Uremia Treatment & Management

The ultimate treatment for uremia is renal replacement therapy, which can be accomplished by hemodialysis, peritoneal dialysis, or kidney transplantation. Initiation of dialysis is indicated when signs or symptoms of uremia (eg, nausea, vomiting, volume overload, hyperkalemia, severe acidosis) are present and are not treatable by other medical means. Patients with uremia must have dialysis initiated as soon as symptoms appear, regardless of the glomerular filtration rate (GFR).

Unfortunately, although dialysis effectively removes urea, it is less effective than the normal kidney at removing a number of toxic solutes, the accumulation of which is thought to lead to signs and symptoms that have been labeled residual syndrome. ^[28] For patients with uremic pruritus, Shirazian et al propose a multifaceted approach that includes the following ^[29] :

• Ensure that patients are meeting goals for dialysis efficiency and mineral bone disease treatment, as defined by Kidney Disease: Improving Global Outcomes (KDIGO).
• Treat patients with xerosis with a trial of emollient cream.

Treatment for refractory pruritus remains less clearly defined, according to these authors. Various approaches have been studied, including gabapentin and phototherapy. ^[30] Results with these have been mixed. Nalbuphine hydrochloride, a mu-opioid receptor antagonist and kappa-opioid receptor agonist approved as an analgesic, is used off-label for opioid-induced pruritus and may have an effect on uremic pruritus. Nalfurafine, a kappa opioid receptor agonist, has shown promising results in large, double-blind, randomized controlled clinical trials, but neither agent is currently available in the United States. ^[29]

Surgery

Once the modality for renal replacement therapy has been determined (ie, hemodialysis, peritoneal dialysis, or kidney transplantation), referral to an appropriate surgeon (ie, vascular, general, transplant) is made.

Kidney transplantation is the best renal replacement therapy and results in improved survival and quality of life. Patients with renal failure and uremia should be considered for transplantation using a living, related donor; a living, nonrelated donor; or a cadaveric donor. Transplants from living, related donors are best. Consider transplantation prior to the need for dialysis because the waiting list for cadaver transplants often exceeds 2-3 years.

Consider any type of surgery carefully in patients with uremia because of the increased risk for uremic bleeding, cardiovascular events, acute kidney injury, respiratory depression, and decreased metabolism of certain drugs. Vasopressin may be considered if uremic bleeding is substantial.

Consultations

Consider consultation with a nephrologist as soon as possible in the course of the patient's disease, particularly when renal function test results are only mildly abnormal. Acute hyperkalemia, volume overload, severe acidemia, or a change in mental status, which can progress to stupor or coma, requires emergent consultation with a nephrologist and, possibly, the initiation of dialysis.

Transfer

Consider transferring patients to centers with dialysis capabilities if a nephrologist and/or dialysis facilities are not available to assist with management and potential interventions.

Activity

Activity for patients with uremia is self-restricted based on their level of fatigue. Early treatment of anemia with iron and erythropoietin (EPO) can improve the patient’s quality of life and energy levels even before dialysis is required.

Bleeding secondary to uremia may occur Consequently, dangerous activities may need to be restricted and potential bleeding sites may need to be assessed in the event of a fall (eg, for a subdural hematoma).

Special considerations

Pregnant patients with uremia require specialized evaluation and treatment; in this situation, seek immediate consultation with a specialist. Pregnant women should be under the care of an obstetrician who specializes in the management of high-risk pregnancies. A nephrologist should also be consulted, to help with hypertension control and the potential need for dialysis during the pregnancy. Medications contraindicated in pregnancy, such as angiotensin-converting enzyme (ACE) inhibitors, should be immediately discontinued.

Pediatric patients also require special consideration. A pediatric nephrologist or an adult nephrologist experienced in the care of pediatric nephrology patients should be involved in the care of children with proteinuria, renal insufficiency, or uremia or of children in whom dialysis is indicated.

For asymptomatic patients, dialysis is generally initiated when the creatinine clearance rate falls to 10 mL/min (creatinine level of 8-10 mg/dL) or less or, for diabetic patients, when the rate is 15 mL/min (creatinine level of 6 mg/dL). Early referral to a nephrologist for evaluation (when the creatinine level is >3 mg/dL) is essential for patient education and preparation for dialysis or transplantation.

Types of dialysis

Patients may decide on peritoneal dialysis or hemodialysis, depending on their preference and level of motivation. Peritoneal dialysis is preferred for patients who are highly motivated, need flexibility in their dialysis schedule, and may have underlying cardiovascular disease. ^[31] Hemodialysis requires a functioning arterial venous dialysis access and may be accomplished at home or in a center. ^[32]

Regardless of whether a patient chooses peritoneal dialysis or hemodialysis, the dialysis access must be discussed and placed early.

Newer methods of dialysis include daily hemodialysis and nocturnal hemodialysis, the advantages of which include improvements in volume control, cardiovascular disease, calcium-phosphate balance, dietary parameters, and quality of life.

A recent advance in hemodialysis is the development of improved molecular cut-off hemodialysis filters. These medium-cut-off (MCO) filters have enhanced permeability and selectivity, providing superior removal of medium-–molecular-weight uremic toxins compared with standard-of-care high-flux dialyzers. ^{[33, 34]} Catar et al reported that hemodialysis with improved MCO filters can ameliorate uremia-induced systemic microinflammation and endothelial dysfunction. ^[34]

Dialysis access placement surgery

Surgical referral is necessary for dialysis access placement after the decision regarding dialysis has been made. In general, referral to a vascular surgeon for consideration of dialysis access is initiated by the nephrologist early in the patient's course of renal failure to avoid emergent dialysis access placement.

Hemodialysis access

Arteriovenous fistulas are the dialysis access of choice for hemodialysis. Avoid arteriovenous Gore-Tex grafts if at all possible because of their poor longevity. In addition, avoid long-term use of tunneled catheters because of the increased risk of infection and poor dialysis adequacy. Avoid subclavian catheters because of their association with increased venous stenosis, thrombosis, or both.

Peritoneal dialysis access

A peritoneal dialysis catheter can be used for access in chronic ambulatory or continuous cycling peritoneal dialysis.

Placement of a Tenckhoff peritoneal dialysis catheter is carried out by either an experienced nephrologist or a surgeon. Direct visualization of the peritoneum is associated with fewer complications and better function of the catheter. Peritoneal dialysis allows patients more control over and flexibility with their dialysis treatment regimen.

Patients with kidney failure ̶ associated hyperkalemia of 6.5 mEq/L or greater are candidates for emergent dialysis therapy, particularly if the hyperkalemia is associated with electrocardiographic changes (eg, peaked T waves, atrioventricular block, bradycardia).

Short-term temporizing measures include intravenous infusion of calcium gluconate to stabilize cardiac membranes, bicarbonate, insulin and glucose administration, or inhaled or intravenous beta agonists.

Nonemergent hyperkalemia can be treated with oral potassium binders (eg, sodium polystyrene sulfonate [Kayexalate]). Correction of acidemia may improve the potassium balance.

In addition, it is imperative to discontinue any medicine that might be contributing to the hyperkalemia, including the following:

• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin-receptor blockers (ARBs)
• Beta-blockers
• Potassium-sparing diuretics
• Nonsteroidal anti-inflammatory drugs (NSAIDs)

In patients found to have anemia of CKD, it is important to check iron studies and to begin the initial treatment with iron replacement if there is evidence of iron deficiency. The serum ferritin level should be greater than 100 mcg/mL.

Due to concern about the use of erythropoietic-stimulating agents (ESAs) and increased cardiovascular mortality, major changes have been made to the recommendation for their administration. One should attempt to use the lowest ESA dose possible to reduce the need for transfusion.

Although target hemoglobin levels remain under debate, it is now recommended that patients with CKD who are not on dialysis start ESA treatment only when the hemoglobin level is less than 10 g/dL and reduce the dose or stop the ESA if the hemoglobin level exceeds 10 g/dL.

For patients on dialysis, treatment with an ESA should be administered only when the hemoglobin level is less than 10g/dL, and the dose should be reduced or interrupted if the level approaches or exceeds 11 g/dL. ^[35]

If the anemia is not corrected, then begin treatment with either of two subcutaneous ESA agents: recombinant human EPO, or darbepoetin, a unique molecule that stimulates erythropoiesis and has a longer half-life than erythropoietin.

Initiate iron therapy concurrently with dialysis therapy. Start with one of several intravenous iron preparations, as these are better absorbed than oral formulations. These can be administered with each dialysis treatment to load the patient with iron or once weekly to maintain iron stores.

For patients not yet on dialysis, oral iron preparations are used initially. For significant iron deficiency, intravenous iron (InFeD Injection) may be administered slowly (500 mg over 4-6 h) after the administration of a test dose (25 mg).

Early evaluation and treatment of secondary hyperparathyroidism—manifested by low calcium levels, high phosphate levels, and low levels of 1,25(OH)2 vitamin D-3—is necessary because it is one of the first manifestations of renal osteodystrophy.

There has been significant debate about goal parathyroid hormone (PTH) levels for patients with ESRD. While previous guidelines recommended a goal PTH of 150-300 pg/mL, at least one set of more recent guidelines recommends a goal PTH of 2-9 times the upper normal limit for the assay used to measure the PTH level (approximately 150-600 pg/mL). ^{[36, 37]}

Hypocalcemia

Hypocalcemia can be treated with oral calcium carbonate or calcium acetate at a dose of 500 mg to 1 g orally 3 times daily, taken between meals. If 1,25(OH)2 vitamin D-3 levels are depressed, calcium levels are decreased, and parathyroid levels are elevated (>300), consider initiating oral vitamin D therapy. The dosage of calcitriol is 0.25 mcg orally once daily or 3 times weekly, depending on the levels of 1,25(OH)2 vitamin D-3 and PTH.

Hyperphosphatemia

When the creatinine clearance falls below 25-30 mL/min, the kidney begins to lose the ability to completely excrete excess amounts of phosphorus. Thus, it is not uncommon for many patients with CKD and ESRD to become hyperphosphatemic. Initial treatment is dietary counseling and modification. If this fails, therapy consists of administration of oral phosphate binders given with meals. These can include calcium-based formulations, such as calcium carbonate or calcium acetate, or noncalcium-based formulations, such as sevelamer or lanthanum carbonate.

Acidemia

Acidemia should be treated in patients with a serum bicarbonate level that is consistently less than 20 mEq/dL. Oral bicarbonate solution or tablets can be used; most patients will require 0.5-1 mEq/kg of body weight of bicarbonate. Use this therapy cautiously in persons with significant fluid retention and hypertension because of the risk of worsening the fluid retention.

Evidence suggests that plant-based and low-protein diets have the potential to slow progression of chronic kidney disease, while the use of prebiotics, probiotics, and synbiotics and laxatives may have beneficial effects on uremic toxin generation. ^[38] However, dietary changes should be made only with the help of a dietitian knowledgeable in renal dietary treatment, particularly in patients who have not yet started dialysis therapy.

A low-protein diet has been advocated for persons with mild to moderate kidney failure, although this matter remains controversial. ^{[39, 38]} Low-protein diets may alleviate some of the symptoms of uremia, such as nausea; however, data regarding the renoprotective effect of low-protein diets are conflicting.

The Modification of Diet in Renal Disease (MDRD) study, which analyzed 585 patients with nondiabetic chronic kidney disease and a mean GFR of 39 mL/min, found that even with good compliance, there appeared to be little overall benefit from a low-protein diet. In the study, patients were randomized to protein intakes of either 1.1 g/kg/day or 0.7 g/kg/day. ^[40]

Another caveat is that low-protein diets can cause a patient to become malnourished; malnourishment has been associated with higher mortality upon the initiation of dialysis.

On the other hand, in an analysis of studies comparing the consumption of different protein levels by nondiabetic adults with moderate to severe kidney failure, Fouque and Laville concluded that a low-protein diet can lower the rate of "renal death" by 32%. ^[39] (The authors defined renal death as kidney transplantation, the need to begin dialysis, or the death of a patient.)

Incorporating results from 2000 patients, including 1002 who had consumed a reduced-protein diet, Fouque and Laville found that 113 renal deaths had occurred in the low-protein group and 168 in the higher-protein group. However, the authors stated that they were unable to confirm through their analysis an optimal protein intake level for persons with kidney failure. ^[39]

Current recommendations for a low-protein diet prior to the initiation of dialysis are 0.8-1 g of protein/kg of weight, with an additional gram of protein added for each gram of protein lost in the urine (for patients with nephrotic syndrome). Patients with advanced uremia or malnutrition are not candidates for a low-protein diet.

Patients with CKD should be on a diet low in potassium (2-3 g/day), phosphate (2 g/day), and sodium (2 g/day).

Inpatient care

Inpatient care is required when patients have a uremic emergency, such as hyperkalemia, hypervolemia, acidosis, pericardial effusion with symptoms, or uremic encephalopathy; these patients require emergent dialysis.

Initiate dialysis gently (2-h initial session) to avoid dialysis disequilibrium syndrome, but dialysis should continue long enough to remove potassium if it is being initiated for this reason.

Therapy should be initiated with the care and oversight of a nephrologist and may need to occur in the intensive care unit if the patient is unstable or has cardiac abnormalities secondary to acidemia or hyperkalemia.

Outpatient care

Outpatient care should be administered under the direction of the consulting nephrologist. Outpatient care may include the initiation of chronic renal replacement therapy, such as peritoneal dialysis or hemodialysis.

In/out patient medications

Inpatient medications include those that are necessary for emergent treatment of underlying disorders associated with uremia (emergent treatment of hyperkalemia, acidosis, and hypocalcemia).

Outpatient medications include EPO for anemia, iron, phosphate binders, calcitriol for PTH suppression and hypocalcemia, water-soluble vitamins (eg, folate, vitamin C), and, potentially, oral bicarbonate solution or tablets for acidosis.

Avoid nephrotoxic medications such as NSAIDs, renal toxic aminoglycoside antibiotics, and other potential renal toxins.

N -acetyl-cysteine can be administered before and after radiologic imaging that requires intravenous contrast (eg, CT scan, renal angiogram, intravenous pyelogram), to avoid nephrotoxicity. However, consider an alternative method of imaging (eg, ultrasonography, MRI) in this setting to avoid AKI, particularly in patients with diabetes.