G.B.’s mild acidosis should be treated with a goal of normalizing the plasma
bicarbonate concentration or at least achieving bicarbonate levels of at least 22
mEq/L. Treatment includes use of preparations containing sodium bicarbonate or
sodium citrate. Each 650-mg tablet of sodium bicarbonate provides 8 mEq of sodium
and 8 mEq of bicarbonate. Shohl’s solution and Bicitra contain 1 mEq of sodium and
the amount of citrate or citric acid to provide 1 mEq of bicarbonate/mL. These latter
agents may be used in patients who experience excessive GI distress with sodium
bicarbonate because of production and elimination of carbon dioxide. If a patient
such as G.B. is sodium and fluid overloaded, it is important to consider that sodium
bicarbonate can exacerbate this problem. Polycitra, or potassium citrate, is a
possible alternative; however, the potassium content limits its use in patients with
more severe kidney disease. Citrate also promotes aluminum absorption and should
not be used in patients taking aluminum-containing agents. The amount of bicarbonate
supplementation to achieve a bicarbonate of 22 mEq/L can range from 0.3 to 1
89–91 Typical starting regimens can be two to four 650mg sodium
bicarbonate tablets/days (divided into two to three doses). Afterwards, doses should
be titrated to desired bicarbonate levels. Equations based on the serum bicarbonate
level are available if an immediate correction of the metabolic acidosis is
Once dialysis therapy is initiated in patients with kidney disease, IV and oral
supplementation with bicarbonate or citrate or citric acid preparations is generally
not required. At this point, dialysis therapy is used to chronically manage metabolic
acidosis through use of dialysate baths containing bicarbonate. Bicarbonate is added
to the dialysate solution and is delivered through the process of diffusion from the
dialysate bath into the plasma (see Chapter 30, Renal Dialysis). If dialysis therapy is
initiated in G.B., the continued need for oral bicarbonate supplementation should be
Other Electrolyte and Metabolic Disturbances of
CASE 28-1, QUESTION 9: What other electrolyte and metabolic disturbances are exhibited by G.B.?
G.B.’s hyperphosphatemia is a result of decreased phosphorus elimination by the
kidneys (see Case 28-3, Question 2, for a more detailed discussion of
hyperphosphatemia). The KDIGO guidelines for Diagnosis, Evaluation, Prevention,
and Treatment of CKD Mineral and Bone Disorder recommend reducing dietary
phosphorus to 800 to 1,000 mg/day while maintaining adequate nutritional needs.
Phosphorus-containing laxatives and enemas should also be avoided.
Hyperphosphatemia is associated with low serum calcium concentrations.
The mild degree of hypermagnesemia seen in G.B. is a common finding in patients
with CKD owing to decreased elimination of magnesium by the kidney. Magnesium
is eliminated by the kidney to the extent required to achieve normal serum magnesium
concentrations until eGFR is less than 30 mL/minute/1.73 m2
concentrations less than 4 mEq/L rarely cause symptoms. Higher concentrations can
lead to nausea, vomiting, lethargy, confusion, and diminished tendon reflexes,
whereas severe hypermagnesemia may depress cardiac conduction. The risk of
hypermagnesemia can be reduced by avoiding magnesium-containing antacids and
laxatives and by use of a magnesium-free dialysate in patients with CKD 5D.
G.B. also has mild hyperuricemia. Asymptomatic hyperuricemia frequently
develops in patients with kidney disease owing to diminished urinary excretion of
uric acid. In the absence of a history of gout or urate nephropathy, asymptomatic
hyperuricemia does not require treatment.
ANEMIA OF CHRONIC KIDNEY DISEASE
what is the etiology of this disorder?
G.B.’s hemoglobin of 9.3 g/dL is substantially lower than the normal range for
premenopausal females, indicating that she has anemia. Her normal RBC indices
suggest her red cells are of normal size, but the absence of an elevated reticulocyte
count suggests an impaired bone marrow response for her degree of anemia. Her
recent history of peptic ulcer disease may also have contributed to the observed drop
in hemoglobin as a result of blood loss. Her complaint of general malaise is
consistent with the symptoms of anemia.
Anemia, which affects most patients with CKD, is caused by a decreased production
of EPO, a glycoprotein that stimulates RBC production in the bone marrow and is
released in response to hypoxia. Approximately 90% of the total EPO is produced in
the peritubular cells of the kidney; the remainder is produced by the liver. EPO
concentrations in patients with kidney failure are lower than in individuals with
normal kidney function who have the same degree of anemia and the same stimulus
for EPO production and release.
Anemia appears as early as CKD 3 and is characterized by normochromic (normal
color) and normocytic (normal size) RBCs unless a concomitant iron, folate, or
vitamin B12 deficiency exists. A direct correlation between eGFR and hematocrit has
been demonstrated, with a 3.1% decrease in hematocrit for every 10 mL/minute/1.73
94 A higher prevalence of anemia occurs in the population with
an eGFR less than 60 mL/minute/1.73 m2
1 Pallor and fatigue are the earliest clinical
signs, with other manifestations developing as anemia progresses with declining
kidney function. A significant consequence of anemia is development of left
ventricular hypertrophy (LVH), further contributing to cardiovascular complications
and mortality in patients with CKD. LVH has been observed in approximately 30%
of patients with eGFR 50 to 75 mL/minute/1.73 m2
(CKD 2 and 3) and in up to 74%
of patients at the start of dialysis.
95 These findings support the need for early and
aggressive treatment of anemia of CKD before the development of CKD 5.
A complete workup for anemia of CKD is recommended for patients with an
eGFR of less than 60 mL/minute/1.73 m2
93 This workup includes a complete blood
count including hemoglobin, assessment of iron indices with correction if iron
deficiency is present, and evaluation for sources of blood loss, such as bleeding from
the GI tract. This workup should be done at least twice per year for the stage of CKD
because of the association between anemia and the progressive decline in eGFR.
Iron deficiency substantially contributes to anemia development and is the primary
cause of erythropoiesis-stimulating agent (ESA) hyporesponsiveness; thus, iron status
assessment is essential before considering or initiating erythropoietic therapy. The
two tests that best evaluate iron status are the transferrin saturation percent (TSAT)
93 Transferrin is a carrier protein, and its concentration depends on
nutritional status. The TSAT indicates the saturation of the protein transferrin with
iron and is determined as follows (Eq. 28-6):
where TIBC is the total iron-binding capacity of the transferrin protein. The TSAT is
considered iron readily available for RBC production. Serum ferritin is a marker for
iron reserves, which are stored primarily in the reticuloendothelial system (e.g.,
liver, spleen). The goal of iron replacement therapy is to maintain the TSAT greater
than 30% and a serum ferritin greater than 500 ng/mL for CKD to provide sufficient
iron for erythrocyte production. Values below these targets are indicative of absolute
iron deficiency. A functional iron deficiency may exist when ferritin is greater than
500 ng/mL, TSAT is less than 20%, and anemia persists despite appropriate ESA
therapy. In these cases, iron supplementation may lead to improved erythropoiesis.
Other tests, including the percentage of hypochromic RBCs, reticulocyte hemoglobin
content, serum transferrin receptor, RBC ferritin, and zinc protoporphyrin, have been
proposed as indicators of iron status.
93 Although some of these markers have
demonstrated predictive value in assessing iron status, either alone or in conjunction
with other laboratory data, further investigation is warranted to determine their utility
and to make such testing procedures readily available.
The availability of recombinant human EPO to directly stimulate erythrocyte
production revolutionized the treatment of CKD-associated anemia. However, iron
deficiency is the leading cause of ESA hyporesponsiveness and must be corrected
before ESA therapy is initiated. Iron deficiency can develop as a result of increased
requirements for RBC production with ESA administration and from chronic blood
loss owing to bleeding or HD. Identification and management of iron deficiency
through regular follow-up testing and iron supplementation is essential for adequate
RBC production (see Case 28-1, Question 12, for Iron Therapy, and also Chapter 92,
Other factors that contribute to anemia include a shortened RBC life span
secondary to uremia, blood loss from frequent phlebotomy and HD, GI bleeding,
severe hyperparathyroidism, protein malnutrition, aluminum accumulation, severe
infections, and inflammatory conditions.
93 Substances present in the plasma of
patients with CKD, collectively termed uremic toxins, may inhibit the production of
EPO, the bone marrow response to EPO, and the synthesis of heme. The negative
effects of these substances on RBC production are supported by improvement in
erythropoiesis with dialysis, which removes these uremic toxins. This uremic
environment also causes a decrease in the RBC life span, from a normal life span of
120 days to approximately 60 days in patients with severe CKD. A shortened RBC
life span has been observed in uremic patients transfused with RBCs from
individuals with normal kidney function, whereas RBCs from uremic individuals
maintain a normal survival time when transfused into patients without kidney failure.
Blood loss also contributes to anemia of CKD, particularly in patients requiring
HD. With each HD session, generally performed 3 times a week, blood loss occurs.
In addition, these patients are usually administered heparin during dialysis or
antiplatelet drugs to prevent vascular access clotting, which further increases the risk
of bleeding. Although a stool guaiac test was not performed in G.B., many patients
with uremia and CKD will have a positive guaiac reaction because of the risk of
bleeding from uremia itself. G.B. also has a peptic ulcer, which increases her
Other deficiencies can contribute to anemia of CKD. Deficiency of folic acid, as
evidenced by low serum folate concentrations and macrocytosis, is relatively
uncommon in patients with early kidney disease, but occurs most often in patients on
dialysis because folic acid is removed by dialysis. Therefore, the daily prophylactic
administration of the water-soluble vitamins, including 1 mg of folic acid, is
recommended. Routine use of fat-soluble vitamin A is discouraged, because
hypervitaminosis A may develop, contributing to anemia.
preparations devoid of vitamin A (e.g., Nephrocaps) are available for patients with
kidney failure. Pyridoxine (vitamin B6
) deficiency can also occur in both dialyzed
and nondialyzed patients with CKD. Significant similarities are seen between this
deficiency and the symptoms of uremia, which include skin hyperpigmentation and
peripheral neuropathy. Current multivitamin products for patients with CKD 5D
contain adequate amounts of pyridoxine to prevent deficiency.
CASE 28-1, QUESTION 11: What are the goals of therapy for anemia of CKD in G.B.?
Normalization of hemoglobin (i.e., ≥13 g/dL) in CKD should be avoided. In early
2007, an FDA-mandated black box warning was added to the safety labeling for all
ESA products, which states that use of ESA therapy may increase the risk for death
and for serious cardiovascular events when administered to achieve a hemoglobin
greater than 12 g/dL. This came as a result of four completed cancer trials that
evaluated new dosing regimens, use of ESA in a new patient population, and use of
new unapproved ESA. Three trials have evaluated the efficacy and safety of
hemoglobin targets in patients with CKD not on HD. In each study, the higher target
hemoglobin groups (hemoglobin ≥13 g/dL) experienced increased cardiovascular
events, stroke, or mortality rates; thus, observing these black box warnings in CKD is
96–98 Partial correction of anemia to approximately 11 g/dL is considered
to offer improvements in quality of life, reduction in hospitalizations, and
It is at these targets that benefits such as increased
survival, exercise capacity, quality of life, cardiac output, cognitive function, and
decreased risk of LVH were observed in the CKD population. The KDIGO Clinical
Practice Guideline for Anemia in Chronic Kidney Disease recommends a target
hemoglobin of up to 11.5 g/dL.
93 Furthermore, for non-dialysis CKD patients with a
hemoglobin <10.0 g/dL, the decision to start ESA therapy is based on the rate of fall
Hemoglobin, rather than hematocrit, should be used to evaluate anemia in this
population for several reasons. Hematocrit is dependent on volume status, which can
be problematic for patients with fluctuations in plasma water (e.g., dialysis, volume
overload). In addition, a number of variables can affect the hematocrit value
including temperature, hyperglycemia, the size of the RBC, and the counters used for
the test. These variables do not significantly affect hemoglobin, making it the
G.B.’s iron status should be evaluated first, and corrected if necessary. If
achieving an adequate iron status does not improve anemia management, ESA therapy
may be started (see Treatment section, and also Chapter 92, Anemias).
Before initiating ESA therapy, G.B.’s iron indices should be determined. If G.B. is
iron deficient, as indicated by the TSAT and serum ferritin and other supporting
laboratory data (see Chapter 92, Anemias), supplemental iron therapy should be
administered. If iron deficiency is the cause of anemia, G.B. may benefit from iron
supplementation alone (i.e., without erythropoietic therapy) to increase hemoglobin.
Peptic ulcer disease will need to be evaluated as a source of blood loss. Given the
poor bioavailability of oral iron and patient noncompliance, oral iron is usually
inadequate for repletion of iron in patients receiving HD who experience chronic
102 For the population with early CKD and for patients receiving PD, an
initial trial of oral iron may correct the deficiency because these patients do not have
the same degree of blood loss. However, IV therapy will be required to replenish
iron and meet the increased demands once erythropoiesis is stimulated with ESA
therapy. Administration of IV iron requires IV access and frequent outpatient visits,
which are drawbacks to therapy with IV iron in CKD 3 and 4. A trial examined an
accelerated dosing regimen (500 mg given on two consecutive days) of IV iron
sucrose to address these issues. This regimen was adequate to restore iron stores
with only two patients experiencing hypotension related to iron therapy.
IV iron sucrose given 200 mg every 2 weeks for a total 1 g repletion in CKD 3 and 4
was associated with increased risk of cardiovascular causes and infectious diseases
compared to oral ferrous sulfate.
Common infusion-related effects associated with IV iron include hypotension,
myalgias, and arthralgias. Despite the controversy about the best strategy for iron
supplementation in patients with early CKD, current recommendations support
reserving IV iron for patients in whom oral iron has failed.
iron is reasonable for G.B. Oral iron supplementation with 200 mg/day of elemental
iron should be started to address iron deficiency, if present, and this regimen should
be continued to maintain sufficient iron status while receiving ESA therapy. Many
oral iron preparations are available, and their iron content varies as will the number
of tablets or capsules that must be taken per day to provide the required elemental
iron (Table 28-8). Some oral formulations include ascorbic acid to enhance iron
absorption. A heme iron product, Proferrin-ES, has recently been approved. Heme
iron is more readily absorbed; however, a large number of tablets are required to
supply the required 200 mg of elemental iron (Table 28-8). G.B. should be advised
to take oral iron on an empty stomach to maximize absorption, unless side effects
prevent this strategy. She also should be counseled on potential drug interactions
with oral iron (e.g., antacids, quinolones) and GI side effects (e.g., nausea,
abdominal pain, diarrhea, constipation, dark stools). Noncompliance with therapy as
a result of side effects is a common cause of therapeutic failure with oral iron. An
acidic environment is needed for adequate iron absorption, and acid-suppression
therapies (e.g., proton-pump inhibitors) may limit the absorption of oral iron. Oral
iron is a mucosal toxin, and her previous history of peptic ulcer disease requires
caution with the use of oral iron.
Preparation Common Brand Names
Ferrous sulfate Slow FE, Fer-In-Sol 325 (65) 3 tablets
Ferrous gluconate Feratab 325 (36) 5 tablets
Ferrous fumarate Femiron, Feostat 200 (66) 3 capsules
Iron polysaccharide Niferex, Nu-Iron 150 (150) 2 capsules
Heme iron polypeptide Proferrin-ES 12 (12) 17 tablets
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