitusandCKDwithestimatedGFRof≥30mL/min/1.73m2andareshowntodecreasethe
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riskofasustaineddeclineinrenalfunction,progressiontoESRD,ordeathfromrenalorcardiovascular
causes.25SGLT2inhibitorsshouldbeavoidedinpatientswithactivefootulcers,lowerextremity
ischemia,oradvancedliverdisease.
DepositionDisorders/Dysproteinemias
GENERALPRINCIPLES
Dysproteinemias,includingthoseobservedinmultiplemyeloma,encompassamyloidosis,lightchain
depositiondisease(LCDD),heavychaindepositiondisease(HCDD),andmonoclonal
immunoglobulindepositiondisease.Thesedisorderscanaffectthekidneyinavarietyofways,including
glomerularortubulardeposition,formationofinsolubleproteincastsinthetubules(micro-obstructive
castnephropathy),orthroughhypercalcemiaandvolumedepletion.Glomerulardepositionistypically
associatedwithheavyproteinuriaduetooverflowaswellasdisruptionofthefiltrationbarrierintegrity.
DIAGNOSIS
DiagnosticTesting
DiagnosisissuggestedbyanabnormalmonoclonalproteinfoundonSPEPorurineimmunofixation,oran
imbalanceintheκ/λserumfreelightchainratio.Routineurinedipsticktestsfornegativelycharged
albumin,andthereforemaymissthepositivelychargedIgchains,unlessglomerularinvolvementhasled
toageneralizedproteinleakage.Insomecases,allofthesetestsarenegativeandonlytissuebiopsycan
makethediagnosis.
Biopsyofthekidneycanshowcharacteristicdeposits.Foramyloidosis,theseappearasCongoRed–
positive β-pleated fibrils of10 nm indiameter underelectron microscopy. Immunofluorescence can
identifythe specific Igchainsforamyloidosis (morelikelyto be lambdalight chains),LCDD(more
likely to be kappa light chains), and HCDD. Fibrillary glomerulopathy and immunotactoid
glomerulopathy are distinct deposition diseases that are characterized by Congo Red–negative
deposits. The fibrils of fibrillary glomerulopathy (12–20 nm) are typically thicker than those for
amyloid,whereasthemicrotubulesofimmunotactoidglomerulopathyareeventhicker(20–60nm)with
a visible lumenincross section.Immunotactoid glomerulonephropathy hasa strong associationwith
myelodysplasticdisorders.
When cast nephropathy develops in a dysproteinemic disorder, the biopsy shows enlarged tubules
filled withproteinaceousmaterial.Immunofluorescencecanidentifythespecificcomponentsofthese
casts.
TREATMENT
Chemotherapyaimedattheunderlyingdiseasecanbeeffectiveinreversingrenaldisease;thismaybe
particularlyimportantinmyelomawhencastnephropathyispresentonbiopsy.Smallstudieshave
previouslysuggestedrenalbenefitwithplasmapheresistoaccomplishanaggressivereductioninlight
chainburden.However,withimprovementsinchemotherapeuticoptions,thereisnosignificantbenefitof
plasmapheresisorhigh-cutoffhemodialysisforshort-termoutcomeswhencomparedtoconventional
supportivemeasures.26Thereisnospecifictreatmentforfibrillaryorimmunotactoidglomerulopathy,
althoughtreatmentofunderlyingmalignancy,ifidentified,mayslowrenaldiseaseprogression.
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MembranoproliferativeGlomerulonephritis
GENERALPRINCIPLES
MPGNcanpresentwithnephroticsyndrome,nephriticsyndrome,oracombinationofboth.Traditional
MPGNisdistinguishedbyhavinganimmunoglobulin-mediatedbasis,whilenonimmunoglobulinforms
arenowcategorizedunderadistinctC3glomerulopathyclassification.27PrimaryidiopathicMPGNis
uncommon.HepatitisCaccountsformostcasesofsecondaryMPGNandcanbeseeninassociationwith
cryoglobulinemia.OthersecondarycausesincludeHIV,SLE,chronicinfections,andvarious
malignancies.
DIAGNOSIS
ClinicalPresentation
MPGNresultsfromimmunecomplex–mediatedactivationofthe classical complementpathway,with
the finding of both immunoglobulin and complement on immunofluorescence staining of the biopsy
specimen.IgMandC3aremostcommonlyseen,particularlyinhepatitisC–associatedcases.
The separately classified entity, C3 glomerulopathy, encompasses C3 glomerulonephritis (C3GN),
anddensedepositdisease(DDD),definedbythedominantstainingforC3onimmunofluorescence,in
theabsenceofimmunoglobulin.TheantibodyC3nephriticfactormaybepresentinC3GN,stabilizing
theC3-convertaseandpromotingcomplementconsumption.Thisleadstoadisorganizedregulationof
thealternatepathway.Deficienciesofcomplementregulators(factorH,factorI,complementfactorH–
relatedproteins),antibodiesagainstthecomplementregulators,oragainoffunctionmutationinfactor
Bmayalsoactivatethecomplementcascade.DDDalsoshowscomplementdepositionintheabsence
ofimmunoglobulinbutischaracterizedbyelectrondensedepositsintheGBM.
DiagnosticTesting
InMPGN,thekidneybiopsyshowsdiffusemesangialproliferationandhypercellularityonlight
microscopy,with“lobulization”oftheglomerulartuft,givingita“cauliflower”appearance.
Accumulationofdebrisalongthefiltrationbarriermayleadtoadamage–repaircyclethatresultsin
duplicationoftheGBM,givingadouble-contouror“tramtrack”appearanceonsilverstain.
ImmunofluorescencecanshowgranularmesangialandcapillarywalldepositsofIgintheimmune
complex–mediatedforms,whereasonlytheC3stainingispositiveinC3GNorDDD.Electron
microscopycanshowsubendothelialorintramembranousdeposits.
TREATMENT
In adult idiopathic MPGN, treatment with immunosuppression has not shown a consistent benefit,
although this may have been a result of lumping together diseases with dissimilar pathophysiology
underanolderclassificationscheme.
Treatmentofthesecondary forms istargetedattheunderlyingdisease.However,inaggressiveforms
wherethere is rapid deteriorationofrenalfunctioninthepresenceofcryoglobulins,plasmapheresis
mayhelpslowdowndiseaseprogressionandstabilizerenalfunction.Caseserieshavedemonstrateda
potentialroleoftheanti-C5monoclonalantibodyeculizumabinthetreatmentofC3glomerulopathy.
28,29
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IgANephropathy/Henoch–SchönleinPurpura
GENERALPRINCIPLES
IgAnephropathyis a resultofabnormal glycosylationofthe hingeregionofimmunoglobulinA.This
results in autoantibodies which interact with abnormally glycosylated protein and cause glomerular
disease.AlthoughserumIgAlevelsdonotcorrelatewithdiseaseactivity,eventsthatpotentiallyleadto
overproduction(concurrentupperrespiratoryinfection)ordecreasedclearance(hepaticcirrhosis)may
predisposetodevelopmentofthisdisease.
Thisdiseaseprocessistypicallyidiopathic,characterizedbyanephriticpicturewithmicroscopic(and
lesscommonly,macroscopic)hematuriaandnonnephroticrangeproteinuria.
Presentation is usually in the second or third decade of life, often following a slowly progressive
course. Multiple forms of pathology exist, from mild lesions and mesangial proliferation to global
sclerosisresultinginprogressiontoESRD.
Henoch–Schönleinpurpuraisarelateddisorderthatmayrepresentasystemicformofthedisease,with
vasculitisoftheskin(palpablepurpuraofthe lowertrunkandextremities),gastrointestinaltract,and
joints.
DIAGNOSIS
DiagnosticTesting
Kidneybiopsyshowsincreasedmesangialcellularityonlightmicroscopy,withpredominantIgAandC3
depositiononimmunofluorescence.Onelectronmicroscopy,thereareelectrondensedepositsinthe
mesangium.
TREATMENT
Aggressiveness of therapy depends on the severity of disease. For patients with a benign course,
conservativemanagementwithACEinhibitorsorARBsisrecommended.Thebenefitofomega-3fatty
acidfishoilremainscontroversial.
For patients with persistent proteinuria of >1 g/d despite maximally tolerated RAAS blockade,
corticosteroidshavebeenshowntoprovidebenefitwithreductionofproteinuriaandsloweddeclinein
GFR.30Long-termsustainedbenefitwithimmunosuppressionislesswell-established.31Theincidence
ofadverseeventswashigherinsubjectsreceivingimmunosuppressionratherthanconservativetherapy
alone,thustreatmentdecisionsneedtobeindividualized.
PostinfectiousGlomerulonephropathy
GENERALPRINCIPLES
Postinfectious glomerulonephropathy classically presents as nephritic syndrome, with hematuria,
hypertension, edema, and renal insufficiency. Proteinuria may be present and is usually in the
subnephroticrange.
Thisentityisclassicallyassociatedwithstreptococcalinfection,whichtypicallyaffectschildrenunder
theageof10,afteralatentperiodof2–4weeksfromonsetofpharyngitisorskininfection.However,
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