(i) Clinically distinct forms of nephrotoxicity (nephritic syndrome, acute and chronic tubular necrosis, acute vs. chronic interstitial nephritis, forms of renal failure etc.).

(ii) Mechanism of action of prototype nephrotoxins (NSAIDs, ACE inhibitors, antimicrobials, antineoplastics, radiocontrast agents etc.).

(iii) Nephrotoxicity originating from iatrogenic episodes (EDs, hospitals, health care settings).

(v) Kidney injury prevention strategies, anti-nephrotoxic antidotes.

(vi) Clinical diagnosis of kidney injury, prevention strategies; Clinical management of kidney injury (Ex. Cisplatin & Radio Contrast Agents)

[Iatrogenic episode and Case study]

PRINCIPLES OF NEPHROTOXICITY AND IATROGENIC KIDNEY INJURY: 2 HOURS

This topic will assist in Meeting the Following Curricular Endpoints pertaining to Nephrotoxicity-

Gather and organize accurately and comprehensive patient information to identify ongoing or potential drug therapy problems. (A1a)

Interpret and evaluate patient and drug-related data needed to identify actual or potential drug therapy problems. (A1b)

Counsel patients to ensure appropriate pharmaceutical care outcomes, and institute programs to maximize compliance to drug regimens. (A1e)

Identify and report medication errors and adverse drug reactions to appropriate individuals and organizations. (B2a)

Evaluate information obtained from adverse drug reaction and medication error reporting systems to identify preventable causes. (B2b)

Recommend and implement actions to minimize the occurrence of adverse drug reactions and medication errors in a healthcare system. (B2c)

This section will assist in Meeting some of the Following Course-specific Endpoints pertaining to Drug-Induced Nephrotoxicity and Kidney Diseases of Iatrogenic Origin--

Select appropriate drug therapy based on mechanism of drug action via integration of knowledge gained from the drug structure with concepts of organic chemistry, anatomy, physiology, pharmacotherapy and pharmacology. (A1c)Given patient-specific information, select optimal therapeutic agents based on their binding sites and molecular mechanisms of action, which account for relative drug potencies, efficacies and therapeutic outcomes. (A1c, A1g, B2b)Discuss the pathophysiological factors contributing to a specific patient problem and disease state. (A1a, A1b, A1c)Predict therapeutic applications for individual drugs based on knowledge of chemical and/or pharmacologic classification, and address appropriately adverse drug reactions, drug-drug interactions, nutritional effects, and lack of efficacy. (A1a, A1b, A1g)Predict and prevent drug-drug interactions, drug-food interactions, drug-herbal interactions, and drug side effects and toxicities by applying knowledge of structural features and other chemical principles. (A1g, B2b) Identify the cause and significance of adverse drug effects (A1b).Address and prevent side effects and toxicities from therapeutic agents and xenobiotics by applying knowledge of mechanisms of toxicity. (A1g, B2b)Address and prevent drug-drug interactions, drug-food interactions, and drug-nutraceutical interactions by applying knowledge of pharmacodynamic and pharmacokinetic principles. (A1g, B2b)Respond accurately and appropriately to questions related, either directly or indirectly, to biological activity of drugs/chemicals, posed by patients and other health care professionals. (A1e)Recognize potential problems in disease prevention initiatives by utilizing knowledge of toxicological principles. (A1g, A2b, B2b)

Course-specific Learning/Behavioral Objectives: After taking this course the student should be able to:

Describe the mechanisms for drug-induced nephrotoxicity including various forms of kidney injury. Describe nephrotoxicity specifically originating from iatrogenic causes [in pharmacies, EDs, hospitals, and in several other health-care settings and care-givers]. Describe the importance of the bioactivation process for those drugs which become pharmacologically & toxicologically more active as compared to the parent compound following biotransformation. Describe the importance of poisoning and overdose, their manifestations (iatrogenically or non-iatrogenically), prevention strategies utilized in the management for some prototype prescription and non-prescription drugs. To understand the general principles of clinical toxicology and know general factors (both iatrogenic and non-iatrogenic) that influence toxicity.To understand the initial approach to the poisoned patient in terms of setting immediate priorities, and to appreciate the necessity to conduct, as the first order of business, those procedures that evaluate and preserve vital signs.To understand role and function of Poison Control Centers and TESS in toxicity management. To determine what aspects of the physical examination and what diagnostic tests are to be conducted to evaluate the general type as well as the specifics of the poisoning, and to understand the goals of treatment e.g. to treat the patient, not the poison, promptly and design strategies for treatment.To understand and design specific approaches for reducing the body burden of various toxic substances/poisons and minimizing iatrogenic episodes caused in healthcare settings. Incorporate biologic markers into iatrogenic/toxicologic evaluations of human populations; and recognize, evaluate and control specific sources of iatrogenic exposures, including air pollution, water pollution and hazardous waste. Identify important iatrogenic, chemical, physical and other exposures in the environment that can affect the health of human populations.

Many substances are known to cause renal toxicity or dysfunction. The kidneys are particularly susceptible to toxic injury for a number of reasons:

I. The kidneys are a pair of fist-sized organs that are located on either side of the spinal column just behind the lower abdomen (l1-3).

Ii. A kidney consists of an outer layer (renal cortex) and an inner region (renal medulla).

Iii. The functional unit of the kidney is the nephron; each kidney has approximately 106 nephrons.

Iv. Kidneys handle 20-25% of cardiac output, yet make up less than 1% of the total body mass; hence any toxic substance in the blood is likely to affect the kidneys.

V. The kidneys are metabolically active & thus vulnerable to agents that disrupt metabolism.

Vi. They remove water from the filtrate and are capable of building up a high conc. Of toxic substances.

Vii. The renal glomeruli & interstitium are susceptible to activation of the immune mechanisms.

Viii. The other factors such as renal perfusion, may uniquely affect an individual’s reaction to a particular nephrotoxin.

FYI--NEPHROTOXICITY OVERVIEW

After injury, changes can occur in the cytoskeleton and in the normal distribution of membrane proteins such as Na+, K+-ATPase and integrins in sublethally injured renal tubular cells.

These changes result in:i) Loss of cell polarity,ii) Tight junction integrity, and Iii) Cell-substrate adhesion

Lethally injured cells undergo necrosis or apoptosis, And both dead and viable cells may be sloughed-off into the tubular lumen

Adhesion of sloughed cells to other sloughed cells, & to cells remaining adherent to the basement membrane may result in cast formation, tubular obstruction, & further compromise the glomerular filtration rate.

MECHANISMS THAT BY-AND-LARGE CONTRIBUTE TO THE DEVELOPMENT OF

NEPHROTOXICITY

Q. HOW MANY NEPHRONS OUR KIDNEYS HAVE?

1 MIL IN EACH2 MIL TOTAL

SLOUGHING-OFF OF VIABLE & NON-VIABLE CELLS WITH INTRALUMINAL CELL-CELL ADHESION

INTACT TUBULAR EPITHELIUM

I) LOSS OF CELL POLARITYII) TIGHT JUNCTION INTEGRITY III) CELL-SUBSTRATE ADHESION

CAST FORMATION & TUBULAR OBSTRUCTION

TOXIC INJURY

• RADIOCONTRAST AGENTS

• AMINOGLYCOSIDES

• CHEMOTHERAPY (CISPLATIN)

• HEAVY METALS (LITHIUM, CADMIUM, LEAD, MERCURY)

• AMPHOTHERICIN B

• NSAIDS/ACETAMINOPHEN

• ACE INHIBITORS (ACEI’s)

• CRYSTAL-INDUCED ACUTE RENAL FAILURE

• CALCINEURIN INHIBITORS (CYCLOSPORINE, TACROLIMUS)

DRUGS AND CHEMICALS WITH NEPHROTOXIC POTENTIAL (FYI)

APPEARANCE AFTER RENAL FAILURE

WHOLE KIDNEY

LONGITUDINAL SECTION

HUMAN KIDNEY:OVERVIEW OF GROSS ANATOMY

POLYCYSTIC KIDNEY DISEASE (PKD): AN EXAMPLE OF A KIDNEY DISEASEPKD is a disorder in which clusters of cysts develop primarily on kidneys. Cysts are noncancerous sacs containing water-like fluid. Kidneys usually are the most severely affected organs. The greatest risk for people with PKD is developing HIGH BLOOD PRESSURE. Kidney failure also is very common. PKD varies greatly in its severity, and some complications are preventable. Regular checkups plus HBP treatments can reduce kidneys damage.

NORMAL PKD

MICROSCOPIC VIEW OF THE GLOMERULUS

STRUCTURE OF KIDNEY

TOP-- SEVERE ATHEROSCLEROSIS IN A PATIENT WITH DIABETES MELLITUS LED TO SEVERE AORTIC ATHEROSCLEROSIS WITH RENAL ARTERIAL STENOSIS AS WELL AS NEPHROSCLEROSIS AND NODULAR GLOMERULOSCLEROSIS OF THE KIDNEYS.

THE END STAGE RENAL DISEASE WAS TREATED WITH RENAL TRANSPLANTATION. THE TRANSPLANT KIDNEY IS PLACED IN THE PELVIS BECAUSE THIS IS TECHNICALLY EASIER AND THERE IS USUALLY NO POINT IN TRYING TO REMOVE THE NATIVE KIDNEYS.

IN THIS CASE, THE PATIENT DEVELOPED CHRONIC REJECTION AND THAT IS WHY FOCAL HEMORRHAGES ARE SEEN IN THE KIDNEY THAT IS SLIGHTLY SWOLLEN. A RADIOGRAPHIC STUDY WOULD SHOW DECREASED RENAL BLOOD FLOW IN THE TRANSPLANT KIDNEY.

S1

S2

S3

DICLOFENAC-INDUCED NEPHROTOXICITY AND INDUCTION OF APOPTOSIS

DCLF 300 MG/KG

CONTROL KIDNEY SECTION

CYCLOSPORIN-A EXPOSEDHYPERLIPOPROTEINEMIC

KIDNEY SECTION

http://www.siumed.edu/~dking2/crr/rnguide.htm#glomerulus

RENAL CELL CARCINOMA DEVELOPING IN THE ADULT FORM OF POLYCYSTIC RENAL

DISEASE. THE TUMOR WAS MULTICENTRIC.

Estimated new cases and deaths from kidney (renal cell and renal pelvis) cancer in the United States in 2010:

                 

NCI REPORTS—Estimated new cases and deaths from kidney (renal cell and renal pelvis) cancer in the United States in 2010:

New cases: 58,240

Deaths: 13,040

POLYCYSTIC KIDNEY DISEASEThe two forms of polycystic kidney disease (PKD) are:Autosomal dominant PKD, a form that usually causes symptoms in adulthoodAutosomal recessive PKD, a rare form that usually causes symptoms in infancy and early childhood. PKD has no cure.

The symptoms and signs of PKD include:Pain in the back and lower sides/headachesUTIs (urinary tract infections)/blood in the urinecysts in the kidneys and other organs

Diagnosis of PKD is obtained by:Ultrasound imaging of kidney cysts (CT scans/MRIs etc.)Ultrasound imaging of cysts in other organsFamily medical history, including genetic testing

Treatments include:Medicine to control high blood pressure/Medicine and surgery to reduce painAntibiotics to resolve infectionsDialysis to replace functions of failed kidneysKidney transplantation

KIDNEY FAILURE DUE TO IATROGENIC AND NONISTROGENIC CAUSES

ACUTE KIDNEY FAILURE OCCURS WHEN KIDNEYS SUDDENLY STOP FILTERING WASTE PRODUCTS FROM BLOOD. THE SIGNS AND SYMPTOMS MAY INCLUDE:

FLUID RETENTION

STOMACH OR INTESTINAL BLEEDING

CONFUSION

SEIZURES

COMA

HIGH BLOOD PRESSURE; UNEXPLAINED WEIGHT LOSS, ANEMIA

NAUSEA OR VOMITING/ MALAISE OR FATIGUEHEADACHES THAT SEEM UNRELATED TO ANY

OTHER CAUSE

DECREASED URINE OUTPUT DECREASED MENTAL SHARPNESS

MUSCLE TWITCHES AND CRAMPS BLEEDING IN THE INTESTINAL TRACT

YELLOWISH-BROWN CAST TO THE SKIN PERSISTENT ITCHING

SLEEP DISORDERS AND END-STAGE RENAL DISEASE

SIGNS AND SYMPTOMS OF CHRONIC KIDNEY FAILURE

VIABLE IATROGENIC & NONIATROGENIC MODELS OF CKD PROGRESSION TO KIDNEY FAILURE/DEATH

SCREENING FOR CKDRISK FACTORS:DIABETESHYPERTENSIONAGE >60FAMILYHISTORYUS ETHNICMINORITIES

REPLACEMENT

BY DIALYSIS &

TRANSPLANT

CKD RISKREDUCTION;SCREENING FOR CKD

DIAGNOSIS& TREATMENT;TREATCOMORBIDCONDITIONS;SLOWPROGRESSION

ESTIMATEPROGRESSION;TREATCOMPLICATIONS;PREPARE FORREPLACEMENT

NORMAL

INCREASED RISK

DAMAGE

GFR

KIDNEY FAILURE

TREAT COMPLICATIO

NS

1

23 4

5

CKDDEATH

ACUTE PRE-RENAL FAILURE AMPHOTERICIN,

ANTIHYPERTENSIVES, DIURETICS, DOXORUBICIN,

NSAIDS, CYCLOSPORIN-A

CHRONIC INTERSTITIAL NEPHRITIS ANALGESIC COMBINATIONS, CHINESE HERBS, CYCLOSPORINE, METALS (PB,

Cd, Li, Ge), METHYL-CCNU

------------------------------------------------------------

-----------------------------------------------------------

OBSTRUCTION

ACYCLOVIR, ANTICHOLINERGICS,

BROMOCRIPTINE, ERGOT ALKALOIDS,

FLUOROQUINOLONE, MTX

OUTER MEDULLA

INNER MEDULLA

VASCULITIS AMPHETAMINES,

NSAIDS, PENICILLINS,SULFONA

MIDES

NEPHROTIC SYNDROME

NSAIDS, PENICILLAMINE

CAPTOPRILHEROIN/COCAINEMETALS (Au, Hg)

ATN(P): ACUTE TUBULAR NECROSIS AMINOGLYCOSIDES, ANTINEOPLASTICS, GLYCOLS,

RADIOCONTRAST AGENTS

ATN(D): ACUTE TUBULAR NECROSIS

AMPHOTERICIN, CISPLATIN, GLYCOLS

ACUTE INTERSTITIAL NEPHRITIS

ALLOPURINOL, RIFAMPIN, VANCOMYCIN, NSAIDS

CORTEX

KID

NEY D

ISEA

SE V

IDEO

Shtt

p:/

/vod

pod

.com

/watc

h/1

38

50

8-k

idney-m

em

bra

nous-

glo

meru

lonep

hri

tis

#1. NEPHROTIC SYNDROME?

Ж Collection of symptoms

Ж Tiny blood vessels (the glomeruli) in the kidney become leaky.

Ж Protein leakage of in large amounts.

PROTEINURIA (> 3G/D) EDEMA HYPERLIPIDEMIA

HYPOALBUMINEMIA

DRUGS THAT CAUSE NEPHROTIC SYNDROMECAPTOPRIL

HEROIN/COCAINEMETALS (GOLD, MERCURY)

NSAIDSPENICILLAMINE

--------------------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER MEDULLA

NSAIDS PENICILLAMINE

CAPTOPRILHEROIN/COCAINEMETALS (Au, Hg)

CORTEX

NEPHROTIC SYNDROME

#2. ACUTE TUBULAR NECROSISATN is pathologically characterized by: varying degrees of tubular cell damage; cell death; that usually results from prolonged exposure to drugs or iatrogenic conditions.

Ж Toxic ATN (when the tubular cells are exposed to a toxicants). Ischemic ATN occurs when the tubular cells do not get enough oxygen.

Ж ATN involves tubular cell death (tubule transports urine to the ureters while reabsorbing 99% of the water and highly concentrating the salts and metabolic byproducts).

Ж Tubular cells continually replace themselves.

Ж If the cause of ATN is removed then this condition is considered reversible.

Ж ATN presents with acute renal failure and is one of the most common causes of ARF.

Ж This condition shows "MUDDY BROWN CASTS" of epithelial cells found in the urine during urinalysis which is pathognomonic for ATN.

------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER MEDULLA

ATN(P):

PROXIMAL

ACUTE TUBULAR NECROSIS

AMINOGLYCOSIDES

ANTINEOPLAST

ICS

GLYCOLS

RADIOCONTRAST AGENTS

METALS(AS,CR,HG)

FLORINATED -ANESTHETICS

ATN(D):

DISTAL

ACUTE TUBULAR NECROSIS

AMPHOTERICIN

CISPLATIN

GLYCOLS

CORTEX

ACUTE TUBULAR NECROSIS (ATN)?

#3. VASCULITIS

Ж Vasculitis involves a number of probably autoimmune conditions.

Ж Inflammation of blood vessels.

Ж Small-vessel vasculitis (SVV) commonly affects glomeruli.

Ж Medium or large-vessel vasculitis alone will only cause renal disease if arterial involvement leads to hypertension or renal infarction.

------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER

MEDULLA

DRUGS THAT CAN CAUSE VASCULITIS

AMPHETAMIN

ES

NSAIDS

PENICILLINS

SULFONAMIDES

CORTEX

#3. DRUGS THAT CAUSE KIDNEY VASCULITIS

#4. CAUSE OF ACUTE PRERENAL FAILURE

Ж Sudden loss of kidney’s ability to remove waste and concentrate urine without losing electrolytes.

Ж Prerenal ARF is characterized by inadequate blood circulation (perfusion) to the kidneys, which leaves them unable to clean the blood properly.

------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER MEDULLA

CORTEX

#4. ACUTE PRE-RENAL FAILURE

AMPHOTERICIN ANTIHYPERTENSIVE AGENTS

CYCLOSPORINE

DIURETICSDOXORUBICIN

METHOTREXATE NSAIDS

#5. ACUTE INTERSTITIAL NEPHRITIS

Ж Involves structures in the kidney outside the glomerulus (primarily tubules and interstitium; glomeruli is not involved).

Ж Tubular damage may lead to renal tubular dysfunction, with or without renal failure.

Ж Regardless of the severity of the damage, this renal dysfunction is generally reversible.

Ж Reflects the regenerative capacity of tubules with preserved basement membrane.

------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER MEDULLA

CORTEX

ACUTE INTERSTITIAL NEPHRITIS

ALLOPURINOL, RIFAMPIN, VANCOMYCIN, NSAIDS

ACUTE INTERSTITIAL NEPHRITIS

ALLOPURINOL, RIFAMPIN, VANCOMYCIN, NSAIDS

Unchecked acute nephritis can lead to chronic interstitial nephritis; Shows scarring, fibrosis, tubular atrophy

#5. SEQUALE OF -CHRONIC INTERSTITIAL NEPHRITIS

Ж When xenobiotic exposure is prolonged-- Acute interstitial nephritis progresses into chronic interstitial nephritis.

Ж The onset is usually insidious and relatively asymptomatic.

Ж Often presents seconadry hypertension or unexplained chronic azotemia.

Ж The major symptom is unexplained nocturia.

Ж Papillary necrosis may lead to uretral colic via papillary sloughing off of cells into uretral space.

Ж May lead to: Metabolic imbalanceSodium wastingHypercholeremic metabolic acidosis,May involve destruction of erythropoietin-secreting cells.

------------------------------------------------------------

-----------------------------------------------------------

OUTER MEDULLA

INNER MEDULLA

CORTEX

CHRONIC INTERSTITIAL NEPHRITIS

ANALGESIC COMBINATIONS, CHINESE HERBS, CYCLOSPORINE, METALS (PB, Cd, Li, Ge), METHYL-

CCNU

Ж Cause#1: Prolonged vasoconstriction:Decreased renal blood flowDecreased glomerular

filtration rateIncreased BUNIschemia

Ж Cause#2: Decreased blood pressure/ decreased blood flow (as from shock, hemorrhage) may lead to ischemia.

Ж Cause#3: Via effects on sympathetic nerve activity: ↑Increased sympathetic activity ▬↑Increased arteriolar

constriction Decreased glomerular capillary pressure--decreased GFRDecreased Sodium excretion or Increased BUN

#6. INDIRECT TOXICITY

------------------------------------------------------------

-----------------------------------------------------------

#6. INDIRECT TOXICITY: OBSTRUCTION

OUTER MEDULLA

INNER MEDULLA

CORTEX

ACYCLOVIR, ANTICHOLINERGICS, BROMOCRIPTINE, ERGOT ALKALOIDS, FLUOROQUINOLONE, MTX

PATIENT- RELATED RISK FACTORS [APPLICABLE TO ALL CATEGORIES OF DISEASE MANAGEMENT]

• AGE, SEX

• PREVIOUS RENAL DISEASE

• DIABETES, MULTIPLE MYELOMA, LUPUS, PROTEINURIC DISEASE

• SALT RETAINING DISEASES (CHIRROSIS, HEART FAIURE, NEPHROSIS)

• ACIDOSIS, POTASSIUM OR MAGNESIUM DEPLETION

• HYPERURICEMIA, HYPERURICOSURIA

• KIDNEY TRANSPLANT

DRUG - RELATED RISK FACTORS

• INHERENT NEPHROTOXIC EFFECTS

• DOSE

• DURATION, FREQUENCY AND FORM OF ADMINISTRATION

• REPEATED EXPOSURE

• DRUG INTERACTIONS (SYNERGISTIC AND/OR POTENTIATING TOXIC EFFECTS)

MARKERS OF NEPHROTOXICITY

1. BLOOD OR SERUM UREA NITROGEN.

2. BLOOD OR SERUM CREATININE LEVEL.

3. BUN/CREATININE RATIO.

4. PRESENCE OF 2-MICROGLOBULIN

5. TOTAL SERUM PROTEIN.

6. SERUM ALBUMIN (1 + 2)

7. URINE GLUCOSEEXCRETION RATES OF COMMON URINE PROTEINS

PROTEIN RELATIVE MOLECULAR MASS NORMAL RANGE (DALTONS)

ALBUMIN 68 000 < 30 MG/DAY ß2-MICROGLOBULIN 12 800 < 0.3 MG/DAY RETINOL-BINDING PROTEIN 21 400 < 0.3 MG/DAY IgG 160 000 2-3 MG/DAY2-MICROGLOBULIN ± 30 000 ?

RENAL PANEL

TOTAL PROTEINRENAL ALBUMINCALCIUMGLUCOSEBUNCREATININEINORGANIC PHOSPHORUSSOD/POT/CHLORIDE

ENZYMES CELLULAR LOCATIONALANINE AMINOPEPTIDASE BRUSH BORDERALKALINE PHOSPHATASEGAMMA-GLUTAMYLTRANSFERASEMALTASETREHALASE

GLUTAMIC OXALOACETIC TRANSAMINASE CYTOSOLGLUTAMIC PYRUVIC TRANSAMINASELACTATE DEHYDROGENASEMALATE DEHYDROGENASEN-ACETYL-ß-D-GLUCOSAMINIDASE

LYSOSOMEACID PHOSPHATASEß-GALACTOSIDASEß-GLUCOSIDASEß-GLUCURONIDASEGLUTAMATE DEHYDROGENASE MITOCHONDRIA

SOME ENZYME MARKERS THAT CAN BE USED AS AN INDEX OF NEPHROTOXICITY

Ж Normal kidneys filter excess proteins from the blood, thus preventing levels from getting too high.

Ж When the kidneys don't work properly, as in patients receiving dialysis, another type of protein called beta-2-microglobulin (2-globulin) may build up in the blood.

Ж When this occurs, -2-microglobulin molecules may join together, like the links of a chain, forming a few very large molecules from many smaller ones.

Ж These large molecules can form deposits and eventually damage the surrounding tissues and cause great discomfort. This condition is called dialysis-related amyloidosis (DRA).

#1. SPECIAL TOPICS IN NEPHROTOXICITYAMYLOIDOSIS AND KIDNEY DISEASE

Ж Anemia may begin to develop in the early stages of kidney disease, when the patient still has 20 to 50% of kidney function.

Ж This partial loss of kidney function is often called chronic renal insufficiency. Anemia tends to worsen as kidney disease progresses.

Ж End-stage kidney failure, the point at which dialysis or kidney transplantation becomes necessary, doesn't occur until you have only about 10 percent of your kidney function remaining. Nearly everyone with end-stage kidney failure has anemia.

#2. SPECIAL TOPICS IN NEPHROTOXICITYANEMIA IN KIDNEY DISEASE AND DIALYSIS

Ж IONIC VS. NONIONIC

Ж HIGH (1500-1800) LOW (600-850) ISO-OSMOLAL (~ 290 MOSM/KG)

Ж PLASMA: 285 MOSM/KGCSF: 310 MOSM/KG

• 1ST GENERATION - IONIC MONOMERS, HYPEROSMOLAL; EXAMPLES: DIATRIZOATE, IOTHALAMATE

• 2ND GENERATION: NONIONIC MONOMERS, LOWER OSMOLALITYEXAMPLES: IOPAMIDOL, IOHEXOL, IOPROMIDE,

IOVERSOL

• NEWEST AGENTS: NONIONIC DIMERS, ISO-OSMOLAL EXAMPLE: IODIXANOL

#3. SPECIAL TOPICS IN NEPHROTOXICITYRADIOCONTRAST AGENTS-INDUCED NEPHROTOXICITYRADIOCONTRAST AGENTS-INDUCED NEPHROTOXICITY

Ж ARF (Acute renal failure)– Even with the use of the newer agents [renal failure often begins within 24 hours of the contrast

administration and followed by an oliguric phase. Renal function usually begins to improve within a week, but dialysis is sometimes necessary.]

Ж All contrast agents deliver an osmotic load.

Ж Their injection leads to a period of volume expansion and diuresis.

Ж There is a period of vasodilation followed by an intense vasoconstriction.

Ж Ischemia may play a role in the pathogenesis of contrast nephropathy.

Ж Iodinated contrast media used for the imaging of tissues have a very high osmolality (>1200 mosm/l) and are potentially nephrotoxic.

POSSIBLE CLINICAL CONSEQUENCES OF CM-EXPOSURE

McCullough, P. A. J Am Coll Cardiol 2008;51:1419-1428

POSTULATED PATHOPHYSIOLOGY OF CONTRAST-INDUCED AKI

McCullough, P. A. J Am Coll Cardiol 2008;51:1419-142

MANAGEMENT OF PATIENTS RECEIVING IODINATED CONTRAST MEDIA

INCIDENCE OF CM-INDUCED NEPHROTOXICITY

NEGLIGIBLE WHEN RENAL FUNCTION IS NORMAL (EVEN IF DIABETIC)

4 -11% IN PATIENTS WITH CR 1.5 – 4.0 MG/DL

50% IF CR > 4.0 MG/DL AND IN DIABETIC NEPHROPATHY

DIAGNOSISCHARACTERISTIC RISE IN PLASMA CREATININE FOLLOWING

ADMINISTRATION OF THE AGENT

THERAPY HYDRATION ; MANNITOL ? DIURETICS ? ACETYLCYSTEINE, THEOPHYLLINE, CALCIUM CHANNEL BLOCKERS

– PREVENTIONUSE OF ALTERNATIVE DIAGNOSTIC PROCEDURES IN HIGH RISK PATIENTS

AVOIDANCE OF VOLUME DELETION OR OTHER NEPHROTOXINS

LOW-DOSES OF LOW- OR ISO-SOMOLAR AGENT

IV SALINE OR ACETYLCYSTEINE

Vila-Torres E, Albert-Marí A, Almenar-Cubells D, Jiménez-Torres NV. Cisplatin preparation error; patient management and morbidity. J Oncol Pharm Pract. 15(4):249-53, 2009.Pharmacy Department, Hospital General de Ciudad Real, Ciudad Real, Spain. vila_eli@gva.es

ABSTRACTINTRODUCTION: Antineoplastic drug therapy errors represent a high iatrogenic potential due to antineoplastic drugs narrow therapeutic ranges and the complexity of chemotherapy regimens that may increase the risk of morbidity and mortality for oncology patients.

SETTING: We report a 57-year-old man with head and neck cancer who mistakenly received 180 mg/ m(2) of cisplatin overdose despite the safety measures and validations carried out during preparation. The patient developed moderate nausea and vomiting, acute renal failure, hearing difficulty (tinnitus), and severe myelodepression.

PATIENT MANAGEMENT: Prophylactic and symptomatic treatments were applied in order to prevent and correct toxicity during the 9 days stay at hospital.

RESULT: He recovered with mild tinnitus and mild renal impairment as the only sequelae. This case presents a hospital stay and treatment quite different to others used to reverse all cisplatin overdose toxicity and it shows the benefits of prompt management.

Calvin AD, Misra S, Pflueger A. Contrast-induced acute kidney injury and diabetic nephropathy. Nat Rev Nephrol. 2010 Nov;6(11):679-88.Department of Medicine, Mayo Clinic College of Medicine, SW, Rochester, MN 55905, USA.

AbstractContrast-induced acute kidney injury (CIAKI) is a leading cause of iatrogenic renal failure. Multiple studies have shown that patients with diabetic nephropathy are at high risk of CIAKI. This Review presents an overview of the pathogenesis of CIAKI in patients with diabetic nephropathy and discusses the currently available and potential future strategies for CIAKI prevention.

Approx. 10-15% of all acute renal failure is due to aminoglycoside toxicity.

Approx. In 10-20% of patients increase in plasma Cr of 0.5-1 mg/dL.

These agents damage the glomerulus, Proximal Convoluted Tubule, and may also produce cellular necrosis by interacting with intracellular endoplasmic reticula and lysosomes.

STREPTOMYCINNEOMICIN AMIKACIN [AMIKIN ®]GENTAMICIN [GARAMYCIN ®]NETILMICIN [NETROMYCIN ®]KANAMICIN [KANTREX ®]TOBRAMYCIN [TOBREX, NEBCIN ®]

#4. SPECIAL TOPICS IN NEPHROTOXICITYAMINOGLYCOSIDES-INDUCED NEPHROTOXICITY

Aminoglycoside antibiotics usually:

(i) Induce a lysosomal phospholipidosis in proximal tubular cells.

(ii) Produce ROS, deplete ATP, interfere with mitochondrial functions.

(iii) Several of the aminoglycosides induce site specific features of apoptosis,

Of Note: *Aminoglycosides are cationic (recall that bowman's capsule surrounding the glomerulus is anionic and prevents the filtration of anionic proteins such as albumin) and as such may neutralize and disrupt the epithelium of bowman's capsule and the brush border of the PCT, thus disrupting the filtration and reabsorption of each, respectively.

Renal cortical mitochondria is the source of reactive oxygen metabolites, which usually induces renal injury.

#6. SPECIAL TOPICS CADMIUM (Cd)-INDUCED NEPHROTOXICITY

Cd is a widespread heavy metal in the environment and in our bodies. It is very poisonous, and we only excrete in very small amounts. Cd can cause damage to all types of body cells. By damaging the cell membrane, Cd increases the permeability of the cells, one of the consequences being that the transfer of other heavy metals into the cells is facilitated. In the acute stage, Cd intoxication causes enteritis. A slow accumulation of Cd takes place, mainly in the kidneys; the liver and bones are other important sites for Cd storage.

Cd is absorbed more efficiently by the lungs (30 to 60%) than by the gastrointestinal tract, the latter being a saturable process. Cd is transported in the blood and widely distributed in the body but accumulates primarily in the liver and kidneys. Cd burden (specially in the kidneys and liver) tends to increase in a linear fashion up to about 50-60 years of age afterwards remains somewhat constant.

Injury produced by administration of the Cd-metallothionein complex is localized to the first and second segments of the proximal tubule and is manifested by proteinuria, aminoaciduria, glucosuria, and decreased tubular reabsorption of phosphate.

Biotransformations of Cd are limited to its binding to protein and nonprotein sulfhydryl groups, & various macromolecules, such as metallothionein, which is especially important in the kidneys and liver. Cd is excreted primarily in the urine.

Cd is an interesting metal in that following exposure of the metal the liver shows enhanced synthesis of the metal-binding protein metallothionein. This compound seems to have a paradoxical effect on the systemic toxicity of Cd.

Metallothionein appears to bind Cd and in this way protect certain organs such as the testes from Cd toxicity. Yet, at the same time, metallothionein may enhance Cd nephrotoxicity, possibly because the Cd-metallothionein complex is taken up by the kidney more readily than is the free ion.

As Cd nephropathy progresses, it increasingly presents the signs of a complete Fanconi's syndrome, i.e. Aminoaciduria, glucosuria, increased urinary excretion of calcium, phosphorus, and uric acid, and decreased concentrating ability of the kidneys. In the most severe cases, the gfr decreases. The disturbances in calcium and phosphorus metabolism may lead to a demineralization of the bones and the formation of kidney stones.

Food products account for more than 90 percent of human exposure to cad, except in the vicinity of Cd-emitting industries. The atsdr says: cad. Has fast uptake through the roots to edible leaves, fruits and seeds. Cd builds up in animal milk and fatty tissues. A 1990 study showed that acute cad toxicity from food is rare, but chronic exposure at lower levels increases Cd in certain organs.

One source of Cd In our environment & main reason for Cd. Accumulating in the body, is tobacco smoke. One cigarette contains 16-24 micrograms of Cd of which the body absorbs approximately half. In addition to this, 5 - 10% of the Cd from our food and other sources is absorbed; therefore, a substantial amount of Cd is stored in our body system over a number of years.

Increased concentrations of Cd had been found in the placenta of women who have given birth to children with low birth weight, neural damage, and down's syndrome. Children who are exposed to large concentrations of Cd in their environment often have learning disabilities.

Prolonged accumulation of cad in the body may: I) STAINING TEETH; ii) DAMAGE THE NERVOUS SYSTEM; iii) DECREASE THE DETOXICATIVE POWER OF THE ORGANISM; iv)may CAUSE HIGH BLOOD PRESSURE AND ATHEROSCLEROSIS, v) DAMAGE THE IMMUNE SYSTEM; MOST IMPORTANTLY THE ANTIBODY PRODUCTION; AND vi) DECREASE FERTILITY, CAUSE ANAEMIA, EMPHYSEMA,& CANCER

#7. MECHANISM OF TETRAFLUOROETHYLENE-NEPHROTOXICITY

[A flammable, colorless, heavy gas, insoluble in water, boils at 78°c; used as a monomer to make polytetrafluoroethylene polymers, for example, teflon.]

Tetrafluoroethylene is conjugated with glutathione in the liver.

The glutathione conjugate is secreted into the bile and small intestine, where it is degraded to the cysteine s-conjugate (TFEC), reabsorbed, and transported to the kidney.

Although several metabolites are formed, the cysteine s-conjugate is the penultimate nephrotoxicant.

After transport into the proximal tubule, the cysteine s-conjugate is a substrate for the cytosolic and mitochondrial forms of the enzyme cysteine conjugate /6-lyase.

The products of the reaction are ammonia, pyruvate and a reactive thiol that is capable of binding covalently to cellular macromolecules, causing cellular damage.

Functionally, increases in urinary glucose, protein, cellular enzymes, and BUN are noted.

#8. BROMOBENZENE-INDUCED NEPHROTOXICITY[Used as an industrial solvent and in organic synthesis. It is also used as an additive to motor oils. The probable lethal dose is between 1 teaspoon to 1 oz for a 154-pound human]

Biotransformation of bromobenzene and other halogenated benzenes is critical for their nephrotoxicity.

Hepatic cytochrome p450 metabolizes bromobenzene, to reactive benzene-epoxides. Epoxides are detoxified by glutathione transferase and epoxide hydratase (also known as epoxide hydrolase).

Epoxides primarily conjugate with glutathione, and then release it in a form that can cause nephrotoxicity.

The diglutathione conjugate of the hydroquinone is approximately a thousand-fold more potent than is bromobenzene in causing nephrotoxicity, producing the same pathologic changes in the S3 segment and increasing the amount of protein, glucose, and cellular enzymes in the urine.

Alport syndrome (AS) is defined as:i)Progressive hereditary hematuric non-immune nephritis.ii) Characterized by ultrastructurally by irregular thickening, thinning and lamellation of the glomerular basement membrane (GBM).(iii) Some patients may experience hearing losse, ocular defects (15-30% of patients), abnormal platelet count number and abnormal platelet function, and esophageal, upper GI and genital leiomyomatosis.

[Alport syndrome is a genetic disorder of type IV (basement membrane) collagen with X-linked dominant inheritance. Alport locus was mapped to the long arm of the X chromosome (Xg 22) and gene (COL4A5) for BM collagen chain was identified. In addition to the X-linked dominant form of AS, autosomal dominant and autosomal receive varieties of disease are well documented. ]  Clinical Features of AS:

Persistent or episodic gross hematouria is the major presentation of the AS in boys (as early as 1 year old) and affected females (virtually always heterozygous). Proteinuria, usually absent at the beginning, appears eventually in affected males; NS (nephrotic syndrome) is not unusual in these patients and indicate the worse prognosis.

#4. SPECIAL TOPICS IN NEPHROTOXICITYGENETICALLY-INDUCED KIDNEY DISEASE (ALPORT SYNDROME: AS )

Hypertension is found in increased percentage in AS affected males. End-stage renal disease develops inevitably in males but with variable frequency in females. Hearing losses are never congenital, usually clinically obvious by age 15, but can be detected earlier by audiometry (reduction in sensitivity to tones in 2000 - 8000 HZ range). Ocular defects include anterior lenticonus, protrusion of the lens into anterior capsule and variety of other ocular lesions.

Thus, a careful family history, examination for hematuria, proteinuria, hearing loss, ophthalmologic abnormalities together with biopsy findings (which are not necessary, but helpful) are important for diagnosis of AS.

There is no currently available treatment to alter the course of AS, although management of hypertension is mandatory on general grounds and dialysis and renal transplantation are indicated for patient with ESRD. Living related kidney donors for AS patients must be selected with care. Molecular genetic studies can identify asymptomatic carriers of Alport gene(s).

Anti-GBM nephritis can develop in transplanted kidney, since the normal BM of transplanted kidney will be recognized as forgein Ag by AS patient. Transplanted AS males should be regularly screen for circulating anti-GBM Ab and they may benefit from treatment with plasmapheresis

LITHIUM-INDUCED NEPHROTOXICITY &

ITS CLINICAL MANAGEMENT

1. For what condition is lithium classically indicated?Bipolar disorder (manic-depression) and other affective disorders.

2. What other disorders is lithium used for?During the 19th century, it was used to treat arthritis and nephrolithiasis. Currently, lithium is used for the prevention of cluster headaches and as a cell stimulator in patients with neutropenia.

3. Do lithium levels correlate with toxicity?No. Lithium levels do not predict or correlate with clinical manifestations. This may be explained by lithium's slow distribution time. The therapeutic range for lithium serum concentrations is commonly reported as 0.6-1.2 meq/L.

4. Which organ systems does lithium affect?Neurologic abnormalities: A fine tremor of the handsHyperreflexia and agitation; Fasciculations, muscular irritability, choreoathetosis, clonus, seizures, and altered mental status, including confusion, lethargy, and even coma. Nystagmus, dysarthria, and ataxia also have been reported.

5. What is the mechanism of action of lithium? The definite mechanism of action of lithium is unknown. Proposed mechanisms include:

Interferance with magnesium metabolism because of its similar atomic radius.

Competition with sodium and potassium as discussed in questions 1 & 6.

Interactions with PKC & g-proteins, which may ultimately decrease the brain’s concentration of inositol (an important mediator of intracellular calcium release)

Decreasing the effects of norepinephrine by interfering with the second-messenger cyclic adenosine monophosphate (C-AMP).

7. What are the clinical manifestations of patients with chronic lithium intoxication?Patients on chronic lithium therapy who acutely overdose may show manifestations of both acute & chronic poisoning—a diagnostic and therapeutic challenge. The GI symptoms seen in acute toxicity are usually lacking or missed; changes in mental status prompt patient evaluation & care.

6. List the clinical manifestations of patients with acute lithium intoxication.In addition to neurologic manifestations, GI symptoms such as nausea vomiting, and diarrhea predominate. Fluid loss leads to dizziness, light-headedness, and orthostatic hypotension. Nonspecific T-wave changes may develop on ECG. Because there is no direct cardiotoxic effect, malignant dysarrhythmias and cardiac dysfunction are rare.

8- what should GI decontamination entail?Unless there are co-ingestants, activated charcoal has no role in lithium overdoses. Lithium, like iron, does not adsorb to AC. A cathartic such as sorbitol may be given if the patient does not have diarrhea. Whole bowel irrigation with PEG-ELS (polyethylene glycol-electrolyte soln.) be considered, particularly if a sustained release preparation such as Lithobid was ingested.

(i) Start with ABCs as always, although lithium toxicity is not known to cause problems with airway or breathing.

(ii) IV access should be established, and the patient should be placed on a monitor because, rarely, a prolonged qt interval may occur.

(iii) Cardiogenic shock and dysrhythmias also may occur secondary to excessive GI and urinary losses and accompanying electrolyte imbalances.

(iv) In addition to basic laboratory tests, a lithium concentration should be drawn at presentation. Serial concentrations should be drawn, initially at 2-hour intervals, to assess if absorption is continuing.

(v) In an acute overdose, once concentrations begin declining, expect an initial apparent half-life of less than 12 hours. This reflects tissue distribution.

9. General approach to the poisoned patient is as follows:

Correcting dehydration and electrolyte imbalance is most important in maximizing lithium excretion.

Loop diuretics or the less-potent thiazides are not recommended.

Initially they may increase excretion, but if the patient becomes water- or salt-depleted, lithium reabsorption will increase and toxicity will worsen.

Similarly, mannitol, carbonic anhydrase inhibitors, and phosphodiesterase inhibitors initially may produce a small increase in elimination but will be overcome by lithium retention and are therefore not recommended.

10. How should renal elimination be enhanced?

11. What other therapeutic modalities are there for lithium toxicity?

Because lithium is a small ion, is not protein bound, and has a small apparent volume of distribution (VD), it is dialyzable.

Hemodialysis removes 70-170 ml/min, which is 10-15 times more than the clearance of lithium by peritoneal dialysis.

Indications include severe neurologic dysfunction or toxicity in the face of renal failure.

Patients with hyponatremic, edematous states (cong. Heart failure, pulmonary edema) who cannot tolerate sodium repletion also should be considered for hemodialysis.

The slow distribution half-life provides significant potential for the benefit of these procedures in acute overdoses and possibly chronic overdose.

However, in the absence of other indications, hemodialysis offers minimal benefit in chronic intoxication.

11A. What other therapeutic modalities are there for lithium toxicity?

The goal of hemodialysis is to decrease the possibility of long-term neurologic complications.

A patient with two or more lithium levels of > 4.0 meq/l and no previous acute lithium overdose should be considered for dialysis because the rate of excretion will not be fast enough to prevent a significant lithium load from entering the central nervous system.

12. At what lithium levels is hemodialysis indicated?

Dialysis removes lithium from plasma. Once lithium from the intracellular space equilibrates with the plasma, a "rebound" level may develop. If the level is high or if neurologic symptoms persist, the patient should be dialyzed again.

13. A lithium level should be checked 6 hours after dialysis. Why?

14. WHAT IS THE ROLE OF SODIUM POLYSTYRENE SULFONATE (SPS)?

SPS (Kayexalate), a cation-exchange ion, is commonly used to treat hyperkalemia dispensed as a suspension in 70% sorbitol.

In theory, it has the potential to bind lithium; however, animal studies have shown that large doses of SPS (up to 10 gm/kg) are required.

These doses are large enough that hypokalemia is a concern.

Human studies of SPS-induced hypokalemia are equivocal.

Additionally, the potential for sorbitol-induced diarrhea and volume depletion resulting in increased lithium reabsorption must be considered.

CYCLOSPORIN-ACYCLOSPORIN-A

MECHANISMS OF MECHANISMS OF NEPHROTOXICITY & NEPHROTOXICITY &

CLINICAL MANAGEMENTCLINICAL MANAGEMENT

Cyclosporin A [SANDIMMUNE®, NEORAL®]

Tracolimus [PRO-GRAF®]

Chronic nephrotoxicity

Factors responsible for chronic nephrotoxicity are not well understood.

Relatively less dose-dependent

Sustained renal vasoconstriction/renal ischemia; Renin Angiotensin System perturbations…

Cyclosporine–induced hypertension

CALCINEURIN INHIBITORS GENERAL CHARACTERISTICS

Acute nephrotoxicity

Azotemia: renal vasoconstriction, reduced RBF and GFR; Oliguric ATN with high doses

Relatively more dose-dependent

Largely reversible; Calcium channel blockers (+/-)

Difficult to differentiate from acute rejection (renal biopsy)

CS-A is fungal hydrophobic 11-amino acid cyclic polypeptide.

Effective both in the preventn. & In the treatment of ongoing acute rejection.

Production of IL-2 by helper T-cells

Blocks T cell activn. & Prolifern (amplification of immune response).

CS-A (& Tacrolimus) binds in the T-cell cytoplasm with a protein called immunophilin (cis-trans isomerase).

The CS-A-immunophilin complex in turn binds to and blocks a phosphatase called Calcineurin.

Calcineurin is required for the translocation of an activation factor from the cytosol to the nucleus.

MECHANISM OF ACTION

The calcineurin would normally bind to and activate enhancers/promotors of certain genes.

In the presence of CS, the cytosolic activation factor is unable to reach the nucleus.

The transcription of IL-2 (and other early activation factors) is strongly inhibited.

Net result: T-cells do not proliferate, secretion of γ-interferon is inhibited, no MHC class II antigens are induced, and no further activation of the macrophages occurs.

Final result -- Immunosuppression

CS-A—DRUG- Interactions: drugs that inhibit CYP450 enzymes such as ketoconazole, verapamil, diltiazem, and erythromycin increase the concentration of cs & can precipitate renal side effects.

CISPLATIN-INDUCED NEPHROTOXICITY

After a single injection of cisplatin, 28 to 36% of patients develop dose-dependent nephrotoxicity.

Can cause both Acute and chronic renal failure

Renal magnesium wasting and polyuria are common.

ARF is characterized by decreases in RBF and GFR, enzymuria, β2-microglobulinuria, and inappropriate urinary losses of magnesium.

The primary cellular target associated with ARF is the proximal tubule.

The chronic renal failure observed with cisplatin is due to prolonged exposure and is characterized by focal tubular necrosis in numerous segments of nephron without a significant effect on the glomerulus.

Cisplatin may produce nephrotoxicity through its ability to inhibit DNA synthesis as well as transport functions.

XIN YAO, Cisplatin Nephrotoxicity: A Review. Am J Med Sci 2007;334(2):115–124.]

ABSTRACT Background: Cisplatin is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal toxicity. Methods: We reviewed clinical and experimental literature on cisplatin nephrotoxicity to identify new information on the mechanism of injury and potential approaches to prevention and/or treatment.Results: Unbound cisplatin is freely filtered at the glomerulus and taken up into renal tubular cells mainly by a transport-mediated process. The drug is at least partially metabolized into toxic species. Cisplatin has multiple intracellular effects, including regulating genes, causing direct cytotoxicity with reactive oxygen species, activating mitogen-activated protein kinases, inducing apoptosis, and stimulating inflammation and fibrogenesis. These events cause tubular damage and tubular dysfunction with sodium, potassium, and magnesium wasting. Most patients have a reversible decrease in glomerular filtration, but some have an irreversible decrease in glomerular filtration. Volume expansion and saline diuresis remain the most effective preventive strategies.Conclusions: Understanding the mechanisms of injury has led to multiple approaches to prevention. Furthermore, the experimental approaches in these studies with cisplatin are potentially applicable to other drugs causing renal dysfunction.

Last name: A to F-Q1. What is the mechanism by which INH treats TB?

Last name: G to L-Q2. How does INH cause hepatotoxicity?

Last name: M to R-Q3. What is the currently recommended regimen for the use of INH in patients with latent TB?

Last name: S to V-Q3. What are the current recommendations for INH hepatotoxicity surveillance?

Last name: X to Z-Q3. What is the management of INH-induced hepatotoxicity?

PH-430: QUIZZ# 4 2/16/2010

ANSWER ANY ONE OF THE FOLLOWING (Q1 THRU Q4) PLUS WRITE THE NAME OF ANY

ONE TOXICANT AND ITS ANTIDOTE!

Q1. What is the differential diagnosis of drug-induced seizures?

Q2. What is the mechanism by which this particular xenobiotic produces status epilepticus?

Q3. How should the patient in this case be managed?

Q4. What antidotes, if any, should be used in the management of a patient with status epilepticus?