# Disease State: Kidney Disease

Method

Equation

Cockcroft-Gault

[(140—Age in years) × (Weight in kg) × (0.85 if female)]/(72 × Scr in mg/dL)

MDRD

186 × (Scr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if African American)

CKD-EPI

A × (Scr/B)C × (0.993)Age

A: African American female = 166; African American male = 163; White/other female = 144; White/other male = 141

B: Female = 0.7; Male = 0.9

C: If female and creatinine ≤0.7: −0.329; if female and creatinine >0.7: −1.209; if male and creatinine ≤0.7: −0.411; if male and creatinine >0.7: −1.209

Table 1.2
Prevalence of anemia based on stage of kidney disease

Stage

eGFR or CrCl

Prevalence of anemia

1

>90 with proteinuria

2

60–90

26.7%

3

30–60

41.6%

4

15–30

53.6%

5

<15 or on dialysis

75.5%

Based on data from [4]

## Epidemiology

In general, most kidney diseases are associated with an increased risk of anemia. The notable exception is polycystic kidney disease in which not only is anemia decidedly uncommon, but hemoglobin and hematocrit values are commonly in the upper range of normal. In individuals with one of the polycystic syndromes, the presence of anemia should prompt an evaluation of causes of anemia unrelated to kidney disease.

For the most common causes of kidney disease, such as diabetes mellitus and hypertension, the likelihood of anemia is related to the stage of kidney disease. As kidney function declines (or stage of kidney disease increases), the likelihood of anemia due to kidney function increases (Table 1.2).

A key point here is that as detailed below, anemia “related” to CKD is really a diagnosis of exclusion. Therefore, in circumstances where CKD-related anemia is less likely (e.g., stage 2 kidney disease), other factors such as hemolysis in patients with autoimmune kidney disease or occult GI bleeding due to a malignancy in appropriate groups should be considered.

## Pathophysiology

Because erythropoietin levels are not increased among persons with CKD and anemia as would be expected for their degree of anemia, it was assumed that this represented a failure in the ability of the kidney to respond with an appropriate elevation in erythropoietin due to inability to produce erythropoietin related to decreased functioning nephron mass. However, additional studies on the pathophysiology of anemia in kidney disease suggests a far more complex mechanism that involves a change in the relationship between the ability of the kidney to sense hypoxia and the production of erythropoietin.

When the kidney senses hypoxia , through the production of hypoxia-inducing factors (HIF) , it is able to affect a series of events that results in the stimulation of erythropoietin production (Fig. 1.1). The enzyme responsible for the degradation of HIF (prolyl hydroxylase) requires oxygen to function. In the presence of lower oxygen concentrations, it is less active in degrading HIF (Fig. 1.1) resulting in an increase in endogenously produced erythropoietin [57].

Fig. 1.1
Interactions between HIF, O2, and prolyl hydroxylase

## Screening for Anemia

As kidney function declines, the prevalence of anemia increases. Because anemia can be present along the entire spectrum of kidney function, it is recommended by current clinical practice guidelines that anemia be screened for using hemoglobin at least annually among all persons with CKD irrespective of etiology [8]. While there are multiple thresholds that have been used to define anemia and the threshold for the diagnosis may be higher than the threshold for treatment with an erythrocytosis-stimulating agent (ESA), nephrology clinical practice guidelines define anemia as <13.5 g/dL in adult males and <12.0 g/dL in adult females.

When screening for and treating anemia in CKD, it is important to utilize hemoglobin rather than hematocrit for a number of reasons. Mean corpuscular volume may be affected by hyperglycemia falsely elevating red cell volume and potentially affecting hematocrit. In addition, the variability within a sample for hematocrit is greater than hemoglobin. Issues such as this make the accuracy of hemoglobin measure more reliable.

## Laboratory Evaluation of Anemia

It has been estimated that 16.8% of the US population has CKD [9]. Therefore, it cannot be underscored enough that it is important to consider in every patient the potential for other causes of anemia, consider what work up for anemia would be undertaken in the absence of kidney disease, and weigh on an individual basis how much of that work up needs to be performed in any given individual. For example, consider these two individuals.

• A 40-year-old black female with lupus has a hemoglobin of 9.5 and a creatinine of 1.2 mg/dL.

• A 60-year-old white male with autosomal dominant polycystic kidney disease presents with fatigue. His eGFR is 30 mL/min, and his hemoglobin is 10.6.

Each of these patients has CKD given their elevation in creatinine or decrease in eGFR. However, the degree to which you would expect anemia related to decreased kidney function in the woman with lupus is low given her mild CKD. Further, the man with PCKD might not experience anemia until late stage if at all. Therefore, the extent to which one should expect anemia should dictate whether a further diagnostic investigation should be performed. In the two examples, the likelihood of anemia related to their decreased kidney function alone is lower therefore additional work up relevant to their history is warranted. This might include a work up of anemia related to lupus such as hemolysis and a work up of anemia appropriate for a person who is 60 years such as occult gastrointestinal bleed.

Laboratory measures relevant to people with CKD include those measures in Table 1.3.

Table 1.3
Laboratory measures relevant to people with CKD

Categories

Specific tests

“Usual normal” ranges

Red cell parameters

MCV

MCHC

MCH

82–103

30–37

26–34

• In general, the anemia of CKD is a normochromic, normocytic anemia

• Consider other causes of anemia if these parameters are outside of their normal ranges

Iron stores

Transferrin saturation

Ferritin

Content of hemoglobin in reticulocytes (CHr)

20%a

100 ng/mLa

>29 pg/cella

• Iron deficiency anemia is common among persons with kidney disease. This is directly relevant to the treatment of anemia

• Serum ferritin is an acute phase reactant. Among persons who have CKD related to inflammatory processes such as lupus, serum ferritin may be elevated in the presence of iron deficiency due to the effect of inflammation on this parameter

• Important to reassess periodically [e.g., every 3 months particularly if your patient is on erythropoiesis-stimulating agent (ESA therapy)]

• Provides insight into internal distribution of iron (i.e., is it “available” for incorporation into hemoglobin and reticulocytes)

Reticulocyte response

Absolute reticulocyte count

3–7%

• Reticulocyte index = observed absolute reticulocyte count/normal absolute reticulocyte count

Vitamin deficiency