Slides includes the introduction to drug induced renal disease, pathogenic mechanism by which drug acts on kidney, list of drugs and risk factors. pathogenic mechanism like altered Interglomerular, Rhabdomyolysis, tubular toxicity, etc.

1. DRUG INDUCED RENAL
DISEASE & RENAL DIALYSIS
Presented By-
Vaishnavi Kishor Nikte
M pharmacy (Clinical Pharmacy)
First Year Sem 2nd
Guided By-
Dr. S. D. Patil Mam
Head of Department
Dept of Clinical Pharmacy

2. Content
 Introduction
 Epidemiology
 Pathogenic Mechanism
1. Altered Intraglomerular Hemodynamics
2. Tubular Cell Toxicity
3. Inflammation
4. Crystal Nephropathy
5. Rhabdomyolysis
6. Thrombotic Microangiopathy
 Drugs

3. Introduction & Epidemiology
 Nephrotoxic drugs generally induce inflammation in glomerulus and proximal tubules which
disturbs the kidney functions and leads to toxicity known as glomerulonephritis and
intestinal nephritis
 Drugs cause approximately 20 percent of community-and hospital-acquired episodes of acute
renal failure.
 Among older adults, the incidence of drug-induced nephrotoxicity may be as high as 66
percent.
 Patients at highest risk of drug-induced nephrotoxicity are those with one or more of the
following: age older than 60 years, baseline renal insufficiency (e.g., GFR < 60 mL per
minute per 1.73 m2), volume depletion, multiple exposures to nephrotoxins, diabetes, heart
failure, and sepsis.
 Aminoglycosides, ACE Inhibitors, NSAIDS most common Nephrotoxic Drugs.

4. The drug-related renal syndromes include:
1. Acute renal failure.
2. Nephrotoxic syndrome..
3. Renal tubular dysfunction.
4. Chronic renal failure.
5. Glomerulonephritis.
6. Cytotoxicity of renal tubular cells.

6. Pathogenic Mechanisms-
1. ALTERED INTRAGLOMERULAR HEMODYNAMICS
 The kidney maintains or autoregulates intraglomerular pressure by modulating the afferent and
efferent arterial tone to preserve GFR and urine output.
 For instance, in patients with volume depletion, renal perfusion depends on circulating
prostaglandins to vasodilate the afferent arterioles, allowing more blood flow through the
glomerulus.
 Drugs
a) Angiotensin-converting enzyme ACE inhibitors.
b) Angiotensin receptor blockers ARBs.
c) Nonsteroidal anti-inflammatory drugs [NSAIDs].
d) Calcineurin inhibitors (e.g., cyclosporine [Neoral], tacrolimus [Prograf]).

7. 2. TUBULAR CELL TOXICITY-
 In particular proximal tubule cells, are vulnerable to the toxic effects of drugs.
 Their role in concentrating and reabsorbing glomerular filtrate exposes them to high
levels of circulating toxins.
 Drugs that cause tubular cell toxicity do so by impairing mitochondrial function, interfering
with tubular transport, increasing oxidative stress, or forming free radicals.
a) Aminoglycosides,
b) Amphotericin B (Fungizone; brand not available in the United States)
c) Antiretrovirals (adefovir [Hepsera], cidofovir [Vistide], tenofovir [Viread])
d) Cisplatin (Platinol),
e) Contrast dye,
f) Oscarnet (Foscavir),
g) Zoledronate (Zometa)

8. 3. INFLAMMATION- Glomerulonephritis
 Drugs
a) Gold therapy,
b) Hydralazine (Apresoline; brand not available in the United States),
c) Interferon-alfa (Intron A),
d) Lithium,
e) NSAIDs,
f) Propylthiouracil,
g) Pamidronate.
 Acute interstitial nephritis are thought to bind to antigens in the kidney or act as antigens that are then
deposited into the interstitium, inducing an immune reaction. However, classic symptoms of a
hypersensitivity reaction (i.e., fever, rash, and eosinophilia) are not always observed.
a) Allopurinol (Zyloprim);
b) Antibiotics (especially beta lactams, quinolones, rifampin [Rifadin], sulfonamides, and vancomycin
[Vancocin]);
c) Antivirals (especially acyclovir [Zovirax] and indinavir [Crixivan]);
d) Diuretics (loops, thiazides);
e) NSAIDs; phenytoin (Dilantin);
f) Proton pump inhibitors (especially omeprazole [Prilosec],
g) Pantoprazole [Protonix], lansoprazole [Prevacid]); ranitidine (Zantac).

9.  Chronic interstitial nephritis is less likely than acute interstitial nephritis to be drug
induced; it is also insidious in onset, and signs of hypersensitivity are often lacking.
Drugs
a) Calcineurin inhibitors (e.g., cyclosporine, tacrolimus),
b) Chemotherapy agents,
c) Aristocholic acid,
d) Lithium
e) Analgesics such as acetaminophen, aspirin,
f) NSAIDs when used chronically in high dosage.
(more than 1 gram daily for more than two years) or in patients with preexisting kidney disease.)
chronic interstitial nephritis has been known to progress to end-stage renal disease

10. 4. CRYSTAL NEPHROPATHY-
 Renal impairment may result from the use of drugs that produce crystals that
are insoluble in human urine.
 The crystals precipitate, usually within the distal tubular lumen, obstructing
urine flow and eliciting an interstitial reaction.
a) Antibiotics (e.g., ampicillin, ciprofloxacin [Cipro], sulfonamides);
b) Antivirals (e.g., acyclovir, foscarnet, ganciclovir [Cytovene]); indinavir;
methotrexate; triamterene (Dyrenium).
Chemotherapy for lymphoproliferative disease, leading to tumor lysis syndrome
with uric acid and calcium phosphate crystal deposition, has also been associated
with renal failure.

11. 5. RHABDOMYOLYSIS-
 Rhabdomyolysis is a syndrome in which skeletal muscle injury leads to lysis of the myocyte, releasing
intracellular contents including myoglobin and creatine kinase into the plasma.
 Myoglobin induces renal injury secondary to direct toxicity, tubular obstruction, and alterations in GFR.
 Drugs may induce rhabdomyolysis directly secondary to a toxic effect on myocyte function, or indirectly
by predisposing the myocyte to injury.
 Clinical manifestations of rhabdomyolysis include
 Weakness,
 Myalgia,
 Tea colored urine.
Drugs-
a) Statins
b) Cocaine,
c) Heroin,
d) Ketamine (Ketalar),
e) Methadone,
f) Methamphetamine.

12. 6. THROMBOTIC MICROANGIOPATHY
 In thrombotic microangiopathy, organ damage is caused by platelet thrombi in the
microcirculation, as in thrombotic thrombocytopenic purpura.
 Mechanisms of renal injury secondary to drug-induced thrombotic microangiopathy
include an immune-mediated reaction or direct endothelial toxicity.
Drugs
Antiplatelet agents
(e.g., clopidogrel [Plavix], ticlopidine [Ticlid]), cyclosporine, mitomycin-C (Mutamycin), and
quinine (Qualaquin).

13. Aminoglycosides (AMG)-
Clinical features –
Classically it presents as acute tubular necrosis which is generally milder than oliguric ARF.
Features include:
Non-oliguric ARF, proximal tubular dysfunction, enzymuria, proteinuria, glycosuria, hypokalemia,
hypocalcemia, hypomagnesemia.
Some patients may progress to chronic interstitial nephritis.
Mechanisms-
 The drug is actively concentrated in the renal cortex and proximal tubular cells achieve maximum
concentration.
 After entering the cortical cells AMG bind to lysosomes with formation of myeloid bodies/secondary
lysosomes.
 There after mechanisms are unclear. It is believed that the release of AMG into cytoplasm interferes
with the phosphatidyl-inositol pathway.
Relative toxicities (in decreasing order)
Neomycin > Gentamycin > Tobramycin > Netilmicin > Amikacin > Streptomycin

14. B-Lactams and vancomycin-
True nephrotoxicity is rare. Acute interstitial nephritis (AIN) may be seen especially with
methicillin.
Early formulations of vancomycin had substantial nephrotoxic potential due to impurities but
current preparations are free from adverse effect.
AMG + vancomycin combination may have synergistic toxicity.
Sulfonamides-
Spectrum of nephrotoxicity includes
1.Acute interstitial nephritis (not common)
2.Necrotizing arteritis
3.ARF due to massive hemolytic anemia in G-6-PD deficient patients
4.ARF due to crystalluria (seen only with long-acting agents like sulphadiazine)
Sulfadiazine-
prototype drug causing crystalluria and ARF.

15. Acyclovir-
 Doses > 500 mg/m2 given i.e. leads to nephrotoxicity.10 Its low solubility leads to intratubular
symptoms of obstructive uropathy and hematuria.
 Urine analysis reveals birefringent needle-shaped crystals.
 Interstitial inflammation is seen adjacent to areas of intratubular obstruction.
 Oliguria is very rare.
Amphotericin-B (Am-B)-
 It contains hydrophilic as well as lipophilic regions; allowing it to easily mingle with cellular
membranes, disrupting them and increasing their permeability.
 Disruption of cell membranes leads to endothelial damage with vasoconstriction of afferent and
efferent arterioles, causing an acute fall in GFR and an initial oliguric ARF in some patients.
 Tubular toxicity is related to direct effect on cellular membrane and also medullary ischemia
caused by sudden vasoconstriction.

16. Clinical spectrum of amphotericin nephrotoxicity
1.Azotemia : It is almost universal with Am-B. GFR falls to 40% in first 2-3 weeks and stabilizes at 20-60% of
normal throughout course of treatment; normalizing on cessation of therapy. Cumulative doses of 3-4g have
greater risk; implying a greater incidence with longer duration of therapy and greater chances of irreversibility as
well.
2.Inability to concentrate urine occurs universally within 1-2 weeks of therapy even in absence of decrease in
GFR and is not related to occurrence of azotemia. It occurs due to failure of arginine-vasopression (AVP)
response on medullary collecting tubule.
3.Electrolyte disturbance occurs as a consequence of distal tubulopathy with predominantly- Mg2+ and K+ loss
is important as it may cause worsening of renal function with impairment of concentration ability, urinary
acidification, renal insufficiency.
4.Renal tubular acidosis can occur at cumulative doses of 0.5-1 g but is reversible.

17. NSAID-induced renal diseases-
Syndromes of NSAID nephrotoxicity
 ARF - usually oliguric
 Acute interstitial nephritis (AIN) - Associated with heavy proteinuria (> 3 g/24 hr); usually
non-oliguric; rarely without proteinuria; takes weeks or months to resolve
 Hyperkalemia
 Sodium and water retention 5. Hypertension

18. Gold and D-penicillamine
• Penicillamine –
7% develop nephrotic syndrome with kidney biopsy demonstrating membranous
nephropathy.
Proteinuria may occur at six months to six years.
• Gold –
Proteinuria
Parenteral gold is more likely to cause proteinuria.

19. Renal Dialysis-
A process for separating substances from a liquid,
especially for taking waste substances out
of the blood of people with damaged kidneys.
You need dialysis when you develop end stage kidney
failure --usually by the time you lose about 85 to 90
percent of your kidney function and have a GFR of <15.
What are the types of dialysis?
There are two ways to get dialysis:
•Hemodialysis.
•Peritoneal dialysis.
What is hemodialysis?
With hemodialysis, a machine removes blood from your body, filters it through a dialyzer
(artificial kidney) and returns the cleaned blood to your body. This 3- to 5-hour process may
take place in a hospital or a dialysis center three times a week.

20. Cont.…
Before you start hemodialysis, you’ll undergo a minor surgical procedure to make it easier to
access the bloodstream. You may have:
•Arteriovenous fistula (AV fistula): A surgeon connects an artery and vein in your arm.
•Arteriovenous graft (AV graft): If the artery and vein are too short to connect, your
surgeon will use a graft (soft, hollow tube) to connect the artery and vein.
AV fistulas and grafts enlarge the connected artery and vein, which makes dialysis access
easier. They also help blood flow in and out of your body faster.
If dialysis needs to happen quickly, your provider may place a catheter (thin tube) into a vein
in your neck, chest or leg for temporary access.

21. What is Peritoneal Dialysis?
With peritoneal dialysis, tiny blood vessels inside
the abdominal lining (peritoneum) filter blood
through the aid of a dialysis solution.
This solution is a type of cleansing liquid
that contains water, salt and other additives.
There are two ways to do this treatment:
•Automated peritoneal dialysis uses a machine called a cycler.
•Continuous ambulatory peritoneal dialysis (CAPD) takes place manually.
About three weeks before you start peritoneal dialysis, you’ll have a minor surgical procedure.
A surgeon inserts a soft, thin tube (catheter) through your belly and into the peritoneum. This
catheter stays in place permanently.

22. MCQs
Pathogenic Mechanism by which Drug cause Kidney Disease?
1. Altered Intraglomerular Hemodynamics
2. Tubular Cell Toxicity
3. Inflammation
4. Crystal Nephropathy
5. Rhabdomyolysis
6. Thrombotic Microangiopathy
7. All
Most common Drug causing nephrotoxicity
1. Amphotericin B
2. Aminoglycosides
3. ACE inhibitors
4. All
Risk factors GFR <60 ml/1.73m2
1. True
2. False

23. What is Rhabdomyolysis?
1. Skeletal muscle injury leads to lysis of the myocyte, releasing intracellular contents including
myoglobin and creatine kinase into the plasma.
2. Tissue injury
3. None
4. Both
Biomarkers to estimate Nephrotoxicity
1. Creatinine Clearance
2. Urine output
3. Serum Creatinine
4. eGFR
5. All
Which Drug cause toxicity by precipitation
1. Ampicillin
2. Ciprofloxacin
3. Anti-viral drugs
4. All

24. Aminoglycosides pathogenic pathway
1. Tubular cell toxicity
2. Rhabdomyolysis
3. Inflammation
4. None
Types of Dialysis
1. Haemodialysis
2. Peritoneal dialysis
3. Both
What is dialysate
cleansing liquid that contains water, salt and other additives.

25. References-
1) Naughton C. A. (2008). Drug-induced nephrotoxicity. American family physician, 78(6), 743–750.
2) Ghane Shahrbaf, F., & Assadi, F. (2015). Drug-induced renal disorders. Journal of renal injury
prevention, 4(3), 57–60. https://doi.org/10.12861/jrip.2015.12
3) Drug-induced Kidney Diseases NP Singh*, A Ganguli**, A Prakash *Professor; **Postgraduate Student;
***Senior Resident; Nephrology Division, Department of Medicine, Maulana Azad Medical College and Lok
Nayak Hospital, New Delhi - 110 002. Received : 3.4.2003; Revised : 22.5.2003; Accepted : 1.9.2003.
4) www.Lexicomp.com
5) Joseph T. Dipiro et al. Pharmacotherapy: a Pathophysiologic Approach - Appleton & Lange; Drug Induced
Renal Disease; Page no. 871-887.
6) https://my.clevelandclinic.org/health/treatments/14618-dialysis
7) https://www.kidney.org/atoz/content/dialysisinfo