The kidney maintains the vital functions of clearing excess body fluid and removing metabolic and exogenous toxins from the blood The kidney is particularly vulnerable to drugs and other agents that cause renal damage The heart pumps approximately 25% of cardiac output into the kidneys Any drug in the blood will eventually reach the highly vascularized kidneys It may potentially cause drug induced renal failure If the drug is primarily cleared by the kidney, the drug will become increasingly concentrated as it moves from the renal artery into the smaller vasculature of the kidney The drug may be filtered or secreted into the lumen of the renal tubules The concentrated drug exposes the kidney tissue to far greater drug concentration per surface area Drug-induced kidney disease or nephrotoxicity (DIN) is a relatively common complication of several diagnostic and therapeutic agents.

1. ANTIMICROBIAL INDUCED RENAL FAILURE
PRESENTED BY:
Dr.SHAISTA SUMAYYA
PHARMD, DEPT. OF PHARMACY PRACTICE
SULTAN UL ULOOM COLLEGE OF PHARMACY,
HYDERABAD
GUIDED BY:
Dr. S.P
.SRINIVAS NAYAK
ASSISTANT PROFESSOR, SUCP
1

2. INTRODUCTION
 The kidney maintains the vital functions of clearing excess body fluid and removing
metabolic and exogenous toxins from the blood
 The kidney is particularly vulnerable to drugs and other agents that cause renal damage
 The heart pumps approximately 25% of cardiac output into the kidneys
 Any drug in the blood will eventually reach the highly vascularized kidneys
 It may potentially cause drug induced renal failure
 If the drug is primarily cleared by the kidney, the drug will become increasingly concentrated
as it moves from the renal artery into the smaller vasculature of the kidney
 The drug may be filtered or secreted into the lumen of the renal tubules
 The concentrated drug exposes the kidney tissue to far greater drug concentration per
surface area
 Drug-induced kidney disease or nephrotoxicity (DIN) is a relatively common complication of
several diagnostic and therapeutic agents.
2

3. CLINICAL PRESENTATION
GENERAL
• Decline in GFR leading to
rise in Scr and BUN
• Malaise, anorexia, SOB,
oedema, vomiting
SIGNS
• Decreased urine output
• Proximal tubular injury:
Metabolic acidosis,
glycosuria, reduction in
serum phosphate, uric acid,
K, Mg
• Distal tubular injury:
Polyuria, metabolic acidosis,
hyperkalaemia
DIAGNOSTIC TESTS
• Proximal tubular injury
markers: Gamma glutamyl
transpeptidase, glutathione
S transferase, interleukin –
18
• Kidney injury molecule –
1: Expressed in proximal
tubular injury and
upregulated in ischemic
acute tubular necrosis –
appears within 12 hrs.
• Neutrophil gelatinase
associated lipocalin:
protein detected in urine
within 3hrs of ischemic injury
3

4. PATHOGENIC MECHANISMS
CLASSIFICATION PATHOGENESIS DRUGS
 Tubular epithelial cell damage  Acute tubular necrosis • Aminoglycoside antibiotics
• Amphotericin B
• Cisplatin, carboplatin
 Hemodynamically mediated kidney
injury
------------ • Angiotensin-converting enzyme
inhibitors
• Angiotensin II receptor blockers
• Nonsteroidal anti-inflammatory drugs
 Obstructive nephropathy  Intratubular obstruction
 Nephrolithiasis
• Acyclovir
• Sulphonamides
 Glomerular disease • Nonsteroidal anti-inflammatory drugs,
cyclooxygenase-2 inhibitors
 Tubulointerstitial disease  Acute allergic interstitial nephritis
 Papillary necrosis
• Ciprofloxacin
• Penicillins
• Nonsteroidal anti-inflammatory drugs,
combined phenacetin, aspirin, and
caffeine analgesics
 Renal vasculitis, thrombosis, and
cholesterol emboli
 Vasculitis and thrombosis
 Cholesterol emboli
• Allopurinol
• Penicillamine
• Warfarin
4

5. DRUGS CAUSING ACUTE RENAL FAILURE
 Many medicines can cause acute kidney injury (which used to be called acute renal failure), such
as:
 Antibiotics. These include aminoglycosides, cephalosporins, amphotericin B, bacitracin, and
vancomycin.
 Antihypertensive: ACE inhibitors, such as lisinopril and ramipril; Angiotensin receptor blockers,
such as candesartan and valsartan.
 Anticancer drugs (chemotherapy): Examples are cisplatin, carboplatin, and methotrexate.
 Dyes (contrast media):These are used in medical imaging tests.
 Illegal drugs: Examples are heroin and methamphetamine.
 Antiviral drugs: Examples are indinavir and ritonavir, acyclovir
 Non-steroidal anti-inflammatory drugs: These include ibuprofen, ketoprofen, and naproxen.
 Anti Ulcer medicines: One example is cimetidine.
5

6. ANTIMICROBIALS CAUSING RENAL FAILURE
 Aminoglycosides
 Amphotericin – B
 Trimethoprim
 B – lactam antibiotics
 Fluoroquinolones
 Vancomycin
 Acyclovir
 Tetracyclins
6

7. MECHANISMS OF ANTIMICROBIAL
INDUCED AUTE RENAL FAILURE
7

8. Aminoglycoside Nephrotoxicity
 Pathogenesis:
 Aminoglycosides are believed to cause nephrotoxicity via Tubular epithelial cell
damage i.e. acute tubular necrosis
 The reduction of GFR in patients receiving aminoglycosides is predominantly the
result of proximal tubular epithelial cell damage leading to obstruction of the tubular
lumen and back leakage of the glomerular filtrate across the damaged tubular
epithelium.
 Toxicity may be related to cationic charge, which facilitates binding of filtered
aminoglycosides to renal tubular epithelial cell luminal membranes, followed by
intracellular transport and concentration in lysosomes.
8

9.  Cellular dysfunction and death may result from release of lysosomal enzymes
into the cytosol, generation of reactive oxygen species, altered cellular
metabolism, and alterations in cell membrane fluidity, leading to reduced
activity of membrane-bound enzymes, including Na+-K+- ATPase, dipeptidyl
peptidase IV, and neutral amino peptidase.
 Aminoglycosides preferentially affect the proximal tubular cells.
 These agents are freely filtered by the glomeruli and quickly taken up by the
proximal tubular epithelial cells, where they are incorporated into lysosomes
after first interacting with phospholipids on the brush border membranes.
 They exert their main toxic effect within the tubular cell by altering
phospholipid metabolism.
 In addition to their direct effect on cells, aminoglycosides cause renal
vasoconstriction.
9

10.  Approximately 5% of the administered dose accumulates within epithelial
cells after glomerular filtration
 Aminoglycoside uptake by the tubules is a saturable phenomenon, so
uptake is limited after a single dose.
 Thus, a single daily large dose is preferable to 3 doses per day.
 Aminoglycosides have molecular weight of approximately 500 Dalton and
are water-soluble and minimally protein bound.
 The primary route of elimination from the body is glomerular filtration,
which is nearly equal to inulin clearance.
 The serum half-life of aminoglycosides is a few hours as compared to 4 to
5 days in proximal tubule cells.
10

11. 11

12. RISK FACTORS
Increased risk
 Fluid depletion
 Potassium and magnesium deficiency
 Endotoxaemia
 Pre-existing renal disease
 Advanced age
 Co-administration of other nephrotoxins
 Lengthy duration of treatment
 Repeated courses of aminoglycosides
 Liver disease
 Obesity/male sex
Decreased risk
 Organic polycations
 Urinary alkalinisation
 Thyroid hormone
 Potassium loading
12

13. PREVENTION
 Use of alternative antibiotics - fluoroquinolones (e.g., ciprofloxacin or levofloxacin) and
third- or fourth-generation cephalosporins (e.g., ceftazidime or cefepime)
 When aminoglycosides are necessary, the specific drug used does not appear to
significantly affect the risk of nephrotoxicity, and therapy should be selected to optimize
antimicrobial efficacy
 Avoid volume depletion
 Limit the total aminoglycoside dose administered
 Avoid concomitant therapy with other nephrotoxic drugs
 once-daily dosing. (Although greater clinical efficacy and reduced nephrotoxicity may be
realized with once-daily compared to standard dosing, seriously ill, immunocompromised,
and elderly patients, as well as patients with preexisting kidney disease, are not ideal
candidates for this approach because of altered aminoglycoside clearance in these
patients).
13

14. AMPHOTERICIN B NEPHROTOXICITY
 Amphotericin B remains the anti-fungal drug of choice for most systemic infections, but a
limiting factor for its use is the development of nephrotoxicity.
 Amphotericin B is believed to cause nephrotoxicity via Tubular epithelial cell damage i.e.
acute tubular necrosis
 The mechanisms of kidney injury include direct tubular epithelial cell toxicity with increased
tubular permeability and necrosis, as well as arterial vasoconstriction and ischemic injury.
 Overall, the combined effects of increased cell energy and oxygen requirements because of
greater cell membrane permeability, and reduced cellular oxygen delivery because of renal
vasoconstriction, result in renal medullary tubular epithelial cell necrosis and kidney injury
 Direct cell membrane actions increase permeability, as well as indirect effects secondary to
activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators
(thromboxane A2).
 The back-leak of hydrogen ions in the collecting duct leads to distal renal tubular acidosis
(dRTA).
14

15.  Amphotericin B binds to sterols in cell membranes, thereby creating pores that
compromise membrane integrity and increase membrane permeability.
 It binds not only to ergosterol in fungal cell walls but also to cholesterol in human cell
membranes; this is what accounts for its nephrotoxicity.
 The prediction of the kidney for amphotericin B toxicity is unclear as little drug is excreted
by the kidneys.
 Toxicity is manifested by increased renal vascular resistance, depression of RBF and
GFR, and altered tubular function that reflects the capacity of this drug to interact with
cholesterol-containing membranes and increase membrane permeability to ions
including potassium, hydrogen, calcium, and magnesium.
 Lipid-based preparations of amphotericin B decrease but do not eliminate the
nephrotoxicity compared with traditional amphotericin B.
 This may be due to a direct nephrotoxic effect of the conventional preparation.
15

16. 16

17. Risk Factors
 CKD
 Higher average daily doses
 Volume depletion
 Concomitant administration of diuretics and other nephrotoxins
(cyclosporine in particular).
 Rapid infusions of amphotericin B [A recent comparison of 24-hour
continuous infusions with conventional 4- hour infusions revealed a
significant reduction of toxicity, attributed to decreased “pretubular” effects
(e.g., effects on renal blood flow and GFR).]
17

18. Prevention
 Several liposomal amphotericin B formulations are now available and
should be used in most high-risk patients as they have been reported to
reduce nephrotoxicity by enhancing drug delivery to sites of infection,
thereby reducing exposure of mammalian cell membranes.
 Nephrotoxicity can also be minimized by limiting the cumulative dose and
avoiding concomitant administration of other nephrotoxins, particularly
cyclosporine.
 Additionally, providing hydration with 1 L intravenous 0.9% sodium chloride
daily during the course of therapy appears to reduce toxicity.
18

19. TRIMETHOPRIM
 Acute interstitial nephritis (AIN) is thought to be the usual mechanism.
 Trimethoprim (TMP) is known to cause reversible increases in serum creatinine, reportedly
by inhibiting its renal tubular secretion without causing a change in the glomerular filtration
rate.
 Patients with an initially normal renal function also needed to have an increase in BUN of
10 mg/dL, and those with chronic kidney disease needed to exhibit an increase in BUN of
≥50% in order to be classified in the AKI group
 The increase in serum creatinine causes an apparent decrease in the
calculated creatinine clearance.
 Renal disorders associated with its use include decreased creatinine secretion,
interstitial nephritis, and hypernatremia
 Hyperkalemia has been demonstrated to occur with the administration of both high and
standard dosages of trimethoprim
19

20.  Trimethoprim reduces renal potassium excretion through the competitive inhibition of epithelial
sodium channels in the distal nephron, in a manner identical to the potassium-sparing diuretic
amiloride
 Hyperkalemia and non-oliguric renal failure has been associated with trimethoprim use
 Trimethoprim alone can cause an important but reversible increase in serum creatinine
concentration in acute uncomplicated cystitis and in chronic renal failure
20

21. RISK FACTORS
 Acute uncomplicated cystitis
 Chronic renal failure
 Patients with hypertension and diabetes mellitus had an increased risk
for AKI, especially if these conditions were poorly controlled
 Disturbances in potassium homeostasis:
 Hyopoaldosteronism
 Treatment with medications that impair renal potassium excretion
21

22. PREVENTION
 Recognition of patients at risk of developing hyperkalemia as well as
proper dosage selection of trimethoprim for the patient's prevailing
glomerular filtration rate
 Volume repletion with isotonic fluids
 Other therapies specific to hyperkalemia
 Discontinuation of the drug
 In circumstances where continued treatment with trimethoprim is
required, induction of high urinary flow rates with intravenous fluids
and a loop diuretic, as well as alkalinisation of the urine, have been
shown to block the antikaliuretic effect of trimethoprim on distal
nephron cells
22

23. B – LACTAM ANTIBIOTICS
 Acute interstitial nephritis (AIN) is thought to be the usual mechanism.
 The nephrotoxic beta-lactam antibiotics cause acute proximal tubular necrosis.
 Significant renal toxicity, which has been rare with the penicillins and uncommon with the cephalosporins, with a
greater risk with the penems.
 The beta-lactams most nephrotoxic are cephaloridine, cephaloglycin, and imipenem
 Antibiotic concentrations in the tubular cell, determined by the net effects of contraluminal secretory transport and
subsequent movement across the luminal membrane, make the proximal tubule the sole target of injury, and are
important determinants of the nephrotoxic potentials of different beta-lactams
 Mechanisms of injury include:
 (1) Transport into the tubular cell, mainly through the antiluminal organic anion secretory carrier;
 (2) Acylation of target proteins, causing respiratory toxicity by inactivation of mitochondrial anionic substrate carriers;
and
 (3) Lipid peroxidation.
 Depressed mitochondrial respiration secondary to acylation of the mitochondrial transporter for succinate has been
implicated in the pathogenesis of toxicity caused by cephalosporins and carbapenems
 Lipid peroxidation appears to play a major role in the toxicity of cephaloridine.
23

24.  Cephaloridine has several unique properties, probably all caused by its pyridinium
side-group:
 (1) Its secretory transport into the tubular cell is followed by minimal cell to luminal fluid
movement, resulting in extreme intracellular sequestration;
 (2) It is the only beta-lactam shown to cause significant oxidative injury;
 (3) It has a limited ability to attack the mitochondrial carriers for pyruvate and the short-
chain fatty anions.
 Cephaloglycin and imipenem undergo less intracellular trapping than cephaloridine, but
have sufficient tubular cell uptake, reactivity, and generalized toxicity to mitochondrial
substrate carriers to be severely nephrotoxic.
 Several of the cephalosporin and carbapenem antibiotics produce acute renal failure
when given in large single doses.
 Imipenem, the first carbapenem released for c1inical use, and the one with the best-
described nephrotoxic potential
24

25. Clinical presentation
 Clinical signs present approximately 14 days after initiation of therapy
 Fever, maculopapular rash, eosinophilia, pyuria and haematuria, low-level
proteinuria, and oliguria
 Systemic hypersensitivity findings of fever, rash, eosinophilia, and
eosinophiluria
 Eosinophiluria, an important marker of drug-induced AIN, is frequently absent,
possibly because of fragility of eosinophils in urine and inadequate laboratory
methodology
 Anaemia, leucocytosis, and elevated immunoglobulin E levels may occur.
 Tubular dysfunction may be manifested by acidosis, hyperkalaemia, salt
wasting, and concentrating defects.
25

26. RISK FACTORS AND PREVENTION
 Concomitant administration with
Aminoglycosides
 Renal ischemia and
 Endotoxemia
 Prevention of nephrotoxicity of imipenem:
 Use cilastatin along with imipenem
26

27. FLUROQUINOLONES
 Nephrotoxic reactions to ciprofloxacin appear to be unusual but potentially serious.
 It has previously been reported that fluoroquinolones could cause acute renal failure
(ARF) after the ingestion of large quantities, but it is now recognized that therapeutic
doses of fluoroquinolones can also cause renal injury.
 Allergic interstitial nephritis (AIN) is thought to be the most common cause and is
attributed to hypersensitivity reaction type III, while a ciprofloxacin overdose often
causes acute tubular necrosis (ATN);
 The normal dose range for ciprofloxacin is between 500 and 750 mg/12 h).
 Fluoroquinolones have also been reported to cause granulomatous interstitial
nephritis, characterized by infiltration of the renal tissue by histiocytes and T
lymphocytes, leading to the formation of granulomas
27

28.  Ciprofloxacin causes crystal nephropathy
 Ciprofloxacin crystals precipitate in alkaline urine and provoke renal failure
through intra-tubular precipitation.
 Ciprofloxacin can cause crystalluria in alkaline urine especially at pH>7.3
 The combined use of fluoroquinolones and renin-angiotensin system
blockers was associated with a greater risk for acute kidney injury
28

29. VANCOMYCIN
 Vancomycin has been used for over 60 years to treat methicillin-resistant S. aureus and
various resistant gram-positive infections. This antibiotic is commonly linked to
nephrotoxicity, leading to the need for aggressive monitoring with regularly measured
vancomycin trough levels
 Vancomycin is eliminated primarily through glomerular filtration and active tubular
secretion.
 The half-life in adults with normal renal function is 4 to 8 hours.
 Vancomycin-induced acute kidney injury is histologically characterized by acute
interstitial nephritis and/or acute tubular necrosis.
 use of the antibiotic causes oxidative effects on the proximal renal tubule resulting in
renal tubular ischemia.
 The drug has also been shown to interfere with the normal reabsorption function of the
proximal renal tubule epithelium and alter the mitochondrial function of these cells.
 Ultimately, vancomycin-induced renal toxicity is likely due to a combination of these
oxidative effects and allergic interstitial nephritis.
29

30. 30

31. RISK FACTORS
 Vancomycin exposure related
factors
• Doses of vancomycin in excess of 4 g/day
• Prolonged duration of treatment
• Larger vancomycin exposures, such as troughs >15 mg/L
• Treatment with vancomycin beyond 1 week increases the incidence of
nephrotoxicity from 6% to 21%, and the incidence is close to 30% with more than
2 weeks of therapy.
 Host-related factors • Previous history of acute kidney injury
• Preexisting renal insufficiency
• Sepsis
• Critical illnesses.
 use of concurrent nephrotoxins • Loop diuretics
• Acyclovir
• Amphotericin B
• Aminoglycosides (The concurrent use of aminoglycosides with vancomycin has
been associated with a 20% to 30% increase in renal injury)
31

32. PREVENTION
 Most mild cases of vancomycin nephrotoxicity resolve upon discontinuation of the
medication.
 Aggressive drug elimination is indicated in patients with severely elevated plasma
vancomycin concentrations compounded by impaired clearance due to oliguria, as
this further increases the risk of permanent renal damage.
 Standard membrane dialysis is ineffective in clearing large mass molecules such as
vancomycin, but high-flux hemodialysis allows for improved elimination of large
molecules, with a reported vancomycin removal rate of up to 79%
 Oral prednisone and high-flux hemodialysis have led to the successful recovery of
renal function in some biopsy-proven cases.
32

33. ACYCLOVIR
 Acyclovir is an important antiviral agent in the therapy of herpes simplex and varicella
zoster virus infections. Although the drug is well tolerated, severe nephrotoxicity, which
often leads to acute renal failure, has been observed in patients
 A diagnosis of drug-related acute tubulointerstitial nephritis with focal tubular necrosis
was made.
 Acyclovir-induced renal failure occurs in approximately 12–48 % of cases.
 The optimal usage of acyclovir is very important in order to avoid its potentially life-
threatening complications.
 Acyclovir-induced nephrotoxicity is typically evident by an increase in the plasma
creatinine level, abnormal urine sediment, or acute renal injury.
 Acyclovir is rapidly excreted in the urine via glomerular filtration and tubular secretion, and
reaches high concentrations in the tubular lumen.
33

34.  Renal excretion of unchanged drug reaches approximately
60–90 % .
 Acyclovir is relatively insoluble in the urine, particularly in
the distal tubular lumen.
 Rapid intravenous administration of high-dose acyclovir is
associated with high luminal concentrations of this drug and
the intratubular precipitation of crystals can cause renal
injury.
 Typically, crystalluria develops within 24–48 h of the
initiation of acyclovir therapy.
 Severe intraparenchymal precipitation of crystals can cause
interstitial congestion and hemorrhage, leading to a
decrease of renal blood flow
34

35. RISK FACTORS AND PREVENTION
 RISK FACTORS
 The administration of high doses of acyclovir (≥1500 mg/m2 per day) with other nephrotoxic agents
 pre-existing renal disease
 dehydration
 Rapid intravenous administration of high-dose acyclovir
 PREVENTION
 Acyclovir dose should be reduced in patients with underlying renal insufficiency.
 Slow drug infusion, over 1–2 h
 Adequate fluid replacement
 Induction of high urinary flow rates (100–150 ml/h) should be encouraged in order to prevent crystal
precipitation and subsequent tubular obstruction
 Initiation of dialysis when indicated.
 Hemodialysis removes substantial amounts of acyclovir.
 Peritoneal dialysis is less effective and should not be used
35

36. TETRACYCLINS
 Kidney damage:
 It is a risk only in the presence of existing kidney disease.
 All tetracyclines, except doxycycline, accumulate and enhance renal
failure.
 A reversible Fanconi syndrome like condition is produced by outdated
tetracyclines.
 This is caused by degraded products—epitetracycline, anhydrotetracycline
and epianhydrotetracycline which damage proximal tubules.
 Exposure to acidic pH, moisture and heat favours such degradation.
36

37. THANK YOU
37