Common Posttransplant Abnormal Laboratory Findings
Phuong-Chi T. Pham
Phuong-Mai T. Pham
Phuong-Truc T. Pham
Phuong-Thu T. Pham
Etiologies relating to end-stage kidney disease (ESKD) transplant candidates
Iron (vitamin B12, folate) deficiencies, malnutrition
Blood loss related to hemodialysis or vascular access repair
Underlying inflammatory processes
Occult gastrointestinal (GI) bleeding
Hyperparathyroidism (due to direct effects of excess parathyroid hormone on erythropoietin synthesis, erythroid progenitors, and red cell survival, and indirect effect via induction of bone marrow fibrosis)
Etiologies relating to transplantation
Dilutional anemia due to aggressive perioperative volume expansion
Discontinuation of Erythroipoiesis-stimulating agents (ESAs): ESA is typically discontinued in the early postoperative period following a successful transplant.
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs)
Dapsone can cause anemia including hemolytic anemia especially in the presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD level should be checked prior to initiation of dapsone.
Mammalian target of rapamycin (mTOR) inhibitors: sirolimus, everolimus. Although rare, erythropoietin (EPO)-resistant anemia has been described in patients receiving sirolimus.1
Antimetabolites: azathioprine, mycophenolic acid derivatives
The xanthine oxidase inhibitors allopurinol and febuxostat inhibit the metabolism of azathioprine, and their concomitant use should be avoided. However, if azathioprine and xanthine oxidase inhibitor combination therapy must be used, consider azathioprine dose reduction by 25% with close monitoring of complete blood count.2
The calcineurin inhibitors (CNIs) cyclosporine and tacrolimus do not cause anemia. The presence of unexplained drop in hemoglobin (Hb)/hematocrit (Hct) levels and acute kidney injury should raise the possibility of CNI-induced thrombotic microangiopathy (TMA). The absence of thrombocytopenia or hemolytic anemia does not exclude CNI-associated TMA.3 Diagnosis requires an allograft biopsy.
Etiologies relating to complications of transplantation
Intraoperative or postoperative bleeding complications
Impaired graft function, acute rejection episodes
Underlying inflammatory conditions, infections other than parvovirus B19
Management of anemia
Assessment of baseline iron stores at the time of transplantation is recommended.
Profound iron deficiency should be treated with intravenous (IV) iron as tolerated. Note: Avoid use of IV iron in patients with systemic infections.
ESA therapy is effective in the treatment of anemia in kidney transplant recipients. Patients should be iron repleted prior to initiation of ESA therapy. Note: Avoid ESA use in patients with a history of stroke or malignancy, particularly in those with active malignancy when cure is anticipated.5
Consider leukocyte-reduced blood products (although allosensitization may not be prevented or reduced to any significant degree; see chapter 20).6
Although continuation of low-dose immunosuppression in patients with a failed transplant has been shown to be associated with reduced human leukocyte antigen (HLA) allosensitization,7 whether the use of immunosuppression in the posttransplant period may reduce transfusion-related sensitization risk remains speculative.
Use of cytomegalovirus (CMV)-negative blood products should be considered in CMV-seronegative kidney transplant recipients to prevent primary CMV infection.
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) anemia guidelines recommend initiating ESA in chronic kidney disease (CKD) patients when Hb values are <9 to 10 g/dL, provided that iron stores are adequate. A target Hb level of 10 to 11 g/dL is recommended.5 Large CKD anemia trials demonstrated a possible harmful effect of higher Hb levels associated with high ESA doses.8
Observational studies in kidney transplant recipients similarly suggested that mortality may be increased with Hb levels above 12.5 g/dL in association with the use of ESA. This increase was significant at hemoglobin concentrations >14.0 g/dL.9
Although evidence-based recommendations in the setting of posttransplant anemia are lacking, ESA therapy to keep Hb level in the range of 10 to 11 g/dL seems reasonable (opinion based).
LEUKOPENIA AND THROMBOCYTOPENIA
Immunosuppressive agents (see chapter 2)
Lymphocyte-depleting agents (eg, the antithymocyte globulin [Thymoglobulin] or alemtuzumab)
Antimetabolites: mycophenolic acid derivatives (mycophenolate mofetil or mycophenolate sodium), azathioprine, mTOR inhibitors (sirolimus or everolimus), and bortezomib (proteasome inhibitor)
Prophylactic drugs commonly used posttransplant
Acyclovir, ganciclovir, or valacyclovir
Other commonly used drugs posttransplant
Inhibitors of the renin-angiotensin system
Proton pump inhibitors, H2 blockers
Diagnostic test: plasma CMV DNA by polymerase chain reaction (PCR)
Treatment of CMV DNAemia and CMV disease is discussed in chapter 13.
Parvovirus B19 infection may present with refractory anemia, pancytopenia, and TMA.
Diagnostic test: parvovirus DNA PCR
Treatment: IV immunoglobulin (IVIG)
Upper respiratory viral infections
Bone marrow suppression (eg, overwhelming systemic infections, tuberculosis [TB], or fungal infections)
Newly acquired human immunodeficiency virus (HIV) infection
TMA (Differential diagnosis of TMA and management of the underlying disorder are discussed in chapters 7 and 8.)
Disseminated intravascular coagulation
Other rare causes, particularly in the setting of immunosuppression: posttransfusion purpura, lupus flare
Withhold or reduce dose of the offending agent.
Treat underlying infections if possible.
Severe leukopenia may be safely treated with granulocyte-stimulating factor.
Defined as persistently elevated Hct to>51% or Hb >17 g/dL after transplant
Hct and Hb thresholds to define posttransplant erythrocytosis (PTE) may differ among centers due to differences in institutional reference range (and age- and gender-adjusted Hct and Hb levels).
Incidence appears to have decreased to <10% with the more frequent use of ACE inhibitors and ARBs.
May develop within the first 2 years posttransplant (usually between 8 and 24 months) and generally affects those with good allograft function
Spontaneous remission within 2 years of onset is observed in one-fourth of patients but may persist for several years in others.10
Persistent PTE or PTE occurring late after transplant warrants further evaluation to exclude
EPO-producing neoplasms: renal cell carcinoma (RCC) in the native or transplanted kidneys, hepatocellular carcinoma, cerebellar hemangioblastoma. Imaging studies of the allograft and native kidneys should be performed particularly when RCC risk factors are present (eg, pretransplant increased dialysis duration or known acquired cystic kidney disease).
EPO-producing kidney disease/disorder: autosomal dominant polycystic kidney disease, hydronephrosis, renal artery stenosis.
Hypoxemia-associated increased EPO production: sleep apnea, high altitude, chronic pulmonary disease.
Drug-related use: androgen, anabolic steroids, or surreptitious exogenous ESA.
Hemoconcentration associated with diuretic use.
Risk factors for PTE2
Presence of native kidneys, male gender, absence of rejection episodes, high baseline Hb before transplant, and hypertension
Others: polycystic kidney disease and glomerulonephritis as the cause of ESKD
Smoking and diabetes have been shown to be risk factors for PTE in some but not all studies.
Renal artery stenosis: Although transplant renal artery stenosis has not consistently been shown to be a risk factor for PTE, imaging studies to evaluate the iliac and renal arteries should be considered in patients with refractory PTE.
Suggested pathogenic mechanisms
Defective feedback regulation of EPO metabolism
Direct stimulation of erythroid precursors by angiotensin II
Abnormalities in level of circulating insulin-like growth factor 1 (IGF-1) and its binding protein
Increase in serum-soluble stem cell factors, which stimulate the growth of erythroid progenitor cells. Serum-soluble stem cell factors have been shown to correlate with both Hct values and with the observed and expected EPO values in kidney transplant recipients with PTE.11
The Hb/Hct threshold for treatment may vary depending on gender and institutional reference range.
Generally, treatment is recommended for Hb levels exceeding 17 to 18 g/dL or Hct levels >51% to 54% because of the associated risk of thromboembolic complications, hypertension, and headaches.
Treatment with ACE inhibitors or ARBs is often sufficient. Relapse is common and often necessitates long-term ACE inhibitors or ARB treatment.
Phlebotomy may be considered in severe PTE after optimization/treatment of any associated hypoxia-driven PTE.
Low-dose aspirin 81 mg daily may be considered if there is no contraindication (opinion based).
A negative association between the use of sirolimus and PTE has been reported. However, modification of immunosuppressive medications to treat PTE is uncommon in clinical practice.
COMMON ELECTROLYTE, ACID-BASE, AND CALCIUM AND PHOSPHOROUS ABNORMALITIES
Electrolyte and acid-base disorders are common posttransplant due to varying requirement for fluid replacement, rapid changes in kidney function, and/or exacerbation of pretransplant disturbances. Common electrolyte abnormalities include hyponatremia, hyperkalemia, hypomagnesemia (discussed in the following text), hypocalcemia, hypercalcemia, and hypophosphatemia (also discussed in chapters 11 and 17). Common etiologies of electrolyte and acid-base disturbances specific to the transplant setting are herein discussed.
Common posttransplant etiologies
Extracellular free water shifts in the presence of osmotically active agents or pseudohyponatremia
Hyperglycemia with the use of high-dose corticosteroids in the early postoperative period
Administration of high-dose sucrose-containing IVIG. Note: Sucrose-containing IVIG can also cause osmotic nephrosis and should be avoided. Only sucrose-free preparations should be used in the transplant setting.
IVIG may be packaged in a large volume of free water, which may also lead to dilutional hyponatremia.
Hyperproteinemia from IVIG infusion may be lead to “pseudohyponatremia” with the old flame photometry sodium measuring technique.
Inappropriate use of relative hypotonic fluid as replacement fluid for bodily fluid losses (eg, blood loss, diarrheal fluids, high urine output)
Poor dietary (solute and sodium) relative to free water intake, inadequate saline fluid replacement
Use of thiazide diuretics
In the postoperative state, patients may have excess antidiuretic hormone (ADH) secretion (syndrome of inappropriate antidiuretic hormone secretion [SIADH]) due to stress, pain, and/or nausea. The use of hypotonic solutions (eg, 5% dextrose water or even 5% dextrose 1/2 normal saline) as maintenance fluid, infusion of multiple IV medications mixed in hypotonic solutions, and/or excessive free water intake can easily contribute to hyponatremia.
Release of free water intake restriction with the newly functioning allograft may unmask underlying SIADH and other preexisting causes of euvolemic hyponatremia (eg, hypocortisolism, hypothyroidism, nephrogenic syndrome of inappropriate diuresis).
Nonfunctioning or poor-functioning allograft in association with excess free water relative to sodium administration/intake
Newly developed cardiopulmonary event (eg, heart failure with postoperative myocardial infarction, acute pulmonary embolism)
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