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Interstitial nephritis, also known as tubulointerstitial nephritis, is
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
of the area of the
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
known as the renal interstitium, which consists of a collection of cells,
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struct ...
, and fluid surrounding the
renal tubules The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
. 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 The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...
functions of the kidney. 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. 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. 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. With modern drugs causing between 70 and 90% of current cases, the possibility of a change in presentation exists.


Causes

Common causes include infection, or reaction to medication such as an
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It i ...
,
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as op ...
, or
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s such as methicillin (
meticillin Methicillin ( USAN), also known as meticillin ( INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class. Methicillin was discovered in 1960. Medical uses Compared to other penicillins that face antimicrobial resistance d ...
). Reaction to medications causes 71% to 92% of cases.


Drugs


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
pyelonephritis Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may i ...
, 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
β-lactam antibiotic β-lactam antibiotics (beta-lactam antibiotics) are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives ( penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and ...
s such as
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
and
cephalexin Cefalexin, also spelled cephalexin, is an antibiotic that can treat a number of bacterial infections. It kills gram-positive and some gram-negative bacteria by disrupting the growth of the bacterial cell wall. Cefalexin is a beta-lactam antibio ...
, and nonsteroidal anti-inflammatory drugs (
aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...
less frequently than others), as well as
proton-pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitors ...
s,
rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used t ...
, sulfa medications,
fluoroquinolone A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as we ...
s,
diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s,
allopurinol Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...
,
mesalamine Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is a medication used to treat inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is generally used for mildly to moderately severe disease. It ...
, and
phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The int ...
. The time between exposure to the drug and the development of acute tubulointerstitial nephritis can be anywhere from 5 days to 5 months (
fenoprofen Fenoprofen is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. Fenoprofen is ...
-induced).


Diagnosis

The condition can appear without symptoms. When present they may appear widely varied and can occur rapidly or gradually. When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are fever (27% of patients), rash (15% of patients), and enlarged kidneys. Some people experience
dysuria Dysuria refers to painful or uncomfortable urination. It is one of a constellation of ''irritative'' bladder symptoms (also sometimes referred to as lower urinary tract symptoms), which includes nocturia and urinary frequency. Diagnosis The clin ...
, 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 high concentration of potassium in the blood,
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, and kidney failure.


Blood tests

About 23% of patients have a high level of eosinophils in the blood.


Urinary findings

Urinary findings include: *
Eosinophiluria Eosinophiluria is the abnormal presence of eosinophils in the urine. It can be measured by detecting levels of eosinophil cationic protein. Associated conditions It can be associated with a wide variety of conditions, including: * Kidney disorders ...
: Original studies with Methicillin-induced AIN showed sensitivity of 67% and specificity of 83%. The sensitivity is higher in patients with interstitial nephritis induced by
methicillin Methicillin ( USAN), also known as meticillin ( INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class. Methicillin was discovered in 1960. Medical uses Compared to other penicillins that face antimicrobial resistance du ...
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. *
Isosthenuria Isosthenuria refers to the excretion of urine whose specific gravity (concentration) is neither greater (more concentrated) nor less (more diluted) than that of protein-free plasma, typically 1.008-1.012. Isosthenuria reflects damage to the kidney' ...
*
Blood in the urine Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...
and occasional RBC casts * Sterile
pyuria Pyuria is the condition of urine containing white blood cells or pus. Defined as the presence of 6-10 or more neutrophils per high power field of unspun, voided mid-stream urine, it can be a sign of a bacterial urinary tract infection. Pyuria ma ...
: white blood cells and no bacteria. About 50% of patients with AIN have pyuria.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 * 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. * White blood cell (WBC) casts: Fewer than one in five patients with AIN have WBC casts in urine.


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
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s,
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. ...
s, and
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
s. Generally, blood vessels and
glomeruli ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filt ...
are not affected. Electron microscopy shows mitochondrial damage in the tubular epithelial cells, vacuoles in the cytoplasm, and enlarged endoplasmic reticulum.


Gallium scan

The sensitivity of an abnormal
gallium scan A gallium scan is a type of nuclear medicine test that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gal ...
has been reported to range from 60% to 100%. A study of Gallium scan in 76 patients 3 with AIN, 8 with biopsy-proven AINshowed an AUC of 0.75.


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). 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. 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.


Treatment

Treatment consists of addressing the cause, such as by removing an offending drug. There is no clear evidence that
corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
help. Nutrition therapy consists of adequate fluid intake, which can require several liters of extra fluid.


Prognosis

The
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s 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. In chronic tubulointerstitial nephritis, the most serious long-term effect is kidney failure. When the proximal tubule is injured, sodium, potassium, bicarbonate,
uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown o ...
, and phosphate reabsorption may be reduced or changed, resulting in low bicarbonate, known as
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, low potassium, low uric acid known as
hypouricemia Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper thres ...
, and low phosphate known as
hypophosphatemia Hypophosphatemia is an electrolyte disorder in which there is a low level of phosphate in the blood. Symptoms may include weakness, trouble breathing, and loss of appetite. Complications may include seizures, coma, rhabdomyolysis, or softening o ...
. Damage to the distal tubule may cause loss of urine-concentrating ability and
polyuria Polyuria () is excessive or an abnormally large production or passage of urine (greater than 2.5 L or 3 L over 24 hours in adults). Increased production and passage of urine may also be termed diuresis. Polyuria often appears in conjunction wit ...
. 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 dialysis. Eventually, a kidney transplant may be needed.


Epidemiology

Interstitial nephritis is uncommon (<1% incidence) in patients without any symptoms but occurs in about 10-15% of hospitalized patients with
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are cl ...
of unknown cause. 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.


References


External links


Merck Manual
{{DEFAULTSORT:Interstitial Nephritis IgG4-related disease Kidney diseases Nephrology