33 ellabban care of the kidney during daily

Care of the kidney during daily Care of the kidney during daily Ortho- Rheumatology practiceOrtho- Rheumatology practice

ABDOU ELLABBANABDOU ELLABBAN

PROFESSOR OF RHEUMATOLOGY PROFESSOR OF RHEUMATOLOGY

MINIA UNIVERSITYMINIA UNIVERSITY

April – 30 - 2009April – 30 - 2009

Kidney DiagramKidney Diagram

Capsule

Renal VeinRenal ArteryCortex

Pyramid

PapillaCalyx

Pelvis

Ureter

Column

Medulla

Nephron

Renal prostaglandinsRenal prostaglandins PGs are a chemical mediators produced as a result of the PGs are a chemical mediators produced as a result of the

sequential action of cyclooxygenase and prostanoid sequential action of cyclooxygenase and prostanoid synthase on arachidonic acid in the cell wall.synthase on arachidonic acid in the cell wall.

It mediates it’s action through Interaction with its It mediates it’s action through Interaction with its receptors.receptors.

PGs act in an autocrine or a paracrine fashion, serving as PGs act in an autocrine or a paracrine fashion, serving as physiological buffers, protecting the kidney from excessive physiological buffers, protecting the kidney from excessive functional changes during physiological stress.functional changes during physiological stress.

PGE1 stimulate adenylcyclase enzyme resulting in an PGE1 stimulate adenylcyclase enzyme resulting in an increase in C-AMP, which relax vascular smooth muscle, increase in C-AMP, which relax vascular smooth muscle, leading to leading to reduction of vascular reactivity that protects reduction of vascular reactivity that protects vessels from the influence of catecholamines, angiotensin, vessels from the influence of catecholamines, angiotensin, renin-aldosterone system.renin-aldosterone system. (Okada 1993).(Okada 1993).

PGE1 reduces plasma endothelin-1 concentrationPGE1 reduces plasma endothelin-1 concentration. . (ITOH 2001)(ITOH 2001)

Renal PGsRenal PGs Renal cortical PGs Renal cortical PGs ((PGI2 and PGI2 and

PGE2),PGE2), play a roles in play a roles in maintaining blood pressure and maintaining blood pressure and renal function in hypovolemic renal function in hypovolemic states states (VC effect), (VC effect), and chair in and chair in the pathogenesis of renal the pathogenesis of renal vascular hypertension through vascular hypertension through stimulating renal renin synthesis stimulating renal renin synthesis and releaseand release..

Renal medullary PGs Renal medullary PGs Have an antihypertensive effect Have an antihypertensive effect

in persons with a high-salt diet in persons with a high-salt diet (VD effect).(VD effect).

Renal cortexRenal cortex

Renal medulla

Renal Renal prostaglandinsprostaglandins

The VD effect of PGs preserve renal The VD effect of PGs preserve renal blood flow and GFR (In G disease with blood flow and GFR (In G disease with marked reduction in G capillary marked reduction in G capillary permeability) by relaxing pre G permeability) by relaxing pre G resistance. resistance.

In volume depletion PGs antagonize the In volume depletion PGs antagonize the VC effects of angiotensin II and VC effects of angiotensin II and norepinephrine. norepinephrine.

Inhibition of PGs synthesis with an Inhibition of PGs synthesis with an NSAID lead to reversible renal NSAID lead to reversible renal ischemia, and decline in G Capillary ischemia, and decline in G Capillary hydrostatic pressure ( major driving hydrostatic pressure ( major driving force for G filtration).force for G filtration).

Plasma creatinine conc. rises within the Plasma creatinine conc. rises within the 11stst three to seven days of therapy, (time three to seven days of therapy, (time required for attainment of steady state required for attainment of steady state drug levels) and therefore maximum drug levels) and therefore maximum inhibition of PGs synthesis inhibition of PGs synthesis

Glomerular Glomerular filtration rate filtration rate

(GFR)(GFR)

GFR is a measurement of the amount of GFR is a measurement of the amount of glomerular filtrate (glomerular filtrate (blood plasma without blood plasma without proteinsproteins) in the kidneys per minute, it is equal ) in the kidneys per minute, it is equal to the sum of the filtration rates in all of the to the sum of the filtration rates in all of the functioning nephrons.functioning nephrons.

It is used to evaluate the kidneys’ ability to It is used to evaluate the kidneys’ ability to remove waste products from the body.remove waste products from the body.

GFR is used to screen for:GFR is used to screen for:

1.1. Early signs of kidney damageEarly signs of kidney damage

It can be assessed by:It can be assessed by:

1.1. Creatinine clearance (U x V / P Cr.).Creatinine clearance (U x V / P Cr.).

U = Creatinine conc in 24 hr. urine, V = Urine U = Creatinine conc in 24 hr. urine, V = Urine volume in 24 hr., P Cr. = Plasma creatinine. volume in 24 hr., P Cr. = Plasma creatinine.

1.1. Inulin clearanceInulin clearance

2.2. Cystatin C clearance. Cystatin C clearance.

Creatinine & Cystatin C clearanceCreatinine & Cystatin C clearance Creatinine clearance estimates are Creatinine clearance estimates are difficult and imprecisedifficult and imprecise

because they because they require 24-hour urine collectionsrequire 24-hour urine collections.. Because of the problems with changes in creatinine production Because of the problems with changes in creatinine production

and secretion, other endogenous compounds have been and secretion, other endogenous compounds have been evaluated to provide a more accurate estimation of GFR. evaluated to provide a more accurate estimation of GFR.

The most promising is The most promising is cystatin Ccystatin C, a low molecular weight , a low molecular weight protein that is protein that is a member of the cystatin superfamily ofa member of the cystatin superfamily of cysteine cysteine protease inhibitors. protease inhibitors.

Cystatin C is Cystatin C is produced by all nucleated cells,produced by all nucleated cells, and its and its rate of rate of production is relatively constantproduction is relatively constant and is and is unalteredunaltered by by inflammatory conditions or changes in diet. inflammatory conditions or changes in diet.

The plasma cystatin C concentration may correlate more The plasma cystatin C concentration may correlate more closely with the GFR than with the PCr.closely with the GFR than with the PCr.

StageDescriptionGFR

At increased

risk

Risk factors for kidney disease (e.g., diabetes, high blood pressure, family history, older age.

More than 90

1Kidney damage (protein in the urine) and normal

GFRMore than 90

2Kidney damage and mild decrease in GFR60 to 89

3Moderate decrease in GFR30 to 59

4Severe decrease in GFR15 to 29

5Kidney failure (dialysis or kidney transplant

needed)Less than 15

5 Stages of Chronic Kidney Disease ((K/DOQI) define CKD as K/DOQI) define CKD as

The presence of kidney damage or a reduction in the GFR for The presence of kidney damage or a reduction in the GFR for >> 3 months. 3 months.

Acute interstitial nephritis (AINAcute interstitial nephritis (AIN((Tubulointerstitial nephritis (TIN)Tubulointerstitial nephritis (TIN)

Acute interstitial nephritis can be Acute interstitial nephritis can be categorized into 5 groups based on the categorized into 5 groups based on the

inciting etiology:inciting etiology: (1) Drug hypersensitivity reactions (1) Drug hypersensitivity reactions

(2) infections.(2) infections. (3) immune-mediated disease.(3) immune-mediated disease.

(4) glomerular.(4) glomerular. (5) idiopathic. (5) idiopathic.

Acute interstitial nephritis can also be Acute interstitial nephritis can also be grouped into grouped into acuteacute and and chronicchronic

subgroupssubgroups..

AAcute TIN are caused by cute TIN are caused by hypersensitivity reactionshypersensitivity reactions to drugs and are to drugs and are

not mediated by direct toxicitynot mediated by direct toxicity.. Drugs cause a hypersensitivity reaction include:Drugs cause a hypersensitivity reaction include:

Antibiotics (eg, penicillins, cephalosporins, sulfa Antibiotics (eg, penicillins, cephalosporins, sulfa drugs, quinolones) drugs, quinolones)

NSAIDs NSAIDs Diuretics (eg, thiazides, furosemide) Diuretics (eg, thiazides, furosemide) Allopurinol Allopurinol Phenytoin Phenytoin Rifampin Rifampin Interferon Interferon αα. . Proton pump inhibitors.Proton pump inhibitors.

TIN are diseases TIN are diseases involving tubules and involving tubules and or the interstitium or the interstitium outside the outside the glomerulus. glomerulus. The renal cortex shows a diffuse interstitial, mononuclear infiltrate with intact glomerulus.

Tubules in the center of the field are separated by inflammation and edema.

NSAIDs induced acute TIN.NSAIDs induced acute TIN. More common in elderly More common in elderly

because of the higher because of the higher incidence of arthritis.incidence of arthritis.

Patients may present with: Patients may present with: nephrotic syndrome, nephrotic syndrome, edema, massive proteinuria, edema, massive proteinuria, and hypoalbuminemiaand hypoalbuminemia..

Mononuclear inflammatory infiltrate, and edema in the interstitium.

Acute tubular damage is present; some tubules are distended with granular casts.

Antibiotic-induced acute TIN.Antibiotic-induced acute TIN.

Seen in hospital setting during Seen in hospital setting during treatment of serious infections, treatment of serious infections, within several days to weeks of within several days to weeks of initiation of antibiotic therapy. initiation of antibiotic therapy.

Rash, eosinophilia, and Rash, eosinophilia, and eosinophiluria, sterile pyuria, eosinophiluria, sterile pyuria, hematuria, and modest hematuria, and modest proteinuria (usually <1 g/ d).proteinuria (usually <1 g/ d).

Renal biopsy shows eosinophils, Renal biopsy shows eosinophils, ill-defined granulomas may be ill-defined granulomas may be present.present.

Rifampin is unique in inducing Rifampin is unique in inducing TIN, does not manifest with TIN, does not manifest with eosinophilia. eosinophilia.

Manifest by Flulike , flank pain, Manifest by Flulike , flank pain, hypertension, and oliguric acute hypertension, and oliguric acute renal failure. renal failure.

Inflammatory infiltrate (ill-defined granuloma) with a partially destroyed

tubule.

Mononuclear infiltrate with abundant eosinophils, (allergic

etiology). Severe tubular damage is

observed

Cyclosporine- and tacrolimus-Cyclosporine- and tacrolimus-induced nephropathyinduced nephropathy

The mechanism appears to The mechanism appears to be be dependent largely on the dependent largely on the potent vasoconstrictive potent vasoconstrictive effects of these drugs. effects of these drugs.

Both cyclosporine and Both cyclosporine and tacrolimus frequently cause tacrolimus frequently cause hypertension, hyperkalemia hypertension, hyperkalemia and hypomagnesemia.and hypomagnesemia.

Concomitant use of Concomitant use of calcium channel blockers calcium channel blockers reduces nephrotoxicity. reduces nephrotoxicity.

Long-term use of Long-term use of cyclosporine associated with cyclosporine associated with patchy interstitial fibrosis, patchy interstitial fibrosis, and tubular atrophy. and tubular atrophy.

Chronic TIN, with interstitial fibrosis, distortion of tubules and periglomerular fibrosis. Intact glomeruli.

Assessment of CKDAssessment of CKD 1- Urine examination.1- Urine examination.

1.1. 2- Estimation of the GFR. 2- Estimation of the GFR. Fresh urine examination:Fresh urine examination:

I- Multitest detectionI- Multitest detection strip (dipstick) test [proteinuria (then strip (dipstick) test [proteinuria (then PCR ), hematuria, pyuria] .PCR ), hematuria, pyuria] .

II- Urine microscopyII- Urine microscopy is performed on a centrifuge-spun urine is performed on a centrifuge-spun urine specimen to look for RBCs, WBCs, and casts. specimen to look for RBCs, WBCs, and casts.

The presence of The presence of muddy-brown granular casts and epithelial muddy-brown granular casts and epithelial cell castscell casts is highly suggestive of acute tubular necrosis. is highly suggestive of acute tubular necrosis.

Red cell castsRed cell casts would suggest an acute nephritic process. would suggest an acute nephritic process. CKD have broad hyaline casts.CKD have broad hyaline casts.

Estimation of the serum BUN, creatinine, sodium, potassium, Estimation of the serum BUN, creatinine, sodium, potassium, calcium, phosphorus, bicarbonate, alkaline phosphatase, calcium, phosphorus, bicarbonate, alkaline phosphatase, parathyroid hormone (PTH), and cholesterol and fractionated parathyroid hormone (PTH), and cholesterol and fractionated lipid levels are important in the treatment and prevention of lipid levels are important in the treatment and prevention of various CKD-related complications.various CKD-related complications.

Imaging Imaging StudiesStudies

I- Renal ultrasoundI- Renal ultrasound is of minimal is of minimal value. value. Normal-sized kidneys with a Normal-sized kidneys with a slight increase in echogenicity are slight increase in echogenicity are typically noted.typically noted.

II- Gallium scansII- Gallium scans often show diffuse often show diffuse positive bilateral uptake. positive bilateral uptake.

This can be helpful in differentiating This can be helpful in differentiating acute acute interstitial nephritis interstitial nephritis (+ve scan)(+ve scan) from from acute tubular necrosisacute tubular necrosis, which has a , which has a

uniformly uniformly negative scan result.negative scan result. III- Renal biopsy:III- Renal biopsy:1.1. Considered the Considered the standard diagnostic standard diagnostic

testtest for AIN. for AIN.2.2. Biopsy frequently reveals either a Biopsy frequently reveals either a

diffuse or segmental mixed infiltrate.diffuse or segmental mixed infiltrate.3.3. Renal biopsy reveal a Renal biopsy reveal a diffuse or diffuse or

patchy inflammatory cell infiltrate,patchy inflammatory cell infiltrate, mainly of T lymphocytes, plasma cells, mainly of T lymphocytes, plasma cells, eosinophils, and monocyteseosinophils, and monocytes

Treatment of AINTreatment of AIN I- Offending agents removal and correction of underling factors:I- Offending agents removal and correction of underling factors:

1.1. Volume depletion.Volume depletion.2.2. Drugs (NSAIDs, contrast agents).Drugs (NSAIDs, contrast agents).

3.3. Infection.Infection.4.4. lipid lowering therapy, and correction of anemia. lipid lowering therapy, and correction of anemia. 5.5. Control of both proteinuria and blood pressure. Control of both proteinuria and blood pressure. 6.6. Antihypertensive therapy leads to ( renal and CV Antihypertensive therapy leads to ( renal and CV

protection).protection).7.7. Management of complications Management of complications

II- Corticosteroids: II- Corticosteroids: If If removing the inciting agentsremoving the inciting agents or or treating the treating the underlying infectionunderlying infection does not improve renal function, does not improve renal function, consider consider steroids.steroids.

III- Cyclophosphamide: III- Cyclophosphamide: therapy is controversial.therapy is controversial. PrognosisPrognosis

Early diagnosis of AIN and early holding of the offending agent will help Early diagnosis of AIN and early holding of the offending agent will help renal function back to baseline.. While renal function back to baseline.. While Delay in diagnosis or rechallenging Delay in diagnosis or rechallenging enhance the chronicity of the inflammatory response, leading to fibrosis and enhance the chronicity of the inflammatory response, leading to fibrosis and tubular atrophy. tubular atrophy.

Biopsy with diffuse infiltrate have a poorer prognosis. Biopsy with diffuse infiltrate have a poorer prognosis. 1-6% neutrophils of the infiltrate suggests a poorer prognosis.1-6% neutrophils of the infiltrate suggests a poorer prognosis.

Why CKD should be prevented and Why CKD should be prevented and early detectedearly detected

CKD is characterized by an irreversible deterioration of renal function CKD is characterized by an irreversible deterioration of renal function that gradually progresses to end-stage renal disease (ESRD).that gradually progresses to end-stage renal disease (ESRD).

In children:In children:

70% with CKD develop ESRD by age 20 Ys.70% with CKD develop ESRD by age 20 Ys. 80% of those with ESRD have 10-year survival rate.80% of those with ESRD have 10-year survival rate. Age-specific mortality rate is 30 times that seen in children without ESRD.Age-specific mortality rate is 30 times that seen in children without ESRD. CV disease, followed by infection are the most common cause of death.CV disease, followed by infection are the most common cause of death.

Deaths due to CV causes, are 25% (cardiac arrest with unknown cause), 16% Deaths due to CV causes, are 25% (cardiac arrest with unknown cause), 16% (stroke), 14% (myocardial ischemia), 12% (pulmonary edema), 11% (stroke), 14% (myocardial ischemia), 12% (pulmonary edema), 11% (hyperkalemia), and 22% (arrhythmia). (hyperkalemia), and 22% (arrhythmia).

Up to 15% of patients receiving a 2-week course of drugs can developed AIN.Up to 15% of patients receiving a 2-week course of drugs can developed AIN.

AIN presents with AIN presents with nephrotic syndrome (lower extremity edema, lethargy) , nephrotic syndrome (lower extremity edema, lethargy) , Fever, rash, proteinuria and eosinophilia Fever, rash, proteinuria and eosinophilia

So early detection of kidney disease is important because it increases a So early detection of kidney disease is important because it increases a person’s chance of preventing or delaying the progression of the disease.person’s chance of preventing or delaying the progression of the disease.

HyperlipidemiaHyperlipidemia The K/DOQI guidelines on dyslipidemias recommend The K/DOQI guidelines on dyslipidemias recommend

that all children and adults with CKD be evaluated for that all children and adults with CKD be evaluated for dyslipidemia.dyslipidemia.

1.1. Baseline complete fasting lipid profile Baseline complete fasting lipid profile (total cholesterol, LDL, HDL, and TG at presentation. (total cholesterol, LDL, HDL, and TG at presentation. 1.1. Annually thereafterAnnually thereafter2.2. or 2-3 months after a change in treatment or 2-3 months after a change in treatment 3.3. or other conditions known to cause dyslipidemia.or other conditions known to cause dyslipidemia.

Treatment options of dyslipidemiaTreatment options of dyslipidemia Hepatic 3-methylglutaryl coenzyme A reductase Hepatic 3-methylglutaryl coenzyme A reductase

inhibitors (inhibitors (statins).statins). Fibrates, plant stanols, bile acid–binding resins, and Fibrates, plant stanols, bile acid–binding resins, and

dietary manipulation. dietary manipulation.

Analgesic nephropathyAnalgesic nephropathy All analgesics, including acetaminophen, aspirin, All analgesics, including acetaminophen, aspirin,

and NSAIDs can cause Analgesic nephropathy and NSAIDs can cause Analgesic nephropathy which is the most common form chronic TIN .which is the most common form chronic TIN .

ItIt’’s severe form, associated with papillary necrosis. s severe form, associated with papillary necrosis. The amount of phenacetin -acetaminophen The amount of phenacetin -acetaminophen

required to cause chronic TIN is required to cause chronic TIN is 2-3 kg over many 2-3 kg over many yearsyears. .

It is most It is most common in women in the 6common in women in the 6thth and 7 and 7thth decadesdecades of life with chronic musculoskeletal of life with chronic musculoskeletal disorders. disorders.

Patients can be presented with episodes of Patients can be presented with episodes of papillary necrosis (gross hematuria with flank papillary necrosis (gross hematuria with flank painpain) and occasionally obstruction and infection, ) and occasionally obstruction and infection, renal insufficiency, renal insufficiency, modest proteinuria, sterile modest proteinuria, sterile pyuria, and anemia. pyuria, and anemia.

Diagnosis by Diagnosis by history of analgesic use, and CT scan history of analgesic use, and CT scan may reveal microcalcifications at the papillary tips.may reveal microcalcifications at the papillary tips.

Treatment includes Treatment includes supportive measures and supportive measures and discontinuation of analgesic use.discontinuation of analgesic use.

Renal Renal prostaglandinsprostaglandins

The VD effect of PGs The VD effect of PGs preserve renal preserve renal blood flow and GFRblood flow and GFR (In G disease with (In G disease with marked reduction in G capillary marked reduction in G capillary permeability) permeability) by relaxing pre G by relaxing pre G resistance. resistance.

In volume depletion PGs antagonize the In volume depletion PGs antagonize the VC effects of angiotensin II and VC effects of angiotensin II and norepinephrine. norepinephrine.

Inhibition of PGs synthesis with an Inhibition of PGs synthesis with an NSAID lead to reversible renal NSAID lead to reversible renal ischemia, and decline in G Capillary ischemia, and decline in G Capillary hydrostatic pressure ( major driving hydrostatic pressure ( major driving force for G filtration).force for G filtration).

Plasma creatinine concentration rises Plasma creatinine concentration rises within the 1within the 1stst three to seven days of three to seven days of therapy, (time required for attainment therapy, (time required for attainment of steady state drug levels) and of steady state drug levels) and therefore maximum inhibition of PGs therefore maximum inhibition of PGs synthesis synthesis

NSAIDsNSAIDs Elimination enhancement Elimination enhancement

NSAIDs are highly protein bound, so hemodialysis and NSAIDs are highly protein bound, so hemodialysis and charcoal hemoperfusion are not beneficial for overdose charcoal hemoperfusion are not beneficial for overdose treatments. treatments.

NSAIDs mostly metabolized by the liver with less than NSAIDs mostly metabolized by the liver with less than 10% excreted unchanged by the kidney. 10% excreted unchanged by the kidney.

Most NSAIDs, have half-life of elimination < 8 hrs.Most NSAIDs, have half-life of elimination < 8 hrs. However, the half-life is 8-30 hr. for diflunisal, However, the half-life is 8-30 hr. for diflunisal,

nabumetone, naproxen sodium, and sulindac.nabumetone, naproxen sodium, and sulindac. Approximately 30 hr. for piroxicam , phenylbutazone.Approximately 30 hr. for piroxicam , phenylbutazone. Urine alkalinization and forced diuresis are unlikely to Urine alkalinization and forced diuresis are unlikely to

affect the clinical outcome in poisoning with NSAIDs affect the clinical outcome in poisoning with NSAIDs because the kidney excretes only a small portion of the because the kidney excretes only a small portion of the absorbed dose unchanged.absorbed dose unchanged.

Analgesic agents: Analgesic agents: Meperidine, dextropropoxyphene, morphine, tramadol, Meperidine, dextropropoxyphene, morphine, tramadol,

and codeine metabolites are not recommended in and codeine metabolites are not recommended in stage stage 4 or 5 disease4 or 5 disease. .

No adjustment needed for acetaminophen.No adjustment needed for acetaminophen. NSAIDs: NSAIDs:

Use is linked to Use is linked to 3-times-higher risk for acute renal 3-times-higher risk for acute renal failurefailure. .

Use can cause Use can cause nephrotic syndrome with interstitial nephrotic syndrome with interstitial nephritis.nephritis.

Decreased potassium excretion can lead to Decreased potassium excretion can lead to hyperkalemia. hyperkalemia.

Decreased sodium excretion can lead to Decreased sodium excretion can lead to peripheral peripheral edema, elevated blood pressureedema, elevated blood pressure, and exacerbation of , and exacerbation of heart failure. heart failure.

Antihypertensive Antihypertensive effects of β-blockers, ACE inhibitors, effects of β-blockers, ACE inhibitors, or ARBs can be decreased. or ARBs can be decreased.

Cyclooxygenase 2 inhibitors have similar renal effect. Cyclooxygenase 2 inhibitors have similar renal effect. Short-term NSAID use is well tolerated if patient is Short-term NSAID use is well tolerated if patient is

well hydratedwell hydrated and has good renal function and absence and has good renal function and absence of heart failure, diabetes, or hypertension. of heart failure, diabetes, or hypertension.

Long-term use not recommended. Long-term use not recommended. Serum creatinine should be checked every 2 to 4 weeksSerum creatinine should be checked every 2 to 4 weeks

in early treatment.in early treatment.

Chloroquine / Hydroxychloroquine ToxicityChloroquine / Hydroxychloroquine Toxicity

The drug is The drug is retained in the pigmented structures long after its use is stopped .retained in the pigmented structures long after its use is stopped . The drug kinetics is linked to The drug kinetics is linked to ½ life that is increased as the dosage increased½ life that is increased as the dosage increased. . In patients with retinopathy, 5 years or more after discontinuation, traces of In patients with retinopathy, 5 years or more after discontinuation, traces of

Chloroquine have been found in plasma, erythrocytes, and urine.Chloroquine have been found in plasma, erythrocytes, and urine.

Renal handlingRenal handling Acidification of the urine increases renal excretion of the 4-aminoquinoline Acidification of the urine increases renal excretion of the 4-aminoquinoline

compounds by 20-90%. compounds by 20-90%. Impaired renal function and/or metabolic acidosis have direct impact on Impaired renal function and/or metabolic acidosis have direct impact on

it’s renal handling. it’s renal handling. Special ConcernsSpecial Concerns

PediatricPediatric: Use of quinolones in children should be monitored closely. : Use of quinolones in children should be monitored closely. GeriatricGeriatric: Elderly patients should be considered part of a high-risk group; : Elderly patients should be considered part of a high-risk group;

therefore, they should be monitored closely. therefore, they should be monitored closely. Renal insufficiencyRenal insufficiency: Dose adjustments should be made. : Dose adjustments should be made. Hepatic insufficiencyHepatic insufficiency: Dose adjustments should be made.: Dose adjustments should be made.

MTX renal handlingMTX renal handling MTX is MTX is excreted primarily by the kidneysexcreted primarily by the kidneys, so impaired , so impaired

renal function can lead to drug accumulation and renal function can lead to drug accumulation and renal toxicity. renal toxicity.

Pre-existing kidney disease is a contraindication to Pre-existing kidney disease is a contraindication to MTX. MTX.

Drug dosage should be reduced or discontinued until Drug dosage should be reduced or discontinued until renal function is improved or restored.renal function is improved or restored.

Assessment of renal status is recommended prior to Assessment of renal status is recommended prior to MTX therapy .MTX therapy .

Urinary alkalinization (>7 PH), by IV or oral sodium bicarbonate.Urinary alkalinization (>7 PH), by IV or oral sodium bicarbonate. Adequate hydrationAdequate hydration Aspirin and Aspirin and NSAID (decrease MTX clearance and displace MTX from NSAID (decrease MTX clearance and displace MTX from

protein bindings).protein bindings). Phynytoin and sulphonamidePhynytoin and sulphonamide inhibit tubular secretion of MTX. inhibit tubular secretion of MTX. Drainage of Drainage of 33rdrd space space fluid is essential to reduce MTX toxicity. fluid is essential to reduce MTX toxicity. LeucovorinLeucovorin administration till MTX blood level <10 n mol/L administration till MTX blood level <10 n mol/L. . Not used if creatinine clearance <60 ml/hr. in dose of Not used if creatinine clearance <60 ml/hr. in dose of

300 mg/m2. 300 mg/m2.

Leucovorin (citrovorum Leucovorin (citrovorum factor).factor). MTX over dosage can be corrected with leucovorin MTX over dosage can be corrected with leucovorin

(citrovorum factor) which is a (citrovorum factor) which is a potent agent for potent agent for neutralizing the immediate toxic effects of large doses neutralizing the immediate toxic effects of large doses of MTXof MTX using a using a dose equal to or higher than the MTX dose equal to or higher than the MTX dose and is best administered within the first hoursdose and is best administered within the first hours. .

Calcium leucovorin can be administered by:Calcium leucovorin can be administered by:

1.1. i. v. infusion in i. v. infusion in doses up to 75 mg within 12 hoursdoses up to 75 mg within 12 hours, , followed by followed by 12 mg i. m. every 6 hours for 4 doses12 mg i. m. every 6 hours for 4 doses..

2.2. When average doses of methotrexate appear to have When average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of leucovorin calcium an adverse effect, 6 to 12 mg of leucovorin calcium may be given i. m. every 6 hours for 4 doses.may be given i. m. every 6 hours for 4 doses.

Cyclosporin A (CSA)Cyclosporin A (CSA) Cyclosporin Cyclosporin inhibits IL-2 release and T-cell activationinhibits IL-2 release and T-cell activation

and, secondarily, affects B-cell function. and, secondarily, affects B-cell function. It also inhibits bone resorption, at least in vitro.It also inhibits bone resorption, at least in vitro. This drug's This drug's bio-availability averages 25bio-availability averages 25––35%35% but is but is

highly variable. highly variable. It is highly concentrated in fatty tissues and red It is highly concentrated in fatty tissues and red

blood cells but does not cross the blood-brain barrier. blood cells but does not cross the blood-brain barrier. CSA is CSA is metabolized to numerous metabolites by the metabolized to numerous metabolites by the

liver and its elimination half-life is 6liver and its elimination half-life is 6––12 hours12 hours in the in the absence of severe liver disease. absence of severe liver disease.

Biliary excretion accounts for 94% of CSAs Biliary excretion accounts for 94% of CSAs elimination.elimination.

Its metabolism can be inhibited by other drugs (e.g. Its metabolism can be inhibited by other drugs (e.g. ketoconazole and erythromycin) or its metabolism ketoconazole and erythromycin) or its metabolism can be induced (e.g. anticonvulsants).can be induced (e.g. anticonvulsants).

The principal toxicities of cyclosporin are gastro-The principal toxicities of cyclosporin are gastro-intestinal and intestinal and renal, with the latter being of more renal, with the latter being of more concern.concern.

Leflunomide (LF)Leflunomide (LF) Leflunomide Leflunomide is a pyrinidine synthesis is a pyrinidine synthesis

inhibitorinhibitor, although tyrosine kinase , although tyrosine kinase inhibition may also be part of its inhibition may also be part of its mechanism of action.mechanism of action.

Its Its active metabolite is excreted renallyactive metabolite is excreted renally to a large degree, with a prolonged to a large degree, with a prolonged elimination half-life of about 11 days. elimination half-life of about 11 days.

Since LF is activated by liver Since LF is activated by liver metabolism, renal failure may have less metabolism, renal failure may have less effect on kinetics than severe liver effect on kinetics than severe liver disease.disease.

Toxicity relates to the skin, liver and GI Toxicity relates to the skin, liver and GI tract, although some degree of weight tract, although some degree of weight loss was also found.loss was also found.

Antihypertensive agentsAntihypertensive agents:: Thiazide diureticsThiazide diuretics not recommended if serum creatinine not recommended if serum creatinine

greater than 2.5 mg/dL or creatinine clearance less than greater than 2.5 mg/dL or creatinine clearance less than 30 mL/minute.30 mL/minute.

Loop diureticsLoop diuretics are most common drugs for are most common drugs for uncomplicated hypertension in chronic kidney disease.uncomplicated hypertension in chronic kidney disease.

Potassium-sparing diuretics and aldosterone blockersPotassium-sparing diuretics and aldosterone blockers can increase serum potassium. can increase serum potassium.

Angiotensin-converting enzyme (ACE) inhibitorsAngiotensin-converting enzyme (ACE) inhibitors and and angiotensin receptor blockers (ARBsangiotensin receptor blockers (ARBs) are first line for ) are first line for patients with diabetes mellitus and early kidney disease.patients with diabetes mellitus and early kidney disease.

ACE inhibitors and ARBs ACE inhibitors and ARBs can decrease can decrease GFR and GFR and increase creatinine,increase creatinine, especially in presence of CHF. especially in presence of CHF.

Discontinuation of high doses of diuretic and NSAID is Discontinuation of high doses of diuretic and NSAID is recommended if serum creatinine increases more than recommended if serum creatinine increases more than 30% or serum potassium at least 5.6 m Eq/L. 30% or serum potassium at least 5.6 m Eq/L.

Hypoglycemic agents:Hypoglycemic agents: MetforminMetformin increases risk for lactic acidosis and increases risk for lactic acidosis and

not not recommended recommended if serum creatinine is greater than 1.5 if serum creatinine is greater than 1.5 mg/dL in men or 1.4 mg/dL in women, age is older than 80 mg/dL in men or 1.4 mg/dL in women, age is older than 80 yearsyears, or there is chronic heart failure. , or there is chronic heart failure.

SulfonylureasSulfonylureas can cause severe hypoglycemia and can cause severe hypoglycemia and should not should not be used in stages 3 to 5 CKD. be used in stages 3 to 5 CKD.

No adjustment needed for No adjustment needed for glipizide.glipizide. Antimicrobial agents:Antimicrobial agents:

Penicillin G or carbenicillinPenicillin G or carbenicillin can cause neuromuscular toxicity, can cause neuromuscular toxicity, myoclonus, seizures, or coma. myoclonus, seizures, or coma.

Imipenem / cilastatinImipenem / cilastatin can cause seizures. can cause seizures. Tetracyclines, except doxycyclineTetracyclines, except doxycycline, can exacerbate uremia. , can exacerbate uremia. Nitrofurantoin metaboliteNitrofurantoin metabolite can cause peripheral neuritis. can cause peripheral neuritis. AminoglycosidesAminoglycosides should not be used if possible. should not be used if possible.

Pearls for PracticePearls for Practice In patients with CKD:In patients with CKD:

1.1. Dosing Dosing of renally excreted drugs should of renally excreted drugs should be based on GFR and creatinine be based on GFR and creatinine clearance or clearance or

2.2. Adjusted Adjusted by reducing the dose, increasing by reducing the dose, increasing the dosing interval, or both. the dosing interval, or both. Patients with CDK require dosing Patients with CDK require dosing

adjustments for:adjustments for:

1.1. Some antihypertensive agents.Some antihypertensive agents.

2.2. Hypoglycemic agents, antimicrobial Hypoglycemic agents, antimicrobial agents.agents.

3.3. Analgesic agents, NSAIDs, and herbal Analgesic agents, NSAIDs, and herbal products. products.

Pearls for PracticePearls for Practice

Initial dosagesInitial dosages are determined and adjusted are determined and adjusted using published guidelines and patient response.using published guidelines and patient response.

Serum drug concentrationsSerum drug concentrations should be used to should be used to monitor effectiveness and toxicity.monitor effectiveness and toxicity.

Loading dosesLoading doses do not generally need adjustment. do not generally need adjustment. Dosing adjustmentDosing adjustment methods include dose methods include dose

reduction, lengthening of dosing interval, or reduction, lengthening of dosing interval, or both. both.

Dose reductionDose reduction allows more constant drug level, allows more constant drug level, but higher risk for toxicity. but higher risk for toxicity.

Lengthening of dosingLengthening of dosing interval has lower risk for interval has lower risk for toxicity but higher risk for subtherapeutic level. toxicity but higher risk for subtherapeutic level.