Chronic Kidney disease (CKD)-,,,,,1.pptx

Chronic kidney disease is a disease that affects the renal system particularly the kidneys

1. Chronic Kidney disease (CKD) Management of Complications

2. Introduction K idney a complex organ with many functions. It excretes water, electrolytes and drugs, and controls the rate of loss of water and electrolytes to maintain homeostasis . K idney involved in blood pressure control by controlling the excretion or retention of water and sodium and by producing renin , which causes vasoconstriction and increases in blood pressure. K idneys are also involved in calcium homeostasis and erythropoietin production

3. Introduction II CKD is a result of primary renal disease (e.g. Glomerulonephritis ) or a renal complication of multisystem disease e.g. Hypertension. R esultant failure of kidney regulatory function manifests in a number of ways/symptoms Extent of the reduction in renal function indicated by glomerular filtration rate (GFR), determines the severity of the symptoms experienced. Drug treatment of CKD mainly aims to control these symptoms and it is often their severity that determines when renal replacement therapy will begin Discussion will focus on drugs commonly used for symptom control in CKD

4. Symptoms/complications of CKD Anaemia Hypocalcemia & hyperphosphatemia Hypertension Oedema Electrolyte imbalance Acidosis Restless legs Pruritus Nausea

5. Anaemia C ommon complication of chronic kidney disease associated with adverse cardiovascular complications An independent risk factor for poor outcomes in patients with chronic kidney disease ( CKD) L eads to substantial mortality and morbidity among these patients if left untreated or not properly treated

6. Causes Largely reduced production of renal erythropoietin and uraemia Others and aggravating factors Stress ulceration/proton pump inhibitors Phosphate binders & modification of diet Loss of functional erythrocytes thru hemodialysis Overzealous blood sampling for analysis Disturbances of blood chemistry: infections, inflammations, uremia, hyperphosphatemia , hyperaluminiumia , hyperparathyroidism

7. Diagnosis P resent when the levels of blood Hb is below that needed to ensure adequate tissue oxygenation CKD patients with anemia often present with mild breathlessness on exertion, tiredness and lethargy However , because of its insidious onset, patients are often asymptomatic and anemia indicated by routine blood analysis. Some times presentation of anemia precipitates angina or pulmonary congestion. According to European best practices guidelines (EBPG), anemia should be investigated in patients when Hb levels fall below the following references: 11.5g/dl in adult females 13.5g/dl in adult males 12g/dl in adult males over the age 70 years

8. Treatment of anaemia V arious ways to treat anaemia Blood transfusions can be given, effect is transient and can cause fluid and iron overload E rythropoietin can be given intravenously (IV) or subcutaneously (SC), usually two or three times a week SC route more efficacious, larger doses are needed if erythropoietin is given IV. D ose required titrated against the patient’s Hb levels EBPG recommends target Hb level of > 11g/dl achieved within 4 months of starting therapy R enal association standards (RAS) recommends Hb level of > 10g/dl within six months on therapy. The EBPG recommends limiting the Hb to < 14g/dl in hemodialysis patients due post dialysis hemoconcentration and potential risk of thrombosis, and <12g/dl in patients with severe cardiovascular disease or in diabetic patients with peripheral vascular disease .

9. Iron therapy CKD patients have increased risk of iron deficiency , hemodialysis patients iron requirement three times that of normal healthy individuals I nitiation of patients on erythropoiesis stimulating agents (ESAs) rapidly depletes iron stores, important to replete the iron stores before patients are initiated on ESAs. If the anemia is due to iron deficiency rather than the presumed erythropoietin deficiency, Hb will start to rise once iron stores are adequate T o sustain efficient erythropoiesis , all patients must be on maintenance iron therapy.

10. Iron therapy II Oral iron supplements adequate in non dialyzing patients or patients on peritoneal dialysis but periodic intravenous therapy may be required Some of the set backs to oral therapy is reduction in absorption by uraemia and by the phosphate binders that patients with renal disease often have to take. Hemodialysis patients almost always need IV therapy with iron sucrose or dextran because of the increased requirements.

11. Iron therapy-Adverse effects Oral iron associated with gastrointestinal disturbances such as nausea, vomiting, abdominal pain and constipation resulting in low compliance For intravenous preparations, iron sucrose is better tolerated than iron dextran but both are associated with rare life threatening anaphylactic reactions. A test dose of 25mg is recommended for both preparations at the initiation of therapy

12. Iron therapy- Doses D oses individualized and based on the patients iron studies S tudies include: measuring serum iron concentration, total iron binding capacity (TIBC), percentage hypochromic red blood cells (per cent hrbc ), percentage transferrin saturation (TSAT) and serum ferritin For patients on ESAs to achieve and maintain target Hb levels sufficient iron should be administered to maintain a TSAT of > 20 percent, serum ferritin of > 100µg/L and a percentage hrbc lower than 5 per cent Patients on hemodialysis typical require doses of up to 100-200mg weekly.

13. ESA therapy R educe the need for blood transfusions to correct anemia, decreasing the risks of transmission of blood borne viruses, iron overload and sensitization of patients to future transplants H ave a positive impact on exercise capacity, sleep patterns, cognitive function, immune response and sexual function. T heir use improves quality of life and reduces cardiovascular disease risks often associated with declining renal function . G iven to patients with CKD whose Hb levels are consistently below 11g/dl and in whom other causes of anemia have been excluded. For patients who receive ESAs before dialysis, it is given SC

14. ESA therapy- Doses S tarting doses based on weight i.e. Epoetin beta subcutaneously 60units/kg/weekly given in three divided doses (usually 2,000-3000 units three times weekly) Darbepoetin 450ng/weekly. A im of therapy to achieve 1-2g/dl/month rise in the Hb level until the target level is achieved More rapid control can lead to uncontrolled hypertension and thrombosis.

15. ESA therapy- Adverse effects Most common is hypertension mainly due rapid increase in Hb levels BP should therefore be monitored especially during initiation of ESAs Hypertension should be managed aggressively if it does occur without compromising on ESA therapy.

16. ESA resistance S hould be considered if a patient fails to achieve target Hb level despite receiving more than 20,000units of epoetin beta or 100µg of darbepoetin per week Inadequate response may be due to conditions that predispose to anemia such as iron, vitamin B12 and folate deficiencies and other conditions like aluminium toxicity, chronic blood loss, parathyroid over activity and malignancies.

17. Hyperphosphatemia & hypocalcemia Decline in renal function , reduction in phosphate filtration in the kidney resulting in higher phosphate levels (causing itching), which in turn contributes to a lower plasma calcium level As serum calcium declines , a compensatory increase in the release of parathyroid hormone (PTH) occurs, resulting in secondary hyperparathyroidism Lack of active vitamin D results in decreased absorption and utilisation of calcium . Cumulative effects of low serum calcium & vitamin D3 levels, in addition to secondary hyperparathyroidism, cause renal osteodystrophy

18. Hyperphosphatemia & hypocalcemia II At concentrations of > 55 mg2/ dL the calcium–phosphate product crystallizes, leading to crystal deposition within the soft tissue and vasculature. Patients with a calcium–phosphate product concentration of >70 mg2/ dL have an increased risk of death, independent of their phosphate status. The increased risk of mortality may be the result of vascular calcification and the subsequent decreases in vessel elasticity , potentially causing left ventricular hypertrophy

19. Management Diet Phosphate binders Hydroxylated vitamin D/active vitamin D Dialysis calcimimetics

20. Diet restrictions Diet low in phosphates Phosphate rich foods: diary products, eggs, meat & fish Advice from dieticians how much phosphate to eat Restrictions should be balanced against protein requirement of the patient who might have low albumin level

21. Phosphate binders Binding agent Initial total daily dosage Phosphorus binding capacity Comments Aluminium hydroxide ( Alu -cap) 5.7g 22.3mg phosphorus bound/5ml Risk of osteomalacia & encephalopathy; reserve for use when phos . Conc. > 7mg/ dL Calcium carbonate ( calchiew ) 5g 43mg phosphorus bound/1g elemental ca Risk of hypercalcemia , less effective at high pH (max effect at pH 1.5 ) Calcium acetate ( Phosex ) 4002mg 106mg phosphorus bound/1g elemental ca Less elemental ca than CaCo3; Less risk of hypercalcemia , effective over wide pH range Sevelamer hydrochloride ( Renegal) 2400mg 80mg phosphorus boudn /1g sevelamer Maximal phosphate binding at pH 7 Lanthanum carbonate ( fosrenol ) 750mg NA Binding occurs across a wide pH range

22. Vitamin D analogues Correct hypocalcemia and inhibit PTH release Active vitamin D analogues: alfacalcidol & calcitriol Therapy initiated at dose of 0.25µg daily and titrated upwards Weekly (pulsed) calcitriol or alfacalcidol (2 or 3 times), given at a higher dose than the more usual daily dose has the advantage of down regulating parathyroid hormone receptors on the parathyroid glands, reducing parathyroid hormone levels If these measures fail and the patient acquires tertiary hyperparathyroidism (where parathyroid hormone levels remain high despite correction of calcium and phosphate), removal of the parathyroid glands may be necessary

23. Calcimimetics Cinacalcet first calcimimetic binds to the calcium sensing receptor on the parathyroid glands causing a conformational change which increases sensitivity to circulating calcium PTH is suppressed by lower levels of calcium Effective at reducing PTH, serum calcium and phosphate Most units use it when PTH levels are high remain high despite max pulsed alfacalcidiol that a patient can tolerate without producing hypercalcemia

24. Calcimimetics II Cinacalcet started at a dose of 30mg daily, then increased slowly, titrating against serum PTH Few patients require maximum licensed dose of 180mg daily Little evidence to support use in tertiary hyperparathyroidism Less useful when the regulatory function of the parathyroid gland is lost

25. Hypertension Cause of renal disease or a complication of renal impairment, arising as a result of activation of the renin-angiotensin system A number of drug treatments for hypertension can be tried, but often complex drug regimens are required Drugs should be introduced at a low dose and gradually increased

26. Drugs that can be used Diuretics Beta blockers ACE inhibitors and receptor blockers Calcium channel blockers Vasodilators Centrally acting antihypertensives

27. Diuretics Once the GFR falls below 25ml/min, thiazides become ineffective and side effects can increase because of accumulation. Metolazone effective when used with a loop diuretic Hypokalaemia and fluid depletion can be complications of using loop diuretics and metolazone together. Loop diuretics often given in large doses, either orally or IV, and are effective even when the GFR is as low as 5ml/min, or when the patient is on dialysis but still passing urine. Frusemide is excreted by tubular secretion, so, patients with severe renal impairment might need higher doses (500mg a day of frusemide orally is not uncommon), because they have fewer functioning nephrons . Potassium-sparing diuretics are not appropriate for patients with renal failure because they increase potassium levels. Should even be avoided in hypokalaemic patients, for whom potassium supplementation is more appropriate.

28. Beta blockers Patients with renal disease respond well to beta-blockers. Choice of drug would be a cardioselective , hepatically excreted drug like metoprolol . In practice, atenolol , renally excreted, can be given safely, if introduced at low doses.

29. Angiotensin -converting enzyme (ACE) inhibitors Useful since hypertension can be caused by activation of the renin-angiotensin system. Renal function should be closely monitored in pre-dialysis patients when these drugs are introduced, in case the patient has renal artery stenosis . Are renally excreted ( ramipril and fosinopril also partially hepatically excreted) and the half-life is increased in patients with renal impairments Can increase the rate of decline of renal function by widening the efferent arteriole, thus reducing the filtration pressure across the glomerulus Used to advantage in patients with diabetes, where a reduction in hyperfiltration can delay the progression of diabetic nephropathy. Can also cause an increase in potassium levels, which can be a problem when renal function declines. When given to the right patients, they can be invaluable.

30. Angiotensin II receptor antagonists Beneficial in patients with CKD, since they block the effects of angiotensin II (a vasoconstrictor), causing vasodilation . Renal function should be closely monitored Useful when used in combination with an ACE inhibitor .

31. Calcium channel blockers Can be used safely in patients with chronic renal failure, although they should be introduced at low doses One of the side effects of this group, especially of nifedipine , is ankle swelling, unresponsive to diuretics, which can be mistaken for fluid overload Ankle swelling is less of a problem with longer-acting agents, such as amlodipine .

32. Vasodilators Vasodilating drugs include: doxazocin , prazosin , hydralazine and minoxidil , all of which are hepatically metabolised Usually added when other drugs are ineffective Doxazocin is most commonly used Minoxidil is best given with a beta-blocker and a diuretic, since it can cause tachycardia and fluid retention.

33. Centrally acting drugs Moxonidine is a centrally acting drug Its use is limited It should be used with caution in mild renal impairment and is contraindicated in moderate and severe renal disease Useful for patients with hypertension that is unresponsive to other agents

34. Oedema Restrict fluid intake to as little as 500 to 1,000ml per day. This means any fluid, including foods like gravy and custard Diuretics can force a little extra fluid out of the kidneys, which, while it may not be useful in terms of excretion, will allow the patient to drink more

35. Electrolyte imbalance- Hyperkalemia Levels of potassium of particular concern Hyperkalaemia can cause muscle weakness, arrhythmias and cardiac arrest. Dialysis is the best way of reducing raised potassium levels but, if this is not possible, diet or drugs are used

36. Treatment of hyperkalaemia Moving potassium into cells Insulin (with glucose to prevent hypoglycaemia), sodium bicarbonate and salbutamol nebules can all be used to lower potassium levels, as they encourage potassium to move back into cells. Calcium gluconate might also be needed to prevent arrhythmias

37. Treatment II Ion-exchange resin Calcium resonium /calcium polystyerene sulphonate an ion-exchange resin 15g given orally or rectally 6hrly Exchanges calcium for potassium as it passes through the gut, thereby reducing serum potassium levels Continues to work for 24 to 48 hours after being discontinued, and potassium will continue to fall during this time.

38. Treatment III Diet Foods high in potassium include fruit, coffee, chocolate and tomatoes Dietitians may restrict potassium intake according to the patient’s needs Patients on a low potassium diet might require supplementation with vitamins B and C especially the case if they are dialysis-dependent, because these water soluble vitamins will be removed

39. Acidosis Manifests as low bicarbonate levels Treated by giving sodium bicarbonate Exact dose is not critical, but 600mg to 1.2g two or three times a day is commonly used

40. RESTLESS LEGS Described as a feeling that the legs are “jumping”. often occurs at night and can prevent sleep but the cause is not fully understood. Most common treatment is clonazepam (0.5 to 1mg at night) Carbamazepine , haloperidol and baclofen have also been tried with varying degrees of success

41. PRURITUS Common complaint in patients with CKD and can be caused by high phosphate levels or uraemia Dialysis and phosphate binders can help, but many patients need to be prescribed antihistamines Chlorphenamine the most common drug given and more effective than the less sedative antihistamines Some patients also find transient relief from topical preparations, such as urea or menthol cream.

42. NAUSEA Accumulation of toxins can cause nausea Dialysis the best treatment, but anti-emetics, such as metoclopramide , cyclizine and prochlorperazine can help in the short term

43. ANALGESIA Analgesia a common area for concern for patients with CKD Opiate analgesics can be given, but side effects are increased, so these drugs should be started at low doses increased gradually Opiates accumulate easily in patients with CKD, which can lead to respiratory depression Pethidine is best avoided because its metabolite norpethidine accumulates, and can cause seizures as well as respiratory depression. NSAIDs should be used with caution because they increase sodium and water retention, can also increase the rate of decline of renal function, so serum creatinine should be checked 48 to 72 hours after starting one of these drugs Increased risk of gastrointestinal bleeding in uraemic patients. Paracetamol can be given safely

44. C onclusion Drug therapy of chronic renal disease can be complex The choice and dose of every drug needs to be considered carefully Nephrotoxic drugs should be used with caution if a patient is pre-dialysis, as conserving renal function and delaying onset of dialysis is paramount. Renally excreted drugs should be monitored in case they begin to accumulate and cause more side effects than would be expected with normal renal function. Removal of drugs by dialysis is important, as it can determine the dose given and the dosage timing. Drugs are likely to be removed by dialysis if they are renally excreted water soluble, small molecules that are not highly protein bound and have a small volume of distribution.