RENAL_ICS_PATH_MS2

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soren101
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105612
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RENAL_ICS_PATH_MS2
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2011-12-16 10:24:53
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RENAL PATHOLOGY MS2
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RENAL ICS PATHOLOGY MS2
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  1. GLOMERULUS ANATOMY
    CAPILLARIES LINED BY THIN FENESTRATED ENDOTHELIUM

    VISCERAL EPITHELIUM COVERS CAPILLARIES~ PODOCYTES

    PARIETAL EPITH ~ OUTER LAYER

    BETWEEN VISCERAL AND PARIETAL IS BOWMAN'S SPACE, AND ITS LUMEN IS CONTINUOUS WITH PROX TUBULE

    BETWEEN ENDOTHELIUM OF CAPs AND PODOCYTES IS GLOMERULAR BASEMENT MEM (GBM)

    PODOCYTE FEET INTERDIGITATE BETWEEN EACH OTHER; BETWEEN FEET ARE FILTRATION SLITS WHICH ARE BRIDGED BY THIN PROTEINACEOUS MEMs CALLED FILTRATION SLIT DIAPHRAGMS ~ MODIFIED TIGHT JUNCTIONS -->

    -->HAVE POROUS STRCTURE THAT AIDS IN GLOM ULTRAFILTRATE TOGETHER w ENDOTHELIUM AND GBM -->

    -->PROTs NEPHRIN, PODOCIN, AND CD2AP ~ WHEN ABN CAUSE PROTEINURIA AND NEPHROTIC SYNDROME

    MESANGIUM IS EXTRAVASCULAR REGION BETWEEN GLOM CAPs --> CONTAIN MES CELLS AND MES MATRIX-->

    --> IN GLOM Dz IF IMMUNE ORIGIN, IMMUNE COMPLEXES BY DEPOSITE HERE
  2. JGA
    JUXTA GLOM APP

    CORE OF R-A-A AXIS

    RENIN GRAN CONTAINING CELLS OF AFFERENT ARTERIOLE

    GOORMAGHTIGH CELLS BETWEEN AFF AND EFF ARTERIOLES AND EXTEND INTO VASCULAR POLE OF GLOM (aka extraglom mesangium)

    MACULA DENSA SENSES COMPOSITION OF FLUID IN TUBLILE AND COMMUNICATES w GOORMA CELLS AND w RENIN PRO CELLS OF AFF ARTERIOLE
  3. COLLECTION METHODS FOR URINALYSIS
    CLEAN-CATCH MEDSTREAM URINE

    EARLY MORNING AFTER CLEANSING URETHRAL MEATUS

    WELL-MIXED

    • FRESH < 1hr OLD AT ROOM TEMP, OTHERWISE:
    • --BAC
    • --INC pH AND TURBIDITY
    • --CELLS AND CASTS DEGENERATE
    • --LOSS OF BILIRUBIN AND KETONES
  4. URINE SPECIFIC GRAVITY
    DIR PROP TO OSMOLALITY --> SOLUTE CONC. URINE DENSITY

    ABILITY OF KIDNEY TO CONC OR DILUTE URINE RELATIVE TO PLASMA

    MEASURE USING REFRACTOMETER; DIPSTICK MAY GIVE APPROX VAL

    nL 1.001 : 1.035

    IF NOT > 1.022 AFTER 12hr w/o FOOD/WATER RENAL CONC ABILITY IS IMPAIRED

    SG AT END STAGE RENAL Ds 250-300 ~ PLASMA

    SG > 1.035 IS WITHER CONTAMINATED, INC GLUC, OR RADIOPAQUE DYE OR DEXTRAN
  5. nL URINE SEDIMENT COUNTS
    • WBC ____________0-5/HPF
    • RBC _____________0-3/HPF
    • TUBULAR CELLS __0-5/HPF
    • HYLINE CASTS ____0-1/LPF
    • GRAN CASTS ______0-1/LPF
    • RED CELL CASTS ___NONE
  6. DYSMORPHIC RBCs IN URINE
    FORM ONLY IN KIDNEY AND INDICATE GN
  7. TUBULAR EPITHELIAL CELLS
    INC IN DISORDERS w TUBULAR NECROSIS OR DEGENERATION

    WHEN LIPIDURIA OCCURS, TEC STUFFED w FAT AND CALLEDC OVAL FAT BODIES THAT SHOW "MALTESE CROSS" IN POLARIZED LIGHT
  8. CASTS IN URINE
    FORMED ONLY IN KIDNEY & NOT IN LOWER UT

    HYALIN CASTS COMPOSED OF MUCOPROTEIN (TAMM-HORSFALL PROTS) SECRETED BY TUBULAR CELLS THAT BECOME MOLDED IN TUBULE. MAY ENCASE OTHER URINARY CELLS, CELLULAR DEBRIS, AND FAT DROPLETS

    • HYALIN -- POST EXCERCISE, DEHYDRATION
    • RBC -- NEPHRITIC SYND (GN)
    • WBC -- ACUTE PYELONEPHRITIS OR ACTIVE _______INFLAM
    • TUBULAR -- TUBULAR INJ / NECROSIS
    • FATTY -- LIPIDURIA (NEPHROTIC SYND)
    • GRANULAR -- RENAL Dz (nonspecific)
    • BROAD WAXY -- CHRONIC RENAL FAILURE
  9. CRYSTALS IN URINE
    COMMON INCLUDE CALCIUM OXALATE, TRIPLE PHOSPHATE AND AMORPHOUS PHOSPHATES

    CYSTINE CRYSTALS "BENZINE RINGS" ARE RARE AND SEEN IN CONG CYSTENURIA OR SEVERE LIVER Dz
  10. 4 TRAITS OF NEPHROTIC SYND
    1) HEAVY PROTEINURIA >= 3.5gm/24hrs

    2) HYPOALBUMINEMIA (plasma <3gm/dl)

    3) GENERALIZED EDEMA

    4) HYPERLIPIDEMIA AND LIPIDURIA
  11. PATHOPHYS OF NEPHROTIC SYND
    MOST COMMON IN GLOM DAMAGE

    INC PERM OF GLOM CAP WALL TO PLASMA PROTS (esp albumin)

    LOSS OF OSMOTIC PRESSURE --> EDEMA AND HYPOVOLEMIA

    HYPOVOLEMIA --> DEC GFR --> INC ADH FROM PIT --> INC Na AND H20 RETENTION --> INC EDEMA AND ANASARCA (massive edema)

    PLASMA VOL DOESN'T INC IN HYPOALBUMINEMIA

    HT USUALLY NOT A FEATURE IN EARLY STAGES
  12. SELECTIVE vs. NONSELECTIVE PROTEINURIA
    SELECTIVE: LEAK OF LOW MW PROTS LIKE ALBUMIN, TRANSFERRIN AND IgG

    OCCUR IN MINIMAL CHANGE Dz (nephrotic)

    NONSELECTIVE: LEAK OF LOW AND HIGH MW PROTS LIKE IgM AND IgA

    OCCUR IN Dz OTHER THAN MINIMAL CHANGE Dz
  13. HYPERLIPIDEMIA AND LIPIDURIA
    • INC CIRC CHOL AND TRI DUE TO:
    • --HYPOAMBUMINEMIA --> INC LIVER SYNTH
    • --ABN TRANSPORT w DEC UPTAKE INTO TISSUES
    • --IMPAIRED BREAKDOWN OF LIPOPROTEINS

    NEPHROTIC SYND

    HYPERLIPIDEMIA LEADS TO LIPIDURIA: LIPOPROTS LEAK INTO URINE --> FREE FAT OR OVAL FAT BODIES IN URINE
  14. 6 CAUSES OF NEPHROTIC SYND
    1) MINIMAL CHANGE Dz

    2) FOCAL SEGMENTAL GN

    3) MEMBRANOUS GN (MGN)

    4) MEMBTANOPROLIFERATIVE GN (MPGN)

    • 5) SYSTEMIC Dzs:
    • --DIABETES MELLITUS
    • --AMYLOIDOSIS
    • --SYSTEMIC LUPUS

    • 6) OTHER
    • --DRUGS (nsaids
    • --INF (hep b,c, hiv)
    • --NEOPLASMS
  15. MINIMAL CHANGE Dz
    MOST COMMON CAUSE OF NEPHROTIC SYND IN CHILDREN, PEAK 2-6 yrs

    INCIDENCE: KIDS 65%, ADULTS 10%

    • PRESENTS WITH:
    • --EDEMA
    • --SELECTIVE PROTEINURIA
    • --nL RENAL FUNC

    • USUALLY NO HT OR HEMATURIA
    • --------------------------------------
    • PATHOGENESIS

    ABN IMMUNE FUNC

    • ASSOC WITH:
    • -- ATOPIC AND LYMPHOPROLIFERATIVE
    • -- RESP INF
    • -- IMMUNIZATIONS
    • -- STERIODS

    PROD OF UNKNOWN SOL CIRC SUBSTANCE, POSS LYMPHOKINE --> TOX TO GLOM VISCERAL EPI CELLS-->

    --> REVERSIBLE EPI INJ AND DEC IN BASEMENT MEM ANION CHARGE --> PROTEINURIA

    • NONIMMUNOLOGIC CAUSE OF MCD: HEREDITARY --> MUT IN NEPHRIN GENE (nphs1) --> CONGENITAL NEPHROTIC SYND OF FINNISH TYPE
    • --------------------------------
    • PATHOLOGY

    • LIGHT MICRO
    • --nL

    • IMMUNOFLUOR
    • --nL

    • EM
    • -- DIFFUSE EFFACEMENT OF PODOCYTES (HALLMARK)
    • -- NO IMMUNE COMPLEXES
    • -----------------------------------------------
    • CLINICAL COURSE

    nL RENAL FUNC

    90% KIDS RESPOND TO CORTICOSTEROIDS

    ADULTS SLOWER BUT PROG IN EXCELLENT

    PODOCYTE EFFACEMENT REVERSIBLE w STEROIDS

    SOME Pts GET WORSE AND BECOME STEROID DEPPENDENT OR RESISTANT --> USE IMMUNOSUPPRESSIVES
  16. FOCAL SEGMENTAL GN
    PRIMARY IDIOPATHIC FSGN --> NEPHROTIC SYND IN 35% ADULTS AND 10% KIDS

    • INC IN HISPANIC AND AA ADULTS
    • ----------------------------------------------
    • PATHOGENESIS
    • -- MAY EVOLVE FROM MCD
    • -- MORE SEVERE EPI DAMAGE RELATIVE TO MCD
    • -- HALLMARK: PODOCYTE DEGENERATION AND DETACHMENT FROM BASEMENT MEM

    • IMMUNE DYSFUNC MAY CONTRIBUTE
    • --TRANSPLANT Pts
    • --RECURRENT FSGN --> CIRC NON-Ig FACTOR

    • MUTATIONS IN GENES ENCODE SLIT DIAPHRAGM PROTS
    • --PODOCIN, a-ACTIN 4, TRPC6, ADHESION MOLECULES
    • ---------------------------------------------
    • PATHOLOGY

    • BEGINS IN JUXTA GLOM
    • -- ONLY SOME GLOM AFFECTED (focal)
    • -- SCLEROSIS ON PORTION OF GLOM (segmental)

    • LIGHT MICRO
    • -- SCLEROTIC SEGS SHOW WRINKLING OF BM
    • -- MATRIX EXPANSION
    • -- HYALIN DEPOSITION & ADHESION TO BOWMAN
    • --INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY PRESENT

    • IMMUNOFLUOR
    • --SEGMENTAL
    • -- NONSPECIFIC ENTRAP OF IgM AND C3 AS COARSE "CLUMPS" IN SCLEROTIC SEGS ONLY

    • EM
    • -- EFFACEMENT OF PODOCYTE (like mcd)
    • -- DETACHMENT OF PODO FROM BM (irrev)
    • -- NO IMMUNE COMLEXES
    • -- PROG TO DIFFUSE GLOBAL GN AND INC INTERSTIT FIBROSIS
    • ---------------------------------------
    • CLINICAL

    POOR RESPONSE TO STEROIDS ALONE

    LONG COURSE STEROIDS + CYCLOSPORINE OR CYCLOPHOSPHAMIDE MAY HELP

    • PROG BETTER IN KIDS
    • -- PROG TO RENAL FAILURE AT VAR RATE
    • -- 50% PROG TO END STAGE IN 10yrs
    • -- FSGN RECURS IN 25-50% TRANSPLANTS

    -----------------------------------------------
  17. SECONDARY FOCAL SEGMENTAL GN
    • SECONDARY FSGN
    • --HIV, HEROIN
    • --OBESITY
    • --FOCAL GN --> ACTIVE LESION HEALED BUT LOSS OF NEPHRON MASS (ABLATION FSGN)

    ABLATION: LOSS OF NEPHRONS --> INC GLOM HYPERFILTRATION, HT AND HYPERTROPHY AND SYSTEMIC HT

    --> EPI/ENDO INJ AND LEAKAGE OF PLASMA PROTS INTO MESANGIUM --> ORGANIZE TO FORM HYALINE

    • MATRIX EXPANDS --> FSGN --> FURTHER
    • DAMAGE
  18. HIV ASSOC NEPHROPATHY (HIVAN)
    FSGN

    5-10% OF HIV Pts DEV HIVAN

    PRESENT w SEVERE PROTEINURIA AND SEVERE FORM OF FSGN KNOWN AS COLLAPSING VARIANT

    INC IN AAs AND IV DRUG USERS

    • LIGHT MICRO
    • --COLLAPSED GLOM TUFTS
    • --PROLIF AND HYPERTROPH OF VISC EPI THAT HAVE HYALINE DROPLETS
    • --INTERSTIT FIBROSIS AND TUBULES SHOW SEVERE INJ LIKE CYSTIC DILATION

    • EM
    • --NUMEROUS TUBULORETICULAR STRUCTs IN ENDO CELLS

    POOR PROG, RESISTANT TO STEROIDS, END STAGE BY 1 yr
  19. MEMBRANOUS GLOM NEUROPATHY (MGN)
    85% IDIOPATHIC

    ONE OF MOST COMMON NEPHROTIC SYNDs IN ADULTS

    • THOSE w NEPHROTIC SYND
    • --30% OF ADULTS
    • --5% KIDS

    • NONSELECTIVE PROTEINURIA, HEMATURIA, HT IN 15-35%
    • ----------------------------------------------

    PATHOGENESIS

    • AUTOIMMUNE Dz
    • --POSS LINK TO MHC LOCUS
    • -- PROD OF AUTO-Ab TO NEPHROGENIC Ag (megalin-like complex; phospholipase a2 receptor)
    • -- 70% w IDIOPATHIC HAVE Ab AGAINST PLA2 REC
    • -- FORM IN-SITU ON EPI

    ACTIVATE COMPLEMENT (C5b-9) AND MAC --> GLOMs RELEASE PROTEASES/OXIDANTS --> CAP WALL INJ & PROT LEAK --> Ag-Ab SHED ONTO SUBEPI SIDE OF GBM

    • ---------------------------------------
    • PATH

    • LIGHT MICRO
    • --DIFFUSE UNIFORM THICK GBM OF ALL GLOM w/o PROLIF (2ndary w prolif)

    • IMMUNOFLUOR
    • -- UNIFORM GRAN DEPOTS OF IgG AND C3 ON GBM (cap loop pattern)
    • -- NEG MESANGIAL (pos in 2ndary)

    • EM
    • -- EARLY, Ab-Ag DENSITIES IN SUBEPI
    • -- LATER, GBM "SPIKES"
    • ---------------------------------------------

    CLINICAL

    MUST RULE OUT 2NDARY CAUSES

    • INDOLENT & UNPREDICTABLE
    • --30% REMISSION
    • --10% GO TO END STAGE IN 10yrs
    • --40% TO END STAGE EVENTUALLY

    POOR RESPONSE TO STEROIDS

    CYCLOSPORIN BY INDUSE REMISSIONS IN PROTEINURIA AND PROG RENAL DYSF
  20. SECONDARY MGN
    • ASSOC WITH
    • --LUPUS
    • --TUMOR (lung, colon, melanoma)
    • --DRUGS (nsaids, penicillamine, gold)
    • --INF (hep b,c, syphilis, malaria)
    • --METABOLIC DISORDERS (diabetes, thyroiditis)

    MUST EXCLUDE THESE CAUSES TO Dx PRIMARY MGN

    CAN Tx 2NDARY
  21. NEPHRITIC SYND DEFINITION
    2ND MAJOR SYND ASSOC w GLOM Dz

    • CHARACTERIZED BY
    • 1) HEMATURIA w DYSMORPH RBCs AND RBC CASTS

    2) AZOTEMIA (inc bun, creatinine)

    3) OLIGURIA (<400 ml urin / 24hrs)

    4) HT

    5) MILD EDEMA AND MILD PROTEINURIA (<nephrotic range, ~<1gm / 24hr)
  22. NEPHRITIC PATHOPHYS
    INFLAM CELLS IN GLOM INJ CAP WALL --> LEAK RBCs

    INFLAM --> HEMODYNAMIC CHANGES INCLUDING DEC PERF w DEC GFR --> OLIGURIA AND AZOTEMIA --> SALT WATER RET

    HEMODYNAMIC CHANGES --> INC RENIN/ALDO THAT FURTHER INC SALT WATER RET

    NO HYPOALBUMINEMIA --> SALT AND WATER RET IN VASC TREE --> INC PLASMA VOL --> HT AND MILD EDEMA
  23. CAUSES OF NEPHRITIC SYND
    INFLAM LESIONS OF GLOM

    • PRIMARY
    • --ACUTE POSTINFECTIOUS GN
    • --IgA NEPHROPATHY
    • --RAPIDLY PROG crescent GN (RPGN)

    • SYSTEMIC Dzs
    • --CRYOGLOBULINEMIC GN
    • --HENOCH-SCHONLEIN PURPURA
    • --RPGN (goodpasture, microscopic polyangitis, wegener granulomatosis)
    • --LUPUS GRANULOMATOSIS

    • MIXED NEPHRITIC AND NEPHROTIC SYND
    • --MPG TYPES I & II

    • HALLMARK OF INFLAM GLOM: HYPERCELLULAR DUE TO PROLIF IN
    • --MESANGIUM
    • --ENDO
    • --EPI
    • --INFILT BY INFLAM CELLS
  24. ACUTE POSTINFECTIOUS GN
    PSGN (post strep) MOST COMMON CAUSE OF APGN

    MOST COMMON IN KIDS 6-10yrs, BUT SEEN @ ALL AGES

    SEEN 1-4 WEEKS AFTER GROUP A b-HEME STREP OF PHARYNX OR SKIN

    • ABRUPT ONSET OF NEPHRITIC SYND w INC ASO TITRE AND DEC SERUM COMPLEMENT
    • --------------------------------

    PATHOGENESIS

    Ag-Ab IMMUNE COMPLEX MEDIATED Dz

    ONLY CERTAIN STAINS OF GAS ARE NEPHRITOGENIC: TYPES 1,4,12

    • GLOM INJ DUE TO PLANTED Ag --> IN-SITU FORMATION OF Ag-Ab OR DUE TO ENTRAP OF PREFORMED CIRC Ag-Ab
    • ------------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --DIFFUSE PROLIF GN FROM ENDO AND MESANGIAL, AND INFILT OF NEUTS THAT OBLITERATES CAP LUMINA
    • --GBM NOT THICK
    • --SOME SHOW CRESCENTS
    • --TUBULES CONTAIN RBCs

    • IMMUNOFLUOR
    • --IgG AND C3 POS
    • --GRANULAR LUMPY BUMPY DEPOTS ON GBM AND MESANGIUM

    • EM
    • --MANY LARGE SUBEPI ELECTRON DENSE DEPOTS "HUMPS" ALONG GBM AND SOME IN MESANGIUM
    • --POSS SUBENDO DEPOTS
    • ------------------------------------------------

    CLINICAL

    • GOOD PROG
    • -- >95% OF KIDS RECOVER
    • -- ADULTS LESS FAVORABLE

    SUPPORTIVE THERAPY; NO STEROIDS / IMMUNOSUPP

    1% DEV RAPID COURSE, WHILE 1-2% PROG TO CHRONIC GLOM
  25. MEMBRANOPROLIFERATIVE GN (MPGN) CLINICAL, PATHOLOGY, AND PROGNOSIS
    DIVIDED INTO PRIMARY IDIOPATHIC (TYPE I & II) AND 2NDARY

    TYPE I MORE FREQ THAN TYPE II

    MOST COMMON IN OLDER KIDS OR YOUNG ADULTS

    MOST PRESENT WITH NEPHROTIC SYND, USUALLY w NEPHRITIC COMPONENT AND SERUM HYPOCOMPLIMENTEMIA

    • 2NDARY MPGN USUALLY TYPE I AND MAY BE ASSOC w
    • --LUPUS
    • --AV SHUNTS
    • --BAC ENDOCARDITIS
    • --HEP B,C
    • ---------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --TI&II SHOW DIFFUSE GLOBAL HYPERCELLULARITY
    • --ACCENTUATION OF LOBAR ARCHITECTURE "CAULIFLOWERS" DUE TO ENDOCAP PROLIF AND INFLUX OF INFLAM CELLS
    • --MESANGIUM EXPANDED AND GBM THICKENED
    • --SILVER STAIN --> DUP OF GBM "TRAM-TRACK"
    • --SOME CRESCENTS

    • IMMUNOFLUOR
    • --TI --> GRAN C3 DEPOTS AND SOME IgG AND C1q, BOTH IN MESANGIUM AND GBM "BROKEN CURVILINEAR"
    • --TII --> C3 DEPOT AS IRREG GRAN FOCI ALONG GBM on either sides but not within dense depots AS "RINGS" IN MESANGIUM. IgG AND C1q USUALLY NEG

    • EM
    • --TI --> DUP OF BM w EXTENSION OF MESANGIUM AND MATRIX INTO SUBENDO SPACE "MESAN CELL INTERPOSITIONING" AND IMMUNE COMP DEPOTS IN SUBENDO AND MESANGIUM

    • --TII --> INTRAMEM ELEC DENSE RIBBON-LIKE MATERIAL OF UNKNOWN COMP (nL GBM ON EACH SIDE --> TRAM-TRACK) AND SAME DENSE MATERIAL IN MESANGIUM
    • ---------------------------------------------------

    CLINICAL COURSE

    REMISSIONS RARE AND Dz HAS SLOW PROGRESSIVE, UNREMITTING COURSE

    50% DEV CHRON RENAL FAILURE IN 10yrs

    SOME HAVE CRESCENTS AND RAPIDLY DET RENAL FUNC

    CORTICOSTEROIDS & IMMUNOSUPP NOT AFFECTIVE

    HIGH RECURRENCE IN TRANSPLANTS, 90% RECUR IN TII
  26. TYPE I MPGN
    IMMUNE COMPLEX MEDIATED Dz w ACTIVATION OF BOTH CLASSICAL AND ALT COMPLEMENT PATH

    Ag UNKNOWN, poss FROM INF AGENT LIKE HEP B,C

    GLOM INJ MAY BE DUE TO PLANTED Ag --> IN-SITU FORMATION OF IMMUNE COMP OR DUE TO ENTRAP OF PROFORMED CIRC Ag-Ab

    • IMMUNOFLUOR
    • --GRAN C3 DEPOTS AND SOME IgG AND C1q, BOTH IN MESANGIUM AND GBM "BROKEN CURVILINEAR"

    • EM
    • --DUP OF BM w EXTENSION OF MESANGIUM AND MATRIX INTO SUBENDO SPACE "MESAN CELL INTERPOSITIONING" AND IMMUNE COMP DEPOTS IN SUBENDO AND MESANGIUM
  27. TYPE II MPGN
    COMPLEMENT ACTIVATION OCCURES THROUGH ALT PATH

    CIRC IgG AUTO-Ab KNOWN AS C3 NEPHRITIC FACTOR (C3NeF), BINDS TO AND STABILIZES C3 CONVERTASE C3bBb OF THE ALT PATH AND LEADS TO PERSISTENT C3 DEG AND HYPOCOMPLEMENTEMIA

    • IMMUNOFLUOR
    • --C3 DEPOT AS IRREG GRAN FOCI ALONG GBM on either sides but not within dense depots AS "RINGS" IN MESANGIUM. IgG AND C1q USUALLY NEG

    • EM
    • -- INTRAMEM ELEC DENSE RIBBON-LIKE MATERIAL OF UNKNOWN COMP (nL GBM ON EACH SIDE --> TRAM-TRACK) AND SAME DENSE MATERIAL IN MESANGIUM
  28. CRYOGLOBULINEMIC GN (CGN)
    Ig THAT PRECIP IN THE COLD (4*C) AND DISSOLVE WHEN HEATED (37*C)

    • 3 TYPES:
    • 1) SINGLE MONOCLONAL Ig -- MYELOMA AND LYMPHOMA

    2) POLYCLONAL IgG-MONOCLONAL IgMk -- MIXED CRYO MOST COMMON IN CONNECT TISS Dz (lupus, ra) AND HEP C

    • 3) POLY IgG - POLY IgM
    • ---------------------------------------------

    CLINICAL

    SYSTEMIC SMALL VESSEL VASCULITIS INVOLVES ARTERIOLS, CAPs, AND VENULES like hsp

    CRYO PRECIPs IN VESSELS --> THROMBI IN ALL ORGANS AND SYSTEMIC VASCULITIS

    • FEATURES INCLUDE
    • --SKIN PURPURA
    • --ARTHRALGIAS
    • --UNDERLYING Dz (lupus, hep)
    • --LOW COMPLEMENT

    SKIN BIOPSY DIAGNOSTIC FOR LEUKOCYTOCLASTIC VASCULITIS

    25% DEV RENAL Dz

    • MOST COMMON IN CASES w TII CRYO
    • --PROTEINURIA
    • --HEMATURIA
    • --NEPHRITIC
    • --NEPHROTIC
    • --RAPID PROG COURSE
    • -------------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --MPGN TYPE I PATTERN
    • --CRYO THROMBI OFTEN IN CAP LUMENS
    • --CRESCENTS RARE
    • --INFLAM VASC POSS

    • IMMUNOFLUOR
    • --TYPE I SHOW MONOCLONAL usually IgGk AS GRAN DEPOTS IN MESANGIUM AND ALONG GBM AND POS STAINING THROMBI
    • --TYPE II ASSOC w HEP C --> STAIN IgG IgM C3 C1q KAPPA AND LAMBDA IN SAME LOC AS TI

    • EM
    • --DIAGNOSTIC
    • --SUBENDO AND MESANGIAL DEPOTS SHOWING MICROTUBULAR STRUCTURES (10-25 nm) SOMETIMES "THUMBPRINT" APPEARENCE
    • ------------------------------------------------

    INDOLENT w REMISSIONS/RECURRENCES

    10% PROG TO END STAGE

    Tx w CORTs AND CYTOXAN; PLASMAPHERESIS
  29. IgA NEPHROPATHY (BERGER'S Dz)
    MOST COMMON TYPE OF GN WORLDWIDE

    1* AND 2* FORMS

    MOST COMMON IN OLDER KIDS AND YOUNG ADULTS

    • RECURRENT SELF LIMITING EPISODES OF GROSS OR MICRO HEMATURIA, OFTEN FOLLOWING RESP TRACT INF AND POSS GI INF
    • --------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --WIDE SPECTURM (INCLUDING nL)
    • --MESANGIOPROLIF IgA
    • --FOCAL PROLIF IgA
    • --DIFFUSE PROLIF IgA
    • --CRESCENTIC (diffuse prolif) IgA

    • IMMUNOFLUOR
    • --Dx DEPENDS ON IgA AS DOMINANT Ig
    • --ALL GLOM SHOW STRONG IgA AND C3 AS GRAN DEPOTS IN MESANGIUM AND OCC IN SUBENDO
    • --NEG C1q

    • EM
    • --ELEC DENSE DEPOTS IN MESANGIUM AND OCC IN SUBENDO
    • -------------------------------------------------

    CLINICAL PROG

    DEPENDS ON IgA NEPHROPATHY TYPE

    MOST nL FOR DECADES

    SLOW PROG TO CHRON IN 15-40% OVER 20yrs

    STERIODS MAY REDUCE PROTEINURIA; IMMUNOSUPP MAY BE NEEDED. FISH OIL

    RECURS IN 20-60% OF TRANSPLANTS
  30. HENOCH-SCHONLEIN PURPURA (HSP)
    MOST COMMON FORM OF CHILDHOOD SYSTEMIC SMALL VESSEL VASC (3-8yrs)

    OFTEN FOLLOWS URT INF AND HAS RAPIDLY PROG CLINICAL COURSE

    GENERALIZED PURPURIC RASH, ABD PAIN, MELENA black stool, VOM, ARTH

    • RENAL INVOLVEMENT IN 10-25%
    • --HEMATURIA / PROTEINURIA (occ nephrotic range)

    SKIN BIOPSY DIAGNOSTIC FOR LEUKOCYTOCLASTIC VASCULITIS AND IgA IN VESSELS

    PROG IN KIDS SELF LIMITED AND GOOD; LESS FAV IN ADULTS

    Tx SUPPORTIVE
  31. ALPORT'S SYND
    HEREDITARY SYND OF ISOLATED HEMATURIA

    HETEROGENOUS, 85% ARE X-LINKED. SOME AUTOSOMAL DOM OR REC

    • X-LINKED
    • --5-20yrs OLD
    • --HEMATURIA / PROTEINURIA
    • --NERVE DEAFNESS
    • --EYE DISORDERS
    • --END STAGE BETWEEN 20-50yrs
    • ----------------------------------------------

    PATHOGENESIS

    • X-LINKED
    • MUTATION IN a5 CHAIN OF COLLAGEN T-IV (COL4A5) --> DEC SYNTH OF a3 AND a4 CHAINS --> INTERFERES w ASSEMBLY OF COLL T-IV --> ALTERED STRUCT/FUNC OF GBM

    • AUTOSOMAL
    • --MUTATION IN a3 (COL4A3) OR a4 CHAINS OF COLL T-IV

    • a3 CHAIN INCLUDES ANTI-GBM (goodpastures) Ag AND GLOM IN Pts w ALPORT'S WHO LACK THIS CHAIN FAIL TO REACT w ANTI-GBM Ab
    • -------------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --SPECTRUM FROM FOCAL TO GLOBAL GLOM-SCLEROSIS

    • IMMUNOFLUOR
    • --NEG IgG IgA IgM C3 C1q

    • EM
    • --HALLMARK: GBM IRREG THICK AND THIN AND SHOWS SPLITTING "BASKET-WOVEN"
  32. THIN BM Dz (TBMD) (BENINGN FAMILIAL HEMATURIA)
    HEREDITARY SYND OF ISOLATED HEMATURIA

    • FAMILIAL OR SPORADIC FORMS
    • --MICRO HEMATURIA
    • --OFTEN DISCOVERED IN ROUTINE URINANALYSIS
    • --MILD PROTEINURIA
    • --nL RENAL FUNC & EXCELLENT PROG
    • ---------------------------------------------

    • PATHOGENESIS
    • --AUTOSOMAL DOM (FAMILIAL)
    • --HETEROZYGOUS FOR MUTATIONS IN a3 a4 COLL T-IV GENES
    • --ALPORT'S AND TBMD MAY REPRESENT SPECTRUM OF COLL MUTATIONS
    • ------------------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --nL GLOM

    • IMMUNOFLUOR
    • --NEG

    • EM
    • --HALLMARK: DIFFUSE THINNING OF GBM MEASURING 150-250 nm (nL 300-350)
  33. RAPIDLY PROGRESSIVE (crescent) GN (RPGN) DEFINITION AND CLINICAL FEATURES
    CLINICAL SYND ASSOC w SEVERE GLOM INJ (crescents) AND RAPID DEC IN RENAL FUNC

    NOT A SPECIFIC FORM OF GN

    DIAGNOSTIC FEATURE IS PRESENCE OF CRESCENTS IN MOST GLOM

    Tx AS EMERGENCY

    EARLY Dx KEY SINCE Tx MUST BE GIVEN SOON TO PREVENT MORBIDITY

    3 CATEGORIES:

    • TYPE I (ANTI-GBM Ab 2-10%)
    • --IDIOPATHIC
    • --GOODPASTURE'S

    • TYPE II (IMMUNE COMPLEX 15-40%)
    • --IDIOPATHIC
    • --POST-INF GN
    • --DIFFUSE LUPUS GN CLASS IV
    • --DIFFUSE IgA NEPHROPATHY/HEN-SCHON
    • --MPGN

    • TYPE III (PAUCI-IMMUNE) 40-80%
    • --IDIOPATHIC
    • --MICROSCOPIC POLYANGITIS
    • --WEGENER'S GRANULOMATOSIS
    • --CHURG-STRAUSS
  34. TYPE I RPGN
    CRESCENT ANTI-GBM

    • DIVIDED INTO IDIOPATHIC (KIDNEY) AND GOODPASTURE'S (KIDNEY AND LUNG)
    • -------------------------------------------

    • PATHOGENESIS
    • --AUTOIMMUNE DYSFUNCTION (poss virus, HLA)
    • --INC PROD OF CIRC IgG AUTO-Ab --> BINDS TO NONCOLLAGENOUS DOMAIN OF a3 CHAIN OF COLL T-IV ALONG ENTIRE GBM --> SEEN ON IMMUNOFLUOR AS LINEAR STAINING

    • --> INFLAM REACTION RESULTS IN CRESCENTIC GN
    • --------------------------------------------------

    • PATHOLOGY
    • --NECROSIS OF GLOM SEGs --> BREAKS IN GBM AND ESCAPE OF FIBRINOGEN, LEUKOs, PLASMA PROTs AND INFLAM MEDIATORS INTO BOWMAN'S --> STIM PARIETAL EPI CELLS TO FORM CRESCENTS

    --CRESCENT FORMATION INVOLVES EXTRACAP PROLIF, THE TERM USED FOR PROLIF OF PARIETAL PEI CELLS

    --CRESCENT DEFINED AS: >2 LAYERS OF PARIETAL EPI CELLS SURR AT LEAST 1/4th THE CIRCUMPH OF THE GLOM. MAY ALSO CONTAIN INFLAM CELLS AND FIBRIN

    • LIGHT MICRO
    • --EARLY, ONLT FOCAL SEG NEC OF GLOM
    • --LATEER, GLOM DEV GLOBAL NEC AND EXTENSIVE CRESCENT FORMATION
    • --NON-NEC SEGs AND GLOM ARE TYPICALLY nL APPEARING AND DO NOT SHOW ENDOCAP PROLIF

    • IMMUNOFLUOR
    • --HALLMARK, STRONG LINEAR STAINING w IgG AND C3 ALONG GBM

    • EM
    • --BREAKS IN GBM, INFLAM CELLS AND FIBRIN IN AREAS OF NEC
    • --NO IMMUNE COMPLEXES
    • --SOMETIMES SIMILAR TO ALPORT'S w RENAL TRANSPLANT WHO DEV AUTOANTIBODIES AGAINST nL T-IV COLL
    • --------------------------------------------------

    CLINICAL COURSE

    CIRC ANTI-GBM Ab CAN BE USED TO FOLLOW Dz

    COMBO IMMUNOSUPP AND INTENSIVE PLASMAPHERESIS

    ADVANCED Dz, NEC GLOM AND CRESCENTS MAY UNDERGO SCLEROSIS AND DESPITE THERAPY PROG TO CHRON RENAL FAILURE
  35. TYPE II RPGN
    IMMUNE COMPLEX MEDIATED GN

    ONLY TYPE w HYPERCELLULAR GLOM

    IDIOPATHIC OR ASSOC w CLINICAL DISORDER 75%

    • MOST FREQ IN YOUNG Pts WHO SUFFER FROM
    • --POST-INF GN
    • --LUPUS GN CLASS IV
    • --DIFFUSE IgA
    • --HENOCH-SCHONLEIN PURPURA
    • --MPGN

    RENAL SYMPs SIMILAR TO TYPE I RPGN EXCEPT DEPENDING ON Dz, PROTEINURIA IS MILD TO NEPHROTIC

    • PROG DEPENDS ON ETIOLOGY OF UNDERLYING DISORDER AND RESPONSE TO Tx
    • -------------------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --CRESCENTS IN GLOM
    • --HYPERCELLULAR (ONLY TYPE) FROM ENDOCAP PROLIF AND MATRIX EXPANSION

    • IMMUNOFLUOR
    • --GRANULAR STAINING IN MESANGIUM AND USUALLY ALONG THE GBM (IgA AND C3 FOR IgA NEPHROPATHY; FULL-HOUSE FOR LUPUS)

    • EM
    • --CONFIRMS IMMUNE COMPLEX DEPOTS IN MESANGIUM AND ALONG BM
  36. TYPE III RPGN
    PAUCI-IMMUNE -- LACKS ANTI-GBM Ab

    MAY BE IDIOPATHIC ~ LIMITED TO KIDNEY (crescents) OR A COMPONENT OF SYSTEMIC VASC LIKE MICROSCOPIC POLYANGIITIS, WEGENER GRANULOMATOSIS OR CHURG-STRAUSS

    IDIOPATHIC AND SYSTEMIC MAY BE PART OF CONTINUUM

    90% HAVE CIRC ANTI-NEUT CYTOPLASMIC AUTO-Ab (ANCA) THAT ARE EITHER PANCA (perinuclear) OR CANCA (cytoplasmic)

    • PANCA ~ MICROSCOPIC POLYANGIITIS
    • CANCA ~ WEGENER'S

    • ANCA SEROLOGY
    • --INDIRECT IMMUNOFLUOR TEST USING nL NEUTS
    • --MYELOPEROXIDASE (MPO) AND PROTEINASE 3 (PR3) ARE PROT IN CYTOPLASMIC GRANULES OF NEUTs AND MONOCYTES
    • --PRESENCE OF MPO --> PERINUC IMMUNOFLUOR PATTERN
    • --PRESENCE OF PR3 --> CYTOPLASMIC GRANULAR STAINING PATTERN
    • ------------------------------------------

    PATHOGENESIS

    CYTOKINES RELEASED FROM INF DRUGS OR ENV AGENTS ACTIVATE NEUTs AND MONOs

    --> ANCA Ag MPO OR PR3 IN CYTO RELEASED AND (with neuts & monos) BIND TO ENDO

    -->ANCA Ab THEN BINDS TO MPO OR PR3 ON ENDO AND NEUTs/MONOs --> COMPLEMENT ACTIVATION AND ENDO DAMAGE

    • NEUT AND MONO DAMAGE FURTHER INJ ENDO
    • ---------------------------------

    PATHOLOGY

    • LIGHT MICRO
    • --EARLY, MICROSCOPIC POLYANGIITIS AND WEGENERS MAY SHOW ONLY FOCAL SEG NEC OF OF GLOM
    • --LATER, GLOM DEV GLOBAL NEC AND EXTENSIVE CRESCENT FORMATION
    • --NON-NEC SEGs AND GLOM ARE TYPICALLY nL
    • --SMALL VESSELS MAY SHOW SEG NEC VASC w FIBRINOID NEC OF MUSC WALL AND INFLAM; THOMBOSIS MAY OCCUR
    • --GRANULOMAS ARE USUALLY ABSENT IN MICROSCOPIC POLYANGIITIS, AND WEGENERS GRANULOMATOUS INFLAM WITH GIANT CELLS MAY BE SEEN ADJACENT TO VESSELS AND GLOM

    IMMUNOFLUOR NEG

    • EM
    • --BREAKS IN GBM
    • --INFLAM CELLS AND FIBRIN IN AREAS OF NEC
    • --NO IMMUNE COMPLEXES
    • ------------------------------------------------------

    CLINICAL COURSE

    P&C ANCA TITERS CORRELATE w Dz ACTIVITY

    IF TIII DETECTED EARLY, Tx w CORTs AND OTHER IMMUNOSUPP THERA MAY CAUSE REMISSION

    DESPITE THERAPY, MANY Pts PROG TO CHRON RENAL FAILURE
  37. MICROSCOPIC POLYANGIITIS
    TYPE III RPGN

    NEC VASC PREDOM INV SMALL VESSELS

    PANCA POS IN 70%

    RENAL LESION: CRESCENT GN

    IDIOPATHIC FORM PRESENTS WITH NEPHRITIC SYND

    • SYSTEMIC FORM 90% w CRESCENTIC GN; NEPHRITIC SYND
    • --SKIN PURPURA, HEMOPTYSIS, ARTH, ABD PAIN
    • --SKIN BIOPSY DIAGNOSTIC
    • --PULM CAPILLARITIS ACCOUNTS FOR HEMOPTYSIS
  38. WEGENER'S GRANULOMATOSIS
    RPGN TYPE III

    • NEC VASC w TRIAD
    • 1) NEC GRANULOMAS OF LUNG, URT (sinusitis) OR BOTH

    2) NEC OR GRAN VASC AFFECTING SMALL TO MED VESSELS MAINLY IN LUNG AND INV OTHER SITES

    3) FOCAL NEC OR CRESCENT GN

    CANCA IN 95%

    USUALLY MALES IN 5TH DECADE

    NEPHRITIC SYND AND USUALLY PNEUMONITIS w BILATERAL NODULAR AND CAVITARY INFILTRATES AND CHRON OR RECURRENT SINUSITIS
  39. CLEARANCE
    C = UV/P

    C mL/min

    P PLASMA CONC
  40. SNGFR
    SINGLE NEPH GLOM FILTRATION RATE

    GOVERNED BY STARLING FORCES

    dP = Pgc - Pt

    dONC = ONCgc - ONCt

    • SNGFR EQUATION:
    • Kf (dP - dONC)

    Kf = SURFACE AREA OF CAP + PERMEABILITY COEF
  41. FILTRATION FRACTION
    GFR/RPF x100

    nL 20-25%
  42. ENODCRINE FUNC OF KIDNEY
    R-A-A

    ERYTHROPOIETIN BY TUBULOINTERSTITIAL CELLS

    CONVERTION TO 1:25D vitD3 BY 1ALPHA HYDROXYLASE IN EPI CELLS OF PROX TUBULE --> INC ABS OF Ca & PHOS IN GUT

    PROSTAGLANDINS AND ENDOTHELIN REG BLD FLOW AND HYDRO PRESSURE IN GLOM
  43. PROXIMAL TUBULE Na TRANSPORT
    • 65-70% REABS

    Na-K ATPase ON BASOLATERAL SIDE

    Na-H EXCHANGER ON APICAL SIDE

    Cl-BASE EXCHANGERS ON APICAL AND BASOLATERAL
  44. Na TRANSPORT IN ASCENDING LIMB
    • LOOP
    • OF HENLE

    • •Descending limb of loop of Henle
    • not Na permeable

    • •Ascending limb-thin segment
    • --Passive absorption of Na+ along concentration gradient

    • •Ascending limb- thick segment
    • --Na-K-2Cl transporter promotes active Na reabsorption
    • --BARTTER'S SYND

    No water reabsorption in this segment

    Filtrate is hypotonic as it enters distal tubule

    • •Loop
    • diuretics eg: furosemide, ethacrynic acid, act here
  45. DCT Na TRANSPORT
    • •Nearly 5-8% of sodium reabsorption occurs
    • in this segment

    • •Na is reabsorbed with Cl
    • in an electroneutral manner

    • •Na reabsorption occurs by the action of NaCl
    • co-transporter

    • •This segment is relatively water
    • impermeable

    • •Thiazide diuretics inhibit NaCl
    • transporter and reduce Na reabsorption
  46. COLLECTING TUBULE Na TRANSPORT


    COLLECTING TUBULES

    • Final site of Na+
    • regulation

    • Principal
    • cells

    • •Mineralocorticoid
    • sensitive

    • •Aldosterone
    • effects:

    • Increases
    • Na-K ATPase protein

    • Increases
    • Epithelial Sodium Channel (ENaC) activity

    • Increases
    • K+ secretion

    Type A intercalated Cells

    • •Increase
    • H+ secretion by activating H ATPase
  47. URINE Na TEST
    Urine sodium

    • •Physiological test of Na+ handling by the
    • kidney

    • •Reflects whether the kidney is being
    • stimulated to retain or excrete Na+

    • •UNa <20 mEq/L
    • seen in states with reduced renal blood flow

    • (pre-renal azotemia, e.g.,
    • volume loss, congestive heart failure;
    • the kidney is normal but perfusion is reduced)

    • •UNa >20
    • mEq/L in acute tubular necrosis; direct
    • injury to kidney

    • •Significant overlap exists between
    • pre-renal states and ATN

    • •The differentiation between these states
    • is further refined by FENa
  48. DIURETIC LOCATIONS OF ACTION ON NEPHRON (pic)
  49. ADH ACTION ON CT (pic)
    • SECRETED BY SUPRAOPTIC AND PARAVENTRICULAR NUC IN HYPOTHAL

    ADH aka VASOPRESSIN

    RELEASE STIMed BY INC TONICITY OF PLASMA HYPOVOL, PAIN, NAUSEA

    20% OF H20 REABS
  50. RENAL WATER CLEARANCE EQUATIONS
    Total Urine Volume (V) = COSM + CH2O

    COSM = (Uosm x V) / Posm

    CH2O = V - COSM
  51. URINE ACIDIFICATION IN PT
    • APICAL Na-H EXCHANGER
    • --H PUMPED INTO LUMEN --> REABS HCO3

    Na-HCO3 COTRANSPORTER ON BASOLATERAL SIDE

    70-80% OF HCO3 REABS IN PT
  52. ACIDIFICATION (HCO3 REABS) IN CT
    TYPE A INTERCALATED CELLS

    • H-ATPase PUMP ON APICAL
    • --PUMPS H INTO LUMEN
    • --BINDS HCO3, PHOS, NH3
    • --HCO3 REABS

    Cl-HCO3 EXCHANGER ON BASOLATERAL

    TYPE B INTERCALATED CELLS

    • Cl-HCO3 EXCHANGER ON APICAL SIDE
    • --PUMPS HCO3 INTO LUMEN

    • H-ATPase PUMP ON BASOLATERAL SIDE
    • --PUMPS H INTO CAPILLARY
  53. TYPE I RTA
    RENAL TUBULAR ACIDOSIS - DISTAL

    • ABNORMALITIES
    • IN RENAL H+ SECRETION

    • Inability to generate steep H+
    • gradient across distal tubular epithelia,

    Causes: Sjogren’s syndrome; SLE; amphotericin B; liver disease; idiopathic
  54. TYPE II RTA
    Type II, Proximal RTA

    • ABNORMALITIES
    • IN RENAL H+ SECRETION

    • Reduced threshold for absorption of
    • HCO3 due to impaired H+ secretion,

    May be associated with aminoaciduria, glycosuria and phosphaturia (Fanconi syndrome)

    • Causes: acetazolamide; outdated
    • tetracycline; multiple myeloma; Wilson’s disease; idiopathic

    Clincal features: hyperchloremic metabolic acidosis, hypokalemia

    • Calcium phosphate stones in type 1
    • RTA
  55. TYPE IV RTA
    Renal Tubular Acidoses (RTA) - Type IV RTA

    ABNORM RENAL H+ SECRETION

    • • Reduced secretion of H+ and K+ in distal
    • nephron;

    In some cases hyporeninemic hypoaldosteronism

    • • Causes: diabetes mellitus, obstructive
    • nephropathy, sickle cell nephropathy, renal transplant rejection

    • Clincal features: hyperchloremic metabolic acidosis, HYPERKALEMIA
  56. CLINICAL SIGNIFICANCE OF ACIDOSIS
    • •Chronic metabolic acidosis can contribute
    • to osteopenia and osteoporosis

    • • Renal tubular acidoses
    • can be associated with kidney stones, rickets and osteomalacia

    • • Severe acidosis can affect
    • cardiovascular function

    • • Untreated acidosis in Chronic Kidney
    • Disease is associated with greater mortality
  57. POTASIUM HANDLING BY KIDNEY
    • •Freely filtered and ~ 90% reabsorbed by
    • the proximal tubule and the ascending limb of Loop of Henle

    Reabsorption of K can not be regulated much

    • •K+ secretion by principal cells of the
    • collecting duct is the major mechanism of renal excretion of K+ loads

    •Factors affecting K+ secretion:

    Aldosterone;

    • Rate
    • of filtrate flow

    • Na+
    • delivery in distal nephron

    • Serum
    • K concentration

    • Non-reabsorbable anions in the lumen of the distal
    • nephron

    • Acid
    • base status: alkalosis shifts K into the cells
  58. WINTER'S FORMULA
    Winter’s formula

    pCO2 = [HCO3]p x 1.5 + 8 ± 2

    USED TO TEST FOR nL pCO2 COMPENSATION IN METABOLIC ACIDOSIS
  59. CLINICAL TYPES OF METABOLIC ACIDOSIS
    Increased anion gap acidosis

    Endogenous metabolic derangements

    Renal failure, acute and chronic

    Diabetic ketoacidosis

    Lactic acidosis

    Exogenous causes

    • Salicylate
    • poisoning

    • Ethylene
    • glycol ingestion

    • Toxic
    • ingestion of paraldehyde

    Ethyl alcohol or methyl alcohol toxicity
  60. CAUSES OF nL ANION GAP ACIDOSIS
    •Usually caused by loss of HCO3 from the extracellular fluid.

    •Rise in plasma Cl concentration proportionate to the decrease in serum HCO3 concentration.

    • (a)
    • Renal tubular acidosis

    • (b)
    • Gastrointestinal losses of HCO3 in diarrhea

    (c) Pancreatic fistula
  61. CHLORIDE RESPONSIVE METABOLIC ALKYLOSIS
    Chloride (Volume) responsive metabolic alkalosis

    e.g., Vomiting, naso-gastric suction. Urine chloride <10 mEq/L

    • Generation of alkalosis:
    • --Loss of H+ and Cl-.
    • --Maintenance of alkalosis
    • 1. Chloride depletion.

    INC HCO3 reabsorption by type A intercalated cells

    H+ secretion INC ­activity of H-ATPase pumps, type A intercalated cells DEC secretion of bicarbonate by type B intercalated cells

    • 2. Volume Depletion
    • --INC Aldosterone secretion INC ­H-ATPase pumps in the type A intercalated cells --> ­ INC H+ secretion and return one molecule of HCO3 to blood --> loss of H+ and maintenance of high HCO3 levels

    3. Potassium depletion

    Hypokalemia ­bicarbonate reabsorption.

    Hypokalemia INC K shifts from intracellular fluid to plasma --> opposite movement of H+ into cells to maintain electroneutrality --> secretion of H+ from the collecting tubule cells and thus increases HCO3 reabsorption

    Treatment

    • •Correct
    • chloride/volume deficits with 0.9% saline, K supplements

    • •Identify
    • and treat underlying causes

    • •Carbonic
    • anhydrase inhibitors, watch for hypokalemia

    • •Emergency:
    • consider IV HCl infusion, Hemodialysis
  62. CHLORIDE RESISTANT METABOLIC ACIDOSIS
    • e.g.,
    • glucocorticoid or mineralocorticoid excess, Bartter’s syndrome

    • •Urine
    • chloride concentration is >10 mEq/L

    • •Excess
    • steroids --> Increase in Na reabsorption, H+
    • secretion, K+ secretion

    • •Total
    • body Na is increased and hypokalemia

    Treatment

    • •Correct
    • underlying condition and K supplements
  63. DISORDERS OF TB-Na
    •Na+ is the principal cation in ECF

    •TBNa content determines ECF volume status

    •A decrease in TBNa content due to GI or renal losses of sodium leads to volume depletion (hypovolemia)

    •An increase in TBNa content leads to fluid accumulation (hypervolemia) in states such as congestive heart failure, nephrotic syndrome and cirrhosis
  64. CLINICAL SIGNS OF HYPONATREMIA
    •Caused by shift of water into brain cells with cerebral edema

    •GI: nausea, vomiting and anorexia

    • •Central
    • Nervous System

    • –Altered
    • mental status (delirium, coma)

    –Seizures

    –Death

    • •Symptoms
    • depend on rapidity of onset

    • •Age,
    • female gender, comorbid conditions increase risk
  65. HYPOVOLEMIC HYPONATREMIA
    Clinical signs of volume depletion:orthostatic changes in HR & BP, flat neck veins, dry mucous membranes, decreased skin turgor

    • EXTRA-RENAL LOSSES
    • Vomiting / NG suction
    • Diarrhea
    • “Third-Space” Losses
    • Burns
    • Peritonitis
    • Pancreatitis
    • Rhabdomyolysis
    • Adynamic Ileus
    • Blood loss
    • Excessive sweating

    UNa or UCl < 10 mEq/L

    • RENAL LOSSES
    • Diuretics
    • Osmotic (glucose, mannitol)
    • Thiazides
    • Loop diuretics
    • Addison’s disease
    • Salt-Wasting Nephritis
    • Proximal RTA

    • Tx -- VOL EXPANSION w nL SALINE
    • UNa and UCl > 20 mEq/L
  66. EUVOLEMIC HYPONATREMIA
    SIADH

    • CNS disorders
    • Lung disorders
    • Tumors (oat cell)
    • Postop state / pain
    • Nausea
    • Hypothyroidism
    • Glucocorticoid deficiency
    • Psychosis



    Drugs

    • Phenothiazines
    • Narcotics
    • Amitriptyline
    • NSAID’s
    • Chlorpropamide
    • Carbamazepine
    • Cyclophosphamide
    • Vincristine
    • Clofibrate
    • Thiazide diuretics

    Tx -- FLUID RESTRICTION
  67. HYPERVOLEMIC HYPONATREMIA
    Clinical signs of fluid overload: edema, pulmonary rales, elevated neck veins, pleural effusions, ascites, anasarca

    • EXTRA-RENAL CAUSES
    • Congestive heart failure
    • Nephrotic syndrome
    • Decompensated cirrhosis

    • RENAL CAUSES
    • Acute renal failure
    • Chronic renal failure



    Treatment: Salt restriction & diuretics (TBNa) AND Fluid restriction (TBH2O)
  68. CAUSES OF HYPONATREMIA WITH nL OR INC Posm
    • •Hyperglycemia
    • (estimate decrease in serum [Na] by 1.6 mEq/L for every 100 mg/dl increase in glucose)

    • •Mannitol
    • administration

    • •IV
    • contrast

    •Hyperlipidemia

    • •Hyperproteinemia
    • (multiple myeloma)
  69. OSMOLAR GAP
    • •Osmolar gap:
    • a difference between measured pOsm and
    • calculated pOsm >
    • 10 mOsm/kg

    • •Ethanol
    • - the most common cause of osmolar gap
    • (if it’s not accounted for in the calculation)

    • •Methanol
    • (wood alcohol)

    • •Ethylene
    • glycol (antifreeze and other solvents)

    • •Isopropyl
    • alcohol (rubbing alcohol)

    • •Osmolar gap
    • not elevated in salicylate, or sedative-hypnotic overdose (large MW compounds)
  70. CAUSES OF CENTRAL DI
  71. ETIOLOGIES OF NEPHROGENIC DI
  72. EVALUATE POLYURIA
    URINE VOL > 3 L PER DAY

    • WATER DIURETICS
    • --CENTRAL DI
    • --NEPH DI
    • --PRIMARY POLYDIPSIA (PSYCH, XERO, HYPO-K)

    • OSMOTIC DIURETICS
    • --GLYCOSURIA
    • --MANNITOL
    • --UREA
    • --NaCl -- iv fluids, diuretic use, renal salt wasting
    • --RADIOCONTRAST AGENTS
  73. CLINICAL MANIFESTATIONS OF HYPERNATREMIA
    SHIFT OF WATER OUT OF CELL w DEHYDRATION AND SHRINKAGE OF BRAIN

    CNS SYMPS ARE LIFE-THREATENING

    RESTLESSNESS, IRRIT, LETHARGY, MENTAL STATUS, SEIZURE, COMA, DEATH

    RISK OF RAPID CORRECTION --> CEREBRAL EDEMA
  74. HYPOVOLEMIC HYPERNATREMIA
    EXTRA-RENAL

    • VOMIT / NG SUCTION
    • DIARRHEA
    • BLD LOSS

    U-Na OR U-Cl < 10 mEq/L

    • RENAL LOSSES
    • DIURETICS -- osmotic, diab dehyd synd, thiaz, loop
    • ADDISON'S
    • SALT WASTING NEPHRITIS
    • PROX RTA

    U-Na & U-Cl > 20 mEq/L

    • Tx
    • --nL SALINE FOR VOL DEPLETION
    • --WATER FOR HYPER Na
  75. EUVOLEMIC HYPERNATREMIA
    • RENAL LOSSES
    • CENTRAL DI
    • NEPHROGENIC DI

    • EXTRA RENAL LOSSES
    • UNREPLACED RESPIRATORY AND DERMAL INSENSIBLE LOSSES OF FREE WATER

    Tx -- WATER REPLACEMENT TO SLOWLY CORRECT HYPER-Na
  76. HYPERVOLEMIC HYPERNATREMIA
    FLUID OVERLOAD ICU Pt w INADEQ REP OF RESP AND DERMAL LOSSES OF HYPOTONIC FLUID

    HYPERTONIC DIALYSATE

    HYPERTONIC Na-HCO3 ADMIN

    NaCl TABLETS IN HOT ENV

    Tx -- DIURETICS AND Na RESTRICTION FOR FLUID OVERLOAD. WATER FOR HYPER-Na
  77. INSULIN AND b2 ADREN AGONISTS ON K+ MOVEMENT
    EC --> IC

    STIM NA-K ATPase

    NON-SEL b2 BLOCKERS (PROPRANOLOL) OR LACK OF INSULIN --> HYPERKALEMIA
  78. METABOLIC ACIDOSIS ON K+ CONC
    H+ SHIFTS FROM EC TO IC IN EXCHANGE FOR K+ TO HANDLE ACIDOSIS --> HYPERKALEMIA

    OPPOSITE IN ALKYLOSIS
  79. K+ REABSORPTION IN NEPHRON
    90% PASSIVELY IN PT AND THICK ASCEND LIMB

    MUST SECRETE K+ IN CT TO DEAL w HIGH K+ DIET

    • PRINCIPAL = SECRETION
    • --ALDO STIMS BASO Na-K ATPase AND APICAL ROMK & BK (ENAC FOR Na)
    • --INTERCALATED INH expt for apical k secretion

    • INTERCALATED = REABS
    • --ROMK, BK AND ENAC INH
    • --APICAL H-K EXCHANGER
    • --BASO K CHANNEL
    • ---------------------------------

    • K+ SECRETION DEPENDENT ON
    • --URINE FLOW
    • --Na DELIVERY TO DISTAL NEPH
    • --EXTRA-CELL FLUID pH
    • --SERUM K+ []
    • --[] IMPERMIABLE ANIONS
  80. SYMPTOMS OF HYPOKALEMIA
    MUSCLE WEAKNESS

    ASCENDING PARALYSIS

    RESP DEPRESSION

    CARDIAC ARRHYTHMIAS

    DEC T WAVES

    U WAVES SEEN

    DEATH

    --NOT ALL Pts ARE SYMPTOMATIC w LOW K+
  81. CAUSES OF HYPOKALEMIA
    SERUM K+ < 3.5

    1) EXCESS ALDO (CUSHINGS)

    2) VOMITING AND NASOGASTRIC SUCTION

    3) DUIRETICS

    4) RENAL TUBULAR ACIDOSIS, TYPE I OR II

    5) EXCESS ANIONS IN URINE FROM DRUGS LIKE PEN

    6) AMINOGLYCOSIDES LIKE GENTA AND TOBRA

    7) HIGH URINE FLOW STATES FROM PRIMARY POLYDIPSIA

    • 8) GENETIC DISORDERS OF DISTAL NEPHRON
    • --LIDDLE'S SYND, INC Na ABSORPTION IN CT
    • -- BARTTER'S, DEFECT IN Na-K-2Cl TRANSPORTER IN THICK ASC LIMB
    • --GITELMAN'S, DEFECT IN THIAZIDE SENSITIVE NaCl COTRANSPORTER IN DT
  82. SYMPTOMS OF HYPERKALEMIA
    CHANGES IN CELL MEM POTENTIAL

    VOLUNTARY & INVOLUNTARY MUSCLE

    • CARDIAC CONDUCTION SYSTEM
    • --INC T WAVE
    • --PROLONGED PR INTERVAL
    • --WIDENING OF QRS
    • --LOSS OF P WAVE

    WEAKNESS FATIGUE

    SOMETIMES PROGRESSING TO RESP DEPRESSION
  83. MECHANISMS OF HYPERKALEMIA
    SERUM K+ > 5.5 mEq/L

    • PSEUDOHYPER-K
    • --NOT TRUE INC
    • --HEMOLYSIS OF BLD SAMPLE IN TEST TUBE
    • --RELEASE OF K FROM CELLS TO PLASMA IN TEST TUBE DUE TO LEUKOCYTOSIS OR THROMBOCYTOSIS
    • --MUST EXCLUDE

    • REDISTRIBUTION
    • --FROM IC TO EC (total body k is nL)
    • --CELL DEATH (rhabdo, reabsorp of hematoma, cell lysis
    • --ACIDEMIA
    • --b-BLOCKERS
    • --LACK OF INSULIN OR RESISTANCE
    • --HYPERGLYCEMIA
    • --HYPEROSMOLARITY
    • --DIGITALIS INTOXICATION
    • (blocks na-k atpase

    • TOTAL BODY EXCESS (intake > excretion)
    • --KIDNEY Dz w MAJOR DEC IN GFR
    • --IMPAIRED EXCRETION OF K BY CCT:
    • * Low aldo caused by meds ace inh, heprins
    • * Adrenal insufficiency (Addison's)
    • * Hyporeninemic hypoaldo from diabetic nephropathy or type iv rta
    • * meds that aldo receptor (spironolactone)
    • * meds that block enac
  84. Tx OF HYPERKALEMIA
    • SEVERE w ECG CHANGES
    • --IV CALCIUM GLUCONATE
    • --SHIFT FROM EC TO IC w INSULIN OR b2-AGONIST

    • IF DUE TO INC TOTAL BODY K+
    • --EXCRETE THROUGH KIDNEY (DIURETICs AND MINERALOCORTICOIDS fludrocortisone
  85. CALCULATE ANION GAP
    Anion gap =[UA-] - [UC+] = [Na+] - [Cl-] - [HCO3-]
  86. CAUSES OF INC AG WITHOUT METABOLIC ACIDOSIS
    •Increased unmeasured anion (without addition of H+)

    • –Sodium lactate (lactated Ringer’s Solution, continuous renal therapy dialysate
    • solutions)

    • –Sodium
    • citrate (anticoagulant in blood products)

    • –Sodium
    • acetate (acetate-based dialysate, uncommonly used)

    • –Sodium
    • carbenicillin

    • –Sodium
    • penicillin

    • •Hemoconcentration
    • of plasma proteins

    • •Alkalemia-
    • either metabolic or respiratory alkalosis

    • •Decreased
    • unmeasured cations

    –(Combined hypoCa2+, hypoMg2+, hypoK+)
  87. CAUSES OF DEC ANION GAP
    •Decreased unmeasured anions (UA-)

    –hypoalbuminemia

    • •Increased
    • unmeasured cations
    • (UC-)

    • –IgG
    • multiple myeloma

    • –Lithium
    • intoxication

    –Polymyxin B

    –HyperCa2+

    –HyperMg2+

    –HyperK+

    • •Laboratory
    • analytical errors

    • –Erroneously
    • low [Na]

    • –Erroneously
    • high [Cl]

    • –Bromide
    • intoxication (bromide measured as chloride)
  88. CAUSES OF METABOLIC ACIDOSIS WITH INC ANION GAP
    • ENDOGENOUS
    • --KETOACIDOSIS (diabetic, alc, starvation
    • --LACTIC ACIDOSIS
    • --RENAL FAILURE
    • --NON-KETOTIC HYPEROSMOLAR COMA (diabetic dehydration)
    • --RHABDOMYLOSIS

    • EXOGENOUS
    • --METHANOL
    • --ETHYLENE GLYCOL
    • --CALICYLATES
    • --PARALDEHYDE
    • --TOLUENE
  89. CLASSIFICATION OF LACTIC ACIDOSIS
    TYPE A

    • REDUCED O2 DELIVERY
    • --SHOCK
    • --LOW CARDIAC OUTPUS
    • --SEPSIS
    • --SEVERE HYPOXEMIA

    • INC O2 DEMAND
    • --GEN SEIZURES
    • --SEVERE EXERCISE
    • --HYPOTHERMIC SHIVERING

    TYPE B

    • TOXINS
    • --ETHANOL
    • --METHANOL
    • --ETHYLENE GLYCOL
    • --METAFORMIN

    HIV - HAART

    METASTATIC CANCER

    SEVERE DKA

    TYPE I GLYCOGEN STORAGE Dz

    SEVERE LIVER Dz

    D-LACTIC ACIDOSIS

    PHEOCHROMOCYTOMA
  90. KETONE FORMATION IN INSULIN DEFICIENCY OR GLUCAGON EXCESS
    DEC INSULIN --> INC GLUCAGON --> INC FFA

    GLUCAGON --> CarnAcylTrans --> TRANSPORT INTO MITOCHONDRIA FOR KETONE SYNTH

    MALONYL CoA USUALLY INH CAT
  91. Tx OF SALICYLATE INTOXICATION
    H + S <--> HS

    ALKYLATE BLD FAVORS S-, WHICH IS CHARGED AND TRAPPED

    SAME IF ALKYLATE URINE
  92. CAUSES OF METABILIC ACIDOSIS WITH nL ANION GAP (HYPERCHLOREMIC METABOLIC ACIDOSIS)
    LOW OR nL SERUM K

    • GI DISORDERS
    • --DIARRHEA
    • --PANC, INTEST, OR BIL FISTULA OR DRAINAGE

    RENAL TUBULAR DISORDERS (RTA)

    URETERAL DIVERSION

    RECOVERY PHASE - KETOACIDOSIS

    HCl ADMIN

    HIGH SERUM K (TYPE IV RTA = HYPO-ALDO)

    ALDO DEFICIENCY

    ALDO RESISTANCE
  93. CAUSES OF HYPERALDOSTERONISM w HT, HYPO-K, AND METABOLIC ALKALOSIS
    • •Primary hyperaldosteronism
    • –Aldosterone-producing
    • adenoma (Conn’s syndrome)
    • –Bilateral
    • adrenal hyperplasia

    • •Liddle’s
    • syndrome

    • •Glucocorticoid-remediable
    • hyperaldosteronism

    • •Syndrome
    • of apparent mineralocorticoid excess

    • •Licorice
    • ingestion

    • •Cushing’s
    • syndrome
  94. nL BODY FLUID & LECTROLYTE COMPOSITION
    Na 135 – 145 mEq/L

    K 3.6 – 5.0 mEq/L

    BODY WATER 60 – 75 %

    Sosm 287 ± 2
  95. HOLLIDAY-SEGAR METHOD FOR CALC MAINTENANCE FLUID
    Weight 24 Hour Fluid Hourly Rate
  96. 3 to 10 kg 100 ml/kg/day 4 ml/kg/hr
  97. 11to 20 kg__1000 + 50/kg/day + 2/kg/hr for
    _________for each kg>1040___each kg>10
  98. >20 kg 1500 + 20/kg/day 60____+ 1/kg/hr for
    _________for each kg>20_________each kg>20
  99. CORRECTION OF HYPONATREMIA
    IF ENCEPHALOPATHY Tx w HYPERTONIC SOLUTION

    • CEREBRAL DEMYELINATION AND CENTRAL PONTINE MYELINOLYSIS
    • --CONFUSION
    • --IRREV QUADRIPLEGIA
    • --PSEUDOBULBAR PALSY
    • --DEATH
  100. CORRECTION OF HYPERNATREMIA
    SERUM > 150 mEq/L

    TYPICAL Pts DO NOT HAVE ACCESS TO WATER

    IC TO EC

    LEADS TO TRANSIENT CEREBRAL DEHYDRATION AND CELL SHRINKAGE

    SEPARATION OF BRAIN FROM THE MENINGES AND INTRACRANIAL AND INTRACEREBRAL HEMORRHAGES

    KIDS w HYPER-Na APPEAR AGITATED AND IRRITABLE --> LETHARGY LISTLESSNESS AND COMA

    Tx GIVE FREE WATER

    AGGRESSIVE CORRECTION CAN LEAD TO CEREBRAL EDEMA AND CEREBRAL HERNIATION
  101. SIADH
    SYND OF INAPPROPRIATE ADH SECRETION

    A defect in osmoregulation of ADH resulting in sustained high ADH level despite hypo-osmolality

    • §Normal adrenal, pituitary, thyroid,
    • cardiac and hepatic functions

    §Hypo-osmolality

    • §Urine is inappropriately hypertonic
    • compared to serum

    • §Continued salt excretion despite
    • low serum Na

    §High ADH

    §Correction of DEC Na with fluid restriction
  102. 8 STEPS IN SYSTEMATIC APPROACH TO ANALYSIS OF ACID-BASE DISORDERS
    1) CHECK INTERNAL CONSISTENCY OF THE ABG

    2) DETERMINE IF THE ABG AND HCO3 FROM ELECTROLYTE PANEL ARE WITHIN 1-2 mEq/L

    3) CALC THE ANION GAP

    4) CALC POTENTIAL HCO3

    5) DETERMINE PRIMARY ACID-BASE DISORDER

    6) RULES OF THUMB FOR nL COMPENSATORY RESPONSE

    • 7) CHECK FOR SPECIAL COMPENSATION RULES
    • --MIXED DISORDER (x2 ACIDOSIS/ALKYLOSIS_
    • --OVERCOMPENSATION (nL pH)
    • --ANION GAP VS. HYPERCHLOREMIC METABOLIC ACIDOSIS

    8) CLASSIFY TYPE OF ACID/BASE DISORDER AND DETERMINE CAUSE
  103. CALCULATE POTENTIAL HCO3
    MEASURED HCO3 + EXCESS AG

    nL HCO3 ~ 24

    INC IMPLIES HIDDEN METABOLIC ALKYLOSIS
  104. APPROPRIATE COMPENSATION FOR PRIMARY ACID/BASE DISORDER
    • DEC pCO2 FOR METABOLIC ACIDOSIS
    • --WINTER'S FORMULA
    • pCO2 = 1.5(HCO3) + 8 +/- 2

    INC pCO2 FOR METABOLIC ALKALOSIS

    • pCO2 = .7(HCO3) + 20 +/- 5
    • ~CO2 inc 6-7 for every 10 INC HCO3

    • RESPIRATORY ALKALOSIS
    • HCO3 DEC 2.5 FOR EVERY 10 DEC CO2

    • RESPIRATORY ACIDOSIS
    • HCO3 INC 1 FOR EVERY 10 INC CO2
  105. RULES FOR MIXED ACID/BASE DISORDER, OVERCOMPENSATION, AND AG vs. HYPER-Cl
    • MIXED:
    • HCO3 AND pCO2 CHANGE IN OPPOSITE DIRECTIONS = ACIDOSIS + ACIDOSIS

    • OVERCOMPENSATION
    • --APPROPRIATE COMPENSATION SHOULD NOT RETURN pH BACK TO nL
    • --IF HCO3 AND pCO2 ARE ABnL BUT pH IS nL, THEN MIXED DISORDER MUST BE
    • --ACIDOSIS + ALKALOSIS

    • % METABOLIC ACIDOSIS DUE TO INC AG vs. HYPER-Cl
    • --EXCESS AG / DEC IN HCO3 x 100
    • --IF > 80% THEN PURE AG
    • --IF < 20% THEN PURE HYPER-Cl
    • --IF 20-80 THEN MIXED

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