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Overview of Tubulointerstitial Diseases with clinical Cases and Ace Board Questions | Definition, Pathophysiology, Diagnosis, Evaluation, Causes, Management, Treatment and Epidemiology

    Learning Objectives

    • Pathophysiology and Epidemiology 
    • Diagnosis and Evaluation
    • Causes
    • Management
    • Ace Board questions


    Acute or chronic inflammation, necrosis, fibrosis, atrophy; of the renal tubules or interstitium or both.

    Source: https://www.uniklinikum-jena.de

    Primary categories

    • Acute Tubular Necrosis (ATN)
    • Acute Interstitial Nephritis (AIN)

    • Chronic Interstitial Nephritis (CIN)
    • Chronic Interstitial Fibrosis Tubular Atrophy 
    Can have overlap as similar causes and etiologies (For eg: drugs induced)
    Can have >1 pathologies

    Etiology wise classification

    • Prolonged prerenal/ischemic injury (ATN) → Most common in inpatient setting
    • Drug-Induced (2nd most common cause)
    • Auto-immune disease-related
    • Toxins/heavy metals
    • Hereditary tubulointerstitial nephritis
    • Infection
    • Malignancy
    • Secondary tubulointerstitial injury due to glomerular and vascular disorders
    • Urinary tract obstruction (prolonged)

    Clinical Presentation/ Diagnosis

    Only 10% to 30% of patients with AIN have the classic triad of fever, rash, and eosinophilia
    Medication history: the most important
    Any over the counter meds Or herbal medications
    Urine testing:
    • Mild proteinuria
    • Urine Na variable and >40, FeNa variable >2%
    • Leukocyte casts in AIN (granular muddy brown casts in ATN)
    • Sometimes erythrocytes
    • Eosinophiluria (no longer helpful, neither sensitive nor specific) → More sensitive is eosinophilia


    How is the WBC cast formed?



    • Definitive diagnosis is kidney biopsy
    • But invasive, mostly may not change management
    • Patients already critically ill, coagulopathic
    • But, if high suspicion and would change management and low risk for complications, then kidney biopsy is indicated.


    • Stop the offending drug
    • Control blood pressure
    • Treat underlying cause (infection, immune diseases, etc.)
    • Avoid further renal insults as much as possible
    • Steroids?

    • Conservative management
    • Wait and watch for renal recovery
    • Meanwhile, manage electrolytes, fluid balance to be able to avoid the need for dialysis
    • Giving or not giving fluids or diuretic will not impact the course
    • Decide on fluids/diuretics based on the patient's volume status not based on the kidney function in ATN.

    Case 1

    A 53-year-old woman is evaluated during a routine follow-up visit. Medical history is significant for hypertension and chronic active hepatitis B infection. Her hepatitis B infection has been treated with tenofovir for the past 5 years with suppression of her serum hepatitis B DNA levels. She currently notes mild generalized weakness but otherwise feels well. Medications are ramipril and tenofovir.

    On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 136/79 mm Hg, pulse rate is 70/min, and respiration rate is 14/min. BMI is 22. Abdominal examination shows a normal-sized liver and no splenomegaly. The remainder of the examination is normal. 

    • Creatinine = 1.2 mg/dL (3 years ago: 0.8 mg/dL)
    • Phosphorus = 2.2 mg/dL
    • Bicarbonate = 21 mEq/L
    • Urinalysis = 1+ protein; 2+ glucose; no cells or casts
    • Glucose = 87 mg/dL
    • Kidney ultrasound is done which shows normal sized kidneys, mild echogenicity, no other remarkable findings.

    What do you think is going on here?
    What is the culprit?

    • Drug-induced tubulointerstitial disease and Fanconi syndrome (proximal tubular nephrotoxicity)
    • Tenofovir
    • But the newer form of tenofovir available now: Tenofovir Alafenamide (TAF)
    • A novel prodrug of TDF (tenofovir disoproxil fumarate) which can be given at lower doses with the same efficacy and therefore lower nephrotoxicity.


    Drug-Induced AIN/CIN

    • Most common cause of interstitial nephritis in clinical practice
    • Not biopsied as often so sometimes goes unrecognized
    • Which leads to chronic scarring and chronic interstitial disease which then becomes irreversible
    • If develops over a course of days to weeks, acute decline in renal function, temporal correlation of initiation of a drug then Acute Interstitial Nephritis
    • If slowly declining renal function over months to years, the patient has been on a potential drug for several years, then suspect more of Chronic interstitial nephritis.

    Common drugs
    • Antibiotics: Penicillins, B-lactams, rifampin, sulfonamides, fluoroquinolones
    • NSAIDs, COX-2 inhibitors (Can also cause minimal change disease/nephrotic syndrome along with AIN)
    • Proton pump inhibitors
    • Indinavir, abacavir
    • Triamterene
    • Phenytoin
    • 5-aminosalicylates
    • Chinese herb nephropathy (Aristolochic acid)

    Case 2

    A 57-year-old man is evaluated for a diagnosis of acute kidney injury. He was diagnosed with GERD, 3 weeks ago and was prescribed omeprazole. Several days ago he noticed lower extremity swelling and decreased the frequency of urination. Laboratory evaluation showed a serum creatinine level of 2.2 mg/dL. Medical history is otherwise unremarkable, and he takes no other medications. He reports no allergies.

    On physical examination, the patient is afebrile, blood pressure is 135/77 mm Hg, pulse rate is 88/min, and respiration rate is 12/min. There is no rash. Cardiac examination and estimated central venous pressure are normal. The lungs are clear. Lower extremity edema to the ankles is present bilaterally.

    Dipstick urinalysis reveals blood and trace protein, and urine sediment is notable for 5-10 erythrocytes/hpf, 10-20 leukocytes/hpf, and 1 leukocyte cast. 

    In addition to stopping omeprazole, what would be the next step? 
    • Renal Biopsy 
    • Wait and repeat renal function panel in 5-7 days 
    • Initiate glucocorticoids 
    • Check urine eosinophils

    Wait and repeat renal function panel in 5-7 days

    • Drug-induced AIN is characterized by a slowly increasing serum creatinine 7 to 10 days after exposure; however, it can occur within 1 day of exposure if the patient has been exposed previously.
    • Drug-induced AIN can also occur months after exposure, often with NSAIDs and proton pump inhibitors (PPIs)
    • This patient has a clinical picture consistent with AIN based on clinical and laboratory evidence of kidney injury and urinalysis showing erythrocytes, leukocytes, and leukocyte casts after recently being started on the PPL omeprazole.
    • Discontinuation of the offending agent is the mainstay of therapy.
    • In patients with mild elevations of serum creatinine and minimal clinical findings, stopping the causative drug with close follow-up is usually adequate therapy.
    • Kidney biopsy is usually not necessary to diagnose AIN, particularly in patients with a consistent clinical and laboratory picture, as seen in this patient.
    • However, kidney biopsy may be indicated in situations where there are inconsistent clinical and laboratory findings, or if kidney function does not improve immediately upon stopping the offending agent.
    • The role of glucocorticoids in AIN is controversial, with conflicting evidence of benefit in clinical studies. Glucocorticoids are therefore generally reserved for patients who have not responded to discontinuation of the offending agent.

    Case 3

    A 67-year-old man with metastatic melanoma, initially diagnosed and treated 4 years ago, developed recurrence with metastases 9 months prior to presentation. 4 cycles of concomitant ipilimumab and nivolumab were planned. After cycle 3, he developed fever, chills, some dry cough.

    Gets admitted to the hospital for presumptive diagnosis of community-acquired pneumonia, is started on azithromycin.

    Labs showed serum creatinine (Cr) was 1.79 mg/dl at presentation (baseline 0.8 mg/dl)
    The patient is started on IV fluids, assuming this was pre-renal AKI as he has been febrile and has a possible infection. 

    Case contd..
    • Day 2: Cr remains same
    • Nephrology consulted
    • Physical exam revealed a rash on both hands
    • Day 3: Skin biopsy done which showed granulomatous dermatitis ?? · Cr continues to rise slowly
    • Urine sediment exam done: not very clear but fellow possibly saw 1 leukocyte cast
    • Patient otherwise healthy and had not taken any other medications. No OTC, no herbal
    • Cycle 3 of the Immunotherapy for melanoma was about 3 weeks ago.
    • Cr has now reached 2.65 mg/dL (came in with 1.8) 

    Next step?
    • Kidney biopsy 
    • Wait and repeat renal function test daily in the hospital 
    • Start steroids 
    • Check urine eosinophils

    Kidney biopsy 

    Why did we choose a kidney biopsy in this case?
    • Unexplained rising Cr
    • The patient has been off all medications
    • Diagnosis and Therapy will greatly alter his future course
    • Empiric steroids without a clear diagnosis ?? In a patient with metastatic melanoma who is planned to get more immunotherapy ... also not a good idea 


    • Immune checkpoint inhibitors related granulomatous interstitial nephritis and tubular atrophy
    • Patient started on prednisone 60 mg daily
    • Slowly tapered over 3 months
    • Cr improved to 1.1 mg/dL over time
    • For the melanoma: the patient planned for only one more cycle of one of the agents.

    Immunologic diseases

    Sjogren's syndrome
    • Characterized by lymphocytic and plasmacytic infiltration of the parotid, salivary, and lacrimal glands
    • can produce a similar injury in other nonexocrine glands and in the kidneys
    • kidney biopsy will demonstrate granuloma formation

    Can cause renal dysfunction through different mechanisms:
    • Direct ureteral involvement, retroperitoneal fibrosis, and hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis via excessive production of 1,25-dihydroxy vitamin D in granulomas
    • Therefore, the tubulointerstitial disease usually requires confirmation by kidney biopsy showing the presence of non-caseating granulomas and interstitial nephritis. 
    TINU (tubulointerstitial nephritis and Uveitis): rare

    Case 4

    A 54-year-old woman is evaluated for fatigue, anorexia, polyuria, and nocturia of several weeks' duration. Medical history is significant for autoimmune pancreatitis diagnosed 1 year ago, treated with a prednisone taper that was completed 8 months ago with the resolution of her symptoms. She takes no medications.

    On physical examination, the temperature is 36.2 °C (97.2 °F), blood pressure is 110/58 mm Hg, pulse rate is 72/min, and respiration rate is 16/min. BMI is 25. The estimated central venous pressure is 7 cm H20. The lungs are clear. There are no murmurs or extra heart sounds. An abdominal examination is unremarkable. There is no edema. 

    Case contd..
    • Cr is 5.2 mg/dL
    • Urinalysis: pH 5.0; 1+ protein; 3-5 erythrocytes/hpf; 5-10 leukocytes/hpf; occasional leukocyte casts

    Which of the following is the most likely diagnosis? 
    • ANCA associated vasculitis 
    • Anti GBM antibody disease 
    • IgG4 related interstitial nephritis 
    • Lupus nephritis

    IgG4 related interstitial nephritis

    • An uncommon disorder characterized by infiltration of different organs by lymphoplasmacytic infiltrates of IgG4-positive plasma cells
    • Resultant fibrosis
    • Associated with elevated serum IgG4 levels.
    • Autoimmune pancreatitis is one form of IgG-related disease, although other organs such as the kidney may be affected, most commonly as interstitial nephritis.
    • IgG4-related interstitial nephritis may present with acute or chronic kidney failure as well as renal mass-like lesions on imaging.
    • Kidneys may be diffusely enlarged on imaging due to cellular infiltration.
    • Definitive diagnosis requires kidney biopsy with staining for IgG4-positive plasma cells.

    immunosuppression with glucocorticoids

    Systemic Lupus Erythematosus

    The tubulointerstitial disease of SLE typically occurs with concomitant glomerulonephritis.
    The degree of tubulointerstitial involvement in SLE is a poor prognostic sign with associated increased risk for:
    • Hypertension
    • Progressive kidney dysfunction, and
    • End-stage kidney disease 

    Infections related

    Numerous infections, including those caused by bacteria, mycobacteria, viruses, parasites, and fungi, are associated with acute interstitial nephritis and chronic tubulointerstitial nephritis.

    The pathophysiology of infection-related interstitial nephritis may be:
    • Direct infiltration of the kidney or
    • An inflammatory response triggered by the infecting agent.
    Management is to treat the underlying infection

    • Polyoma BK virus (most commonly post-kidney transplantation)
    • Epstein-Barr virus
    • Mycobacterium tuberculosis
    • Cytomegalovirus
    • Brucellosis
    • Fungal infections
    • Toxoplasmosis
    • Chronic pyelonephritis 
    • Legionella species


    Kidney infiltration by lymphoma and leukemia may occur
    Present with non-nephrotic-range proteinuria, sterile pyuria, and enlarged kidneys on imaging studies.
    The diagnosis may be confirmed by biopsy.

    Gammopathies associated with lymphoproliferative disorders or multiple myeloma may also cause tubulointerstitial disease. (a separate topic in itself)

    Numerous antineoplastic agents have been associated with the tubulointerstitial disease, 
    • cisplatin, carboplatin
    • ifosfamide, cyclophosphamide 
    • nitrosoureas (such as streptozocin, carmustine, semustine, and lomustine)

    Clinical features may include chronic kidney disease (CKD), mild proteinuria, and evidence of tubular dysfunction manifested as Fanconi syndrome and electrolyte abnormalities.


    • Hyperuricemia is associated with chronic uric acid nephropathy
    • Deposition of sodium urate crystals in the interstitium.
    • The inflammatory response causes interstitial fibrosis and CKD.
    • Clinical features include hyperuricemia, CKD, bland urine sediment, subnephrotic proteinuria, and unremarkable kidney imaging.
    • Kidney biopsy is required to make the diagnosis because clinical features are nonspecific. 


    • Urinary obstruction can result in AKI and CKD.
    • Clinical features: hypertension, CKD, and changes in urinary habits such as nocturia, incontinence, and polyuria.
    • Flank pain and renal or ureteral colic are usually not features of chronic obstruction given its insidious course.
    • Imaging (typically U/S) may reveal hydronephrosis and renal cortical thinning.
    • Type 4 (hyperkalemic distal) RTA may occur, consistent with the tubular atrophy and injury on pathology.
    • Treatment includes relief of the obstruction, and prognosis depends on the duration and severity of the obstruction.
    • Recovery is usually diminished with obstruction of longer than 6 to 12 weeks. 

    Toxic/ Heavy metals and Hereditary

    Balkan endemic nephropathy/aristolochic acid nephropathy (with increased risk of transitional cell carcinoma)
    Heavy metal nephropathy:
    • Lead
    • Cadmium
    • Mercury

    Hereditary Tubulointerstitial Nephritis
    • Medullary cystic kidney disease
    • Mitochondrial disorders
    • Nephronophthisis 

    Case 5

    A 45-year-old man is evaluated during a new patient visit. He immigrated to the United States from Serbia 4 years ago and was diagnosed with Balkan endemic nephropathy at that time. His kidney function has remained stable, and his only symptoms are mild nocturia and urinary frequency. Medical history is otherwise unremarkable. He takes no medications. 

    Case contd..
    Laboratory studies:
    • Hemoglobin: 9.6 g/dL (96 g/L)
    • Electrolytes: Normal
    • Creatinine : 1.7 mg/dL
    • Glucose: Normal
    • Estimated glomerular filtration rate: 35 mL/min/1.73 m2
    • Urinalysis: Specific gravity 1.005; 2+ glucose; 10-20 erythrocytes/hpf 

    An increased risk of which of the following is most likely in this patient? 
    • Diabetes mellitus 
    • Intracranial cerebral aneurysm 
    • Renal cell carcinoma 
    • Transitional cell carcinoma 

    • BEN is a slowly progressive tubulointerstitial disease that has been linked to aristolochic acid.
    • Aristolochic acid is a nephrotoxic alkaloid from the plant Aristolochia clematis, which is endemic to the Balkan region and is sometimes a component of herbal therapies used for weight loss.
    • BEN is believed to be due to exposure to low levels of aristolochic acid over years, compared with more acute toxicity associated with ingestion of herbal preparations. 
    • Characteristics of BEN include chronic kidney disease due to tubulointerstitial injury, tubular dysfunction (polyuria and decreased concentrating ability, glucosuria without hyperglycemia, and tubular proteinuria), and anemia. 
    • Because aristolochic acid is also mutagenic, patients with BEN are at increased risk for transitional cell carcinomas of the renal pelvis, ureters, and bladder.
    • Therefore, annual surveillance with urine cytology is recommended.
    • Even higher risk after kidney transplant due to immunosuppression

    Case 6

    A 35-year-old man is evaluated in the hospital for AKI.
    Presented with worsening fatigue, decreased urination, and progressive swelling in the ankles occurring over the course of 2 to 3 weeks.

    Laboratory studies at the time of diagnosis showed a serum creatinine level of 6.7 mg/dL (baseline of 0.9 mg/dL 1 year ago).

    Medical history is significant for a 3-year history of inflammatory bowel disease that has been well controlled with daily mesalamine therapy. He does not take any over-the-counter drugs.

    On physical examination, the temperature is 37.0 °C (98.6 °F), blood pressure is 118/67 mm Hg, pulse rate is 60/min, and respiration rate is 16/min. BMI is 20. A cardiac examination is normal. The lungs show crackles at the bases bilaterally. There is lower extremity edema to the mid-calf. The remainder of the examination is normal.

    Dipstick urinalysis shows 1+ protein but is otherwise normal. Urine microscopy shows 2-3 erythrocytes/hpf, 5-10 leukocytes/hpf, and leukocyte casts. The urine protein-creatinine ratio is 1060 mg/g. Urine cultures are negative.

    What is the cause of his AKI?
    • Mesalamine related interstitial nephritis
    • Mesalamine-induced interstitial nephritis is a well-described complication that can be either acute or chronic and may occur months to years after exposure, even in patients who have safely tolerated the medication in the past. 
    • Management: 
    • challenging, especially if IBD is well controlled with it. Discuss with a gastroenterologist to see if the dose can be reduced or can be switched to another agent

    Case 7

    A 65-year-old man is evaluated for a slowly rising serum creatinine level from 0.8 mg/dL to 1.4 mg/dL noted on laboratory testing over the past 8 months. Medical history is significant for benign prostatic hyperplasia, arthritis and GERD. 1 year ago he developed bleeding gastric ulcer and was admitted in ICU. Currently, he feels well and has no current symptoms. Medications are tamsulosin, naproxen and omeprazole.

    On physical examination, temperature is 37.1 °C (98.7 °F), blood pressure is 134/84 mm Hg, pulse rate is 76/min, and respiration rate is 12/min. BMI is 26. There is no rash. The remainder of the examination is unremarkable. 

    Case contd..
    • Complete blood count with differential Normal
    • Blood urea nitrogen 38 mg/dL
    • Creatinine 1.4 mg/dL
    • Electrolytes Normal
    • Urinalysis: Positive for protein; no blood, glucose, leukocyte esterase, or nitrites; <3 erythrocytes/hpf; 3-5 leukocytes/hpf; no casts or crystals
    • Urine protein-creatinine ratio : 470 mg/g
    • Kidney ultrasound shows normal-sized kidneys without hydronephrosis or calculi. 

    Which of the following is the most appropriate next step in management? 
    • Discontinue omeprazole 
    • Discontinue tamsulosin 
    • Discontinue naproxen 
    • All of the above

    Discontinue naproxen

    Sources:©2019 McGraw-Hill Education. All Rights Reserved.
    Sabljar Matovinovic, Mirjana. (2009). 1. Pathophysiology and Classification of Kidney Diseases. EJIFCC. 20.2-11
    Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clin Nephrol. 2007 Aug;68(2):65-72.
    Saeki T, Kawano M. IgG4-related kidney disease. [erratum in: Kidney Int. 2014 Jun;85(6): 1472.) Kidney Int. 2014 Feb; 85(2):251-7.
    UofL Internal Medicine Lecture Series
    Universitätsklinikum Jena

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