Dr. Leonid Feldman

Nephrology and Hypertension Division

Assaf Harofeh Medical Center

November, 2007

Dr. Leonid Feldman

Nephrology and Hypertension Division

Assaf Harofeh Medical Center

November, 2007

Tubulointerstitial Kidney DiseaseTubulointerstitial Kidney Disease

Differentiating Glomerular from Tubulointerstitial Renal disease

GlomerularTubulointerstitial

ProteinuriaCommonly > 3 g/24 h

< 1.5 g/24h

RBC morphologyDysmorphicNormal

RBC castsPresentAbsent

Dysmorphic glomerular erythrocytes

Isomorphic non–glomerular erythrocytes

Interstitial edema and mononuclear infiltration

Renal biopsyRenal biopsy

The tubular cell becomes activated by a variety of signals including proteinuria, cytokines, and chemokines resulting in the subsequent

activation of macrophages, lymphocytes, and fibroblasts.

Central role of the tubular epithelial cell in the generation of interstitial infiltrates

Injury to the tubule and peritubular capillary leads to the generation of chemotactic and adhesive factors that result in macrophage and T–cell accumulation. Local macrophage and fibroblast activation ensues, driven by growth factors such as platelet–derived growth factor and TGF-beta, which results in collagen production by tubular cells and fibroblasts, eventually culminating in the fibrotic lesion

Allergic Acute Tubulointerstitial Nephritis

Diagnosis of AIN

• Urinary electrolytes

UNa >40 Meq/L and FENa > 1%

Urine osm < 350• Eosinophiluria

– Absence does not exclude• Gallium-67 scanning

– Very sensitive but not specific• Renal biopsy

– sometimes necessary to differentiate between ATN, RPGN, and atherotrombotic disease and vasculitis

Maculopapular rash in a patient with drug–induced acute interstitial nephritis (AIN)

Such cutaneous lesions occur in about 40% of patients with drug–induced AIN

Drugs Associated with Acute Tubulointerstitial Nephritis

• Common– Antibiotics (penicillins, cephalosporins, sulfa drugs,

rifampin and others)– Nonsteroidal anti-inflammatory drugs of all classes

• Uncommon– Anticonvulsants (phentoin, carbamazepine,

phenobarbital)– Diuretics (thiazides and furosemide)– Other (allopurinol, cimetidine, omeprazole, interferon-

alpha)

Eosinophils in urine sediment are detected with Hansel’s stain

Treatment of Acute Drug-induced TIN

1. Discontinuation of the offending drug – usually results in complete recovery

2. If renal function continues to deteriorate – perform kidney biopsy

3. If biopsy is diagnostic, the institution of steroid therapy should be considered

4. A short course of steroids (60mg prednisone per day for 10 to 14 days) can shorten the course of renal insufficiency and hospitalization

NSAIDs-induced Nephritis

Nonsteroidal antiinflammatory drugs (NSAIDs) whose principal detrimental effect on the kidney is hemodynamic,

due to inhibition of prostaglandin synthesis,

cause an acute deterioration of renal function by causing a distinctive form of TIN.

NSAIDs and the Kidney

• Acute Renal Failure• Ischemic acute tubular necrosis• Acute interstitial nephritis (AIN)• AIN plus minimal change nephropathy• ARF plus bilateral flank pain• Sodium and water retention• Hyperkalemia• CRF with papilary necrosis

Histological Appearance of NSAID-TIN

• Diffuse or focal lymphocytic infiltrate• Eosinophils – very rare, few in number• Glomeruli: Minimal change pattern• Occasionally glomerulosclerosis (may be age

related)

• Non specific IF: variable IgG and C3 along TBM

• EM: diffuse foot process fusion

NSAID-induced Tubulointerstitial Nephritis (TIN) vs Typical Drug induced-TIN

Characteristic NSAID-induced TIN Typical Drug induced TIN

Duration of Exposure

5 days to > 1yr 5-26 days

Hypersensitivity symptoms

7-8% 80%

Eosinophilia 17-18% 75-80%

Nephrotic-range Proteinuria

>90% <10%

Eosinophiluria 0-5% 80-85%

Peak S Cr. 1.5->10 mg/dl 3.7->10 mg/dl

Comparison of Clinical Features of -Lactam and NSAID-associated Acute Interstitial Nephritis

-Lactam NSAIDs No of cases 153 36 Age (yrs) Any 64.6+/-2.1 Male:Female 3:1 1:2 Duration of therapy 15 days 5.4 m Fever, rash, eosinophilia 80% 19% Eosinophiluria 83% 13% Nephrotic syndrome <1% 83% Requirement for dialysis 17% 36% Agent most commonly responsible

Methicillin (65%)

Fenoprofen (61%)

-Lactam NSAIDs No of cases 153 36 Age (yrs) Any 64.6+/-2.1 Male:Female 3:1 1:2 Duration of therapy 15 days 5.4 m Fever, rash, eosinophilia 80% 19% Eosinophiluria 83% 13% Nephrotic syndrome <1% 83% Requirement for dialysis 17% 36% Agent most commonly responsible

Methicillin (65%)

Fenoprofen (61%)

Clinical Course of NSAID-TIN

Spontaneous remission after withdrawal of NSAID. Time to recovery and resolution varies from a few

days to several weeks. Occasionally dialytic support may become necesarry Steroids have been used in some patients but cannot

be generally recommended Relapses have occurred on inadvertent re-exposure

to the same drug

TINU syndrome: TIN with Uveitis

First described by Dobrin in 1975

F:M=3:1

Age of onset 9-74 years (median 15 years)

Uveitis can develop prior to, concurrently, or after TIN

TINU syndrome - systemic features

Fever (53%)

Weight loss (47%)

Fatigue, malaise (44%)

Flank or abdominal pain (28%)

Arthralgia, myalgia ( 17%)

Polyuria, nocturia (8%)

TINU syndrome - ocular features

Bilateral (77%) Eye pain and redness (77%) Decreased vision (20%) Photophobia (14%)

Symptoms

Signs

Anterior uveitis (80%) Posterior uveitis (20%)

TINU syndrome-course and prognosis

Uveitis recurrences (41%)

Good visual prognosis (80% or better)

Renal disease resolves spontaneously or with steroid therapy.

Few patients require dialysis

TINU syndrome - treatment

Systemic corticosteroids for progressive renal failure

Topical/periocular steroids

Immunosuppressive agents

Sarcoidosis

• Classic lesion – noncaseating granulomatous interstitial nephritis

• Clinical features: hypercalcemia in 20%, Ca Oxalate nephrolithiasis

Sarcoidosis

Hereditary Cystic Kidney Diseases

Hereditary Cystic Kidney Diseases

Multiple Myeloma Related Renal DiseaseMultiple Myeloma Related Renal Disease

• Types of Renal Disease– Myeloma kidney, cast nephropathy (light chains deposition

causing tubular injury and intratubular cast formation and interstitial fibrosis)

– Light chain deposition disease (tubular dysfunction such as Fanconi syndrome)

– Hypercalcemia-induced renal disease– Amyloidosis

• The presence of a negative dipstick reaction for protein but positive sulfosalicylic acid reaction is characteristic of Bence-Jones proteinuria

Dr. Watson sent urine sampleto a 31-year-old physician, at St. George's Hospital, London, Dr. Henry Bence Jones

Saturday, November 1, 1845Dear Dr. Jones, The tube contains urine of very high specific gravity; when cooled it becomes highly opaque, heat reliquifies it. What is it?

Dr. Bence Jones calculated that the patient excreted 67 gm of protein, specifically ‘hydrated deutoxide of albumin’. Jones emphasized its role in the diagnosis of Multiple Myeloma. Thus, ‘Bence Jones protein’ was discovered.

Analgesic Np: paracetamol, aspirin,caffein ± codeine

Classic Analgesic Nephropathy High prevalence among women (2-6 X higher)

Mean age 53

Cumulative consumption of 2-3 Kg of the index drug

Addictive and dependent behavior Anemia: GI Blood loss and renal insufficiency CAD, RAS, HTN Uroepithelial tumors Typical time course is 5 yrs

Classic Analgesic Nephropathy High prevalence among women (2-6 X higher)

Mean age 53

Cumulative consumption of 2-3 Kg of the index drug

Addictive and dependent behavior Anemia: GI Blood loss and renal insufficiency CAD, RAS, HTN Uroepithelial tumors Typical time course is 5 yrs

Radiological signs of analgesic nephropathy:

(1) normal calyx;

(2) swollen papilla and calyceal blunting;

(3) partial papillary necrosis, central cavity, and fistula formation;

(4) complete papillary necrosis—ring shadow;

(5) papillary necrosis in situ ;

(6) sequestrated papilla with ureteral occlusion;

(7) 'wavy' outline of the kidney by homogeneously thinned cortex with indentations over the necrotic papillae

(8) urothelial-cell carcinoma

Papillary necrosis.

Autopsy macroscopic appearance of papillary necrosis in a patient with long–standing analgesic nephropathy

1. analgesic nephropathy

2. diabetic nephropathy 3. obstructive uropathy 4. reflux nephropathy

5. sickle-cell nephropathy.

Differential diagnosis of renal papillary necrosis :

Classical Analgesic Nephropathy vs. NSAID Nephropathy

Characteristic Analgesic Nephropathy

NSAID-induced CRF

Age 62 69

F:M ratio 5.8:1 0.9:1

Papillary Necrosis (%)

90 34

CrCl (<20) (%) 20-40 5

UTI 22-34% 2

Pelvic Ca 13-40% 0

Anemia (%) 13 6

Characteristic Analgesic Nephropathy

NSAID-induced CRF

Age 62 69

F:M ratio 5.8:1 0.9:1

Papillary Necrosis (%)

90 34

CrCl (<20) (%) 20-40 5

UTI 22-34% 2

Pelvic Ca 13-40% 0

Anemia (%) 13 6

Reflux Nephropathy

Urate Nephropathy

Uric acid crystals. This rhomboid shape is the most frequent

Urate Nephropathy

Urate Nephropathy

Lead nephropathy

• Chr. Tubulointerstitial Nephritis

• Sources of Lead: paints, electric batteries, weapon firing, illegally distillated alcohol

• Hyperuricemia ( enhanced reabsorption of urate)

• Gout (very unusual in other forms of CKD)

• Hypertension

• Slowly progressive renal failure

Lead nephropathy

Lithium nephropathy

• Chr. Tubulointerstitial Nephritis

• Nephrogenic Diabetes Insipidus

• Tubular Cysts

• May progress to ESRF

• Treatment:

1. Withdrawal of Li

2. Amiloride – blocks distal tubular RLi, attenuates NDI

Sjogren syndrome

• autoimmune disease with lymphocytic infiltration of salivary and lacrimal glands and autoantibody production

• Chr. TIN – early, within 2-4 years

• Chr. GN – late, after 8-10 years

• Distal RTA, Hypokalemia ( renal wasting)

• NDI – 13%

• Corticosteroids help for TIN, not effective for GN, RTA

Radiation Nephritis

Radiation Nephritis

Difference of Chr. TIN from Chr. GN

1. Hypertension is less common

2. Proteinuria < 1.5 g/day

3. Urinary sediment is bland: few RBC, WBC, casts are rare

4. Anemia is disproportionately severe ( damage of EPO-producing cells)

5. RTA ( non-anion gap)

6. Papillary necrosis ( analgesics)

7. Kidney Stones

8. Nephrogenic Diabetes Insipidus

Thank you