1. Interstitial Renal Diseases
Ali M Shendi Mohamed, MSc MD
Lecturer of Nephrology, Zagazig University
ISN Fellow

2. Agenda Background Acute Interstitial Nephritis
Chronic Interstitial Nephritis
Malignant Interstitial Infiltration.

3. Quiz 1- Skin rash occurs in more than 50 % of AIN cases.
2- Esinophiluria is of high sensitivity for diagnosing AIN.
3- Kidney biopsy should not be done for all patients with putative drug-induced AIN
4- In drug-related AIN Steroid treatment is a mainstay of therapy.
5- In AIN, the severity of renal failure is more of prognostic relevance than its duration..
6- Strong immunosuppression is a rescue therapy for Chronic Interstitial Nephritis.

4. Agenda Background Acute Interstitial Nephritis
Chronic Interstitial Nephritis
Malignant Interstitial Infiltration.

5. Normal cortex in a renal biopsy specimen
Normal cortex in a renal biopsy specimen. Adjacent tubular basement membranes are in almost direct contact with one another and separated by a small amount of connective tissue known as the interstitium, which contain peritubular capillaries.

6. Tubules and interstitial tissues are often considered as a unit  tubulo-interstitial disorders. Renal excretory function has more correlation with structural changes in tubules, than with any other structural change in the kidney.

7. Agenda Background Acute Interstitial Nephritis
Chronic Interstitial Nephritis
Malignant Interstitial Infiltration.

8. ACUTE INTERSTITIAL NEPHRITIS

9. Primary Sjögren’s syndrome with distal renal tubular acidosis
Case 1
A 32 year-old female presented with recurrent episodes of acute paralysis.
Lab: sever hypokalemia; normal anion gap metabolic acidosis; urine pH: 7.0; positive SSA/SSB and abnormal sialoscintigraphy.
KUB: bilateral nephrocalcinosis.
Primary Sjögren’s syndrome with distal renal tubular acidosis
Chen Y-M, et al. Joint Bone Spine (2014),

10. Kidney Biopsy was done…….. Drug-induced Acute Interstitial Nephritis
Case 2
68-year-old man with fever and a cutaneous infection of the right elbow.
WBCs: 20,000/mm3, with 88% polymorphonuclear leukocytes.
S Creatinine: 0.9 mg/dL.
Blood cultures were positive for Staphylococcus aureus, and treatment with methicillin (12 g/day) was initiated.
After 12 days: fever resumed, renal function deteriorated (creat: 3.6 mg/dL). The white blood cell count was 12,000/mm3, with 12% eosinophils.
Urinalysis: macroscopic hematuria and 200 white cells/mm3. Proteinuria was 1 g/day.
Kidney Biopsy was done……..
Drug-induced Acute Interstitial Nephritis
Rossert. Kidney International, 60 (2001), 804–817

11. Acute interstitial nephritis (AIN) is a renal lesion that causes a decline in creatinine clearance and is characterized by an inflammatory infiltrate in the kidney interstitium.

12. Under diagnosed cause of AKI
Epidemiology
Under diagnosed cause of AKI
% of cases of AKI.
Unrecognized AIN is the third most common cause of hospital-acquired AKI after prerenal AKI and acute tubular necrosis (ATN).

13. Prevalence of AIN in patients with acute kidney injury
Prevalence of AIN in patients with acute kidney injury. AIN = acute interstitial nephritis.
Pirazella. Clin Nephrol Jun; 81(6): 381–388.

14. ETIOLOGY 

15. What causes AIN ? 1- Drugs (antibiotics: 30 to 49 %) – 70 - 75 %
2- Infections – %
3- Tubulointerstitial nephritis and uveitis (TINU) syndrome – %
4- Systemic disease – %

16. Any drug can cause AIN 1- Drugs: 1- NSAIDs.
2- Antimicrobial agents (β-lactams, sulfonamides, quinolone more with Ciprofloxacin, anti-viral agents (Indinavir), Rifampin, Vancomycin)
3- Diuretics, loop and thiazide-type diuretics
4- anti-ulcer agents (PPIs ‘omeprazole and lansoprazole’, H2-antagonists (Cimetidine (rarely with others ‘ranitidine’)
5- Allopurinol
6- Anti-convulsants (e.g. Phenytoin).
7- 5-aminosalicylates (eg mesalamine)
Any drug can cause AIN

17. 2- Infections Multiple organisms have been associated with AIN:
* Legionella, Leptospira, Streptococcus, Mycobacterium tuberculosis, Corynebacterium diphtheriae, Yersinia, Enterococcus, E coli
* CMV, Epstein-Barr virus (EBV), adenovirus, polyomavirus, Candida, and others.
Immune-mediated mechanism Vs direct invasion (Adenovirus, Leptospira, CMV…)….

18. 3- Systemic disease 1- SLE 2- sarcoidosis 3- Sjögren's syndrome
4- granulomatosis with polyangiitis (Wegener’s)
In SLE and GPA: AIN rarely present in the absence of glomerular disease.
5- Relatively rare causes of AIN:
1-Immunoglobulin G4 (IgG4)-related disease
2- Hypocomplementemic tubulointerstitial nephritis
3- anti-tubular basement membrane (TBM) antibodies.

19. Pathophysiology

20. AIN is immunologically mediated through antigen-driven immunopathology…….
This hypothesis is supported by: 1- Drug-induced AIN is idiosyncratic (not dose dependent and recur with 2nd exposure). 2- Eosinophils in the renal biopsy 3- Signs of a systemic hypersensitivity reaction. 4- An interval of 7–10 days typically exists between drug exposure and development of AKI.
Perazella and Markowitz. Nat. Rev. Nephrol. 6;(2010), 461–470

21. Rossert. Kidney International, 60 (2001), 804–817

23. The central component of renal injury is altered tubular function preceding decrements in filtration rate…

24. Clinical Picture

25. AIN should be considered in any patient with unexplained AKI
Many are asymptomatic.
Nonspecific:
1- Fever (27%)
2- Nausea, vomiting, anorexia
3-Generalized malaise
4-Myalgias and arthralgias
5-Flank pain
6- Pruritic skin rash (15%) – with drugs cause hypersensitivity reaction-
Oliguria
Gross hematuria (approximately 5 % ).
Usually non significant proteinuria. Nephrotic syndrome in <1 %

26. Features related to the cause of the AIN:
1- Patients with drug-induced AIN:
The onset follows drug exposure from days (as with a second exposure) to several weeks to many months (as following a first exposure).
The latent period may be as short as one day with rifampin, or as long as 18 months with an NSAID
May be difficult to identify the culprit drug

27. 2- Features related to an associated infection or systemic condition such as SLE, sarcoidosis, and Sjögren's syndrome. 3- Tubulointerstitial nephritis and uveitis (TINU) syndrome: Most patients with TINU are adolescents and young women, with a median age of 15 years. Interstitial nephritis, Uveitis and occasionally systemic findings.

28. Investigations

29. 1- Increased plasma Creatinine
2- Eosinophilia and eosinophiluria
Eosinophiluria: eosinophils that account for more than 1% of urinary white cells.
Eosinophiluria lack the clinical utility in diagnosing AIN and should no longer be used as a screening test ? Too insensitive and nonspecific

30. Efficacy of eosinophiluria in the diagnosis of AIN
Perazella and Markowitz. Nat. Rev. Nephrol. 6; (2010), 461–470

31. 3- Characteristic Urine sediment
* White cells, red cells, and white cell casts.
* Occasional a bland sediment  a relatively normal urinalysis should not exclude the diagnosis.
4- Variable degree of Proteinuria
From none or minimal to >1 g/day.
Occasional Nephrotic-range proteinuria ?? 1- Concurrent nephrotic syndrome 2- Underlying disease.

32. 5- Evidence of tubulointerstitial damage
Fanconi syndrome, salt-wasting nephropathy, distal renal tubular acidosis, and urinary concentrating defects , may be present.
6- High fractional sodium excretion
FENa may be >1 % (indicative of tubular damage).
7- Non-specific findings:
Anemia, elevated ESR and CRP, Abnormal LFTs  associated drug-induced hepatitis

33. For AIN not believed to be related to a drug:
8- Radiographic findings
No diagnostic radiographic findings… Ultrasound and CT: 1- Exclusion of other causes of AKI. 2- Enlarged, swollen kidneys with increased echogenicity on ultrasound. * Not specific for AIN
For AIN not believed to be related to a drug:
The diagnostic evaluation of systemic disease and infection-related AIN should be guided by extrarenal clinical manifestations

34. DIAGNOSIS Suspect AIN Drug Non-oliguric Confirm Kidney Biopsy
Modest ↑ Creat
Tubular dysfunction
Urine findings
Non-oliguric
Confirm
Kidney Biopsy

35. When to perform a kidney Biopsy ?
1- Characteristic urinalysis + not being treated with a drug known to cause AIN
2- Being treated with a drug known to cause AIN, but do not have a characteristic urinalysis
3- Being considered for treatment with glucocorticoids for AIN (Putative drug induced and do not have a spontaneous recovery following cessation of drug therapy)
4- Advanced renal failure, known to be relatively recent (within 3 Mo)
5- Any features (as high-grade proteinuria) that cause the diagnosis of AIN to be uncertain

36. It is often considered unnecessary to make a definitive diagnosis !!
Clearly documented renal failure after initiation of a common culprit drug + improve immediately upon stopping the offending agent.

37. Histopathology

38. Marked Interstitial infiltrate ( T lymphocytes, monocytes
Marked Interstitial infiltrate ( T lymphocytes, monocytes. Eosinophils, plasma cells, neutrophils)
Tubulitis
Interstitial edema
Diffuse interstitial infiltrate of inflammatory cells on the right and an uninvolved glomerulus on the left.

39. Other histologic features:
1- Granuloma formation
* Any form of AIN…. particularly sarcoidosis.
Suggests a greater likelihood of infection-induced AIN.
2- Concurrent glomerular lesions e.g. with SLE.
3- Features suggesting IgG4-related disease (TBM immune complex deposits and an increase in IgG4-positive plasma cells in the interstitium).

40. Granulomatous change in acute interstitial nephritis
Granulomatous change in acute interstitial nephritis. The interstitial infiltrate is seen on the left, while the granuloma is on the right.

41. Back to case 1…..
Renal biopsy: mononuclear cell infiltration with interstitial nephritis.
Bilateral nephrocalcinosis and distal renal tubular acidosis could be the initial presentation of primary Sjögren’s syndrome with interstitial nephritis.
Chen Y-M, et al. Joint Bone Spine (2014),

42. Treatment

43. 1- General supportive measures
1- General supportive measures. 2- Specific treatment according to the cause.
The optimal therapy of AIN is unknown ?!
No randomized controlled trials or large observational studies.

44. AKI with suspected drug-induced TIN
1- Stop suspected drug
No significant improvement within 3-7 days
Improving Creatinine
Biopsy: confirm + exclude other path & chronic damage
Biopsy not feasible + strongly suggested Drug-induced ATN
2- Steroid therapy:
* 1 mg/kg per day (max 40 to 60 mg) (Pulse MP in sever cases)
* Minimum of one to two weeks + taper when creat near baseline
* Total therapy duration of two to three months
Other immunosuppressive agents:
1- MMF
2- CsA
3- Cyclophosphamide
1- Steroid-dependent
2- Steroid-resistant
3- Steroid-intolerant

45. With Steroid treatment group No steroid-treatment group
Gonza´lez et al. Kidney International (2008) 73, 940–946

46. Acute interstitial nephritis: clinical features and response to corticosteroid therapy
Against
P=0.2
P=0.9
P=0.9
Effect of corticosteroid therapy in AIN compared with conservative management. Values for serum creatinine (µmol/l) are given as median±interquartile range.
Clarkson et al. Nephrol. Dial. Transplant. (2004) 19 (11):

47. Clinical indicators of a decreased likelihood of recovery
Prognosis
AIN is not always benign.
Persistent elevation of the serum creatinine concentration in up to 40 % of patients.
Clinical indicators of a decreased likelihood of recovery
1- Prolonged renal failure (greater than three weeks),
2- AIN associated with NSAID use.
3- Histologic findings: interstitial granulomas, interstitial fibrosis, and tubular atrophy.

48. Agenda Background Acute Interstitial Nephritis
Chronic Interstitial Nephritis
Malignant Interstitial Infiltration.

49. CHRONIC INTERSTITIAL NEPHRITIS

50. Histologic entity characterized by progressive scarring of the tubulointerstitium with:
1- Tubular atrophy
2- Macrophage and lymphocytic infiltration
3- Interstitial fibrosis.
Better predictor than the degree of glomerular injury of present and future renal function.

51. Etiology CIN occurs in a variety of clinical settings…
1- Drugs/Toxins : Analgesics, CNI…. 2- Hereditary Disorders: Polycystic kidney disease 3- Metabolic Disturbances: Hypercalcemia, Hypokalemia, Hyperuricemia…. 4- Immune-Mediated Disorders: Renal allograft rejection, SLE, Vasculitis 5- Hematologic Disturbances:Multiple myeloma, Sickle cell disease 6- Infections 7- Obstruction/Mechanical Disorders 8- Miscellaneous Disorders: Hypertension, Endemic nephropathy, Renal ischemia

52. Diagnosis

53. Presentation Systemic features of primary underlying disease.
Signs of chronic kidney disease.
Incidental Diagnosis.

54. Functional Manifestations of Chronic Interstitial Nephritis1
GFR Deterioration of with insidious onset 2
Renal anemia at a relatively early stage
Tubular proteinuria mainly composed of low-molecular-weight protein (generally <1 g/day) 3 4
Inactive urinary sediment

55. Medullary dysfunction (concentrating defects)
Proximal tubular dysfunction (aminoaciduria, phosphaturia, proximal renal tubular acidosis, Fanconi syndrome) 5
Distal tubular dysfunction (type IV renal tubular acidosis) 6 7
Medullary dysfunction (concentrating defects) 8
Salt-wasting syndrome 9
Salt-sensitive hypertension

56. The interstitial fibrosis and scarring in CIN, and resultant impairment in kidney function, are not currently amenable to therapeutic intervention.
Although definitive diagnosis of CIN requires kidney biopsy, it is probably of limited usefulness in patients with kidney failure.

57. Histopathology

58. Tubular atrophy
Mononuclear cell infiltrate
Interstitial fibrosis
Thyroidization of tubules
Large area of tubular atrophy, interstitial fibrosis, and lymphocytic infiltration

59. Treatment

60. 1- Identification and elimination of any exogenous agents (drugs, heavy metals), metabolic causes (hypercalcemia) or conditions (obstruction, infection) potentially causing the chronic interstitial lesion. 2- General measures include control of blood pressure. 3- Specific treatments may be required for a condition, such as corticosteroids for sarcoidosis.

61. Agenda Background Acute Interstitial Nephritis
Chronic Interstitial Nephritis
Malignant Interstitial Infiltration.

62. Malignant Interstitial Infiltration

63. Malignant infiltration of Kidney Interstitium occur in the course of Different Hematological malignancies:
Acute and Chronic Leukemias
Hodgkin and Non-Hodgkin Lymphomas
Monoclonal Gammopathies

64. It should be considered in the DD of AKI in the course of hematological malignancy It has been reported as 1- First presentation of lymphoma 2- Site for the acute transformation of chronic leukemias.

65. Quiz Answers 1- Skin rash occurs in more than 50 % of AIN cases.
2- Esinophiluria is of high sensitivity for diagnosing AIN.
3- Kidney biopsy should not be done for all patients with putative drug-induced AIN
4- In drug-related AIN Steroid treatment is a mainstay of therapy.
5- In AIN, the severity of renal failure is more of prognostic relevance than its duration..
6- Strong immunosuppression is a rescue therapy for Chronic Interstitial Nephritis.

66. Thank you