33 ellabban care of the kidney during daily


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33 ellabban care of the kidney during daily

  1. 1. Care of the kidney during daily Ortho- Rheumatology practice <ul><li>ABDOU ELLABBAN </li></ul><ul><li>PROFESSOR OF RHEUMATOLOGY </li></ul><ul><li>MINIA UNIVERSITY </li></ul><ul><li>April – 30 - 2009 </li></ul>
  2. 2. Kidney Diagram Capsule Renal Vein Renal Artery Cortex Pyramid Papilla Calyx Pelvis Ureter Column Medulla Nephron
  3. 3. Renal prostaglandins <ul><li>PGs are a chemical mediators produced as a result of the sequential action of cyclooxygenase and prostanoid synthase on arachidonic acid in the cell wall. </li></ul><ul><li>It mediates it’s action through Interaction with its receptors. </li></ul><ul><li>PGs act in an autocrine or a paracrine fashion, serving as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. </li></ul><ul><li>PGE1 stimulate adenylcyclase enzyme resulting in an increase in C-AMP, which relax vascular smooth muscle, leading to reduction of vascular reactivity that protects vessels from the influence of catecholamines, angiotensin, renin-aldosterone system. (Okada 1993). </li></ul><ul><li>PGE1 reduces plasma endothelin-1 concentration . (ITOH 2001) </li></ul>
  4. 4. Renal PGs <ul><li>Renal cortical PGs ( PGI2 and PGE2), play a roles in maintaining blood pressure and renal function in hypovolemic states (VC effect), and chair in the pathogenesis of renal vascular hypertension through stimulating renal renin synthesis and release . </li></ul><ul><li>Renal medullary PGs </li></ul><ul><li>Have an antihypertensive effect in persons with a high-salt diet (VD effect). </li></ul>Renal cortex Renal medulla
  5. 5. Renal prostaglandins <ul><li>The VD effect of PGs preserve renal blood flow and GFR (In G disease with marked reduction in G capillary permeability) by relaxing pre G resistance. </li></ul><ul><li>In volume depletion PGs antagonize the VC effects of angiotensin II and norepinephrine. </li></ul><ul><li>Inhibition of PGs synthesis with an NSAID lead to reversible renal ischemia, and decline in G Capillary hydrostatic pressure ( major driving force for G filtration). </li></ul><ul><li>Plasma creatinine conc. rises within the 1 st three to seven days of therapy, (time required for attainment of steady state drug levels) and therefore maximum inhibition of PGs synthesis </li></ul>
  6. 6. Glomerular filtration rate (GFR) <ul><li>GFR is a measurement of the amount of glomerular filtrate ( blood plasma without proteins ) in the kidneys per minute, it is equal to the sum of the filtration rates in all of the functioning nephrons. </li></ul><ul><li>It is used to evaluate the kidneys’ ability to remove waste products from the body. </li></ul><ul><li>GFR is used to screen for: </li></ul><ul><li>Early signs of kidney damage </li></ul><ul><li>It can be assessed by: </li></ul><ul><li>Creatinine clearance (U x V / P Cr.). </li></ul><ul><li>U = Creatinine conc in 24 hr. urine, V = Urine volume in 24 hr., P Cr. = Plasma creatinine. </li></ul><ul><li>Inulin clearance </li></ul><ul><li>Cystatin C clearance. </li></ul>
  7. 7. Creatinine & Cystatin C clearance <ul><ul><li>Creatinine clearance estimates are difficult and imprecise because they require 24-hour urine collections . </li></ul></ul><ul><ul><li>Because of the problems with changes in creatinine production and secretion, other endogenous compounds have been evaluated to provide a more accurate estimation of GFR. </li></ul></ul><ul><ul><li>The most promising is cystatin C , a low molecular weight protein that is a member of the cystatin superfamily of cysteine protease inhibitors. </li></ul></ul><ul><ul><li>Cystatin C is produced by all nucleated cells, and its rate of production is relatively constant and is unaltered by inflammatory conditions or changes in diet. </li></ul></ul><ul><ul><li>The plasma cystatin C concentration may correlate more closely with the GFR than with the PCr. </li></ul></ul>
  8. 8. 5 Stages of Chronic Kidney Disease ( K/DOQI) define CKD as The presence of kidney damage or a reduction in the GFR for > 3 months. GFR Description Stage More than 90 Risk factors for kidney disease (e.g., diabetes, high blood pressure, family history, older age. At increased risk More than 90 Kidney damage (protein in the urine) and normal GFR 1 60 to 89 Kidney damage and mild decrease in GFR 2 30 to 59 Moderate decrease in GFR 3 15 to 29 Severe decrease in GFR 4 Less than 15 Kidney failure (dialysis or kidney transplant needed) 5
  9. 9. Acute interstitial nephritis (AIN ( Tubulointerstitial nephritis (TIN) <ul><li>Acute interstitial nephritis can be categorized into 5 groups based on the inciting etiology: </li></ul><ul><li>(1) Drug hypersensitivity reactions </li></ul><ul><li>(2) infections. </li></ul><ul><li>(3) immune-mediated disease. </li></ul><ul><li>(4) glomerular. </li></ul><ul><li>(5) idiopathic. </li></ul><ul><li>Acute interstitial nephritis can also be grouped into acute and chronic subgroups . </li></ul>
  10. 10. A cute TIN are caused by hypersensitivity reactions to drugs and are not mediated by direct toxicity . <ul><li>Drugs cause a hypersensitivity reaction include: </li></ul><ul><li>Antibiotics (eg, penicillins, cephalosporins, sulfa drugs, quinolones) </li></ul><ul><li>NSAIDs </li></ul><ul><li>Diuretics (eg, thiazides, furosemide) </li></ul><ul><li>Allopurinol </li></ul><ul><li>Phenytoin </li></ul><ul><li>Rifampin </li></ul><ul><li>Interferon α . </li></ul><ul><li>Proton pump inhibitors. </li></ul>
  11. 11. TIN are diseases involving tubules and or the interstitium outside the 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.
  12. 12. NSAIDs induced acute TIN. <ul><li>More common in elderly because of the higher incidence of arthritis. </li></ul><ul><li>Patients may present with: nephrotic syndrome, edema, massive proteinuria, and hypoalbuminemia . </li></ul><ul><li>Mononuclear inflammatory infiltrate, and edema in the interstitium. </li></ul><ul><li>Acute tubular damage is present; some tubules are distended with granular casts. </li></ul>
  13. 13. Antibiotic-induced acute TIN. <ul><li>Seen in hospital setting during treatment of serious infections, within several days to weeks of initiation of antibiotic therapy. </li></ul><ul><li>Rash, eosinophilia, and eosinophiluria, sterile pyuria, hematuria, and modest proteinuria (usually <1 g/ d). </li></ul><ul><li>Renal biopsy shows eosinophils, ill-defined granulomas may be present. </li></ul><ul><li>Rifampin is unique in inducing TIN, does not manifest with eosinophilia. </li></ul><ul><li>Manifest by Flulike , flank pain, hypertension, and oliguric acute renal failure. </li></ul>Inflammatory infiltrate ( ill-defined granuloma) with a partially destroyed tubule. Mononuclear infiltrate with abundant eosinophils, (allergic etiology). Severe tubular damage is observed
  14. 14. Cyclosporine- and tacrolimus- induced nephropathy <ul><li>The mechanism appears to be dependent largely on the potent vasoconstrictive effects of these drugs. </li></ul><ul><li>Both cyclosporine and tacrolimus frequently cause hypertension, hyperkalemia and hypomagnesemia. </li></ul><ul><li>Concomitant use of calcium channel blockers reduces nephrotoxicity. </li></ul><ul><li>Long-term use of cyclosporine associated with patchy interstitial fibrosis, and tubular atrophy. </li></ul>Chronic TIN, with interstitial fibrosis, distortion of tubules and periglomerular fibrosis . Intact glomeruli.
  15. 15. Assessment of CKD <ul><li>1- Urine examination. </li></ul><ul><li>2- Estimation of the GFR. </li></ul><ul><li>Fresh urine examination: </li></ul><ul><ul><li>I- Multitest detection strip (dipstick) test [proteinuria (then PCR ), hematuria, pyuria] . </li></ul></ul><ul><ul><li>II- Urine microscopy is performed on a centrifuge-spun urine specimen to look for RBCs, WBCs, and casts. </li></ul></ul><ul><ul><li>The presence of muddy-brown granular casts and epithelial cell casts is highly suggestive of acute tubular necrosis. </li></ul></ul><ul><ul><li>Red cell casts would suggest an acute nephritic process. </li></ul></ul><ul><ul><li>CKD have broad hyaline casts. </li></ul></ul><ul><li>Estimation of the serum BUN, creatinine, sodium, potassium, calcium, phosphorus, bicarbonate, alkaline phosphatase, parathyroid hormone (PTH), and cholesterol and fractionated lipid levels are important in the treatment and prevention of various CKD-related complications. </li></ul>
  16. 16. Imaging Studies <ul><li>I- Renal ultrasound is of minimal value. Normal-sized kidneys with a slight increase in echogenicity are typically noted. </li></ul><ul><li>II- Gallium scans often show diffuse positive bilateral uptake. </li></ul><ul><li>This can be helpful in differentiating acute interstitial nephritis (+ve scan) from acute tubular necrosis , which has a uniformly negative scan result. </li></ul><ul><li>III- Renal biopsy: </li></ul><ul><li>Considered the standard diagnostic test for AIN. </li></ul><ul><li>Biopsy frequently reveals either a diffuse or segmental mixed infiltrate. </li></ul><ul><li>Renal biopsy reveal a diffuse or patchy inflammatory cell infiltrate, mainly of T lymphocytes, plasma cells, eosinophils, and monocytes </li></ul>
  17. 17. Treatment of AIN <ul><li>I- Offending agents removal and correction of underling factors: </li></ul><ul><li>Volume depletion. </li></ul><ul><li>Drugs (NSAIDs, contrast agents). </li></ul><ul><li>Infection. </li></ul><ul><li>lipid lowering therapy, and correction of anemia. </li></ul><ul><li>Control of both proteinuria and blood pressure. </li></ul><ul><li>Antihypertensive therapy leads to ( renal and CV protection). </li></ul><ul><li>Management of complications </li></ul><ul><li>II- Corticosteroids: If removing the inciting agents or treating the underlying infection does not improve renal function, consider steroids. </li></ul><ul><li>III- Cyclophosphamide: therapy is controversial. </li></ul><ul><li>Prognosis </li></ul><ul><li>Early diagnosis of AIN and early holding of the offending agent will help renal function back to baseline.. While Delay in diagnosis or rechallenging enhance the chronicity of the inflammatory response, leading to fibrosis and tubular atrophy. </li></ul><ul><li>Biopsy with diffuse infiltrate have a poorer prognosis. </li></ul><ul><li>1-6% neutrophils of the infiltrate suggests a poorer prognosis. </li></ul>
  18. 18. Why CKD should be prevented and early detected <ul><li>CKD is characterized by an irreversible deterioration of renal function that gradually progresses to end-stage renal disease (ESRD). </li></ul><ul><li>In children: </li></ul><ul><li>70% with CKD develop ESRD by age 20 Ys. </li></ul><ul><li>80% of those with ESRD have 10-year survival rate. </li></ul><ul><li>Age-specific mortality rate is 30 times that seen in children without ESRD. </li></ul><ul><li>CV disease, followed by infection are the most common cause of death. </li></ul><ul><li>Deaths due to CV causes, are 25% (cardiac arrest with unknown cause), 16% (stroke), 14% (myocardial ischemia), 12% (pulmonary edema), 11% (hyperkalemia), and 22% (arrhythmia). </li></ul><ul><li>Up to 15% of patients receiving a 2-week course of drugs can developed AIN. </li></ul><ul><li>AIN presents with nephrotic syndrome (lower extremity edema, lethargy) , Fever, rash, proteinuria and eosinophilia </li></ul><ul><li>So early detection of kidney disease is important because it increases a person’s chance of preventing or delaying the progression of the disease. </li></ul>
  19. 19. Hyperlipidemia <ul><li>The K/DOQI guidelines on dyslipidemias recommend that all children and adults with CKD be evaluated for dyslipidemia. </li></ul><ul><li>Baseline complete fasting lipid profile </li></ul><ul><li>(total cholesterol, LDL, HDL, and TG at presentation. </li></ul><ul><li>Annually thereafter </li></ul><ul><li>or 2-3 months after a change in treatment </li></ul><ul><li>or other conditions known to cause dyslipidemia. </li></ul><ul><li>Treatment options of dyslipidemia </li></ul><ul><li>Hepatic 3-methylglutaryl coenzyme A reductase inhibitors ( statins). </li></ul><ul><li>Fibrates, plant stanols, bile acid–binding resins, and dietary manipulation. </li></ul>
  20. 20. Analgesic nephropathy <ul><li>All analgesics, including acetaminophen, aspirin, and NSAIDs can cause Analgesic nephropathy which is the most common form chronic TIN . </li></ul><ul><li>It ’ s severe form, associated with papillary necrosis. </li></ul><ul><li>The amount of phenacetin -acetaminophen required to cause chronic TIN is 2-3 kg over many years . </li></ul><ul><li>It is most common in women in the 6 th and 7 th decades of life with chronic musculoskeletal disorders. </li></ul><ul><li>Patients can be presented with episodes of papillary necrosis (gross hematuria with flank pain ) and occasionally obstruction and infection, renal insufficiency, modest proteinuria, sterile pyuria, and anemia. </li></ul><ul><li>Diagnosis by history of analgesic use, and CT scan may reveal microcalcifications at the papillary tips. </li></ul><ul><li>Treatment includes supportive measures and discontinuation of analgesic use. </li></ul>
  21. 21. Renal prostaglandins <ul><li>The VD effect of PGs preserve renal blood flow and GFR (In G disease with marked reduction in G capillary permeability) by relaxing pre G resistance. </li></ul><ul><li>In volume depletion PGs antagonize the VC effects of angiotensin II and norepinephrine. </li></ul><ul><li>Inhibition of PGs synthesis with an NSAID lead to reversible renal ischemia, and decline in G Capillary hydrostatic pressure ( major driving force for G filtration). </li></ul><ul><li>Plasma creatinine concentration rises within the 1 st three to seven days of therapy, (time required for attainment of steady state drug levels) and therefore maximum inhibition of PGs synthesis </li></ul>
  22. 22. NSAIDs Elimination enhancement <ul><li>NSAIDs are highly protein bound, so hemodialysis and charcoal hemoperfusion are not beneficial for overdose treatments. </li></ul><ul><li>NSAIDs mostly metabolized by the liver with less than 10% excreted unchanged by the kidney. </li></ul><ul><li>Most NSAIDs, have half-life of elimination < 8 hrs. </li></ul><ul><li>However, the half-life is 8-30 hr. for diflunisal, nabumetone, naproxen sodium, and sulindac. </li></ul><ul><li>Approximately 30 hr. for piroxicam , phenylbutazone. </li></ul><ul><li>Urine alkalinization and forced diuresis are unlikely to affect the clinical outcome in poisoning with NSAIDs because the kidney excretes only a small portion of the absorbed dose unchanged. </li></ul>
  23. 23. <ul><li>Analgesic agents: </li></ul><ul><ul><li>Meperidine, dextropropoxyphene, morphine, tramadol, and codeine metabolites are not recommended in stage 4 or 5 disease . </li></ul></ul><ul><ul><li>No adjustment needed for acetaminophen. </li></ul></ul><ul><li>NSAIDs: </li></ul><ul><ul><li>Use is linked to 3-times-higher risk for acute renal failure . </li></ul></ul><ul><ul><li>Use can cause nephrotic syndrome with interstitial nephritis. </li></ul></ul><ul><ul><li>Decreased potassium excretion can lead to hyperkalemia. </li></ul></ul><ul><ul><li>Decreased sodium excretion can lead to peripheral edema, elevated blood pressure , and exacerbation of heart failure. </li></ul></ul><ul><ul><li>Antihypertensive effects of β-blockers, ACE inhibitors, or ARBs can be decreased. </li></ul></ul><ul><ul><li>Cyclooxygenase 2 inhibitors have similar renal effect. </li></ul></ul><ul><ul><li>Short-term NSAID use is well tolerated if patient is well hydrated and has good renal function and absence of heart failure, diabetes, or hypertension. </li></ul></ul><ul><ul><li>Long-term use not recommended. </li></ul></ul><ul><ul><li>Serum creatinine should be checked every 2 to 4 weeks in early treatment. </li></ul></ul>
  24. 24. Chloroquine / Hydroxychloroquine Toxicity <ul><li>The drug is retained in the pigmented structures long after its use is stopped . </li></ul><ul><li>The drug kinetics is linked to ½ life that is increased as the dosage increased . </li></ul><ul><li>In patients with retinopathy, 5 years or more after discontinuation, traces of Chloroquine have been found in plasma, erythrocytes, and urine. </li></ul><ul><li>Renal handling </li></ul><ul><ul><li>Acidification of the urine increases renal excretion of the 4-aminoquinoline compounds by 20-90%. </li></ul></ul><ul><ul><li>Impaired renal function and/or metabolic acidosis have direct impact on it’s renal handling. </li></ul></ul><ul><ul><li>Special Concerns </li></ul></ul><ul><li>Pediatric : Use of quinolones in children should be monitored closely. </li></ul><ul><li>Geriatric : Elderly patients should be considered part of a high-risk group; therefore, they should be monitored closely. </li></ul><ul><li>Renal insufficiency : Dose adjustments should be made. </li></ul><ul><li>Hepatic insufficiency : Dose adjustments should be made. </li></ul>
  25. 25. MTX renal handling <ul><li>MTX is excreted primarily by the kidneys , so impaired renal function can lead to drug accumulation and renal toxicity. </li></ul><ul><li>Pre-existing kidney disease is a contraindication to MTX. </li></ul><ul><li>Drug dosage should be reduced or discontinued until renal function is improved or restored. </li></ul><ul><li>Assessment of renal status is recommended prior to MTX therapy . </li></ul><ul><li>Urinary alkalinization (>7 PH), by IV or oral sodium bicarbonate. </li></ul><ul><li>Adequate hydration </li></ul><ul><li>Aspirin and NSAID (decrease MTX clearance and displace MTX from protein bindings). </li></ul><ul><li>Phynytoin and sulphonamide inhibit tubular secretion of MTX. </li></ul><ul><li>Drainage of 3 rd space fluid is essential to reduce MTX toxicity. </li></ul><ul><li>Leucovorin administration till MTX blood level <10 n mol/L . </li></ul><ul><li>Not used if creatinine clearance <60 ml/hr. in dose of 300 mg/m2. </li></ul>
  26. 26. Leucovorin (citrovorum factor). <ul><li>MTX over dosage can be corrected with leucovorin (citrovorum factor) which is a potent agent for neutralizing the immediate toxic effects of large doses of MTX using a dose equal to or higher than the MTX dose and is best administered within the first hours . </li></ul><ul><li>Calcium leucovorin can be administered by: </li></ul><ul><li>i. v. infusion in doses up to 75 mg within 12 hours , followed by 12 mg i. m. every 6 hours for 4 doses . </li></ul><ul><li>When average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of leucovorin calcium may be given i. m. every 6 hours for 4 doses. </li></ul>
  27. 27. Cyclosporin A (CSA) <ul><li>Cyclosporin inhibits IL-2 release and T-cell activation and, secondarily, affects B-cell function. </li></ul><ul><li>It also inhibits bone resorption, at least in vitro. </li></ul><ul><li>This drug's bio-availability averages 25 – 35% but is highly variable. </li></ul><ul><li>It is highly concentrated in fatty tissues and red blood cells but does not cross the blood-brain barrier. </li></ul><ul><li>CSA is metabolized to numerous metabolites by the liver and its elimination half-life is 6 – 12 hours in the absence of severe liver disease. </li></ul><ul><li>Biliary excretion accounts for 94% of CSAs elimination. </li></ul><ul><li>Its metabolism can be inhibited by other drugs (e.g. ketoconazole and erythromycin) or its metabolism can be induced (e.g. anticonvulsants). </li></ul><ul><li>The principal toxicities of cyclosporin are gastro-intestinal and renal, with the latter being of more concern. </li></ul>
  28. 28. Leflunomide (LF) <ul><li>Leflunomide is a pyrinidine synthesis inhibitor , although tyrosine kinase inhibition may also be part of its mechanism of action. </li></ul><ul><li>Its active metabolite is excreted renally to a large degree, with a prolonged elimination half-life of about 11 days. </li></ul><ul><li>Since LF is activated by liver metabolism, renal failure may have less effect on kinetics than severe liver disease. </li></ul><ul><li>Toxicity relates to the skin, liver and GI tract, although some degree of weight loss was also found. </li></ul>
  29. 29. Antihypertensive agents: <ul><li>Thiazide diuretics not recommended if serum creatinine greater than 2.5 mg/dL or creatinine clearance less than 30 mL/minute. </li></ul><ul><li>Loop diuretics are most common drugs for uncomplicated hypertension in chronic kidney disease. </li></ul><ul><li>Potassium-sparing diuretics and aldosterone blockers can increase serum potassium. </li></ul><ul><li>Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs ) are first line for patients with diabetes mellitus and early kidney disease. </li></ul><ul><li>ACE inhibitors and ARBs can decrease GFR and increase creatinine, especially in presence of CHF. </li></ul><ul><li>Discontinuation of high doses of diuretic and NSAID is recommended if serum creatinine increases more than 30% or serum potassium at least 5.6 m Eq/L. </li></ul>
  30. 30. <ul><li>Hypoglycemic agents: </li></ul><ul><ul><li>Metformin increases risk for lactic acidosis and not recommended if serum creatinine is greater than 1.5 mg/dL in men or 1.4 mg/dL in women, age is older than 80 years , or there is chronic heart failure. </li></ul></ul><ul><ul><li>Sulfonylureas can cause severe hypoglycemia and should not be used in stages 3 to 5 CKD. </li></ul></ul><ul><ul><li>No adjustment needed for glipizide. </li></ul></ul><ul><li>Antimicrobial agents: </li></ul><ul><ul><li>Penicillin G or carbenicillin can cause neuromuscular toxicity, myoclonus, seizures, or coma. </li></ul></ul><ul><ul><li>Imipenem / cilastatin can cause seizures. </li></ul></ul><ul><ul><li>Tetracyclines, except doxycycline , can exacerbate uremia. </li></ul></ul><ul><ul><li>Nitrofurantoin metabolite can cause peripheral neuritis. </li></ul></ul><ul><ul><li>Aminoglycosides should not be used if possible. </li></ul></ul>
  31. 31. Pearls for Practice <ul><li>In patients with CKD: </li></ul><ul><li>Dosing of renally excreted drugs should be based on GFR and creatinine clearance or </li></ul><ul><li>Adjusted by reducing the dose, increasing the dosing interval, or both. </li></ul><ul><li>Patients with CDK require dosing adjustments for: </li></ul><ul><li>Some antihypertensive agents. </li></ul><ul><li>Hypoglycemic agents, antimicrobial agents. </li></ul><ul><li>Analgesic agents, NSAIDs, and herbal products. </li></ul>
  32. 32. Pearls for Practice <ul><li>Initial dosages are determined and adjusted using published guidelines and patient response. </li></ul><ul><li>Serum drug concentrations should be used to monitor effectiveness and toxicity. </li></ul><ul><li>Loading doses do not generally need adjustment. </li></ul><ul><li>Dosing adjustment methods include dose reduction, lengthening of dosing interval, or both. </li></ul><ul><li>Dose reduction allows more constant drug level, but higher risk for toxicity. </li></ul><ul><li>Lengthening of dosing interval has lower risk for toxicity but higher risk for subtherapeutic level. </li></ul>
  33. 33. Thank you
  34. 34. Thank you