بسم الله الرّحمن الرّحیم

Renal Failure Medical Treatment Dr javad zare Pediatric Nephrologist

Management of Acute Kidney Failure

General management of acute kidney injury Treatment of underlying disease Correct electrolyte abnormalities Avoid/manage fluid overload Avoid further renal injury Provision of adequate nutrition Drug dosing for renal function Renal replacement therapy

Prevention avoidance of hypotension by providing appropriate inotropic support nephrotoxic medication use, with re-evaluation of the need for nephrotoxins and closely following serum concentrations Careful evaluation of intravascular volume status is important to determine if AKI is reversible by fluid administration

Fluid Management Patients with pre-renal azotemia will often respond to fluid resuscitation whereas patients with acute tubular necrosis should be treated with volume restriction, to prevent development of worsening fluid overload. Patients with AKI secondary to nephrotoxic medications or interstitial nephritis often demonstrate polyuria, placing them at risk for severe fluid and electrolyte losses.

Electrolyte Management Patients with oligo-aneuric kidney failure or acute tubular necrosis should not receive potassium or phosphorus unless they exhibit hypokalemia or hypophosphatemia. Hyperkalemia Hypocalcemia Sodium intake should be restricted to 2–3 mEq/kg body weight per day

Pharmacologic Therapy There is no proven specific pharmacologic treatment for AKI. At low or so-called ‘‘renal doses’’ (0.5–2 mcg/kg/min), dopamine increases renal plasma flow and sodium excretion

Management of Chronic Kidney Disease

Classification of CKD In 2002, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI) published their CKD classification scheme that is based on estimated GFR and is applicable to adults and children above 2 years of age . CKD is categorized into five different stages, from Stage 1 (mild disease) to Stage 5 (kidney failure)

Characterization of these different stages has allowed nephrologists and general health care providers, both adult and pediatric, to have a common nomenclature when discussing CKD with respect to the anticipation of co-morbidities and treatment plans.

Glomerular Filtration Rate GFR 24 hour urine for creatinine clearance Most accurate indicator of Renal Function Reflects GFR Formula: urine creatinine X urine volume serum creatinine Can estimate creatinine clearance by: Men: {140 – age} x IBW (kg) 72 x serum creatinine Women: {140 – age} x IBW (kg) 85 x serum creatinine What is a normal GFR?

Stages of Chronic Renal Failure NKF Classification System GFR >/= 90 ml/min despite kidney damage

Stages of Chronic Renal Failure NKF Classification System Stage 2: Mild reduction (GFR 60 – 89 ml/min) 1. GFR of 60 may represent 50% loss in function. 2. Parathyroid hormones starts to increase.

During Stage 1 - 2 No symptoms Serum creatinine doubles Up to 50% nephron loss

Stages of Chronic Renal Failure NKF Classification System Stage 3: Moderate reduction (GFR 30 – 59 ml/min) 1. Calcium absorption decreases 2. Malnutrition onset 3. Anemia 4. Left ventricular hypertrophy

Stages of Chronic Renal Failure NKF Classification System Stage 4: Severe reduction (GFR 15 – 29 ml/min) 1. Serum triglycerides increase 2. Hyperphosphatemia 3. Metabolic acidosis 4. Hyperkalemia

During Stage 3 - 4 Signs and symptoms worsen if kidneys are stressed Decreased ability to maintain homeostasis

Stages of Chronic Renal Failure NKF Classification System Stage 5: Kidney failure (GFR < 15 ml/min) 1. Azotemia

During Stage 5 End Stage Renal Disease Residual function < 15% of normal Excretory, regulatory and hormonal functions severely impaired. Metabolic acidosis Marked increase in: BUN, Creatinine, Phosphorous Marked decrease in: Hemoglobin, Hematocrit, Calcium Fluid overload

During Stage 5 Uremic syndrome develops affecting all body systems can be diminished with early diagnosis & treatment Last stage of progressive CRF Fatal if no treatment

Prevention of CKD Progression There is clear and consistent evidence from adult studies that hypertension is a significant and modifiable mediator of CKD progression Proteinuria has also been demonstrated to be a significant, modifiable risk factor for CKD progression, especially in adults Prevention and Treatment of Diabetic Nephropathy

Other methods have been proposed as means by which CKD progression might be slowed, purportedly by targeting other mechanisms, such as oxidative stress and inflammatory pathways. Proposed methods have included treatment of dyslipidemia, early erythropoietin therapy, phosphorus control, and dietary protein restriction.

Anemia in CKD Anemia is one of the most common complications of CKD Multiple factors may contribute to the development of anemia in patients with CKD The principal cause is the diminished production of erythropoietin by the interstitial cells of the renal cortex. which was generally thought to occur when the GFR decreases below 35 ml/min/1.73 m2

Once the diagnosis of anemia is made, the initial evaluation of anemia in patients with CKD should include a complete blood count with red blood cell indices, reticulocyte count, serum ferritin and iron levels, and a total iron binding capacity.

Erythropoietin deficiency typically causes a normocytic anemia with an inappropriately decreased reticulocyte count, although a microcytosis may be seen when the anemia is secondary to iron deficiency or chronic disease.

Transferrin saturation is a measure of iron immediately available for hemoglobin synthesis. It is typically expressed as a percentage and is calculated as the serum iron divided by total iron binding capacity multiplied by 100%, with a therapeutic target of greater than 20% in patients with CKD

Treatment of Anemia The use of erythropoietic stimulating agents (ESA) such as rHuEPO, in addition to iron supplementation, are the key elements of anemia management in patients with CKD related anemia. Generally, an appropriate starting dose for subcutaneous rHuEPO, the route of therapy for most pre-dialysis CKD patients, is 100 units/kg/week divided into semi-weekly doses.

Darbepoetin-alfa (trade name Aranesp) is an effective alternative to rHuEPO with less frequent administration requirements

Oral iron therapy (3–5 mg/kg of oral elemental iron daily) is usually adequate in patients with CKD, although intravenous iron can be provided to patients unable or unwilling to take oral supplement or in those who are unable to meet the targets for iron therapy with oral supplement alone

Mineral and Bone Metabolism Disorders of calcium and phosphorus homeostasis associated with CKD inevitably develop with worsening kidney function. The changes in calcium and phosphorus regulation can cause significant alterations in bone re-modeling and somatic growth.

Pathophysiology of Mineral and Bone Disorders The two basic causes for much of the pathology of the bone and mineral disorders associated with CKD are decreased calcitriol (1,25- dihydroxy vitamin D3) synthesis and decreased phosphate secretion by the kidney

Evaluation of Mineral and Bone Disorder As the bone remodeling of renal osteodystrophy is preventable, patients with CKD should have their serum calcium, phosphorus, CO2, alkaline phosphatase and PTH levels checked regularly.

Frequency of measurement of bone and mineral factors and target ranges of serum PTH by stage of CKD

Treatment of Mineral and Bone Disorder The main tenets of treatment of CKD bone and mineral disorder is the maintenance of normal mineral metabolism and prevention of high turnover bone disease.

The close monitoring of serum calcium, phosphorus, and PTH are used to guide therapy and minimize the development of the secondary complications of impaired growth, adynamic bone disease, and extra-skeletal calcification.

Calcium salts (calcium carbonate or acetate) are frequently first-line treatments as phosphate binders. They are inexpensive and are most often well-tolerated with gastrointestinal complaints as their most common side effect.

Sevelamer hydrochloride is a metal-free phosphate binder which has been shown to effectively lower serum phosphorus levels and may shortly be approved for adult use in non-dialysis CKD.

Aluminum-containing binders were an early mainstay of therapy but are no longer recommended, except for limited time periods in very rare circumstances because of the risk of aluminum toxicity.

Vitamin D deficiency is a relatively common finding in patients with CKD and the current K/DOQI guidelines recommend replacement of vitamin D when 25-OH vitamin D3 levels are less than 30 ng/ml

Recommended supplementation for vitamin D deficiency in patients with CKD

If secondary hyperparathyroidism persists despite normal serum phosphorus and vitamin D levels, treatment with a vitamin D sterol or vitamin D analog is indicated. Calcitriol and its prohormone, alfacalcidol, are widely used and both are effective in suppressing PTH by increasing intestinal calcium absorption and suppressing PTH gene transcription.

Calcitriol may be given orally or intravenously with initial doses from 5–10 ng/kg/day and may be administered daily or intermittently with equivalent effectiveness in controlling secondary hyperparathyroidism .

Calcitriol does increase intestinal absorption of phosphorus by nearly 50% and therefore may worsen hyperphosphatemia. Additionally, there is an increased prevalence of hypercalcemia and an associated increase in the calcium-phosphorus product with its use, especially when it is co-administered with a calcium-based phosphate binder.

Cardiovascular Disease Adults with CKD have significantly increased rates of cardiovascular morbidity and mortality compared to the general population. Much of this increased risk is secondary to the fact that many of the traditional risk factors for adult cardiovascular disease (hypertension, diabetes mellitus, hyperlipidemia) are also primary etiologies of adult kidney disease.

Treatment of Cardiovascular Disease Risk Factors Recommendations for monitoring and treatment of cardiovascular risk factors have focused upon the traditional cardiovascular risk factors of hypertension and dyslipidemia.

The preferred antihypertensive agents to be used for the treatment of hypertension in CKD are ACE inhibitors or ARBs because of their effects on proteinuria and slowing of CKD progression.

Fluid, Electrolyte, and Acid-Base Balance Potassium homeostasis is usually preserved until the GFR is less than 15 ml/min/1.73 m2. This is because aldosterone-stimulated distal tubular potassium secretion is maintained. Aldosterone also stimulates increased potassium secretion within the colon with as much as 35% of dietary potassium able to be excreted in the stool

Unlike sodium and potassium disorders which develop late in the progression of CKD, metabolic acidosis may occur when the GFR declines below 50% of normal.

Oral bicarbonate therapy is the standard treatment for metabolic acidosis as citrate preparations should be avoided because of the aforementioned increase in aluminum absorption seen with their use.

Characteristics of Chronic Renal Failure Cause & onset often unknown Loss of function precedes lab abnormalities Lab abnormalities precede symptoms Symptoms (usually) evolve in orderly sequence Renal size is usually decreased

Causes of Chronic Renal Failure Diabetes Hypertension Glomerulonephritis Cystic disorders Developmental - Congenital Infectious Disease

Causes of Chronic Renal Failure Neoplasms Obstructive disorders Autoimmune diseases Hepatorenal failure Scleroderma Amyloidosis Drug toxicity

Stages of Chronic Renal Failure Old System Reduced Renal Reserve Renal Insufficiency End Stage Renal Disease (ESRD)

What happens when the kidneys don’t function correctly?

Manifestations of CRF Fluid - Electrolyte - pH Volume expansion and fluid overload Metabolic Acidosis Change in urine specific gravity Electrolyte Imbalances Potassium Magnesium Sodium

Manifestations of CRF GI Tract Uremic fetor Anorexia, nausea, vomiting GI bleeding

Manifestations of CRF Hematologic Anemia Platelet dysfunction

Manifestations of CRF Musculoskeletal Muscle cramps Soft tissue calcifications Weakness Related to calcium phosphorous imbalances RENAL OSTEODYSTROPHY

Calcium-Phosphorous Balance

Manifestations of CRF Heart - Lungs Hypertension Congestive heart failure Pericarditis Pulmonary edema Pleural effusions Atherosclerotic vascular disease* Cardiac dysrhythmias

Manifestations of CRF Endocrine - Metabolic Erythropoietin production decreased Hypothyroidism Insulin resistance Growth hormone decreased Gonadal dysfunction Parathyroid hormone and Vitamin D3 Hyperlipidemia

Treatment Options Conservative Therapy Hemodialysis Peritoneal Dialysis Transplant Nothing

Conservative Treatment Goals Detect & treat potentially reversible causes of renal failure Preserve existing renal function Treat manifestations Prevent complications Provide for comfort Heart failure, dehydration, infection, nephrotoxins, urinary traxt obstructions, glomerulonephritis, renal artery stenosis

Conservative Treatment Control Hyperkalemia Hypertension Hyperphosphatemia Hyperparthryoidism Hyperglycemia Anemia Dyslipidemia Hypothyroidism Nutrition

Dietary Restrictions on Hemodialysis Fluid restrictions Phosphorous restrictions Potassium restrictions Sodium restrictions Protein to maintain nitrogen balance too high - waste products too low - decreased albumin, increased mortality Calories to maintain or reach ideal weight

Medications Common to Dialysis Patients Vitamins - water soluble Phosphate binder ---- GIVE WITH MEALS Phoslo (calcium acetate) Renagel (sevelamere hydrochloride) Caltrate (calcium cabonate) Amphojel (aluminum hydroxide) Iron Supplements – don’t give with phosphate binder or calcium Antihypertensives - hold prior to dialysis Calcium may inhibit absorption of iron

Medications Common to Dialysis Patients cont’d Erythropoietin Calcium Supplements Between meals, not with iron Activated Vitamin D3 aids in calcium absorption Antibiotics hold dose prior to dialysis if it dialyzes out

Medications Many drugs or their metabolites are excreted by the kidney Dosages many change when used in renal failure patients Dialyzability many removed by dialysis varies between HD and PD