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

2. 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 
Creatinine up to 3.4
Potassium of 5.6

3. Case
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

4. Case PSH: 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 /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

5. Case mother with HTN, died of breast CA at 76 FHX: SHX: Meds
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
ASA
Lasix
Lisinopril
Neurontin
Niacin
Glipizide
Rosiglitazone
Calcium carbonate
Calcitriol
Atenolol
Flunisolide

6. Case 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 Urea Creat 28 10
140
109 86
7.1
217
162
5.1 20
4.9 30

7. 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

8. Hospital course 10% urine eosinophils
Differential on CBC13% eosinophils of WBC count 7.1
10% urine eosinophils

9. Renal biopsy

10. Tubulointerstitial Nephritis
A brief overview

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

12. 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 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

13. Historical background
1898 Councilman used term AIN

14. 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 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

15. Classification
WHO

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

17. 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

18. 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)

19. Pathology
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

20. 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

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

22. Case
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 pregnancy
Renal biopsy after delivery reveals diffuse fibrosis
Patient noted a significant history of recurrent pyelonephritis as a child and young adult treated in Mexico

23. Chronic TIN Primary idiopathic TIN (EBV) Secondary causes
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 xantho-, which means yellow in ancient Greek) degeneration, FSGS with nephrotic syn
Surgery reduces rate of acute pyelo but does not change outcome

24. Case 55 yo caucasian female with history of chronic headaches
Referred to nephrology clinic for CKD, creatinine 3.8 mg/dL
Mild HTN, no DM, no family history of kidney disease
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 cells
Renal U/S with smaller than expected kidneys (8 cm on Right and 8.3 cm on left)

25. Chronic TIN Analgesic nephropathy 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)

26. 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
Heart
16.8 87
11.0 65

27. Case
49 yo caucasian female with history of bipolar disorder admitted with ESRD now requiring dialysis
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

28. Chronic TIN Lithium induced TIN
Lithium is reabsorbed by tubules at same sites as sodium
Microcyts formation cystic dilatation of distal tubules
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 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

29. Case
57 yo Hispanic male with history of ESRD secondary to DN s/p DDRT 7 years ago
Baseline creat  
Meds included cellcept, tacrolimus and prednisone
Renal biopsy reveals CAN and fibrosis

30. 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

31. 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 effective

32. Chronic TIN Anti-retrovirals
Drugs are transported into PT via OAT1 transporter
Cidofovir- PT mitochondrial damage
ATN with enlarged tubule mitochondria
12% proteinuria, 16% metabolic acidosis, fanconi syn
Probenecid minimizes toxicitypossible txt
Adefovir- PTC mitochondrial damage
ARF and Fanconi syndrome in doses>60mg/d, 10% with TIN
Tenofovir- usually in conjunction with ritonovir (inhibits its secretion)
ATN and Fanconi syndrome
PTC necrosis with enlarged dystrophic nuclei

33. 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

34. 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.
>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
Not useful in reversing advanced lead nephropathy

35. 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 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

36. Case 55 yo admitted with blast crisis, diagnosed with ALL
Also on admission noted to have AKI with creatinine of 4 mg/dL
UA with many wbc’s 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

37. 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

38. 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

39. Chronic TIN Sjogren syndrome
B-cell hyperactivity with ANA and immune complexes
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

40. Chronic TIN Hypokalemia (K<3.0)
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 fibrosis
Intersitial fibrosis, medullary cysts, tubular atrophy
Reversible during first few months (txt of primary hyperaldosteronism)

41. Chronic TIN Hypercalcemic nephropathy Caption
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
Caption

42. 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 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.

43. Case
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

44. Chronic TIN Cystinosis
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

45. 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 30-40
Treat with low salt diet and thiazide, amiloride, citrate, oral phos and vitaminD, renal txplant

46. Chronic TIN Radiation nephritis
Patients receiving > 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

47. 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 <2gm and urine bland sediment
ASA withdrawalCIN unrelated to ASA progresses to ESRD
Also may develop MPGN and amyloid

48. Case 50 yo Caucasian from former Yugoslavia,
First time in your clinic, notes a longstanding history of CKD which he believes runs in his family
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

49. 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 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

50. Chronic TIN TIN with uveitis- first described in 1975
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 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 non-granulomatous

51. 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 disease

52. Case
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 disease
Renal biopsy with fibrosis and no interstitial infiltrate

53. 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

54. 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