Dr. Leonid Feldman Nephrology and Hypertension Division Assaf Harofeh Medical Center November, 2007 Tubulointerstitial Kidney Disease

Differentiating Glomerular from Tubulointerstitial Renal disease TubulointerstitialGlomerular < 1.5 g/24hCommonly > 3 g/24 h Proteinuria NormalDysmorphicRBC morphology AbsentPresentRBC casts

Dysmorphic glomerular erythrocytes Isomorphic non–glomerular erythrocytes

Interstitial edema and mononuclear infiltration Renal 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 U Na >40 Meq/L and FE Na > 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.

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 C 3 along TBM EM: diffuse foot process fusion

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

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

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

Multiple 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 sample to a 31-year-old physician, at St. George's Hospital, London, Dr. Henry Bence Jones Saturday, November 1, 1845 Dear 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

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

Reflux Nephropathy

Urate Nephropathy

Uric acid crystals. This rhomboid shape is the most frequent

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 R Li, 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

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