View source for Medicine:Interstitial nephritis

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'''Interstitial nephritis''', also known as '''tubulointerstitial nephritis''', is [[Medicine:Inflammation|inflammation]] of the area of the kidney known as the renal interstitium, which consists of a collection of cells, [[Biology:Extracellular matrix|extracellular matrix]], and fluid surrounding the renal tubules. It is also known as intestinal nephritis because the clinical picture may include mesenteric lymphadenitis in some cases of acute pyelonephritis (mostly due to use of NSAIDs). More specifically, in case of recurrent [[Medicine:Urinary tract infection|urinary tract infection]], secondary infection can spread to adjacent intestine.<ref name=":02">{{Cite journal|last1=Zeisberg|first1=Michael|last2=Kalluri|first2=Reghu|date=October 2015|title=Physiology of the Renal Interstitium|journal=Clinical Journal of the American Society of Nephrology|volume=10|issue=10|pages=1831–1840|doi=10.2215/CJN.00640114|pmid=25813241|pmc=4594057}}</ref> In addition to providing a scaffolding support for the tubular architecture, the interstitium has been shown to participate in the fluid and electrolyte exchange as well as endocrine functions of the kidney.<ref name=":02" />

There are a variety of known factors that can provoke the inflammatory process within the renal interstitium, including pharmacologic, environmental, infectious and systemic disease contributors. The spectrum of disease presentation can range from an acute process to a chronic condition with progressive tubular cell damage and renal dysfunction.

== Signs and symptoms ==
Interstitial nephritis may present with a variety of signs and symptoms, many of these nonspecific. Fever is the most common, occurring in 30-50% of patients, particularly those with drug-induced interstitial nephritis.<ref name=":0" /> Other general symptoms that occur with variable frequency include nausea, vomiting, fatigue, lack of appetite, and weight loss. More specific symptoms, such as flank pain, pain with urination, and visible blood in the urine, as well as signs like hypertension can be helpful in increasing suspicion for the diagnosis.<ref>{{Citation|last=Meyers|first=Catherine M.|chapter=Chronic Tubulointerstitial Disease|date=2014|pages=390–396|publisher=Elsevier|isbn=9781455746170|doi=10.1016/b978-1-4557-4617-0.00045-5|title=National Kidney Foundation Primer on Kidney Diseases}}</ref> The "classic" triad of symptoms reported in early documented cases consisted of rash, joint pain, and increased eosinophils in the blood; however, more recent epidemiology suggests that this grouping of symptoms only occurs in a small minority (5-10%) of patients.<ref>{{Citation|last1=Brewster|first1=Ursula C.|title=Acute Interstitial Nephritis|date=2014|work=National Kidney Foundation Primer on Kidney Diseases|pages=312–317|publisher=Elsevier|isbn=9781455746170|last2=Rastegar|first2=Asghar|doi=10.1016/b978-1-4557-4617-0.00035-2}}</ref>  With modern drugs causing between 70 and 90% of current cases,<ref name="pmid14671029">{{cite journal |vauthors=Baker R, Pusey C |title=The changing profile of acute tubulointerstitial nephritis |journal=Nephrol Dial Transplant |volume=19 |issue=1 |pages=8–11 |year=2004 |pmid=14671029|doi=10.1093/ndt/gfg464|doi-access=free }}</ref><ref name="pmid15340098">{{cite journal |vauthors=Clarkson M, Giblin L, O'Connell F, O'Kelly P, Walshe J, Conlon P, O'Meara Y, Dormon A, Campbell E, Donohoe J |title=Acute interstitial nephritis: clinical features and response to corticosteroid therapy |journal=Nephrol Dial Transplant |volume=19 |issue=11 |pages=2778–83 |year=2004 |pmid=15340098 |doi=10.1093/ndt/gfh485|doi-access= }}</ref> the possibility of a change in presentation exists.

== Causes ==
Common causes include infection, or reaction to medication such as an [[Medicine:Analgesic nephropathy|analgesic]], [[Chemistry:Anti-inflammatory|anti-inflammatory]],<ref>[https://www.kidney.org/atoz/content/painmeds_analgesics] National Kidney Organization.  “Heavy or long-term use of some of these medicines, such as [[Chemistry:Ibuprofen|ibuprofen]], [[Chemistry:Naproxen|naproxen]], and higher dose aspirin, can cause chronic kidney disease known as chronic interstitial nephritis.”</ref> or [[Chemistry:Antibiotic|antibiotic]]s such as methicillin (meticillin). Reaction to medications causes 71%<ref name="pmid14671029"/> to 92%<ref name="pmid15340098"/> of cases.

=== Drugs ===
<br />
{| class="wikitable"
|+Examples of Drugs Associated With Interstitial Nephritis<ref name=":0" /><ref>{{Cite web|url=https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-acute-interstitial-nephritis|title=Clinical manifestations and diagnosis of acute interstitial nephritis|last1=Praga|first1=Manuel|last2=Appel|first2=Gerald|date=2018-11-01|website=UpToDate|access-date=2018-12-10}}</ref>
!Class
!Examples
|-
|Antibiotic
|β-lactams (e.g. penicillins, cephalosporins), sulfonamides (e.g. trimethoprim-sulfamethoxazole), fluoroquinolones (e.g. ciprofloxacin), macrolides (e.g. erythromycin), anti-tuberculins (e.g. rifampin, ethambutol), chloramphenicol
|-
|Anti-inflammatory
|Nonsteroidal antiinflammatory drugs (e.g. ibuprofen, naproxen), selective COX-2 inhibitors (e.g. celecoxib)
|-
|Antiviral
|Acyclovir, atazanavir, abacavir, indinavir
|-
|Analgesic
|Aspirin, acetaminophen 
|-
|Gastrointestinal
|Proton pump inhibitors (e.g. omeprazole, lansoprazole), H2-receptor blockers (e.g. cimetidine), 5-aminosalicylates (e.g. mesalamine)
|-
|Antiseizure
|Phenytoin, carbamazepine, phenobarbital
|-
|Diuretic
|Hydrochlorothiazide, furosemide, triamterene, chlorthalidone
|-
|Chemotherapy
|Tyrosine kinase inhibitors (e.g. sunitinib), checkpoint inhibitors (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab)
|-
|Contrast agent
|Gadolininum based contrast agent<ref>{{cite journal|title=Nephrogenic Systemic Fibrosis in Denmark– A Nationwide Investigation|year=2013 |pmc=3857209 |language=en|publication-date=|last1=Elmholdt |first1=T. R. |last2=Olesen |first2=A. B. |last3=Jørgensen |first3=B. |last4=Kvist |first4=S. |last5=Skov |first5=L. |last6=Thomsen |first6=H. S. |last7=Marckmann |first7=P. |last8=Pedersen |first8=M. |journal=PLOS ONE |volume=8 |issue=12 |pages=e82037 |doi=10.1371/journal.pone.0082037 |pmid=24349178 |bibcode=2013PLoSO...882037E |doi-access=free }}</ref><ref>{{Cite journal|first1=Hulya|last1=Akgun|first2=Gulfiliz|last2=Gonlusen|first3=Jr, Joiner|last3=Cartwright|first4=Wadi N.|last4=Suki|title=Are Gadolinium-Based Contrast Media Nephrotoxic?: A Renal Biopsy Study|periodical=Archives of Pathology & Laboratory Medicine|volume=130|number=9|date=2006-09-01|issn=0003-9985|doi=10.5858/2006-130-1354-AGCMNA|url=https://doi.org/10.5858/2006-130-1354-AGCMNA|access-date=2022-07-25|pages=1354–1357|pmid=16948524 }}</ref>
|-
|Other
|Allopurinol, Chinese herbs
|}
This disease is also caused by other diseases and toxins that damage the kidney. Both acute and chronic tubulointerstitial nephritis can be caused by a bacterial infection in the kidneys known as [[Medicine:Pyelonephritis|pyelonephritis]], but the most common cause is by an adverse reaction to a medication. The medications that are known to cause this sort of reaction are [[Chemistry:Β-lactam antibiotic|β-lactam antibiotic]]s such as [[Biology:Side effects of penicillin|penicillin]]<ref name="OhlssonShah2014">{{cite journal|last1=Ohlsson|first1=Arne|last2=Shah|first2=Vibhuti S|last3=Ohlsson|first3=Arne|title=Intrapartum antibiotics for known maternal Group B streptococcal colonization|journal=Cochrane Database of Systematic Reviews|issue=6|pages=CD007467|year=2014|doi=10.1002/14651858.CD007467.pub4|pmid=24915629}}</ref>
and cephalexin, and nonsteroidal anti-inflammatory drugs ([[Chemistry:Aspirin|aspirin]] less frequently than others), as well as [[Medicine:Proton-pump inhibitor|proton-pump inhibitor]]s, [[Chemistry:Rifampicin|rifampicin]], sulfa medications, fluoroquinolones, [[Chemistry:Diuretic|diuretic]]s, [[Chemistry:Allopurinol|allopurinol]], mesalamine, and [[Chemistry:Phenytoin|phenytoin]].  The time between exposure to the drug and the development of acute tubulointerstitial nephritis can be anywhere from 5 days to 5 months ([[Chemistry:Fenoprofen|fenoprofen]]-induced).{{citation needed|date=March 2021}}

==Diagnosis==
The condition can appear without symptoms. When present they may appear widely varied and can occur rapidly or gradually.<ref name="pmid14671029"/><ref name="pmid11473672">{{cite journal |author=Rossert J |title=Drug-induced acute interstitial nephritis |journal=Kidney Int |volume=60 |issue=2 |pages=804–17 |year=2001 |pmid=11473672 | doi=10.1046/j.1523-1755.2001.060002804.x|doi-access=free }}</ref><ref name="pmid6604293">{{cite journal |vauthors=Pusey C, Saltissi D, Bloodworth L, Rainford D, Christie J |title=Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy |journal=Q J Med |volume=52 |issue=206 |pages=194–211 |year=1983 |pmid=6604293}}</ref><ref name="pmid3779558">{{cite journal |author=Handa S |title=Drug-induced acute interstitial nephritis: report of 10 cases |journal=CMAJ |volume=135 |issue=11 |pages=1278–81 |year=1986 |pmid=3779558 |pmc=1491384}}</ref><ref name="pmid2113219">{{cite journal |vauthors=Buysen J, Houthoff H, Krediet R, Arisz L |title=Acute interstitial nephritis: a clinical and morphological study in 27 patients |journal=Nephrol Dial Transplant |volume=5 |issue=2 |pages=94–9 |year=1990 |pmid=2113219 |doi=10.1093/ndt/5.2.94}}</ref>  

When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are fever (27% of patients),<ref name="pmid14671029"/> rash (15% of patients),<ref name="pmid14671029"/> and enlarged kidneys.  Some people experience dysuria, and lower back pain.  

In chronic tubulointerstitial nephritis the patient can experience symptoms such as nausea, vomiting, fatigue, and weight loss.  Other conditions that may develop include a [[Medicine:Hyperkalemia|high concentration of potassium in the blood]], metabolic acidosis, and kidney failure.{{citation needed|date=April 2022}}

===Blood tests===
About 23% of patients have a high level of eosinophils in the blood.<ref name="pmid14671029"/>

===Urinary findings===
Urinary findings include:
* Eosinophiluria: Original studies with Methicillin-induced AIN showed sensitivity of 67% and specificity of 83%.<ref name="pmid11473672"/><ref name="pmid11020015">{{cite journal |vauthors=Schwarz A, Krause P, Kunzendorf U, Keller F, Distler A |title=The outcome of acute interstitial nephritis risk factors for the transition from acute to chronic interstitial nephritis |journal=Clin Nephrol |volume=54 |issue=3 |pages=179–90 |year=2000 |pmid=11020015}}</ref> The sensitivity is higher in patients with interstitial nephritis induced by [[Chemistry:Methicillin|methicillin]] or when the Hansel's stain is used. However, a 2013 study showed that the sensitivity and specificity of urine eosinophil testing are 35.6% and 68% respectively.<ref>{{cite journal |pmid=24052222|pmc=3817898|year=2013|last1=Muriithi|first1=A. K.|title=Utility of urine eosinophils in the diagnosis of acute interstitial nephritis|journal=Clinical Journal of the American Society of Nephrology|volume=8|issue=11|pages=1857–62|last2=Nasr|first2=S. H.|last3=Leung|first3=N.|doi=10.2215/CJN.01330213}}</ref><ref>{{cite journal|pmid=24052220|pmc=3817912|year=2013|last1=Perazella|first1=M. A.|title=Urinary eosinophils in AIN: Farewell to an old biomarker?|journal=Clinical Journal of the American Society of Nephrology|volume=8|issue=11|pages=1841–3|last2=Bomback|first2=A. S.|doi=10.2215/CJN.08620813}}</ref>
* Isosthenuria<ref name="pmid3769228">{{cite journal |vauthors=Lins R, Verpooten G, De Clerck D, De Broe M |title=Urinary indices in acute interstitial nephritis |journal=Clin Nephrol |volume=26 |issue=3 |pages=131–3 |year=1986 |pmid=3769228}}</ref>
* [[Medicine:Hematuria|Blood in the urine]] and occasional RBC casts<ref>{{cite journal|pmid=22677261|year=2012|last1=Fogazzi|first1=G. B.|title=Urinary sediment findings in acute interstitial nephritis|journal=American Journal of Kidney Diseases |volume=60|issue=2|pages=330–2|last2=Ferrari|first2=B.|last3=Garigali|first3=G.|last4=Simonini|first4=P.|last5=Consonni|first5=D.|doi=10.1053/j.ajkd.2012.05.002}}</ref>
* Sterile [[Medicine:Pyuria|pyuria]]: white blood cells and no bacteria. About 50% of patients with AIN have pyuria.<ref name="ReferenceA">Frank B. Cortazar, Zoe A. Kibbelaar, Ilya G. Glezerman, Ala Abudayyeh, Omar Mamlouk, Shveta S. Motwani, Naoka Murakami, Sandra M. Herrmann, Sandhya Manohar, Anushree C. Shirali, Abhijat Kitchlu, Shayan Shirazian, Amer Assal, Anitha Vijayan, Amanda DeMauro Renaghan, David I. Ortiz-Melo, Sunil Rangarajan, A. Bilal Malik, Jonathan J. Hogan, Alex R. Dinh, Daniel Sanghoon Shin, Kristen A. Marrone, Zain Mithani, Douglas B. Johnson, Afrooz Hosseini, Deekchha Uprety, Shreyak Sharma, Shruti Gupta, Kerry L. Reynolds, Meghan E. Sise, David E. Leaf
JASN Feb 2020, 31 (2) 435-446; DOI: 10.1681/ASN.2019070676</ref>
* [[Medicine:Nephrotic syndrome|Nephrotic-range]] amount of protein in the urine may be seen with NSAID-associated AIN. Low grade proteinuria may be seen in a majority of other causes of AIN.<ref name="ReferenceA"/>
* White blood cell (WBC) casts: Fewer than one in five patients with AIN have WBC casts in urine.<ref>Urinary Sediment Findings in Acute Interstitial Nephritis
Fogazzi, Giovanni B. et al.
American Journal of Kidney Diseases, Volume 60, Issue 2, 330 - 332</ref>

=== Pathology ===
While non-invasive patient evaluation (physical examination, blood and urine testing, imaging studies) can be suggestive, the only way to definitively diagnosis interstitial nephritis is with a tissue diagnosis obtained by kidney biopsy. Pathologic examination will reveal the presence of interstitial edema and inflammatory infiltration with various white blood cells, including [[Biology:Neutrophil|neutrophil]]s, [[Biology:Eosinophil|eosinophil]]s, and [[Biology:Lymphocyte|lymphocyte]]s. Generally, blood vessels and glomeruli are not affected. Electron microscopy shows mitochondrial damage in the tubular epithelial cells, vacuoles in the cytoplasm, and enlarged endoplasmic reticulum.<ref>{{Citation|last=Alon|first=Uri S.|chapter=Pediatric Tubulointerstitial Nephritis|date=2015-11-12|pages=1407–1428|publisher=Springer Berlin Heidelberg|isbn=9783662435953|doi=10.1007/978-3-662-43596-0_40|title=Pediatric Nephrology}}</ref>

===Gallium scan===
The sensitivity of an abnormal [[Chemistry:Gallium scan|gallium scan]] has been reported to range from 60%<ref name="pmid6864309">{{cite journal |vauthors=Graham G, Lundy M, Moreno A |title=Failure of Gallium-67 scintigraphy to identify reliably noninfectious interstitial nephritis: concise communication |journal=J Nucl Med |volume=24 |issue=7 |pages=568–70 |year=1983 |pmid=6864309}}</ref> to 100%.<ref name="pmid3862487">{{cite journal |vauthors=Linton A, Richmond J, Clark W, Lindsay R, Driedger A, Lamki L |title=Gallium67 scintigraphy in the diagnosis of acute renal disease |journal=Clin Nephrol |volume=24 |issue=2 |pages=84–7 |year=1985 |pmid=3862487}}</ref> A study of Gallium scan in 76 patients [23 with AIN, 8 with biopsy-proven AIN] showed an AUC of 0.75.<ref>Graham F, Lord M, Froment D, Cardinal H, Bollée G. The use of gallium-67 scintigraphy in the diagnosis of acute interstitial nephritis. Clin Kidney J. 2016;9(1):76-81. doi:10.1093/ckj/sfv129</ref>

===Novel biomarkers===
Given the challenges with clinical diagnosis of AIN due to lack of clinical features and lack of accuracy of existing tests, there has been significant interest in identifying non-invasive biomarkers for this disease. One study showed that monocyte chemotactic protein-1 (chemokine CCL-2) and neutrophil gelatinase associated lipocalin (NGAL) were higher in patients with AIN than in controls (in this case healthy participants).<ref>Wu Y, Yang L, Su T, Wang C, Liu G, Li XM. Pathological significance of a panel of urinary biomarkers in patients with drug-induced tubulointerstitial nephritis. Clin J Am Soc Nephrol. 2010;5(11):1954-1959. doi:10.2215/CJN.02370310</ref> A more recent study, showed that urine cytokines interleukin-9 and tumor necrosis factor-α were higher in patients with AIN than in controls without AIN who underwent a biopsy for evaluation of acute kidney injury and showed an AUC of 0.79.<ref>Moledina DG, Wilson FP, Pober JS, et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight. 2019;4(10):e127456. Published 2019 May 16. doi:10.1172/jci.insight.127456</ref> This study also showed that the biomarkers had higher AUC than the clinician's pre-biopsy impression of AIN and, when added to a model of clinical variables, showed an AUC of 0.84. In a subsequent study, interleukin-9 was also shown to identify patients most likely to respond to corticosteroid therapy.<ref>Dennis G Moledina, F Perry Wilson, Lidiya Kukova, Wassim Obeid, Randy Luciano, Michael Kuperman, Gilbert W Moeckel, Michael Kashgarian, Mark A Perazella, Lloyd G Cantley, Chirag R Parikh, Urine interleukin-9 and tumor necrosis factor-α for prognosis of human acute interstitial nephritis, Nephrology Dialysis Transplantation, 2020;, gfaa169, https://doi.org/10.1093/ndt/gfaa169</ref>

==Treatment==
Treatment consists of addressing the cause,  such as by removing an offending drug. There is no clear evidence that corticosteroids help.<ref name="pmid15340098"/>
Nutrition therapy consists of adequate fluid intake, which can require several liters of extra fluid.<ref>{{cite book |vauthors= Mahan KL, Escott-Stump S |editor= Alexopolos Y |title= Krause's Food, Nutrition, & Diet Therapy |edition= 11th |publisher= Saunders |location= Philadelphia Pennsylvania |isbn= 978-0-7216-9784-0 |chapter= 39 |page= [https://archive.org/details/krausesfoodnutri00maha/page/968 968] |year= 2003 |chapter-url-access= registration |chapter-url= https://archive.org/details/krausesfoodnutri00maha |url= https://archive.org/details/krausesfoodnutri00maha/page/968 }}</ref>

==Prognosis==
The kidneys are the only body system that are directly affected by tubulointerstitial nephritis.  Kidney function is usually reduced; the kidneys can be just slightly dysfunctional, or fail completely.{{citation needed|date=March 2021}}

In chronic tubulointerstitial nephritis, the most serious long-term effect is kidney failure.  When the proximal tubule is injured, sodium, potassium, bicarbonate, [[Chemistry:Uric acid|uric acid]], and phosphate reabsorption may be reduced or changed, resulting in low bicarbonate, known as metabolic acidosis, low potassium, low uric acid known as hypouricemia, and low phosphate known as [[Medicine:Hypophosphatemia|hypophosphatemia]].  Damage to the distal tubule may cause loss of urine-concentrating ability and polyuria.{{citation needed|date=March 2021}}

In most cases of acute tubulointerstitial nephritis, the function of the kidneys will return after the harmful drug is discontinued, or when the underlying disease is cured by treatment.  

If the illness is caused by an allergic reaction, a corticosteroid may speed the recovery kidney function; however, this is often not the case.

Chronic tubulointerstitial nephritis has no cure.  Some patients may require [[Engineering:Kidney dialysis|dialysis]].  Eventually, a kidney transplant may be needed.{{citation needed|date=April 2022}}

== Epidemiology ==
Interstitial nephritis is uncommon (<1% incidence) in patients without any symptoms but occurs in about 10-15% of hospitalized patients with [[Medicine:Acute kidney injury|acute kidney injury]] of unknown cause.<ref name=":0">{{Citation|last1=Brewster|first1=Ursula C.|title=Acute Interstitial Nephritis|date=2014|work=National Kidney Foundation Primer on Kidney Diseases|pages=312–317|edition=6th|publisher=Elsevier|isbn=9781455746170|last2=Rastegar|first2=Asghar|doi=10.1016/b978-1-4557-4617-0.00035-2}}</ref> While it can occur in patients of all ages, it is more common in elderly patients, perhaps due to increased exposure to drugs and other triggering causes.<ref name=":0" />

==References==
{{reflist|30em}}

== External links ==
* [http://www.merck.com/mmpe/sec17/ch236/ch236c.html Merck Manual]

{{Medical resources
|   ICD10          = {{ICD10|N|10||n|10}}-{{ICD10|N|12||n|10}}
|   ICD9           = {{ICD9|580.89}}, {{ICD9|581.89}}, {{ICD9|582.89}}, {{ICD9|583.89}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    = 000464
|   eMedicineSubj  = med
|   eMedicineTopic = 1596
|   DiseasesDB     = 6854
|   MeshID         = D009395
}}
{{Nephrology}}

{{DEFAULTSORT:Interstitial Nephritis}}
[[Category:Kidney diseases]]

{{Sourceattribution|Interstitial nephritis}}