European Journal of Internal Medicine xxx (xxxx) xxx
Contents lists available at ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
Review Article
Toxic nephropathy: Adverse renal effects caused by drugs
Robert J. Unwin
Department of Renal Medicine, Royal Free Hospital Trust, University College London, Rowland Hill Street, London NW3 2PF, UK
A R T I C L E I N F O
A B S T R A C T
Keywords:
Drug toxicity
Nephrotoxicity
Kidney
Proximal tubule
Mitochondria
This is a brief overview of toxic nephropathy, which is an increasingly recognised problem with the continual
introduction of new drugs and novel drug modalities, especially in oncology, and the risks associated with
polypharmacy in many patients; although it is important to remember that it may not always be caused by a
drug. It is also important to note that several possibly harmful drugs are now available without prescription
(‘over-the-counter’) and can be purchased easily over the internet, including some poorly characterised herbal
remedies. Knowing exactly what our patients are taking as medication is not always easy and patients often fail
to mention drugs that may not have been prescribed by a doctor or recommended by a pharmacist. Moreover,
patients with several comorbidities often require care from more than one doctor in other specialties, which can
also lead to drug prescribing in isolation.
This article will summarise some key aspects of drug nephrotoxicity and provide a few clinical pointers to
consider, bearing in mind that there is rarely any antidote available, and effective treatment relies on early
detection, prompt drug withdrawal, and supportive care. This short review is intended only as a primer to
highlight some of the more practical aspects of toxic nephropathy; its content is based on a lecture delivered
during the 2021 European Congress of Internal Medicine.
1. Introduction
According to Paracelsus, the Swiss Physician in the 1500s who has
been likened to Hippocrates, ‘only the dose makes the poison’; while this is
still largely true for most drugs or known poisons, it is not so for many
idiosyncratic or ‘allergic’ drug reactions, or for those compounds with a
narrow margin of safety (MOS).1 The kidneys are often the main target
organ affected by many poisons and drug-related adverse reactions;
however, the topic of toxic nephropathy is potentially very broad, since
there is a lot that we cannot know or predict about potential environ­
mental toxins or until some time after a new therapeutic agent has been
introduced clinically and used on a large-scale, which can take several
years of post-marketing surveillance. Therefore, vigilance is paramount
and it is important to be aware of some general principles when it comes
to deciding whether an ingested product or new drug is a cause of renal
injury.
I will try to summarise some topical aspects, including acute versus
chronic kidney injury, and cover nephrotoxicity more generally, as well
as some specific developments with already known potential drug
nephrotoxins still used widely in clinical practice. I will also consider the
ongoing and slightly contentious issue of ’analgesic nephropathy’,
1
especially in relation to commonly prescribed non-steroidal anti-in­
flammatory drugs (NSAID).
2. Early history and some examples
Since mediaeval times, poisoning has been a popular means of
murder or assassination, and if not sudden or immediate, often kidney
failure has been the likely and eventual cause of death, although difficult
to confirm. Commonly used poisons for this purpose have been arsenic
and strychnine, which can both affect the kidneys. Arsenic, as for other
heavy metals, which are all potential environmental toxins [1], can
cause acute and chronic renal toxicity. The free ionised form is directly
toxic to renal tubular cells, although the means by which it enters these
cells is still unclear, but may involve the glucose transporter GLUT1 [2]
present in the proximal tubule, where As3+ then depletes cellular
glutathione, triggers inflammatory cytokine release, and disrupts mito­
chondrial function [3]; chronic toxicity results from the protein bound
and inert form that is conjugated to metallothioneins and glutathione in
the liver (which also expresses GLUT1, as well AQP9, a more important
uptake mechanism for arsenic and confined to hepatocytes [4]), which
when released into the circulation is again reabsorbed by the proximal
E-mail address: robert.unwin@ucl.ac.uk.
MOS = ratio of the lethal dose in 1% of the population to the effective dose in 99% of the population = LD1/ED99
https://doi.org/10.1016/j.ejim.2021.09.008
Received 22 July 2021; Received in revised form 29 August 2021; Accepted 15 September 2021
0953-6205/© 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Robert J. Unwin, European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2021.09.008
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tubule, this time by a megalin-dependent receptor-mediated endocytic
process (see Fig. 1), and once inside the cell is slowly released to cause
chronic damage [5]. A similar pattern of toxicity is seen with cadmium
and lead [6,7].
The renal proximal tubule is particularly sensitive to all forms of
toxic damage (see later), including ischaemic injury as a cause of acute
kidney injury (AKI or what used to be called ATN, acute tubular ne­
crosis). This sensitivity to injury is probably for several reasons [8]. The
proximal tubule is an important site of solute reabsorption, requiring a
lot of energy (in the form of ATP), which is reflected in the large number
of mitochondria these tubular cells contain, and their dependence for
ATP generation on fatty acid oxidation, rather than glycolysis. The
proximal tubule is also a major site for xenobiotic metabolism (cyto­
chrome P450 and conjugating enzymes, cf. liver) and excretion [9,10]. It
also has the distinctive and promiscuous megalin-dependent transport
mechanism already mentioned for the uptake of various filtered mole­
cules, including some drugs, especially antibiotics, and small (low mo­
lecular weight) proteins (LMWP) and peptides (Fig. 1). Thus, given the
rich blood supply to the kidney for filtration, the proximal tubule, which
is the first part of the nephron (Fig. 1), is exposed to high levels of most
circulating factors, including drugs.
In contrast to arsenic, another favoured poison is strychnine, a
neurotoxin that causes kidney injury indirectly as a result of intense
muscle spasm (opisthotonos), leading to muscle injury and rhabdo­
myolysis with release of myoglobin (myoglobinuria). Myoglobin is also
reabsorbed by the megalin-dependent mechanism in the early proximal
tubule (Fig. 1) and transferred to lysosomes from which the toxic ironheme portion of myoglobin is released into the cell causing acute
tubular cell injury (AKI). In the tropics, snake venom is a common cause
of poisoning and can have a similar effect, resulting in acute haemolysis
(with haemoglobinuria), muscle necrosis (myoglobinuria) and severe
coagulation defects (disseminated intravascular coagulation, DIC, and
thrombotic microangiopathy, TMA, which can both also be infrequently
drug-related), leading to AKI with a high mortality [11] (see Fig. 2).
Furthermore, complications similar to those seen after snake venom
poisoning can occur in patients with the not uncommon genetically
X-linked deficiency of the enzyme glucose-6-phosphate dehydrogenase
(G6PD) following exposure to various drugs, particularly sulphonamide
derivatives; G6PD deficiency is found more commonly in Africa, the
Middle East and Southeast Asia, and in up to 10% of African American
males [12].
This is why alerting and reporting schemes are an important part of
long-term monitoring and surveillance, and can help to avoid prescrip­
tion errors and ensure a regular review of medication [20,21]. Patients
with CKD often take more than five different drugs singly or in combi­
nation, and may also take ‘over-the-counter’ (OTC) remedies that do not
require a prescription. A recent CKD cohort study from Germany using
an untargeted mass spectrometry-based approach to analyse for drug
metabolites in urine, found that while this confirmed a generally good
match with self-reported medications, and therefore treatment compli­
ance; it also revealed use of OTC analgesics, mainly NSAID, than was
disclosed by patients, as well as combination drugs that patients may be
unaware of, and drugs prescribed by other specialists such as neurolo­
gists or psychiatrists [22].
Efforts are ongoing to identify and develop biomarkers, particularly
in urine, which can be used to detect kidney glomerular or tubular
injury: the Predictive Safety Testing Consortium (PSTC) has qualified at
least seven biomarkers for approved preclinical and clinical use in drug
safety - see Table 1 [23]. While the markers listed may be of use in
screening for AKI preclinically and in early phase clinical trials, less is
known about any variation in levels in normal urine or in established
CKD, other than for albumin and protein, and how these newer injury
biomarkers may change with treatment.
Six reminders or R’s for DIKD have been proposed by Awdishu and
Mehta [24], which are quite useful in highlighting what should be
considered when faced with a case of suspected nephrotoxicity. The first
step is identify who is at Risk (1) in relation to the drug and patient
characteristics; Recognise (2) a sudden deterioration in renal function
(AKI/DIKD2); Respond (3) promptly by withdrawing the causative drug
and provide whatever support is available and appropriate, including
Renal (4) support; Rehabilitate (5) by careful follow up, including drug
monitoring, if the drug implicated is still required, or avoid drug
re-exposure; and support Research (6) through good documentation and
participation in local and national adverse drug reporting schemes.
Drug targets and mechanisms that commonly underlie nephrotoxi­
city are summarised in Table 2 with some examples. However, most are
based on clinical observation and experience, rather than any detailed
understanding of pathological mechanisms or ability to predict [25]. We
have only a rudimentary knowledge of the pathobiology of renal toxicity
for most drugs and this is still an important area for future research, but
it depends critically on an alert physician recognising and reporting any
clinically observed association between a drug and DIKD.
3. A little more background
4. Predisposing factors and sites of injury
Adverse drug reactions can be broadly classified as either Type A and
dose-dependent or Type B and idiosyncratic (‘allergic’). Drug-induced
kidney damage (DIKD), a term beginning to be used to help stage or
grade nephrotoxicity2, is estimated to cause around 20% of community
and in-hospital AKI in adults and children; it is also more common in an
intensive care setting with multiple drug (mainly high dose antibiotic)
use, in the elderly, and in those with significant co-morbidities such as
diabetes, cardiovascular disease (CVD) and chronic kidney disease
(CKD) [13]. Of those drugs known to have adverse renal effects and may
be taken deliberately to self-harm, or accidentally, over 50% of patients
will experience serious kidney-related complications and are more likely
to need renal replacement (dialysis support). The most commonly
implicated drugs causing more acute toxicity are antibiotics, antivirals,
chemotherapeutics, angiotensin-converting enzyme inhibitors (ACEi),
NSAID, and unspecified herbal remedies, especially those containing
aristolochic acid [14,15].
Kidney-related safety failures in drug development make up about
10% [16], and while in vitro methods for acute nephrotoxicity screening
are improving with, for example, the use of organoids and ‘kid­
ney-on-chip’, and there is a better understanding of some of the key
enzymes involved in drug metabolism (e.g., P450 family mentioned
earlier) [17–19], it is still difficult to reliably predict chronic toxicity.
The kidney receives approximately 20% of the cardiac output and so
drug delivery and exposure are high, and it is important to consider
those factors that can determine the potential for drug toxicity: the drug
itself, for example, if renally excreted, its urine solubility (precipitation –
ampicillin, indinavir), possible direct actions on the kidney, interactions
with other drugs, including effects they may have on excretion, and
patient characteristics, including age, sex and race, which can all affect
drug handling and metabolism, as well as co-morbidities such as CKD or
liver disease [19]. Pharmacogenetics: genetic polymorphisms that sub­
tly alter drug transport or metabolism are becoming increasingly
important and are beginning to be screened for; an early example was
the discovery of ‘fast’ or ‘slow’ acetylator status for the antihypertensive
drug hydralazine, which can affect blood pressure control and the risk of
a lupus-like adverse drug reaction [26,27].
Both drug-related glomerular and tubular cell toxicity can occur.
Direct glomerular podocyte injury leads to proteinuria (minimal change
2
KDIGO definition of Acute Kidney Injury, AKI, is a 50% rise in serum
creatinine in <7 days, often within 24-48 h; AKD, Acute Kidney Disease is
duration of 7-90 days and established CKD > 90 days. DIKD can be defined
similarly as acute (1-7 days), sub-acute (8-90 days) and chronic (>90 days).
2
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European Journal of Internal Medicine xxx (xxxx) xxx
R.J. Unwin
Fig. 1.. Diagram of the proximal tubule showing individual cells with the transport mechanisms discussed (see text for details). The main solute transporters for
bicarbonate (sodium-hydrogen ion exchanger NHE-3), glucose (SGLT2), phosphate (NPT2a and 2c) and amino acids (aa) are shown, together with the megalin- (with
cubilin) dependent uptake mechanism for low molecular weight proteins (LMWP) and peptides, which cycles its ligands through endosomes to lysosomes. The
sodium pump that energises sodium-coupled transport is shown at the basolateral membrane of the cell. The small figure inset (top right) for orientation is a
schematic of a nephron: G, glomerulus; PT, proximal tubule; LOH, loop of Henle; DT, distal tubule; CD, collecting duct.
Fig. 2.. Schematic of the mechanisms involved in snake venom-mediated kidney injury. GFR, glomerular filtration rate; RBF, renal blood flow; AKI, acute kidney
injury. Many of these pathological mechanisms are also seen with some drug-related causes of nephrotoxicity.
Table 1.
See text for details. Examples of approved urinary biomarkers for detecting kidney glomerular and tubular damage. KIM-1, kidney injury marker 1; CLU, clusterin;
TFF3, trefoil factor 3; SCr, serum creatinine; BUN, blood urea nitrogen. Apart from albumin and total protein, the most widely used markers currently are KIM-1 and
cystatin-C. While β2-microglobulin as a low molecular weight protein (LMWP) can be used as an early marker of proximal tubular injury, because its reabsorption is
megalin-dependent; circulating levels can be elevated in a variety of situations, including CKD. The LMWPs retinol binding protein (RBP) and/or α1-microglubulin may
be more useful for this purpose in clinical practice. Other biomarkers of tubular injury include lipocalin (NGAL) and osteopontin, but they have limited specificity.
Biomarker (urine)
Preclinical
Clinical
Complements SCr/BUN
Superior to SCr/BUN
KIM-1
Albumin
CLU
TFF3
Total protein
Cystatin C
β2-microglobulin
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
Y
3
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and has significant energy demands with a heavy reliance on mito­
chondrial ATP generation.
Tenofovir is taken up by proximal tubular cells via the organic anion
transporter, OAT1, expressed on the basolateral cell membrane, and is
eliminated by secretion via the multidrug resistant protein, MRP4, on
the apical membrane. Disturbed secretion by, for example, a drug-drug
interaction (DDI) inhibiting or competing with MRP (e.g., NSAIDs), can
lead to the intracellular accumulation of tenofovir causing mitochon­
drial damage. Probenecid is a well-described inhibitor of OAT1 and has
been shown to reduce the toxicity of the related drug cidofovir [33], but
it can be difficult to predict the outcome of such drug interactions, since
probenecid is not selective and can also inhibit MRP (Fig. 1). A related
example is cisplatin nephrotoxicity. Cisplatin is also taken up by prox­
imal tubular cells, but in this instance via the organic cation transporter,
OCT2 (Fig. 1) and it is secreted via the multidrug and toxin extrusion
protein, MATE1. As with probenecid, in this case cimetidine can be used
to block OCT2 and cisplatin uptake, but it can also inhibit MATE1
responsible for cisplatin extrusion. However, in practice cimetidine’s
overall effect is to limit cisplatin-related nephrotoxicity [34]. Finally, an
important feature of this type of nephrotoxicity is that the tubular injury
markers in urine described earlier (see Table 1), including LMWP like
RBP and other indices of proximal tubular function (e.g., glycosuria with
normoglycaemia), can be used to detect proximal tubular damage. These
urinary biomarkers should be used more widely in conjunction with
changes in serum creatinine or urea when a suspicion of drug nephro­
toxicity is raised. However, efforts to identify nephron site-specific
(Fig. 1) injury biomarkers in urine are still in their infancy, although
certain urinary miRNAs show some promise [35].
Returning briefly to tenofovir, there are currently two forms avail­
able, TDF (tenofovir disoproxil fumarate) and TAV (tenofovir alafena­
mide), the former being the first shown to be nephrotoxic, as described
above. While TAF still has the potential to cause renal toxicity, since it is
also excreted by the kidney, its different pharmacokinetic (PK) proper­
ties are such that it accumulates more rapidly in peripheral blood
monocytes (the target cells) and its peak plasma levels tend to be lower
than with TDF, and so it is less of a renal burden for excretion; these PK
differences make it less nephrotoxic compared with TDF [36].
It is worth mentioning at this point that creatinine excretion is also
dependent on MATE1, OCT2 and (preferentially) OAT2; thus, a rise in
serum creatinine may indicate a DDI, rather than renal toxicity, for
example, with trimethoprim, cimetidine (see above) or pyrimethamine.
These drugs can also reduce metformin excretion, which is MATE1-
Table 2.
Sites of nephrotoxicity, mechanism, and some corresponding examples.
Pathophysiology and Target
Corresponding Examples
Glomerular (MCD, FSGS, MN, TMA,
Inflammatory)
Tubular
Crystal (Nephrolithiasis)
NSAID, IFN, VEGF, CNI, Hydralazine
Acute Interstitial Nephritis (AIN/AKI)
Chronic Interstitial Nephritis (CKD)
Rhabdomyolysis (AKI)
Hyperosmolarity
Antibiotics, Antiretrovirals
Antibiotics, Antiretrovirals, CA
inhibitors
Antibiotics, NSAIDS, PPIs, Any drug
Analgesics(?), Herbal (aristolochic
acid)
Statins, Drugs of abuse (cocaine, MDA,
alcohol)
IV dextrans, IgG
disease and focal segmental glomerulosclerosis, both causes of the
nephrotic syndrome), endothelial injury, microthrombosis (TMA
mentioned earlier), and mesangial cell injury to nodular sclerosis.
Glomerular immune-mediated injury can also occur with some drugs
that induce immune complex formation (causing a lupus-like nephritis see hydralazine above - or membranous nephropathy with proteinuria)
and ANCA-related small vessel vasculitis, again with hydralazine [28].
Tubular injury usually results from mitochondrial or lysosomal toxicity
(see Fig. 2). Because these sites of injury are relatively localised, prog­
ress has been made in creating ‘organs on a chip’, perfused tubules and
isolated glomeruli or ‘organoids’ containing all the cell types referred to
above; these are becoming a valuable means of screening new drugs for
potential nephrotoxicity.
As an example: an interesting case illustrated in Fig. 2 is the toxicity
of the antiretroviral drug tenofovir [29]. This only became apparent
when patients treated with this drug became hypophosphataemic and
complained of musculoskeletal aches and pains, prompting in some
cases bone scans that showed signs of osteomalacia [30] and features
seen typically in patients with oncogenic osteomalacia [31] (Fig. 3).
Many patients were also found to have proteinuria on urine dipstick
testing, which turned out to be mainly albumin and LMWP such as
retinol binding protein (RBP). These findings pointed to an abnormality
of kidney proximal tubular reabsorptive capacity, and disturbed mito­
chondrial function was soon identified as the underlying cause with
typical features of a renal Fanconi syndrome [32]. On stopping the drug
these abnormalities gradually reversed. As mentioned earlier, the
proximal tubule is something of a reabsorbing and secreting ‘workhorse’
Fig. 3.. (a) 99m-Technectium bone appearances in a patient on tenofovir showing an increased bone to soft tissue ratio and ‘hot spot’ pattern typical of osteomalacia
and also seen in patients with oncogenic osteomalacia. (b) Renal biopsy electron micrographs (EM) from a patient on tenofovir showing abnormally enlarged
mitochondria that have lost their normal crista pattern.
4
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dependent, and is an important DDI to look out for in diabetic patients
[33]. Remember also that initial increases in serum creatinine are often
seen with drugs that have short-term haemodynamic effects that can
reduce GFR, including RAAS and SGLT2 inhibitors, which do not herald
nephrotoxicity, although still need monitoring, and that changes in
muscle mass can be an additional confounder.
and macroscopic haematuria occasional. Proteinuria is unusual and
rarely nephrotic range, but when this occurs it is usually due to NSAIDs.
AIN is increasingly associated with other drugs such as proton pump
inhibitors, 5-aminosalicylates and NSAIDs, and may not be evident early
on; however, almost any drug can be implicated and AIN should always
be considered when confronted with a patient with unexplained loss of
renal function, even if not acute. AIN is not dependent on the drug dose
and is an idiosyncratic (Type B) reaction that still has an unclear im­
mune basis and it may take time to develop. There is no known bio­
logical predilection, other than polypharmacy. The topic of AIN has
been reviewed comprehensively by Perazella and co-workers, who have
written extensively on the subject in recent years [47]. As to treatment,
this remains uncertain, although the current consensus is a trial of
high-dose steroids started early and for up to one month [48]. More
recently, immunotherapy with immune checkpoint inhibitors, a class of
drug that has revolutionised cancer therapy, is increasingly being re­
ported as a cause of drug-related AKI, which seems to be due to
immune-related AIN and can be responsive to a course of steroids [49].
However, the need to stop the inhibitor may be problematic for the
patient, as may the use of high-dose steroids, and confirmation of AIN
with a renal biopsy is generally recommended [50].
5. Analgesic nephropathy: does it exist?
This has been a hotly debated topic for many years, the first reports
coming from Switzerland in the 1950s [37] and a seeming epidemic of
cases in reports from Australia in the 1960s of phenacetin-containing
analgesics associated with renal papillary necrosis, particularly in
women, which initially was taken to be ‘cause-and-effect’ [38]. This led
to the withdrawal of phenacetin, which did seem to be associated with a
decline in papillary necrosis cases [39], but there was always some
concern that this drug was often taken in combination with other
compounds, including opiates and caffeine [40], and it wasn’t always
clear what else might have been taken by affected patients, usually for
recurrent or chronic headache. Papillary necrosis with calcification can
be diagnosed on a CT scan, which has been advocated as a screening
examination with a claimed high sensitivity and specificity for the
diagnosis of analgesic nephropathy [41]; although there are other cau­
ses of papillary necrosis that may be coincidentally associated with
increased analgesic use, such as diabetic kidney disease, recurrent uri­
nary tract infections (pyelonephritis), urinary tract obstruction, and
sickle cell disease.
Paracetamol was also invoked as a cause of analgesic nephropathy
early on [42] (prompting widespread disagreement at the time and
since), probably because it was sometimes co-prescribed with phenac­
etin and that a major product of phenacetin metabolism is paracetamol.
But it is now thought that the other metabolite of phenacetin, p-phe­
netidine, is probably the toxic culprit, being an extremely potent in­
hibitor of prostaglandin (PGE2) synthesis, unlike paracetamol or
phenacetin itself [43]. Moreover, subsequent case series have not shown
that paracetamol is a cause of analgesic nephropathy [44,45].
It was later claimed that chronic NSAID use is another potential
cause of analgesic nephropathy and chronic kidney disease (CKD).
Although there are certainly situations in which this might occur more
acutely (AKI), particularly in combination with an ACEi or angiotensin
receptor blocker (ARB), or when given to an elderly and dehydrated
patient, it has not been clearly established that NSAIDs cause analgesic
nephropathy. However, they are a recognised cause of acute interstitial
nephritis (AIN) (see later), which can lead to residual renal damage and
CKD. However, a recent US cohort study in 3000 older (mean age 74)
patients with a record of GFR values for ten years could find no evidence
of an association between self-reported NSAID use and loss of renal
function, including measurement of the renal injury biomarkers IL-18
and KIM-1: mean baseline eGFR was 70 ml/min and did not change
significantly [46]. That said, some caution is still appropriate in those
with pre-existing renal impairment and occasional monitoring of renal
function, especially soon after initiation of treatment, is recommended.
However, bear in mind that NSAIDs can be an important means of
controlling pain and discomfort in those with chronic arthritis and
should not be withheld without good reason.
7. What next?
As mentioned already, awareness is the key, particularly with the
ever-increasing number of new drugs being introduced, including the
newer modalities (monoclonal antibodies, antisense oligonucleotides,
RNA- and DNA- based therapies, etc) and the increasing tendency for
patients to be taking more than one drug or drug combination. Efforts to
improve early drug screening for potential nephrotoxicity are proceed­
ing apace, both with novel biomarkers of kidney injury that can also
indicate the likely nephron site of toxicity, more sophisticated and in­
tegrated cell-based kidney models in vitro [8,18], as well as electronic
alerting systems being introduced and trialled to detect early cases of
AKI that are often drug-related [20].
Finally, the clinical challenge is knowing when a drug is a potential
cause of nephrotoxicity and in always being cognizant of that possibility.
Acknowledgments
The author is currently employed by AstraZeneca Bio­
pharmaceuticals R&D, Cardiovascular, Renal and Metabolism (CVRM),
Cambridge UK.
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6. Acute interstitial nephritis (AIN) and AKI
This is characterised by a sudden decline in renal function (AKI)
associated with an interstitial inflammatory infiltrate seen in biopsy
tissue from the kidney. While an inflammatory infiltrate is detected in
around 1-3% of all renal biopsies, it is found in up to 30% of patients
with AKI, but is not consistently diagnostic of AIN. Approximately 75%
of cases of AIN are drug-related with antibiotics causing a third or more
of cases and often associated with a skin rash, and blood and urine
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5
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6
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10, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.