Medicine Grand Rounds
Hamid Moradi M.D.
Assistant Clinical Professor
Division of Nephrology and Hypertension
Case
 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
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 Creatinine up to 3.4
 Potassium of 5.6
Case
 H/O chronic diarrhea, recent EGD/colonoscopy significant
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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
Case
 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
Case
 FHX:
mother with HTN, died of breast CA at 76
uncle with "heart disease" another uncle with CVA
 SHX:
Patient lives alone in Huntington Beach, was employeed as physical
therapist at Kaiser until recently. Denies tob, EtOH, drugs
 Meds
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ASA
Lasix
Lisinopril
Neurontin
Niacin
Glipizide
Rosiglitazone
Calcium carbonate
Calcitriol
Atenolol
Flunisolide
Case
 Labs
Uric acid 7.8
CPK 128
140
109
86
5.1
20
4.9
LFTs normal
Urine Na 81
217
PSA 4.1
7.1
10
162
30
UA spec grav 1.004, pH 5, glu 70, negative protein, 1 RBC, 3 wbc
Urea 315
Creat 28
Hospital Course
 Admitted foley catheter + IV fluids no change in renal
function
 Ultrasound
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-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 7.1
 10% urine eosinophils
Renal biopsy
Tubulointerstitial
Nephritis
A brief overview
Structure & function
 Tubules and interstitium make up
80% of renal volume
 Cortical interstitium
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Type I interstitial cells resemble
fibroblasts and produce Epo
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Type II interstitial cells monocyte
derived macrophages
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Capable of producing and
degrading ECM
Resemble dendritic cells and
present antigens
Capable of phagocytosis
Interstitial space contains type 1
and 3 collagen
Structure & function
 Medullary interstitium
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Type 1 cells lipid rich cells in inner medulla
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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 collagen
 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 (TIN)
Chronic pyelonephritis is not infectious in origin
 TIN became a category onto itself
Classification
 WHO
Classification
 TIN caused by
primary damage to
tubulointerstitium
vs. secondary process
after damage to
other parts of the
nephron
Epidemiology
 Autopsy study 1.7% of acute renal failure and 0.2% of CKD
 Renal bx study of 109 patients with unexplained renal failure
(GFR<60) 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 >1.6
Pathogenesis
 Direct cytotoxicity
Dependent on dose and duration of exposure
(lead/analgesic)
 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 factor)
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Pathology
 Pattern of response can help define the acuity of process, the
long term prognosis and occasionally etiology of disorder
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Presence of significant inflammatory infiltrate in interstitium
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Structural changes of tubular injury
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If infiltrate present the cell type helps
Sublethal injury to necrosis
Alteration of growth (atrophy, hypertrophy)
Accumulation of cast in tubules
Interstitial changes
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Edema
Leukocytic infiltration
fibrosis
Chronic TIN
 Interstitial infiltrate depending on etiology ie neutrophils,
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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
Case
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20 yo Hispanic female presenting with pre-eclampsia, found to have creatinine
of 5 mg/dL and BUN 80 mg/dL
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Renal ultrasound with small kidneys despite pregnancy
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Renal biopsy after delivery reveals diffuse fibrosis
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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
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Chronic pyelonephritis without reflux
Reflux nephropathy with focal glomerulosclerosis (VUR)
 Due to anomalies in vesicoureteral junction (incompetent valves)
recurrent UTI/pyelo
 Stage 1-5 based on voiding cystourethrogram
 Dx’d in 20-35% infants after first UTI 35-45% siblings VUR
 Xanthogranulomatous (lipid-laden macrophages hence the term
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xantho-, which means yellow in ancient Greek) degeneration, FSGS
with nephrotic syn
Surgery reduces rate of acute pyelo but does not change outcome
Case
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55 yo caucasian female with history of chronic headaches
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Referred to nephrology clinic for CKD, creatinine 3.8 mg/dL
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Mild HTN, no DM, no family history of kidney disease
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Notes significant history of motrin/advil use 800 mg to 1.2gm per day for past
30 years
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UA bland, trace proteinuria, 4-5 WBCs, no red cells
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Renal U/S with smaller than expected kidneys (8 cm on Right and 8.3 cm on
left)
Chronic TIN
 Analgesic nephropathy
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More common in women 6:1
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
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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
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
16.8
87
11.0
65
Renal outer medulla
Heart
Case
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49 yo caucasian female with history of bipolar disorder admitted with ESRD now
requiring dialysis
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No family history of kidney disease
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Significant history of lithium use to control symptoms, stopped by psych when
eGFR was around 20 ml/min/1.72 m2
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No DM, HTN controlled
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UA bland, 100 mg/dL protein, 4-6 WBCs
Chronic TIN
 Lithium induced TIN
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Lithium is reabsorbed by tubules at same sites as sodium
Microcyts formation cystic dilatation of distal tubules
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Causes NDI , distal RTA and chronic TIN
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Rarely causes nephrotic syndrome
Chronic TIN is most common pathologic finding
Mechanism unknown
Patients with FSGS on bx and creat>2.0 progress to ESRD
Patients with minimal change disease and creat<2.0 achieve
remission upon withdrawal of lithium
Amiloride blocks distal reabsorption of Na and attenuates
NDI
Case
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57 yo Hispanic male with history of ESRD secondary to DN s/p DDRT 7 years
ago
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Baseline creat 1.2 2008 2.0 2010 3.9 2012
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Meds included cellcept, tacrolimus and prednisone
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Renal biopsy reveals CAN and fibrosis
Chronic TIN
 Calcineurin inhibitor toxicity
 Acute is reversible by dose adjustment or cessation
 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 hypomagnesemia
Chronic TIN
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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 effective
Chronic TIN
 Anti-retrovirals
 Drugs are transported into PT via OAT1 transporter
 Cidofovir- PT mitochondrial damage
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ATN with enlarged tubule mitochondria
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12% proteinuria, 16% metabolic acidosis, fanconi syn
Probenecid minimizes toxicitypossible txt
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Adefovir- PTC mitochondrial damage
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ATN with enlarged tubule mitochondria
ARF and Fanconi syndrome in doses>60mg/d, 10% with TIN
Tenofovir- usually in conjunction with ritonovir (inhibits its secretion)
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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
hyperuricemia
 Acid-fast intranuclear inclusions of PTC in acute setting
 Focal tubular atrophy, interstitial fibrosis, minimal infiltrate
Chronic TIN
 Lead nephropathy
 Decreased urate excretion, type IV RTA early progressive renal
failure and hypertension late,
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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.
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>90% 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 >600mcg is diagnostic
EDTA chelation useful in mild-moderate renal failure and in
decreaseing gouty attack
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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
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Volume depletion
Hypercalcemia
Hyperuricemia
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
Case
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55 yo admitted with blast crisis, diagnosed with ALL
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Also on admission noted to have AKI with creatinine of 4 mg/dL
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UA with many wbc’s and mod proteinuria
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U/S shows bilaterally enlarged kidneys
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Patient started on chemo therapy after hydration,
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Renal function slowly improved after cancer responded to therapy
Chronic TIN
 Lymphoproliferative disorders (non-Hogkins lymphoma)
 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 function
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, nephrocalcinosis=50% 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 complexes
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Lymphocytic infiltration of epithelial lacrimal and salivary glands
Chronic interstitial nephritis with Tcell infiltrate
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 (K<3.0)
 Can lead to NDI, renal cyst formation and CIN
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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 fibrosis
Intersitial fibrosis, medullary cysts, tubular atrophy
Reversible during first few months (txt of primary hyperaldosteronism)
Chronic TIN
 Hypercalcemic nephropathy
Caption
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Associated with NDI, RTA, kidney
stones, AKI and CIN
Chronic hypercalcemia leads to
intersitial calcification, tubular cell
necrosis, tubular atrophy and interstitial
fibrosis, mainly in the medulla
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 hypercalcemia)
Early correction is key in treatment
Chronic TIN
 Urate nephropathy
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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 interstitium
AKI with oligoanuria, UA>15 and uric acid urine to serum ratio>1
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 medulla.
Case
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24 yo female with history of end stage renal disease on hemodialysis
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Diagnosed with this disease at the age of 2 after failure to thrive
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Became dialysis dependent by the age of 15
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Has thyroid, cornea, neurologic, GI issues among multiple other medical
problems
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Poorly compliant with Cystagon therapy
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Status post failed renal transplant
Chronic TIN
 Cystinosis
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Heterozygotes demonstrated by Schneider et al 1967
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
hypothyroidism
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
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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 30-40
Treat with low salt diet and thiazide, amiloride, citrate, oral phos and vitaminD,
renal txplant
Chronic TIN
 Radiation nephritis
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Patients receiving >1500-2500 rads to kidney endothelial cell injury and
swelling with eventual vascular occlusion and chronic ischemic injury
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 hemolysis
Chronic nephritis occurs between 18 months-years later with proteinuria,
progressive CKD and HTN
Chronic TIN
 Inflammatory bowel disease
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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 <2gm and urine bland sediment
ASA withdrawalCIN unrelated to ASA progresses to ESRD
Also may develop MPGN and amyloid
Case
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50 yo Caucasian from former Yugoslavia,
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First time in your clinic, notes a longstanding history of CKD which he believes
runs in his family
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No HTN or DM
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His father died of transitional cell CA
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Creatinine 2.8 mg/dL, Hgb 8.0 g/dL
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UA bland, 1.5 gm proteinuria/day
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U/S shows medical renal disease
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Serologic work up negative
Chronic TIN
 Balkan endemic nephropathy- first recognized, Dimitrov et al 1950s
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Accounts for up to 10% of ESRD in specific region, mostly farmers
No specific causative agent ? Environmental factors
Slowly progressive TIN, b2macroglobulinuria and progressive renal failure
Anemia out of proportion to renal failure, normotension
Urothelial tumors occur up to 100 times more frequently and bilateral in
14% of cases
Chronic TIN
 TIN with uveitis- first described in 1975
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Presents in adolescence and young adults as AKI (3:1 female predom)
Uveitis can develop after(65%), before or concurrent (35%) with renal failure
Associated with ANCA, EBV and chlamydial infection
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
Uveitis of anterior chamber, Fanconi syndrome, distal RTA and NDI
associat
ed with
Spontaneously remits over 1 year without therapy in young adults
TINU is
mostly
Adults require systemic steroids, uveitis relapses
nongranulo
matous
Chronic TIN
 Ifosfamide toxicity
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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)
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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 disease
Case
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40 yo Asian female with no past medical history referred to you for worsening
creatinine.
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Denies HTN or DM
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No past medical history
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No meds except for Chinese herbs
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Creat 3.0
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UA bland, trace protein, U/S with medical renal disease
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Renal biopsy with fibrosis and no interstitial infiltrate
Chronic TIN
 Chinese herb nephropathy
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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
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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