CHRONIC RENAL FAILURE , CLINICSL FEATURES MANAGEMENT.pptx

CRF DEATILS UG LECTURE

1. CHRONIC RENAL FAILURE

2. The term chronic renal failure applies to the process of continuing significant irreversible reduction in nephron number, and typically corresponds to CKD stages 3–5. End-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome. 2

3. 3 The normal annual mean decline in GFR with age from the peak GFR (~120 mL /min per 1.73 m 2 ) attained during the third decade of life is ~1 mL /min per year per 1.73 m 2 Reaching a mean value of 70 mL /min per 1.73 m 2 at age 70. The mean GFR is lower in women than in men.

4. Classification 4

5. Risk factors Non – modifiable Race/ ethinicity Male gender Older age Low birth weight Modifiable Well documented Diabetes HTN Obesity Smoking Likely Hyperlipidemia High salt ( and protein) diet Oral contraceptives Hormone replacement therapy 5

6. Emerging risk factors and markers of CKD progression 6 Traditinal progression factors or markers Proteinuria HTN High protein intake Obesity Anemia Dyslipidemia Smoking Nephrotoxins Cardiovascular disease Initiating factors Microalbuminuria / albuminuria Ethinicity DM Metabolic syndrome Hyperfiltrate state Dyslipidemia Nephrotoxins Primary kidney disease Urological disorders Obstructive uropathies Vascular disease Heredo familial renal disease Emerging progression factors/markers ADMA FGF23 Phosphate PTH ANP Adrenomedullin Adiponectin Genetic polymorphisms CKD Progression of CKD GFR decline and ESRD ADMA- asymetric dimethylarginine , FGF23 – fibroblast growth factor 23

7. Epidemiology Incidence in INDIA is nearly 1,50,000 new CKD patients that emerge annually. 60-70 thousand need urgent renal replacement. Frequency of disease causing CKD revealed DM (30%), Ch glomerulonephritis (20%), HTN(14%), VUR(13%), obstructive uropathy (9%), other causes (11%). 7

8. Differentiation of acute from chronic kidney disease History Long standing history suggests CKD Renal osteodystrophy Radiographic evidence of osteitis fibrosa cystica , osteomalacia Renal Size Small kidneys (<9cm) CKD of any cause normal or enlarged (9-12 cm) Acute Kdiney disease of any cause CKD HIV nephropathy Diabetic nephropathy Amyloidosis Enlarged kidneys (>12 cm) Autosomal dominant PCKD Tuberous sclerosis Obstructive nephropathy Renal Biopsy Histologic diagnosis 8

9. Causes of Acute Factors on CKD Dehydration , GI illness, Vol. depletion Hypotension due to overuse of antihypertensive treatment Accelerated HTN Cardiac failure, tamponade Nephrotoxic agents (antibiotics, analgesic, cisplatinum ) Contrast media Infection (sepsis, endocarditis , UTI) Obstruction Renal papillary necrosis Atheroembolic disease Renal vein thrombosis Flare up of primary disease Hyprecalcemia , hyponatremia 9

10. Pathophysiology of CKD

11. Pathophysiology of uremia (1)The accumulation of toxins normally undergoing renal excretion, including products of protein metabolism; (2) The loss of other renal functions, such as fluid and electrolyte homeostasis and hormone regulation; and (3) Progressive systemic inflammation and its vascular and nutritional consequences 12

12. Clinical abnormalities in Uremia Fluid, electrolyte and Acid-Base disturbance s Endocrine-metabolic disturbances Neuromuscular disturbances Cardiovascular and pulmonary disturbances Dermatological disturbances Gastrointestinal disturbances Hematologic and immunologic disturbances 13

13. Fluid electrolyte and acid base disorders Sodium and Water Homeostasis Glomerular tubular imbalance dietary intake of sodium >>> urinary excretion sodium retention and attendant extracellular fluid volume (ECFV) expansion hypertension (which accelerate the nephron injury). When an extrarenal cause for fluid loss is present, these patients may be prone to ECFV depletion because of the inability of the failing kidney to reclaim filtered sodium adequate - lead to acute-on-chronic kidney failure and result in overt uremia

14. 15 Potassium Homeostasis In CKD, urinary potassium excretion, which is predominantly mediated by aldosterone -dependent secretory events in the distal nephron segments augmented potassium excretion in the GI tract. Hyperkalemia may be precipitated by- Increased dietary potassium intake, protein catabolism, hemolysis , hemorrhage , transfusion of stored red blood cells, and metabolic acidosis, medications (ACE inhibitors, ARBs, and spironolactone and other potassium-sparing diuretics) Hypokalemia is not common in CKD and can be due to reduced dietary potassium intake, in association with excessive diuretic therapy or concurrent GI losses.

15. 16 Metabolic Acidosis CKD pts produce less ammonia and, therefore, cannot excrete the normal quantity of protons in combination with this urinary buffer. Hyperkalemia , if present, further depresses ammonia production. With worsening renal function, the total urinary net daily acid excretion is usually limited to 30–40 mmol , and the anions of retained organic acids can then lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap metabolic acidosis that can be seen in earlier stages of CKD may be complicated by the addition of an anion-gap metabolic acidosis as CKD progresses.

16. 17 Treatment The dietary intake of salt and use of loop diuretics, occasionally in combination with metolazone , may be needed to maintain euvolemia . Otherwise, patients with CKD and an intact thirst mechanism may be instructed to drink fluids in a quantity that keeps them just ahead of their thirst. Intractable ECFV expansion, despite dietary salt restriction and diuretic therapy, may be an indication to start renal replacement therapy.

17. 18 Hyperkalemia often responds to dietary restriction of potassium, Potassium-binding resins, such as calcium resonium or sodium polystyrene, can promote potassium loss through the GI tract and may reduce the incidence of hyperkalemia in CKD patients. Intractable hyperkalemia is an indication of dialysis. The renal tubular acidosis and subsequent anion-gap metabolic acidosis in progressive CKD will respond to alkali supplementation, typically with sodium bicarbonate. Recent studies suggest that the replacement should be considered when the serum bicarbonate concentration falls to 20 mmol /L to avoid the protein catabolic state seen with even mild degrees of metabolic acidosis

18. Disorders of Calcium and Phosphate Metabolism The principal complications of abnormalities occur in the skeleton and the vascular bed, with occasional severe involvement of extraosseous soft tissues. The major disorders of bone disease can be classified into high bone turnover with increased PTH levels (including osteitis fibrosa cystica , the classic lesion of secondary hyperparathyroidism) low bone turnover with low or normal PTH levels ( adynamic bone disease and osteomalacia ). 19

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20. Other Complications of Abnormal Mineral Metabolism Calciphylaxis is a devastating condition seen almost exclusively in patients with advanced CKD. It is heralded by livedo reticularis and advances to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts. Pathologically, there is evidence of vascular occlusion in association with extensive vascular calcification Risk factors – Hyperparathyrodism , Warfarin Oral Calcium 21

21. 22 Treatment The optimal management of secondary hyperparathyroidism and osteitis fibrosa is prevention. CKD patients should be given phosphate-binding agents. These are agents that are taken with meals and complex the dietary phosphate to limit its GI absorption. Examples are calcium acetate and calcium carbonate. A major side effect of calcium-based phosphate binders is total-body calcium accumulation and hypercalcemia , especially in patients with low-turnover bone disease. Sevelamer , a non-calcium-containing polymer, also functions as a phosphate binder; it does not predispose CKD patients to hypercalcemia

22. 23 Calcitriol therapy may result in hypercalcemia and/or hyperphosphatemia through increased GI absorption of these minerals. analogues of calcitriol are available (e.g., paricalcitol ) that suppress PTH secretion with less attendant hypercalcemia . Current KDOQI recommendations call for a target PTH level between 150 and 300 pg/ mL , recognizing that very low PTH levels are associated with adynamic bone disease and possible consequences of fracture and ectopic calcification.

23. Cardiovascular Abnormalities Ischemic vascular disease Heart failure Hypertension and left ventricular hypertrophy Pericardial disease 24

24. Ischemic Vascular Disease Traditional (classic) risk factors HTN Hypervolemia Dyslipidemia Sympathetic overactivity Hyperhomocysteinemia Nontraditional (CKD- realated ) risk factors Anemia Hyperposphatemia Hyperparathyroidism Sleep apnea Generalized inflammation 25

25. 26 The inflammatory state associated with a reduction in kidney function is reflected in increased circulating acute-phase reactants (inflammatory cytokines and C-reactive protein) and fall in the "negative acute-phase reactants," such as serum albumin and fetuin . The inflammatory state appears to accelerate vascular occlusive disease, and low levels of fetuin may permit more rapid vascular calcification, especially in the face of hyperphosphatemia . Hemodialysis leading to episodes of hypotension and hypovolemia can aggravate coronary ischemia.

26. Heart Failure Abnormal cardiac function secondary to myocardial ischemia, left ventricular hypertrophy, and cardiomyopathy , in combination with the salt and water retention often results in heart failure or even episodes of pulmonary edema . Heart failure can be a consequence of diastolic or systolic dysfunction, or both. Other CKD-related risk factors, including anemia and sleep apnea , may contribute to the risk of heart failure. 27

27. Hypertension and Left Ventricular Hypertrophy Hypertension is one of the most common complications of CKD. It develops early during the course of CKD and is associated with adverse outcomes - development of ventricular hypertrophy and a more rapid loss of renal function. Left ventricular hypertrophy and dilated cardiomyopathy are among the strongest risk factors for cardiovascular morbidity and mortality in patients with CKD and are related primarily to prolonged hypertension and ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state and consequent heart failure 28

28. 29 Management of Hypertension Two goals of therapy: to slow the progression of the kidney disease itself, to prevent the extrarenal complications of high blood pressure, such as cardiovascular disease and stroke. In CKD patients with diabetes or proteinuria > 1 g per 24 h, blood pressure should be reduced to 125/75, if achievable without prohibitive adverse effects. Salt restriction and diuretics should be the first line of therapy. The ACE inhibitors and ARBs slow the rate of decline of kidney function, even in dialysis patients, S/E- hyperkalemia . Use of a kaliuretic diuretic, such as metolazone , can improve potassium excretion in addition to improving blood pressure control.

29. 30 Management of Cardiovascular Disease Lifestyle changes, including regular exercise, should be advocated but are not often implemented. Hyperhomocysteinemia may respond to vitamin therapy, including oral folate supplementation, but this therapy is of unproven benefit. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins , should be used. Again, the use of these agents has not been of proven benefit for patients with advanced CKD

30. Pericardial Disease Pericardial pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of uremic pericarditis . Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis can be accompanied by pericardial effusion that is seen on echocardiography and can rarely lead to tamponade . Pericarditis is observed in advanced uremia , and in underdialyzed , nonadherent patients than in those starting dialysis. 31

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32. 33 Treatment Uremic pericarditis is an absolute indication for the urgent initiation of dialysis. Because of the propensity to hemorrhage in pericardial fluid, hemodialysis should be performed without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion. Nonuremic causes of pericarditis and effusion include viral, malignant, tuberculous , and autoimmune etiologies .

33. Hematologic Abnormalities Anemia Abnormal Hemostasis 34

34. Anemia A normocytic , normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4 35

35. 36 Pathophysiologic consequences- decreased tissue oxygen delivery and utilization, increased cardiac output, ventricular dilatation, and ventricular hypertrophy. Clinical manifestations – angina, heart failure, decreased cognition mental acuity, impaired host defense against infection. growth retardation in children with CKD.

36. 37 Treatment Current practice is to target a hemoglobin concentration of 100 to 115 g/L. Recombinant human EPO and modified EPO products, such as darbopoetin -alpha Iron supplementation is usually essential to ensure an adequate response to EPO in patients with CKD because the demand for iron by the marrow frequently exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well as the amount in iron stores (measured by serum ferritin ). For the CKD patient not yet on dialysis or the patient treated with peritoneal dialysis, oral iron supplementation should be attempted. If there is GI intolerance, the patient may have to undergo IV iron infusion, often during the dialysis session. An adequate supply of other major substrates and cofactors for red cell production must be assured, including vitamin B 12 and folate .

37. 38 Anemia resistant to recommended doses of EPO in the face of adequate iron stores may be due to combination of the following: acute or chronic inflammation, inadequate dialysis, severe hyperparathyroidism, chronic blood loss or hemolysis , chronic infection, or malignancy.

38. Blood transfusion increases the risk of – Hepatitis Iron overload Transplant sensitization (production of allo - antibodies that sensitizes the patient to donar kidney antigens) Should be avoided unless anemia fails to respond to EPO and the pt is symptomatic

39. Abnormal Hemostasis Prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia , and spontaneous GI bleeding. The latter condition results in hypoalbuminemia and renal loss of anticoagulant factors, which can lead to a thrombophilic state. 40

40. 41 Treatment Abnormal bleeding time and coagulopathy in patients with renal failure reversed temporarily with desmopressin (DDAVP), cryoprecipitate, IV conjugated estrogens, blood transfusions, and EPO therapy. Optimal dialysis correct a prolonged bleeding time. Certain anticoagulants, such as fractionated low-molecular-weight heparin, may need to be avoided or dose-adjusted in these patients, with monitoring of factor Xa activity where available. Use conventional high-molecular-weight heparin, titrated to the measured partial thromboplastin time, in hospitalized patients requiring an alternative to warfarin anticoagulation .

41. Neuromuscular Abnormalities Peripheral and autonomic neuropathy ,abnormalities in muscle structure and function are all well-recognized complications of CKD. Retained nitrogenous metabolites and middle molecules, including PTH, contribute to the pathophysiology of neuromuscular abnormalities. Clinical manifestations of uremic neuromuscular disease usually become evident at stage 3 CKD. Early manifestations of CNS complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations or twitching of muscles, becomes evident at later stages. In advanced untreated kidney failure, asterixis , myoclonus , seizures, and coma can be seen. 42

42. 43 Peripheral neuropathy usually becomes clinically evident after the patient reaches stage 4 CKD, although electrophysiologic and histologic evidence occurs earlier. Initially,involvement of sensory nerves >motor, lower extremities >upper, and distal parts of the extremities >proximal. The "restless leg syndrome“ is also seen in patients If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle weakness. Evidence of peripheral neuropathy without another cause (e.g., diabetes mellitus) is a firm indication for starting renal replacement therapy. Successful renal transplantation may reverse residual neurologic changes.

43. Gastrointestinal and Nutritional Abnormalities Uremic fetor , a urine-like odor on the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste ( dysgeusia ). Gastritis, peptic disease, and mucosal ulcerations can lead to abdominal pain, nausea, vomiting, and GI bleeding. These patients are also prone to constipation, which can be worsened by the administration of calcium and iron supplements. The retention of uremic toxins also leads to anorexia, nausea, and vomiting. 44

44. 45 Protein-energy malnutrition is an indication for initiation of renal replacement therapy. Assessment for protein-energy malnutrition should begin at stage 3 CKD. Assessment includes dietary history; serum albumin concentration; and measurement of urinary protein nitrogen . Adjunctive tools - skinfold thickness, mid-arm muscle circumference, and additional laboratory tests such as serum pre-albumin and cholesterol levels.

45. Endocrine-Metabolic Disturbances Glucose metabolism is impaired in CKD, Because the kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients, both in the fasting and postprandial states. Because of this, patients on insulin therapy may need progressive reduction in dose as their renal function worsens. Many hypoglycemic agents require dose reduction in renal failure, and some, such as metformin , are contraindicated when the GFR is less than half of normal. 46

46. 47 In women with CKD, estrogen levels are low, and menstrual abnormalities and inability to carry pregnancies to term are common. When the GFR has declined to ~40 mL /min, pregnancy is associated with a high rate of spontaneous abortion, with only ~20% of pregnancies leading to live births, and pregnancy may hasten the progression of the kidney disease itself. Men with CKD have reduced plasma testosterone levels, and sexual dysfunction and oligospermia . Sexual maturation may be delayed or impaired in adolescent children with CKD, even among those treated with dialysis. Many of these abnormalities improve or reverse with intensive dialysis or successful renal transplantation.

47. Dermatologic Abnormalities Anemic patients may be pale Defective hemostasis may show multiple ecchymoses . Pruritus In advanced CKD, even on dialysis, patients may become more pigmented, and this is felt to reflect the deposition of retained pigmented metabolites, or urochromes . The first lines of management are to rule out unrelated skin disorders, such as scabies, and to control phosphate concentration. In Uremic pruritus - Local moisturizers, mild topical glucocorticoids , oral antihistamines, and ultraviolet radiation is helpful. A skin condition called nephrogenic fibrosing dermopathy - progressive subcutaneous induration , especially on the arms and legs is seen. 48