Tubulointerstitial diseases are conditions of inflammation of the renal tubules and interstitium that can lead to renal failure. Acute tubulointerstitial nephritis (ATIN) is the third most common cause of acute kidney injury (AKI) in hospitalized patients after acute tubular necrosis (ATN) and prerenal AKI, and it is most commonly caused by an allergic reaction to medications. ATIN commonly manifests with a slowly progressive, nonoliguric, intrinsic AKI. The classic triad of fever, morbilliform rash, and eosinophilia is seen in < 10% of cases. Laboratory study findings may suggest interstitial nephritis, but histological confirmation with renal biopsy is required for a definitive diagnosis. Early recognition, removal, or treatment of the suspected cause, and, in select cases, administration of glucocorticoid therapy, will result in complete or partial resolution for most patients, while a minority of patients experience irreversible kidney damage. Chronic tubulointerstitial nephritis (CTIN) is commonly due to the progression of ATIN, but it may also be caused by medications, infections, toxins, or systemic diseases. Treatment involves managing or eliminating the underlying cause and . Crystal-induced nephropathy is a type of kidney damage that results from crystal deposition in the renal vasculature, the renal tubules, or the draining urinary tract and that may lead to crystal-induced AKI, crystal-induced CKD, or urolithiasis. Renal papillary necrosis, a necrosis of the renal medullary pyramids and papillae, is caused by ischemia (due to, e.g., sickle cell disease and sickle cell trait, acute pyelonephritis, or obstruction of the urinary tract). Patients often present with AKI with hematuria and sloughed papillae. Management should include treatment of the underlying cause, IV fluids to prevent blood clot formation and upper urinary tract obstruction, and management of further complications.
- Third most common cause of AKI in hospitalized patients 
- Seen in ∼ 15% of biopsy samples obtained for unexplained AKI 
- Immune-mediated tubulointerstitial damage (allergic interstitial nephritis) is the most widely accepted theory.
- Acute obstruction: crystals (from e.g., uric acid, medications) or proteins (e.g., light chains) obstruct tubules
Medications (most common) 
- Antibiotics: β-lactams, sulfonamides, rifampin, fluoroquinolones
- Proton pump inhibitors and H2 blockers
- Loop diuretics and thiazides
- Anticonvulsants: phenytoin, valproate, carbamazepine, phenobarbital
- Other: allopurinol, immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), mesalamine
- Viruses: HIV, CMV, EBV, HSV, measles, mumps, hantavirus
- Autoimmune: Sjogren syndrome, sarcoidosis, SLE, tubulointerstitial nephritis with uveitis, 
- Other: autosomal dominant tubulointerstitial kidney disease
“Please RSVP:” Rifampin, Sulfa drugs and the V (5) Ps (Proton pump inhibitors, Pain killers (NSAIDs), “Pee pills” (diuretics), Penicillins, and Phenytoin) are the drugs that cause acute tubulointerstitial nephritis.
Clinical features 
- Determine if the patient fulfills .
- Obtain a minimum diagnostic workup for patients with suspected kidney diseases.
- Blood tests and urine studies
- Renal imaging studies
- Identify characteristic clinical features, risk factors, and potential exposures for ATIN.
- Consider renal biopsy ( ) if there is no improvement under supportive care.
Blood tests 
Urine studies 
- Urine microscopy
- Urine chemistries in tubulointerstitial disease (findings depend on the major site of injury) 
Renal ultrasound 
- Indication: to rule out other causes of AKI
Renal biopsy 
- No improvement or the patient worsens after 3–5 days of supportive care and withdrawal of potential causative agent.
- Guiding treatment of suspected causes
Differential diagnoses 
- Other causes of
ATIN, atheroembolic disease, vasculitis, and DRESS syndrome can all manifest with AKI, skin lesions (e.g., livedo reticularis, purpura, or rash), and eosinophilia, and should be considered as differential diagnoses. 
- Stop causative agents or treat underlying systemic disease.
- Provide ; for 3–5 days.
- Consider systemic glucocorticoids under specialist guidance.
- Monitor kidney function; evaluate for .
Glucocorticoid therapy 
- Common indications
- Example regimen (off-label) : methylprednisolone followed by prednisone 
- Important considerations
- Interstitial mononuclear cell infiltration → tubulointerstitial fibrosis and atrophy → glomerular and vascular fibrosis and sclerosis → chronic kidney damage
- Pathophysiology of specific causes of CTIN includes:
- Progression of ATIN: chronic inflammation → fibrosis → chronic renal damage
- Analgesic nephropathy (e.g., resulting from NSAID use)
- Reflux nephropathy: chronic high-pressure reflux and recurrent UTIs → tubular atrophy and patchy interstitial fibrosis 
- Myeloma cast nephropathy: Excessive amounts of light chains are produced and filtered into the primary urine → precipitation of light chains in renal tubules → tubular obstruction
- The overall prevalence of CTIN is unknown.
- Chronic interstitial nephritis in agricultural communities (CINAC) : 
- Analgesic nephropathy; : combination analgesics , NSAIDs, and acetaminophen
- Calcineurin inhibitors: cyclosporine, tacrolimus
- Chemotherapeutic agents: cisplatin, ifosfamide
- Nucleoside inhibitors: cidofovir, tenofovir
- Aristolochic acid: causative agent in aristolochic acid nephropathy
- Other: mesalamine, lithium
- Toxins: lead; (i.e., chronic lead nephropathy), cadmium
- Infections: chronic pyelonephritis, tuberculosis
- Systemic diseases: multiple myeloma, Sjogren syndrome, SLE, sickle cell disease, vasculitis, sarcoidosis, lymphoma, , tubulointerstitial nephritis with uveitis
- Metabolic diseases: hyperuricemia, hypercalcemia, hyperoxaluria, hypokalemia
Clinical features 
CTIN typically follows an indolent course. Clinical features vary according to the etiology.
- Painless hematuria, pyuria, oliguria, or polyuria
- Colicky flank pain
- or other
- Symptoms of an underlying condition (e.g., symptoms of multiple myeloma)
- proximal tubules with resulting from defects in
- distal tubules resulting from defects in
- Obtain BMP, CBC, urinalysis, urine microscopy, and urine chemistries for all patients.
- Renal ultrasound 
- Renal biopsy 
Treatment consists of , including treatment of the underlying cause.
- Definition: : a type of kidney injury that is triggered by crystal deposition and may lead to crystal-induced AKI, crystal-induced CKD, or urolithiasis
|Overview of crystalline nephropathies |
|Renovascular crystallopathy|| |
|Clinical features|| |
- Ischemia → necrosis and sloughing of the papillae → ureteral obstruction → possible scarring
- Usually bilateral; can also affect a single papilla 
- Often multifactorial
- Sickle cell disease and sickle cell trait
- Acute pyelonephritis
- Obstruction of the urinary tract
- Cirrhosis of the liver
- NSAIDs (due to inhibition of prostaglandin-mediated vasodilation in the vasa recta)
- Renal transplant rejection
- Diabetes mellitus
- Systemic vasculitis
POSTCARDS: Pyelonephritis, Obstruction, Sickle cell disease, Tuberculosis, Cirrhosis, Analgesics (NSAIDs), Renal transplant rejection, Diabetes mellitus, and Systemic vasculitis are the causes of renal papillary necrosis.
- Chronic: : usually asymptomatic or mild symptoms
Consider renal papillary necrosis as part of the differential diagnosis for patients presenting with , particularly if risk factors are present (e.g., sickle cell disease, diabetes, chronic oral analgesic use).
- BMP: ↑ BUN and creatinine
- Urine studies 
Imaging studies 
CT urography 
Test of choice for renal papillary necrosis
- Can visualize early ischemic changes (while they may still be reversible)
- Useful for differential diagnosis
- Findings (during the contrast excretory phase) 
- Test of choice for renal papillary necrosis
- Renal ultrasound 
- Intravenous urography 
- Treat the underlying cause: See “Etiology.”
- Prevent blood clot formation: Provide to maintain high urine output.
- Manage complications if present.