Chronic renal failure medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Overview

Treatment is aimed at specific causes of chronic renal failure. It includes optimized glucose levels in patients with diabetes, management of blood pressure, immunomodulators for glomerulonephritis, emerging specific therapies to retard cytogenesis in polycystic kidney disease and replacement of critical hormones and chemicals produced and utilized by normally healthy kidneys. Any acceleration in the disease process should prompt a search for superimposed acute or subacute disease process that is potentially reversible. These include extravascular fluid volume depletion, urinary tract infection, obstructive uropathy, exposure to nephrotoxic agents such as NSAIDS or radiocontrasts, re-activation and flare of the primary disease like SLE or vasculitis.

Medical Therapy

Management plan

GFR in ml/min per 1.73 m²	Management plan
> or equal to 90	Diagnosis and treatment, treatment of comorbid conditions, slow progression of the disease process, cardiovascular disease risk reduction
60-89	Estimate disease progression
30-59	Evaluate and treat complications
15-29	Preparation for renal replacement therapy
<15 (or dialysis)	Kidney replacement (with symptoms of uremia)

Blood pressure management

• According to JNC7 guidelines, goal blood pressure in CKD is <130/80 mm Hg.
• The goal of therapy is to slow down or halt the otherwise relentless progression of CRF.
• In addition to reducing the cardiovascular disease risk, use of antihypertensive therapy in patients with CRF also aims at slowing the progression of nephron injury by reducing intra-glomerular hypertension.
• Elevated blood pressure increases albuminuria by increasing its flux through the renal capillaries.
• Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are used, as they have been found to slow the progression of CRF by reducing intra-glomerular pressure. Thus, the more effective a drug is in reducing protein filtration into renal tubules, the greater is the impact on improving GFR.
• Angiotensin converting enzyme inhibitors act by inhibiting angiotensin mediated vasoconstriction of efferent arterioles, thereby reducing filtration pressures and proteinuria.
• Combination of ACE inhibitors and ARB's is associated with greater reduction in proteinuria than either drug used alone.
• Side effects include cough and angioedema with ACE inhibitors, whereas anaphylaxis and hyperkalemia is common to use of both ACE inhibitors and ARB's. Progressive increase in serum creatinine levels suggests concomitant renovascular disorders.
• Development of the above mentioned side effects may warrant use of other antihypertensive agents like calcium channel blockers like diltiazem and verapamil.
• If proteinuria is strongly associated with the disease progression, like in diabetic nephropathy or glomerular disease, ACE inhibitors should be the first line drugs, whereas in diseases like polycystic kidney and tubulointerstitial diseases in which there is minimal or absent proteinuria, other antihypertensive agents may be used.

Control of blood glucose

• Tight glycemic control reduces the risk of progression of diabetic nephropathy. Ideally, the blood glucose levels should be between 90-130 mg/dL(5.0-7.2 mmol/L) and hemoglobin A1c below 7%.
• If the GFR progressively decreases inspite of tight glycemic control, the use and dose of oral hypoglycemics have to be reevaluated.
• In presence of renal compromise, chlorpropamide has an exaggerated hypoglycemic effect, metfromin can cause lactic acidosis and thiazolidinediones may aggravate volume overload states.
• Renal degradation of administered insulin decreases with reduction in GFR and hence the need to reduce the dose for appropriate glucose control.

Protein restriction

• Protein restricted diets have been believed to not only temporarily reduce symptoms associated with uremia, but also slow the rate of decline in renal function at an earlier stage by reducing protein mediated hyperfiltration.
• The National Kidney Foundation, recommends patients with CKD to maintain a daily protein intake of 0.60 to 0.75 g/kg of body weight.

Proteinuria treatment with medications

• ACE inhibitors, ARBs, and non-dihydropyridine calcium channel blockers (verapamil, diltiazem) can reduce proteinuria and progression of CKD.
• Mineralocorticoid receptor antagonists (MRA) such as spironolactone and finerenone may slow the progression of proteinuria.
• SGLT2 inhibitors reduced outcomes (hazard ratio was 0.72 [0.64 to 0.82]; the benefit tended to be more among diabetics and was confined to subjects with an albumin/creatine ratio > 300) in the EMPA-KIDNEY randomized controlled trial which included patients who had either:
  • Estimated glomerular filtration rate (eGFR) of 20 to 45 ml per minute per 1.73 m2 OR
  • eGFR 45 to 90 and urinary albumin-to-creatinine ratio of at least 200
• GLP1 inhibitors reduced outcomes in the REWIND randomized controlled trial. The hazard ratio was 0.85 (95% CI 0·77-0·93).

Determining whether an anti-hypertensive medication reduces progression of kidney disease independently of the medication's lowering of blood pressure is difficult as demonstrated by the HOPE trial that originally reported of the benefit of ramipril on cardiovascular and maybe renal outcomes independently of blood pressure lowering, but later this was found to be due to the ramipril being taking at night and the blood pressure being measured 12 to 18 hours later.

Anemia

Clinical practice guidelines by the Kidney Disease Improving Global Outcomes (KDIGO) in the United States and National Institute for Health and Care Excellence (NICE) in the United Kingdom guide management.

Meta-analyses summarize the evidence for erythropoiesis-stimulating agents affecting clinical and quality-of-life outcomes.

• Erythropoiesis-stimulating agents improve quality of life compared to placebo, but higher hemoglobin targets do not increase quality of life.

Based on the Federal Drug Administration erythropoietin EPO may be started when hemoglobin is < 10 g/dl, and its dose may be adjusted to maintain a target hemoglobin range of 10-12 g/dl. However, the National Kidney Foundation recommend maintaining a target hemoglobin range of 11-12 g/dl.

Many erythropoiesis-stimulating agents are available with no preparation having a clear advantage.

Hypoxia-Inducible Factor-Prolyl Hydroxylase inhibitors show promise in preliminary studies.

Electrolyte abnormalities

• In chronic kidney disease vitamin D deficiency develops resulting in both hypocalcemia, and hypophosphatemia. Additionally, phosphorus excretion is effected. Thus, hypocalcemia is associated with hyperphosphatemia. In response to hypocalcemia, intact-PTH levels become elevated.
• In stage 3 or 4 CKD, if intact-PTH is above goal, and calcium and phosphate levels are normal, vitamin D levels should be checked.
• The therapy should be guided based on 25OH Vitamin D levels
  • If 25OH Vitamin D levels are >30 ng/ml and PTH intact is normal then no therapy is needed.
  • If 25OH Vitamin D levels are >30 ng/ml and PTH intact is above normal goal then daily therapy with an active vitamin D formulation, such as calcitriol is needed.
  • If 25OH Vitamin D levels are between 20-29 ng/ml, therapy with ergocalciferol or cholecaciferol 800-1000 IU daily should be initiated.
  • If 25OH Vitamin D levels are less than 20 ng/ml, therapy with ergocalciferol or cholecaciferol 50,000 IU weekly for 6-8 weeks followed by 800-1000 IU daily should be initiated.

Phosphorus management in CKD

Once the diagnosis of CKD is made check phosphorus levels and based on the levels following approach can be used:

Low phosphorus

• Consider primary hyperparathyroidism.
• Consider secondary hyperparathyroidism due to vitamin D deficiency.
• Consider familial hypocalcuric hypercalcemia.

Normal phosphorus

• Continue to follow

High phosphorus

• Restrict dietary phosphorus
• Initiate phosphate binder based on calcium level:
  • Low calcium - Use calcium based binder, calcium carbonate or calcium acetate
  • High calcium- Use non-calcium based phosphate binder, Sevelamer carbonate and lanthanum carbonate

Drug dose adjustments

• Drugs that undergo hepatic elimination do not need drug adjustments.
• Moreover, only the maintenance dose of the drug need to be adjusted as the loading dose does not depend on its renal clearance.
• Nonetheless, some drugs should be avoided like NSAID's, oral hypoglycemics, radiocontrast agents and gadolinium.

Kidney Transplant

• Offers the best potential for complete rehabilitation

Contraindicated medications

Severe or progressive kidney disease is considered a relative contraindication to the use of the following medications:

• Triamterene

Severe Renal failure (creatinine clearance (CrCl) < 30ml/min) is considered an absolute contraindication to the use of the following medications:

• Fondaparinux
• Methenamine

Advanced renal impairment is considered an absolute contraindication to the use of the following medications:

• Levocetirizine
• Ketorolac tromethamine

Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance) is considered an absolute contraindication to the use of the following medications:

• Linagliptin and Metformin hydrochloride
• Metformin
• Saxagliptin hydrochloride and Metformin hydrochloride

Hyperkalemia in chronic renal failure is considered a relative contraindication to the use of the following medications:

• Potassium chloride

Patient education

Multidisciplinary approach

• Explain likelihood and timing of initiation of renal replacement therapy and other options available
• Discuss home based dialysis therapy
  • Less expensive
  • Improved quality of life
• Counsel family members about home dialysis helper
• Explore options to look for potential biologically related kidney donor

Contraindicated medications

Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance) is considered an absolute contraindication to the use of the following medications:

• Dapagliflozin
• Glyburide and Metformin
• Mefenamic acid

Marked renal dysfunction is considered an absolute contraindication to the use of the following medications:

• Danazol

End State Renal Disease is considered an absolute contraindication to the use of the following medications:

• Dapagliflozin

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death - End-Stage Renal Failure (DO NOT EDIT)

Class I

"1. The acute management of ventricular arrhythmias in end-stage renal failure should immediately address hemodynamic status and electrolyte (potassium, magnesium, and calcium) imbalance. (Level of Evidence: C). "

"2. Life-threatening ventricular arrhythmias, especially in patients awaiting renal transplantation, should be treated conventionally, including the use of ICD and pacemaker implantation as required, in patients who are receiving chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: C). "

References

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