DRUG THERAPIES.in patients with renal disaesae

for renal /nephrology students

1. DRUG THERAPIES

2. Outline Erythropoietin Phosphate binders Calcium supplements. Proton pump inhibitors.

3. Erythropoetin (EPO)

4. Introduction Human erythropoietin is a glycoprotein containing 165 amino acids and four carbohydrate chains that incorporate sialic acid residues RHuEPO has the same polypeptide backbone and has the equal number of glycosylation sites as the endogenous form. Differences in the glycosylation pattern confers some variations in both pharmacokinetic and pharmacodynamic profiles between the natural and the recombinant forms, and among the RHuEPOs.

5. …. 90% produced by interstitial fibroblasts in the kidney in close association with the peritubular capillary and proximal convoluted tubule. This production is expanded into the outer cortex in response to hypoxia and anemia. 10% produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood.

6. … In circulation, EPO has a half life of 6–9 h. EPO acts by binding to specific receptors on the surface of marrow erythroid precursors, inducing them to proliferate and to mature. With EPO stimulation, red cell production can increase 4 to 5 fold within a 1- 2week period, but only in the presence of adequate nutrients, especially iron. Key to EPO gene regulation is hypoxia-inducible factor (HIF)-1. If O2 becomes limiting, a critical hydroxylation step does not occur, allowing HIF-1 to partner with other proteins, translocate to the nucleus, and upregulate the EPO gene, among others.

7. … EPO governs the day-to-day production of red cells, and ambient levels of the hormone can be measured in the plasma by sensitive immunoassays. The normal EPO level is 10–25 U/L. When the hemoglobin concentration falls below 10–12 g/ dL , plasma EPO levels increase in proportion to the severity of the anemia.

8. Types of rHuEPO Exogenous erythropoietin also called recombinant human erythropoietin (rHuEPO) is produced by recombinant DNA technology in cell culture. Collectively called erythropoiesis-stimulating agents (ESA).  5 forms of erythropoiesis-stimulating agents currently available; epoetin-alpha epoetin-beta epoetin-omega epoetin- delta darbepoetin-alpha.

9. … All have the same amino-acid sequence, but glycosylation varies as a result of type and host cell specific differences in the production process. Darbepoetin-alpha is an erythropoietin analogue, carrying two additional glycosylation sites, which produces a longer half-life and potency.

10. Epoetin alfa and epoetin beta The original recombinant human EPOs. Both products are synthesized in cultures of transformed Chinese hamster ovary (CHO) cells that carry DNA encoding human EPO. The amino acid sequence of both epoetins is therefore identical, and the major difference between these products lies in their glycosylation pattern. The clinical efficacy of both epoetin-alfa and epoetin- beta is similar. Epoetin-alfa (EPOGEN®) is formulated as a colorless liquid.

11. Epoetin delta Another recombinant EPO that has been used for treating patients with CKD. More potent. More stable. Elimination half-life in human after a single intravenous injection increasing three fold (25.3 h) compared with epoetin alfa (8.5 h). The half-life after subcutaneous administration is doubled from approximately 24 h to approximately 48 h. This latter characteristic has allowed less frequent dosing, with most patients receiving injections once weekly or once every other week.

12. Darbepoetin-alpha An erythropoietin analogue, carrying two additional glycosylation sites, which produces a longer half-life and potency. Sold under the brand name Aranesp®. Although very similar to EPO, it has a longer active life than EPO.

13. Name Mode of action Darbepoetin alfa (Aranesp®) Longer acting, weekly/fortnight/ monthly Epoetin alfa (Eprex®) Shorter acting 1–3 times/week Epoetin alfa (Binocrit®) Biosimilar shorter acting 1–3 times/week Epoetin beta (NeoRecormon®) Shorter acting, 1–3 times/week Epoetin beta (Retacrit®) Biosimilar shorter acting 1–3 times/week Methoxy polyethylene glycol-epoetin beta (Mircera®) Longer acting, fortnightly/monthly ESA preparations

14. ESA dosing As per KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease (KDOQI ): The initial ESA dose and ESA dose adjustments should be based on the patient’s Hb level, the target Hb, the observed rate of increase in Hb level, and clinical circumstances. ESA doses should be reduced, but not necessarily withheld, when a downward adjustment of Hb is needed. Scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity.

15. …   Epoetin-alfa or epoetin-beta 20 -50 IU/kg three times a week. (SC) or IV Darbepoetin- alfa 0.45 mcg/kg once weekly by subcutaneous (SC) or IV 0.75 mcg/kg once every 2 weeks SC CERA 0.6 mg/kg once every 2 weeks SC - CKD ND IV - CKD 5D 1.2 mg/kg once every 4 weeks by SC - CKD ND For CKD5 HD patients and those on hemofiltration or hemodiafiltration therapy, either IV or SC administration of ESA. For CKD ND and CKD 5PD patients, subcutaneous administration of ESA.

16. … Initiation In adult patients with Stage 5 chronic kidney disease, ESA therapy is recommended to prevent Hb falling below 9 g/ dL . ESA therapy should be started when Hb is between 9-10 g/ dL (90-100 g/L). Objective of initial ESA therapy is a rate of increase in (Hb) of 1.0 to 2.0 g/dl (10 to 20 g/l) per month Rise in Hb of > 2.0 g/dl (20 g/l) over a 4-week period should be avoided. Target Hb ; not to exceed > 11.5g/ dL

17. … Maintenance In adults with chronic kidney disease, Hb should not exceed 11.5 g/ dL (115 g/L) during ESA therapy. Dose adjustment may be necessary as in some patients quality of life can only improve at Hb levels higher than this. In any case, ESAs should not be used intentionally to raise the Hb above 13 g/ dL (130 g/L). In pediatric chronic kidney disease patients receiving ESA therapy, the Hb target should be in the range of 11.0 to 12.0 g/ dL .

18. … Monitoring Hb should be monitored at least monthly in adults and pediatric patients treated with ESAs.   HB initially monitored weekly , dose adjustment made every 4 weekly. Once stable HB achieved , monitor 4 weekly to 3 monthly , or in between any intercurrent illness or symptomatic. If HB level increases by >1gm%/2wks, reduce dose of EPO by 25%. If HB level does not increases by >1gm%/ month , dose of EPO should be increased by 25%.

19. ESA side effects The side effects that occur most often with ESA use include: High blood pressure Seizures Swelling Fever Dizziness Nausea Pain at the site of the injection.   ESA- related pure red cell aplasia (PRCA)

20. Resistance The most common cause of non-response is iron deficiency. Other causes include: Adherence Concurrent inflammation/infection Inadequate dosing Hyperparathyroidism Bone marrow fibrosis Aluminium toxicity Malnutrition

21. … Haemoglobinopathies Bone marrow disorders; myeloma, myelodysplasia Inadequate dialysis Blood loss Haemolysis Drugs, e.g. ACEI Carnitine deficiency PRCA.

22. Managing ESA resistance Identify cause Treat cause Chronic blood loss: investigate and treat cause Revisit route of administration, check adherence, self-injection technique, dose being administered. Review dose as per unit protocol Iron deficiency: give IV iron and monitor response Aluminium toxicity: (HD patients) desferrioxamine test

23. … Improve dialysis adequacy Hyperparathyroidism: review PTH, bone profile, check appropriate medication being prescribed and patient taking correctly. Review medication, e.g. ACEI dosing Review nutritional status Screen for bone marrow disorders, consider a bone marrow biopsy, refer appropriately.

24. PHOSPHATE BINDERS,VITAMIN ANALOGUES AND CALCIMIMETICS.

25. Introduction  Kidney failure disrupts systemic calcium and phosphate homeostasis and affects the bone, GIT and parathyroid glands. In kidney failure there is decreased renal excretion of phosphate and diminished production of calcitriol (1,25-dihydroxyvitamin D) Calcitriol increases serum calcium levels . The increased phosphate and reduced calcium, feedback and lead to secondary hyperparathyroidism, metabolic bone disease, soft tissue calcifications and other metabolic abnormalities.

26. … Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength. Vascular or other soft tissue calcification.

27. Phosphates Phosphate is an inorganic molecule consisting of a central phosphorus atom and four oxygen atoms. It is the second most abundant element in the human body after calcium. Approximately 85% of phosphorus is located in bones and teeth, 14% is intracellular, and only 1% is extracellular. In normal adults, the fasting plasma phosphate concentration ranges from 2.5 to 4.5 mg/ dL (0.80–1.45 mmol/L); however, the majority of healthy individuals have serum phosphate <4.0 mg/ dL . This represents the net balance of daily dietary intake, intestinal absorption, skeletal influx/efflux, cellular redistribution, and urinary phosphate excretion.

28. … Recommended dietary allowance of phosphorus is 700 mg/day whereas the average dietary intake according to nutritional database information ranges from 1000 to 1800 mg (18–36 mmol) per day. In the steady state, the serum phosphate concentration is determined by the ability of the kidneys to excrete dietary phosphate. Phosphate intake above 4000 mg/day (130 mmol/day) causes small elevations in serum phosphate concentrations (the intake is distributed over the course of the day). If, an acute phosphate load is given over several hours, transient hyperphosphatemia will occur.

29. The normal physiologic regulation of renal phosphate excretion Renal handling of phosphate occurs primarily by the regulation of proximal tubule expression of type II-a and type II-c sodium phosphate cotransporter (NaPi-2a/c). The filtered load of phosphate is approximately 4 to 8 g/day (130 to 194 mmol/day). Only 5 to 20 % of the filtered phosphate is normally excreted, with most being reabsorbed in the proximal tubule.

30. … The following factors are involved in physiologic regulation of renal phosphate excretion; Serum phosphate concentration – hyperphosphatemia diminish proximal tubular reabsorption via suppression of sodium- phosphate cotransporters. Parathyroid hormone (PTH) – increases excretion by diminishing activity of sodium-phosphate cotransporters. Phosphatonins – such as fibroblast growth factor 23 (fgf23) decrease reabsorption by suppressing the luminal expression of sodium phosphate cotransporters.

31. … Two principal modalities are used in an attempt to prevent and/or reverse the hyperphosphatemia of renal failure: phosphate restriction phosphate binders Phosphate restriction Approximately 900 mg/day is acceptable. However a large fraction of dialyzed patients has borderline malnutrition hence protein supplementation rather than protein restriction is the goal. The patient should be encouraged to avoid unnecessary dietary phosphate (as in phosphorus-containing food additives, dairy products, certain vegetables, many processed foods, and colas), while increasing the intake of high biologic value sources of protein (such as, meat and eggs).

32. Phosphate Binder Therapy A variety of agents have been used to create poorly soluble phosphorus complexes in the intestinal lumen and in doing so limit passive phosphate absorption. These agents include; aluminum salts calcium salts magnesium salts Non-absorbed polymers and most recently iron-containing compounds. All of these agents have demonstrated similar clinical efficacy in reducing serum phosphate in patients receiving dialysis.

33. Aluminium containing phosphate binders Aluminum hydroxide is the phosphate binder of choice, forming insoluble and nonabsorbable aluminum phosphate precipitates in the intestinal lumen. Side effects include aluminum intoxication due to the gradual tissue accumulation of absorbed aluminum , in the bone, skeletal muscle, and the central nervous system leading to; vitamin D-resistant osteomalacia a refractory microcytic anemia bone and muscle pain dementia.

34. Magnesium-Based Binders Magnesium-based phosphate binders are less potent than most calcium salts . They have significant systemic absorption. Side effects; Hypermagnesemia GI side effects

35. Calcium-containing phosphate binders After the discovery of the detrimental effects of aluminum-based binders, calcium based binders became the most commonly prescribed phosphate binders . Calcium carbonate and calcium acetate are widely available, relatively inexpensive, and effective at reducing serum phosphate. However, they have a lower affinity for phosphorus compared with aluminum compounds and hence require larger doses with increased number of pills in order to achieve a satisfactory control of phosphate.

36. … Calcium acetate is composed of 25% elemental calcium and is effective across a wide range of intestinal pH . Calcium carbonate is 40% elemental calcium and is less effective at alkaline pH (as in patients receiving H2 blockers or PPIs). Calcium acetate is thus a more efficient phosphate binder than calcium carbonate as calcium carbonate dissolves only at an acid PH, and many patients with advanced renal failure have achlorhydria or are taking h2-blockers.

37. … Calcium citrate should avoided in patients with renal failure since citrate can markedly increase intestinal aluminum absorption and aluminum neurotoxicity or the rapid onset of symptomatic osteomalacia. Use of calcium-containing phosphate binders become less frequent because of concerns about toxicity of calcium accumulation. Calcium- containing phosphate binders should be avoided in: normocalcemic CKD patients CKD patients who are receiving active vitamin D analogs for parathyroid hormone (PTH) suppression.

38. … The dose of calcium-containing phosphate binders is increased until the serum phosphate falls to normal values for patients with stage 3 to 5 CKD not yet on dialysis, or between 4.5 and 5.5 mg/dl for dialysis patients, or until hypercalcemia occur. One potential complication of calcium therapy is that absorption of some of the administered calcium may promote the development of coronary arterial calcification (associated with coronary atherosclerosis). To help decrease this possibility, the total dose of elemental calcium (including dietary sources) should not exceed 2000 mg/day. In addition, the dose of active vitamin D should be lowered or therapy should be discontinued until calcium levels return to 8.4 to 9.5 mg/dl.

39. … Phosphate binders are most effective if taken with meals so as to bind dietary phosphate thus leaving less free calcium available for absorption. In comparison, administration between meals only binds the phosphate present in intestinal secretions and results in a greater degree of calcium absorption. This problem is most likely to occur if a vitamin D preparation is also given or if the patient has decreased bone.

40. … Side effects of calcium based binders; Hypercalcemia PTH suppression GI side effects

41. Nonabsorbable Polymers They include; Sevelamer lanthanum  Sevelamer Sevelamer hydrochloride (renagel®) and sevelamer carbonate (renvela®) are nonabsorbable agents that contain neither calcium nor aluminum. Cationic polymers that bind phosphate through ion exchange. Relatively less progression of vascular calcification with sevelamer versus calcium- containing phosphate binders among patients with CKD. 

42. … One problem associated with sevelamer hydrochloride is the possible induction of metabolic acidosis unlike sevelamer carbonate. Sevelamer carbonate is likely that it will become the preferred binder in this class, but these agents appear to be equivalent in their ability to control phosphate levels. Sevelamer is much more expensive than calcium-based phosphate binders

43. Lanthanum It is a rare earth element, has significant phosphate-binding properties. The risk of lanthanum accumulation and toxicity, however, appears to be quite low with short-term use. The lower pill burden is one consideration that may favor the use of lanthanum. Sevelamer is commonly initially used over lanthanum since, although equally effective in lowering phosphate, as the long-term data on safety of lanthanum are more limited

44. Novel therapies A number of alternative therapies are undergoing evaluation; Nicotinamide Polynuclear iron (iii)-oxyhydroxide phosphate (pa21). Nicotinamide A metabolite of nicotinic acid (niacin, vitamin b3). Inhibits the Na/pi co-transport system in the gastrointestinal tract and kidneys and may be effective in lowering phosphate levels in dialysis patients by reducing gastrointestinal tract phosphate absorption.

45. … Polynuclear iron (iii)-oxyhydroxide phosphate (pa21) Various doses of polynuclear iron (iii)-oxyhydroxide phosphate (pa21) were compared with sevelamer in a randomized, multicenter open-label study, pa21 at doses of 5 and 7.5 g/day produced similar decreases in serum phosphorus to sevelamer dosed at 4.8 g/day. Further study is required to better understand the efficacy and safety of these and related agents in this setting. 

46. CALCIMIMETICS

47. Introduction The body of a young adult human contains about 1100 g (27.5 mol) of calcium. 99% of the calcium is in the skeleton The plasma calcium, normally about 10 mg/ dL (5 meq /L, 2.5 mmol/L), is partly bound to protein and partly diffusible It is the free, ionized calcium in the body fluids that is a vital second messenger and is necessary for:-blood coagulation, muscle contraction, and nerve function.

48. … A large amount of calcium is filtered in the kidneys, but 98-99% of the filtered calcium is reabsorbed. About 60% of the reabsorption occurs in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule. Distal tubular reabsorption is regulated by parathyroid hormone.

49. Calcimimetics Calcimimetics activate the calcium-sensing receptor to inhibit calcium-regulated PTH secretion, effectively mimicking or potentiating the effects of extracellular calcium. By reducing PTH, calcimimetics also decrease bone resorption and thus decrease the contribution of serum phosphorus from bone.  The oral calcimimetic cinacalcet and intravenous calcimimetic etelcalcetide both effectively reduce PTH while simultaneously reducing the serum levels of calcium and phosphorus.

50. … They ↓ release of phosphorus from bone, unlike active/analog vitamin D, which stimulate GI absorption of calcium and phosphorus. Calcimimetics offer minimal (cinacalcet) to no (etelcalcetide) pill burden. Etelcalcetide shows some advantages over cinacalcet, including a stronger efficacy profile, longer half-life, and intravenous mode of administration.

51. … Potential limitations of calcimimetics include hypocalcemia and nausea/vomiting .  Improvement in GI tolerability of cinacalcet can be achieved by administration with meals.

52. Vitamin D analogues Abnormal vitamin D metabolism plays a key role in the development of secondary hyperparathyroidism (SHPT). Low levels of vitamin D are common in patients with CKD due to poor nutrition, limited sun exposure, and reduced ability of the kidney to convert vitamin D into its biologically active form.  Active/analog vitamin D is administered as standard of care, with either oral or intravenous dosing, to CKD-MBD patients to increase calcium and decrease PTH.

53. … Different forms of vitamin D, include; calcitriol paricalcitol doxercalciferol They are generally equally effective at decreasing PTH, with similar safety profiles. Can lead to hypercalcemia and hyperphosphatemia.

54. … Calcitriol : Synthetic vit D that effectively reduces PTH; however, dose-dependent development of hypercalcemia and hyperphosphatemia prompted the development of calcitriol analogs. Paricalcitol is an analog with a wider therapeutic window but similar efficacy and safety as calcitriol. Doxercalcifero l is an analog of vitamin D 2  and undergoes hydroxylation in the liver to become active, without involvement of the kidney.

55. Proton Pump Inhibitors

56. Introduction Compared to the general population, patients with CKD and ESRD have more gastrointestinal symptoms. Specifically, patients with ESRD have a higher incidence of gastrointestinal distress symptoms and peptic ulcers . The recurrence of peptic ulcer disease (PUD) after  Helicobacter pylori  eradication is higher in uremic patients than in non-uremic patients. Patients with ESRD have higher complication rates after ulcer development. H. pylori infection is regarded as a major factor in the development of peptic ulcer disease.

57. Proton Pump inhibitors  Irreversibly bind to H+/K+ ATPase enzyme Block gastric acid secretion resulting in achlorhydria They are the treatment of choice peptic ulcer disease in patients with renal impairment as they rarely need dosage adjustment unlike other drugs. Elimination is primarily accomplished by the hepatic route as negligible amounts of unchanged drug are recovered in the urine. Renal failure does not cause changes in their pharmacokinetics.

58. … Clinically available PPIs used in the treatment of GERD in renal patients include;  lansoprazole (Prevacid) omeprazole (Prilosec) rabeprazole (AcipHex) pantoprazole (Protonix) esomeprazole (Nexium) 

59. PPI side effects. PPIs generally have an encouraging safety profile. The common side effects include: nausea Diarrhea abdominal pain Fatigue dizziness. Vitamin B12 deficiency (long term use).

60. References Oxford Handbook Of Dialysis Therapy, Fifth Edition. KDIGO Clinical Practice Guidelines For Treatment Of Anemia In ESA-treated Hemodialysis Patients. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease (KDOQI ). Management of Hyperphosphatemia in End-Stage Renal Disease: A New Paradigm https://doi.org/10.1053/j.jrn.2020.02.003

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