Page 2521 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 154

HEMATOLOGIC MANIFESTATIONS OF RENAL DISEASE

Mark A. Crowther and Ali Iqbal

Renal dysfunction is associated with a number of hematologic in CKD patients causes depletion of iron stores through increased
abnormalities including anemia, platelet dysfunction, and thrombo- erythropoiesis. Therefore optimization of iron status is a mainstay
sis. Morphologic abnormalities may include the presence of echino- of management for anemia of CKD. The 2012 KDIGO guidelines
cytes characterized by abnormal red blood cell (RBC) membranes recommend a trial of intravenous iron therapy for dialysis patients
1
with multiple small, evenly spaced projections. Certain conditions and oral iron therapy for nondialysis patients for a transferrin satura-
including hemolytic uremic syndrome (HUS) involve complex tion of less than 30% and ferritin less than 500 ng/mL, and when
interactions between glomerular microvasculature and the coagula- an increase in Hb concentration with a decrease in ESA dosing is
tion cascade manifesting as microangiopathic hemolytic anemia and desired. 11
thrombocytopenia. Among renal transplant patients, posttransplant
lymphoproliferative disorder can occur. The underlying pathophysi-
ology and treatment of these hematologic manifestations of renal Disordered Iron Homeostasis
disease are discussed here.
Patients with CKD often have a functional iron deficiency in addition
to true iron deficiency. This is related to an excess of hepcidin, a key
ANEMIA hormone involved in iron homeostasis (see Chapter 35 and Chapter
36). Excess hepcidin in CKD patients is thought to be secondary to
Anemia is common in chronic kidney disease (CKD) and is associ- increased production caused by chronic inflammation as well as
ated with poor outcomes, including reduced quality of life, increased decreased renal clearance. The hepcidin–ferroportin axis is currently
cardiovascular disease, hospitalizations, cognitive impairment, and being investigated as a potential therapeutic target in CKD patients
mortality. In a study of 5222 patients with CKD (defined by serum with anemia. 3
creatinine >1.5 mg/dL and >2.0 mg/dL in females and males, respec-
2
tively) the prevalence of anemia was 47.7%. Anemia in CKD is
usually normocytic, hypoproliferative and is multifactorial, being UREMIC BLEEDING
contributed to by relative erythropoietin (EPO) deficiency, iron
deficiency, and disordered iron homeostasis. 3 Patients with CKD have increased bleeding because of frequent use
of anticoagulant and antiplatelet drugs, defects in platelet aggregation
as well as abnormal platelet-endothelial cell interaction. One of the
Relative Erythropoietin Deficiency major factors contributing to platelet dysfunction is a defect in gly-
13
coprotein IIb/IIIa. Other factors include ineffective ADP response
EPO is a glycoprotein hormone mainly produced in the kidney by to stimulated aggregations and increased production of nitric
4
interstitial fibroblasts. With normal kidney function, hypoxic condi- oxide. 14,15 Anemia also contributes to uremic bleeding caused by
tions in the outer medulla trigger production of EPO, which binds altered flow of platelets with reduced proximity and interaction with
to receptors on erythroid progenitors ultimately leading to increased endothelial cells. 16
5
RBC production. Patients with CKD have insufficient EPO levels Treatment for uremic platelet dysfunction is indicated in patients
because of two proposed mechanisms; decreased production capacity with CKD who are actively bleeding or scheduled to undergo a
caused by tissue damage as well as an altered hypoxic set point for procedure with a risk of bleeding.
6
the production of EPO. As a result, anemic CKD patients have Desmopressin (DDAVP) is an effective therapy in reducing bleed-
10–100 times lower EPO levels compared with similarly anemic ing time within 1 hour of administration through increased release
17
patients with normal renal function. 3 of von Willebrand factor (vWF) multimers from endothelial cells.
Erythropoiesis stimulating agents (ESAs) were introduced in the Another treatment option is conjugated estrogen, which achieves
18
late 1980s for the treatment of anemia of CKD. Several observational peak effect over 5 to 7 days. The mode of action is not well
19
studies have demonstrated clinical benefits with the use of ESAs, understood, but is thought to result from a reduction in nitric oxide
including reduction in heart failure, regression of left ventricular (see Chapter 130). Correction of anemia, whether through ESAs or
hypertrophy, improved energy levels, and improved overall quality of RBC transfusions to a level greater than 10 g/dL, has also been shown
7,8
life. However, targeting near normal hemoglobin (Hb) levels is to improve bleeding time in CKD patients. 20,21 Renal replacement
associated with increased hospitalization, graft/fistula thrombosis, therapy, in the form of peritoneal dialysis, hemodialysis, or renal
stroke, and a trend towards increased mortality. 9,10 Therefore the transplantation, clears uremic toxins and corrects uremic platelet
2012 KDIGO (Kidney Disease Improving Global Outcomes) clinical dysfunction. 22
practice guidelines recommend the use of ESAs to target Hb levels
less than 11.5 g/dL. These guidelines recommend considering initia-
tion of ESAs when Hb is less than 10 g/dL for both dialysis and THROMBOSIS
nondialysis CKD patients. 11
Thromboembolism is a serious and well-established complication
of nephrotic syndrome. The nephrotic syndrome is defined by a
True Iron Deficiency 24-hour urinary protein greater than 3.5 g/day, associated with
edema, hypoalbuminemia, hyperlipidemia, lipiduria, and thrombo-
23
CKD patients, particularly those on hemodialysis, have increased sis. Patients with nephrotic syndrome have an increased risk of
iron losses because of chronic bleeding, phlebotomy, and blood venous and arterial thrombosis as demonstrated in a retrospective
12
loss in the hemodialysis apparatus. Furthermore, the use of ESAs study of 298 patients followed for a mean of 10 years. The absolute
2244