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Medicine Grand Rounds


Title: Renal Grand Rounds Author: akhanifar Last modified by: UCIMC Created Date: 3/26/2007 2:35:17 AM Document presentation format: On-screen Show – PowerPoint PPT presentation

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Title: Medicine Grand Rounds

Medicine Grand Rounds
  • Hamid Moradi M.D.
  • Assistant Clinical Professor
  • Division of Nephrology and Hypertension

  • 57 yo WM with h/o CKD stage III secondary to
    hypertensive nephrosclerosis (presumably)
  • Baseline creatinine 2.0s
  • H/O hyperkalemia at baseline presumed to be due
    to type IV RTA
  • Presented to the renal clinic at LBVAMC with
    acute renal failure ?
  • Creatinine up to 3.4
  • Potassium of 5.6

  • H/O chronic diarrhea, recent EGD/colonoscopy?
    significant diarrhea post procedure
  • Herbal meds which he stopped two weeks ago
  • Started on lasix last month
  • No recent NSAIDs
  • No change in ACEI
  • No nocturia, frequency, dysuria

  • PMH
  • 1. Hyperparathydroism s/p parathyroidectomy
  • 2. Hypocalcemia
  • 3. Clostridium dificile diarrhea
  • 4. CAD s/p CABG 2005
  • 5. Diabetes type II
  • 6. Hypertension
  • 7. Mixed hyperlipidemia
  • 8. H/o nephrolithiasis
  • 9. CKD with basline creat 1.8-2.0 2/2 NSAID
    nephropathy vs. HTN
  • 10. Malignant melanoma
  • 11. Anemia
  • 12. Spondylosis
  • PSH
  • 1. Parathyroidectomy 3/30/06
  • 2. CABG '05- 4 vessel
  • 3. Glass eye placed on right '84
  • 4. Multiple prior melanoma resections x5
  • 5. Tonsillectomy, adenoidectomy

  • FHX
  • mother with HTN, died of breast CA at 76
  • uncle with "heart disease" another uncle with
  • SHX
  • Patient lives alone in Huntington Beach,
    was employeed as physical
  • therapist at Kaiser until recently. Denies
    tob, EtOH, drugs
  • Meds
  • ASA
  • Lasix
  • Lisinopril
  • Neurontin
  • Niacin
  • Glipizide
  • Rosiglitazone
  • Calcium carbonate
  • Calcitriol
  • Atenolol
  • Flunisolide

  • Labs
  • Uric acid 7.8 CPK 128
    PSA 4.1
  • LFTs normal UA spec grav 1.004,
    pH 5, glu 70, negative protein, 1 RBC, 3 wbc
  • Urine Na 81 Urea 315 Creat 28

Hospital Course
  • Admitted? foley catheter IV fluids? no change
    in renal function
  • Ultrasound-
  • -Increased echogenicity of the cortices of
    the kidneys bilaterally consistent with medical
    renal disease.
  • - There are multiple cysts in the cortices
    of the kidneys bilaterally. The largest cyst
    measures 4.3 x 2.7 centimeters and contains a
    septation, the right kidney.
  • - Enlarged prostate

Hospital course
  • Differential on CBC?13 eosinophils of WBC count
  • 10 urine eosinophils

Renal biopsy
Tubulointerstitial Nephritis
  • A brief overview

Structure function
  • Tubules and interstitium make up 80 of renal
  • Cortical interstitium
  • Type I interstitial cells resemble fibroblasts
    and produce Epo
  • Capable of producing and degrading ECM
  • Type II interstitial cells monocyte derived
  • Resemble dendritic cells and present antigens
  • Capable of phagocytosis
  • Interstitial space contains type 1 and 3 collagen

Structure function
  • Medullary interstitium
  • Type 1 cells lipid rich cells in inner medulla
  • produce prostaglandins via COX-2
  • Type 2 cells resemble lymphocytes, ? Role
  • Type 3 cells near vasa recti, ? Role
  • Extracellular matrix contains type 1 and 3
  • Renal matrix is made up of fibrillar net of
    interstitial and basement membrane collagens and
    interstitial fluid
  • Provides structural support and conduit for
    solute transport

Historical background
  • 1898 Councilman used term AIN

Historical background
  • Many decades the term chronic pyelonephritis was
    used to describe chronic injury to interstitium
  • Despite lack of active infection
  • Early 1950s Spuhler and Zollinger described
    analgesic nephropathy
  • Spuhler, O., Zollinger, H. 1953. Z. Kiln. Med
  • Late 1970s Henderson colleagues
  • described lead
    chronic tubulointersitial nephritis
  • Chronic pyelonephritis is not infectious in
  • TIN became a category onto itself

  • WHO

  • TIN caused by
  • primary damage to
  • tubulointerstitium
  • vs. secondary process
  • after damage to
  • other parts of the
  • nephron

  • Autopsy study 1.7 of acute renal failure and
    0.2 of CKD
  • Renal bx study of 109 patients with unexplained
    renal failure (GFRlt60) and normal kidney size
  • TIN was the most common cause 27
  • Finnish study 314,000 asx recruits? 174 had
    hematuria and/or proteinuria? bx? 2 had TIN
  • Incidence of 3 among patients with ESRD
  • By clinical/lab findings, incidence of 32 among
    hospitalized patients with CKD and creat gt1.6

  • Direct cytotoxicity
  • Dependent on dose and duration of exposure
  • Indirect by the induction of systemic
    inflammatory or immunologic reactions
  • Immune complex deposition or anti-GBM Ab
  • Antibodies to cell surface Ag, or Ag presented by
    the dendritic cells? cell mediated reaction
  • Activation of epithelial, fibroblast and
    endothelial cells ? expression of cytokines and
    growth factors (TGF-b or platelet derived growth

  • Pattern of response can help define the acuity of
    process, the long term prognosis and occasionally
    etiology of disorder
  • Presence of significant inflammatory infiltrate
    in interstitium
  • If infiltrate present the cell type helps
  • Structural changes of tubular injury
  • Sublethal injury to necrosis
  • Alteration of growth (atrophy, hypertrophy)
  • Accumulation of cast in tubules
  • Interstitial changes
  • Edema
  • Leukocytic infiltration
  • fibrosis

Chronic TIN
  • Interstitial infiltrate depending on etiology ie
    neutrophils, eosinophils, monocytes, macrophages
    (small lymphocytes)
  • Tubular atrophy , tubular dilation
  • Glomerulosclerosis (loss of glomeruli) severe
    tubular damage
  • Medullary microcyts
  • Cast formation (thyroidization) in MM
  • Interstitial fibrosis
  • IF usually negative except for MM, Sjogrens, lupus

Acute TIN
  • Intersitial edema
  • Cellular infiltrate including eosinophils
  • Invasion of tubules resembling acute rejection
  • Tubular cell proliferation

  • 20 yo Hispanic female presenting with
    pre-eclampsia, found to have creatinine of 5
    mg/dL and BUN 80 mg/dL
  • Renal ultrasound with small kidneys despite
  • Renal biopsy after delivery reveals diffuse
  • Patient noted a significant history of recurrent
    pyelonephritis as a child and young adult?
    treated in Mexico

Chronic TIN
  • Primary idiopathic TIN
  • (EBV)
  • Secondary causes
  • Chronic pyelonephritis without reflux
  • Reflux nephropathy with focal glomerulosclerosis
  • Due to anomalies in vesicoureteral junction
    (incompetent valves)? recurrent UTI/pyelo
  • Stage 1-5 based on voiding cystourethrogram
  • Dxd in 20-35 infants after first UTI? 35-45
    siblings VUR
  • Xanthogranulomatous (lipid-laden macrophages
    hence the term xantho-, which means yellow in
    ancient Greek) degeneration, FSGS with nephrotic
  • Surgery reduces rate of acute pyelo but does not
    change outcome

  • 55 yo caucasian female with history of chronic
  • Referred to nephrology clinic for CKD, creatinine
    3.8 mg/dL
  • Mild HTN, no DM, no family history of kidney
  • Notes significant history of motrin/advil use?
    800 mg to 1.2gm per day for past 30 years
  • UA bland, trace proteinuria, 4-5 WBCs, no red
  • Renal U/S with smaller than expected kidneys (8
    cm on Right and 8.3 cm on left)

Chronic TIN
  • Analgesic nephropathy
  • More common in women 61
  • Decreased urinary concentrating ability,
    acidification defects, sterile pyuria, low-grade
    proteinuria, hypertension, anemia
  • Decreased renal volume, increased papillary
    calcification, bumpy contours
  • Increased risk of transitional cell cancer
  • Classically phenacetin, aspirin and caffeine
  • Usually presents after years of use

interstitial scarring (represented by the green
staining of collagen) and tubular atrophy with no
significant cellular infiltrate. This cortical
change was associated with medullary scars
secondary to papillary necrosis (Masson trichrome)
Chronic TIN
  • Analgesic nephropathy- primarily effects medulla
  • ASA associated with decrease in GFR in patients
    on low sodium diet and elderly ? no long term
    association with IN
  • Acetaminophen is metabolized by prostaglandin H
    pathway? uses glutathione? NSAIDs and ASA deplete
    glutathione? reactive acetaminophen metabolites ?
    O2free radicals, hydroxyl radicals and lipid
    peroxides damage renal tissue
  • NSAIDs, ASA, Cox2 inhibitors ? inhibit renal
    prostaglandin production? medullary
    vasoconstriction? ischemia and papillary necrosis

Region or Organ O2 Delivery ml/min/100 g Blood Flow Rate ml/min/100 g O2 Consumption ml/min/100 g O2 Consumption/O2 Delivery ()
Hepatoportal 11.6 58 2.2 18
Kidney 84.0 420 6.8 8
Renal outer medulla 7.6 190 6.9 79
Brain 10.8 54 3.7 34
Skin 2.6 13 0.38 15
Skeletal muscle 0.5 2.7 0.18 34
Heart 16.8 87 11.0 65
  • 49 yo caucasian female with history of bipolar
    disorder admitted with ESRD now requiring
  • No family history of kidney disease
  • Significant history of lithium use to control
    symptoms, stopped by psych when eGFR was around
    20 ml/min/1.72 m2
  • No DM, HTN controlled
  • UA bland, 100 mg/dL protein, 4-6 WBCs

Chronic TIN
  • Lithium induced TIN
  • Lithium is reabsorbed by tubules at same sites as
  • Microcyts formation? cystic dilatation of distal
  • Rarely causes nephrotic syndrome
  • Causes NDI , distal RTA and chronic TIN
  • Chronic TIN is most common pathologic finding
  • Mechanism unknown
  • Patients with FSGS on bx and creatgt2.0 progress
    to ESRD
  • Patients with minimal change disease and
    creatlt2.0 achieve remission upon withdrawal of
  • Amiloride blocks distal reabsorption of Na and
    attenuates NDI

  • 57 yo Hispanic male with history of ESRD
    secondary to DN s/p DDRT 7 years ago
  • Baseline creat 1.2 2008? 2.0 2010? 3.9 2012
  • Meds included cellcept, tacrolimus and prednisone
  • Renal biopsy reveals CAN and fibrosis

Chronic TIN
  • Calcineurin inhibitor toxicity
  • Acute is reversible by dose adjustment or
  • Chronic use associated with TIN
  • 20 of nonrenal transplants? more typical with
    high dose therapy
  • Insidious development of decrease in GFR
    increased BP
  • Metabolic acidosis, hyperkalemia, hypercalciuria,
    hypophosphatemia, hyperuricemia and

Chronic TIN
  • Chronic afferent arteriolar vasoconstriction?
    glomerular ischemia
  • RAS, TGF-b, osteopontin? interstitial fibrosis
  • Afferent arteriolar hyalinosis, vacuolization of
    tubular epithelium and tubular atrophy
  • ACEI may lessen interstitial fibrosis
  • Fish oil, CCblockers, pentoxifylline not

Chronic TIN
  • Anti-retrovirals
  • Drugs are transported into PT via OAT1
  • Cidofovir- PT mitochondrial damage
  • ATN with enlarged tubule mitochondria
  • 12 proteinuria, 16 metabolic acidosis, fanconi
  • Probenecid minimizes toxicity?possible txt
  • Adefovir- PTC mitochondrial damage
  • ATN with enlarged tubule mitochondria
  • ARF and Fanconi syndrome in dosesgt60mg/d, 10
    with TIN
  • Tenofovir- usually in conjunction with ritonovir
    (inhibits its secretion)
  • ATN and Fanconi syndrome
  • PTC necrosis with enlarged dystrophic nuclei

Chronic TIN
  • Lead nephropathy
  • Accumulation of filtered lead, particularly by S3
    segment? direct tubulotoxic effect and
    interstitial fibrosis? hypertension and
  • Acid-fast intranuclear inclusions of PTC in acute
  • Focal tubular atrophy, interstitial fibrosis,
    minimal infiltrate

Chronic TIN
  • Lead nephropathy
  • Decreased urate excretion, type IV RTA early?
    progressive renal failure and hypertension late,
  • recurrent Saturnine gout - inhibiting effect of
    lead on the tubular urate transport?
    hyperurcemia? more frequent attacks in knees, no
    tophi, polyarticular) Saturn was a demonic god, a
    gloomy and sluggish figure who ate his own
    children. The Romans noticed similarities between
    symptoms of this disorder and the irritable god,
    and named the disease after him.
  • gt90 of body lead resides in bones? serum levels
    not useful in chronic disease
  • EDTA mobilization test with (72 hrs if with CKD)
    urinary lead excretion measurement? gt600mcg is
  • EDTA chelation useful in mild-moderate renal
    failure and in decreaseing gouty attack
  • Not useful in reversing advanced lead nephropathy

Chronic TIN
  • Multiple Myeloma- 50 develop renal disease
  • Light chain toxicity? direct tubular toxicity or
    intrarenal obstruction from cast formation.
    Predisposing factors
  • Volume depletion Hypercalcemia
  • Contrast media light chain isoelectric
    point concentration
  • Acidic intraluminal pH tubular concentration
    of sodium/Ca
  • AKI from light-chain deposition as tubular casts
  • Tubular casts surrounded by multinucleated giant
    cells, interstitial infiltrate of
    monocytes/plasma cells, interstitial fibrosis,
    tubular atrophy

  • 55 yo admitted with blast crisis, diagnosed with
  • Also on admission noted to have AKI with
    creatinine of 4 mg/dL
  • UA with many wbcs and mod proteinuria
  • U/S shows bilaterally enlarged kidneys
  • Patient started on chemo therapy after hydration,
  • Renal function slowly improved after cancer
    responded to therapy

Chronic TIN
  • Lymphoproliferative disorders (non-Hogkins
  • AKI from rapid increase in interstitial pressure
    with cell infiltrate
  • Chronically, tubular atrophy
  • Diffuse lymphocytic infiltration of the
    interstitium, preserved glomerular architecture
  • ARF with proteinuria and enlarged nodular kidney
  • Treatment with chemo or radiation improves renal

Chronic TIN
  • Sarcoidosis
  • Increased production of 1-a hydroxylase from
    activated mononuclear cells? increased 1,25-VitD3
    and hypercalcemia
  • Tissue infiltration with activated T cells (CD-4)
    ? IL-2, IFNg
  • Noncaseating granulomatous interstitial
    nephritis classic
  • Hypercalcemia present in 20 of patient
  • Calcium oxalate nephrolithiasis,
    nephrocalcinosis50 CIN
  • Corticosteroid therapy for 6 months ? inhibits
    macrophage activity
  • Chloroquine, decreases 1,25 VitD3

Chronic TIN
  • Sjogren syndrome
  • B-cell hyperactivity with ANA and immune
  • Lymphocytic infiltration of epithelial lacrimal
    and salivary glands
  • Chronic interstitial nephritis with Tcell
  • Glomerular lesions can occur
  • Distal RTA 5, NDI in 13, hypokalemia with renal
    K wasting
  • CIN occurs early (first 2-4 years) and responds
    to steroids
  • RTA rarely responds to therapy

Chronic TIN
  • Hypokalemia (Klt3.0)
  • Can lead to NDI, renal cyst formation and CIN
  • Increased ammoniagenesis from K depletion may
    induce renal tubular injury by interstitial
    complement activity
  • Stimulate Insulin-like growth factor1 and
    TGF-b?chemotaxis of inflammatory cells and
  • Intersitial fibrosis, medullary cysts, tubular
  • Reversible during first few months (txt of
    primary hyperaldosteronism)

Chronic TIN
  • Hypercalcemic nephropathy
  • Associated with NDI, RTA, kidney stones, AKI and
  • Chronic hypercalcemia leads to intersitial
    calcification, tubular cell necrosis, tubular
    atrophy and interstitial fibrosis, mainly in the
  • NDI due to decreased medullary solute gradient
    and predominantly due to impaired hydro-osmotic
    effect of ADH
  • ARF from renal arterial vasoconstriction and
    volume contraction
  • CIN associated with polyuria, salt wasting,
    calcium oxalate stones and distal RTA (chronic
  • Early correction is key in treatment

Chronic TIN
  • Urate nephropathy
  • AKI in tumor lysis syndrome
  • Deposition of urate crystals in medullary
    interstitium ? secondary chronic inflammatory
    response? interstitial fibrosis
  • Birefringent uric acid crystals in tubules and
  • AKI with oligoanuria, UAgt15 and uric acid urine
    to serum ratiogt1
  • Chronic toxicity presents with HTN, mild
    proteinuria, mild CKD, decreased urinary
    concentrating ability and bland urine sediment

Deposition of uric acid crystals in the
interstitium, forming tophi with surrounding
foreign body inflammation, mononuclear cell
infiltrates, and fibrosis. The long,
needle-shaped crystals form the pale mass shown
here at high magnification.
pale yellowish tan tophaceous deposits in the
  • 24 yo female with history of end stage renal
    disease on hemodialysis
  • Diagnosed with this disease at the age of 2 after
    failure to thrive
  • Became dialysis dependent by the age of 15
  • Has thyroid, cornea, neurologic, GI issues among
    multiple other medical problems
  • Poorly compliant with Cystagon therapy
  • Status post failed renal transplant

Chronic TIN
  • Cystinosis
  • Heterozygotes demonstrated by Schneider et al
  • Autosomal recessive caused by mutation of CTNS?
    abnormal cystinosin? impairs cystine transport
    from lysosomes
  • Hexagonal birefringent cystine crystals present
    in urine, cornea, liver, spleen, LN, kidneys
    etc?extrarenal features such as photophobia and
  • Proximal tubules have swan-neck deformity and
    later develop CIN, Fanconi syndrome? ESRD
  • Cystine deposits in the mesangium and
    interstitial tissue
  • Diagnosed by measuring cystine in peripheral
    blood leukocytes
  • Fanconi syndrome by age 6-12 months?
    hypophosphatemia and polyuria
  • Cysteamine binds cystine in lysosomes and
    transports it? need oral and eye drops

Chronic TIN
  • Dent disease
  • X-linked recessive disorder of proximal tubule?
    Fanconi syndrome, nephrolithiasis,
    nephrocalcinosis, rickets and progressive CKD
  • Mutation in CLC5 chloride channel protein?
    proximal tubule endosomal function is inhibited?
    Fanconi syndrome
  • Hypophosphatemia rickets in 25 males, CIN and
    nephrocalcinosis at early age 75 and ESRD by age
  • Treat with low salt diet and thiazide, amiloride,
    citrate, oral phos and vitaminD, renal txplant

Chronic TIN
  • Radiation nephritis
  • Patients receiving gt1500-2500 rads to kidney?
    endothelial cell injury and swelling with
    eventual vascular occlusion and chronic ischemic
  • Also direct tubular cell injury? chemo may
    potentiate effect
  • Acute radiation nephritis occurs 6-12 months
    after with progressive renal failure,
    proteinuria, renin mediated HTN, edema and occ
  • Chronic nephritis occurs between 18 months-years
    later with proteinuria, progressive CKD and HTN

Chronic TIN
  • Inflammatory bowel disease
  • Acute and chronic IN can occur with IBD
  • AIN associated with ASA
  • Enteric hyperoxaluria is a possible cause of CIN
  • CIN can occur in Crohn without ASA exposure
  • ASA associated CIN occurs in 1/500
  • On path? CIN without hypokalmic changes or
    calcium oxalate deposition
  • Proteinuria lt2gm and urine bland sediment
  • ASA withdrawal?CIN unrelated to ASA progresses to
  • Also may develop MPGN and amyloid

  • 50 yo Caucasian from former Yugoslavia,
  • First time in your clinic, notes a longstanding
    history of CKD which he believes runs in his
  • No HTN or DM
  • His father died of transitional cell CA
  • Creatinine 2.8 mg/dL, Hgb 8.0 g/dL
  • UA bland, 1.5 gm proteinuria/day
  • U/S shows medical renal disease
  • Serologic work up negative

Chronic TIN
  • Balkan endemic nephropathy- first recognized,
    Dimitrov et al 1950s
  • Accounts for up to 10 of ESRD in specific
    region, mostly farmers
  • No specific causative agent? ? Environmental
  • Slowly progressive TIN, b2macroglobulinuria and
    progressive renal failure
  • Anemia out of proportion to renal failure,
  • Urothelial tumors occur up to 100 times more
    frequently and bilateral in 14 of cases

Chronic TIN
  • TIN with uveitis- first described in 1975
  • Presents in adolescence and young adults as AKI
    (31 female predom)
  • Uveitis can develop after(65), before or
    concurrent (35) with renal failure
  • Associated with ANCA, EBV and chlamydial
  • Peripheral smear with increased number of B cells
    without Tcell abn
  • Eosinophilia, ESR, with neg serologic tests
    (main differential sarcoidosis)
  • Present with fever, anemia and asthenia, wt loss,
    fatigue, eye redness
  • Uveitis of anterior chamber, Fanconi syndrome,
    distal RTA and NDI
  • Spontaneously remits over 1 year without therapy
    in young adults
  • Adults require systemic steroids, uveitis relapses

uveitis associated with TINU is mostly
Chronic TIN
  • Ifosfamide toxicity
  • Metabolites chloracetaldehyde or acrolein?
    glutathione depletion
  • Proximal tubule dysfuction?hypophos, met acid,
    hypokalemia, renal failure
  • Cadmium (Europa, daughter of the King of
    Phoenicia, who was abducted by a traveling bull
    and from whom Europe gets it name. Cadmus, her
    brother, was sent by his father to find her)
  • Prolonged low-level exposure? contaminated foods,
    cigarettes, work
  • Causes cellular toxicity after being pinocytosed
    by PTC? hypercalciuria and nephrolithiasis
  • Associated with bone disease, cancer, lung

  • 40 yo Asian female with no past medical history
    referred to you for worsening creatinine.
  • Denies HTN or DM
  • No past medical history
  • No meds except for Chinese herbs
  • Creat 3.0
  • UA bland, trace protein, U/S with medical renal
  • Renal biopsy with fibrosis and no interstitial

Chronic TIN
  • Chinese herb nephropathy
  • 1991 Belgian physicians noted increasing number
    of women with acute, near end stage renal failure
    after exposure to Chinese herbs at weight
    reduction clinics? chronic TIN on biopsy
  • Cortical extensive interstitial fibrosis with
    atrophy and loss of tubules
  • Endothelial cell swelling? thickening of afferent
    and interlobular arteriole? primary insult in
    vessel wall? ischemia? fibrosis, Cellular
    infiltrate rare

Chronic TIN
  • Aristolochia fangchi substituted for Stephania
    tetranda? Aristocholic acid exposure which is
    toxic and carcinogenic
  • Upper tract urothelial tumors in 50 of patients
  • Present with anemia, proteinuria and normotension
  • Prednisone in patients with mod renal
    insufficiency may slow rate of progression

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