Often hematologic complications do not present in isolation but in conjunction with reduced counts across cell lines. These pancytopenias (hemoglobin <13 g/dL in males, <12.0 g/dL in females; neutrophil count <1,500/μL; platelet count <150,000/μL) are most commonly associated with opportunistic infections or medication-related adverse effects.

Opportunistic infections that primarily present as pancytopenias include human herpes virus-6 (HHV-6), human herpes virus-8 (HHV-8), histoplasmosis, and blastomycosis [51]. CMV and parvovirus B19 can present with pancytopenia, but more commonly present with neutropenia and anemia, respectively [25, 70].

HHV–6, the cause of roseola (exanthem subitum), can reactivate in immunocompromised adults or be transmitted via the donor [25]. This often presents 2–4 weeks posttransplant although cases up to 2 years have been described. Clinical presentation can be with pancytopenia, fever, hepatitis, pneumonitis, colitis, and encephalitis. Laboratory investigation should include PCR testing for HHV-6 types A and B or tissue culture. Isolation from BAL fluid or peripheral blood mononuclear cells is unreliable. A positive qualitative test of viral DNA in cerebrospinal fluid is sufficient for the diagnosis of HHV-6 encephalitis [46]. Immunohistochemical stains of tissue biopsies can detect cells with active infection and can allow for differentiation between variants. Variant B is more likely to be resistant to ganciclovir, the preferred therapy. Foscarnet and cidofovir are the most active agents against HHV-6 in vitro, although not preferred given their renal toxicities. Consideration must be given to reduction in immunosuppression. Efficacy monitoring with frequent viral load testing has been suggested [2].

Histoplasma capsulatum often presents in the first year after transplant with fever, night sweats, and weight loss. Though primarily an infection of the lungs, it can also involve the bone marrow causing a pancytopenia [29]. Diagnosis is made via a bone marrow biopsy demonstrating intracellular fungal elements. Treatment includes itraconazole or amphotericin.

Medications, with a particular focus on drug interactions, are a common cause of pancytopenia. This should be evaluated, preferably by enlisting the help of the transplant pharmacist [3]. Common offending agents include mycophenolate, azathioprine (particularly in combination with allopurinol), and TMP-SMX.

Posttransplant erythrocytosis (PTE) is relatively frequent and occurs in 10–15 % of renal transplant recipients [86]. It commonly develops 8–24 months after transplant and is defined as an elevated hematocrit of greater than 51 %, with normal arterial oxygen saturation, along with normal leukocyte and platelet counts. Predisposing factors include male sex, smoking, renal artery stenosis, retention of native kidneys, and adequate erythropoiesis prior to transplantation. It is detected as elevated counts on routine blood tests, concomitantly with hypertension or as the result of a thrombotic event, which can occur in 10–30 % of cases. A large number of patients experience malaise, lethargy, dizziness, and headache, though spontaneous remission of symptoms occurs in approximately 25 % within 2 years from onset [89]. While the pathogenesis of PTE remains uncertain, excessive production of erythropoietin (EPO) due to unrestrained stimulation of the retained native kidneys has been theorized. As PTE may occur with low or even undetectable levels of EPO, its pathogenesis is likely multifactorial. Several other hormonal systems, specifically, the renin-angiotensin system (RAS) and endogenous androgens, likely play a role. Angiotensin II may be responsible for inappropriately enhancing and sustaining erythropoietin levels directly or indirectly via stimulation of adrenal cortical androgen production. This supports the use of an ACEI or an ARB to reduce EPO production via inactivation of the RAS [42]. Inactivation of the RAS leads to a dose-dependent decrease in hematocrit in over 90 % of patients within the first month of treatment. Nadir hematocrit may be reached within 3 months, with stable levels for a period of 1–3 years [89]. A lack of response to these agents may require a trial of alternative therapies like theophylline or serial phlebotomy [51]. Less frequent causes of PTE include ureteral stenosis and hydronephrosis and renal cell carcinoma (RCC) of the native kidney(s), particularly in the presence of cystic disease. In the setting of renal carcinoma or polycystic kidney disease, erythrocytosis is common due to excess and/or uncontrolled production of erythropoietin from the cysts [74]. This often mandates nephrectomy for RCC or placement of ureteral stents if stenosis or hydronephrosis is present.

Fluctuations in white blood cell counts are common in the immediate postoperative period after kidney transplantation. Daily monitoring is frequently warranted [51]. Leukocytosis is defined as a white blood cell count ≥11.0 × 10⁹ cells/L and is most often caused by an increase in mature neutrophils. Surgical inflammation, infection, and the use of corticosteroids posttransplant are prominent sources of leukocytosis. Acute inflammation from the transplant stimulates granulocyte production and stimulates numerous proinflammatory cytokines including tumor necrosis factor-α. The acute leukocytosis demonstrated in the setting of infection results from the rapid release of neutrophils. In the setting of sepsis and septic shock, systemic endotoxin production and inflammation lead to a potentially rapid rise or fall in white blood cell counts. Corticosteroids reduce neutrophil adhesion, inducing migration from the bone marrow into the circulation, with prednisone doses of 40–80 mg/day leading to a mean increase in absolute neutrophil count (ANC) of 4,000/μL [17].

Renal transplant recipients are at risk for conditions peculiar to transplantation (Table 22.2) either through calcineurin toxicity resulting in renal endothelial injury (TMA), exposure to foreign immune cells in a state of immunosuppression (graft-versus-host disease), or immunosuppression-related infection or reactivation (posttransplant lymphoproliferative disorder and hemophagocytic syndrome (HPS)).

TMA presents early posttransplant as a thrombocytopenia and hemolytic anemia, the result of intraluminal platelet thrombosis and obstruction in the lumina of arterioles and capillaries [59]. Histologic changes include glomerular and arteriolar thrombosis with intracapillary accumulation of erythrocytes. Risk factors for TMA include use of calcineurin inhibitors (incidence 4–15 % with cyclosporine, 1 % with tacrolimus) and mTOR inhibitors, acute antibody-mediated rejection (AMR), CMV infection, donation after cardiac death organ, recipient scleroderma, or antiphospholipid antibody syndrome. Treatment should include withdrawal or reduction in CNI therapy in conjunction with plasma exchange therapy, with consideration for use of eculizumab particularly in those with recurrent TMA or those with known risk factors, including mutations in complement factor H or the presence of antiphospholipid antibodies [30, 98, 99]. When associated with AMR, graft loss is common, and treatment with bortezomib and eculizumab has been attempted [59]. Plasma exchange combined with co-stimulation blockade has also been suggested as an alternative to CNIs and has been reasonably successful. Eculizumab may have a role in prevention of TMA in patients receiving grafts for atypical hemolytic uremic syndrome [98].

HPS is an uncommon complication where nonneoplastic macrophages consume leukocytes, erythrocytes, and platelets as a result of uncontrolled stimulation by tumor necrosis factor-α and IL-2. HPS is diagnosed by meeting five of eight clinical criteria: (1) fever, (2) cytopenia of two lines, (3) hypertriglyceridemia and/or hypofibrinogenemia, (4) hyperferritinemia, (5) hemophagocytosis, (6) elevated soluble interleukin-2 receptor, (7) decreased natural killer cell activity, and (8) splenomegaly [68]. Bone marrow biopsy can confirm the diagnosis in 70 % of cases, demonstrating proliferation of mature histiocytes actively consuming other blood cells. Reactive or acquired HPS in transplant recipients occurs in the setting of opportunistic infection (most typically viral, e.g., Epstein–Barr virus (EBV)), mycobacterial or malignancy [80]. Prognosis is poor with a reported mortality rate of 53 % in the small number of reported cases; graft loss rates are high from a combination of rejection, septic shock, and nephrectomy as rescue treatment. Case reports favor the use of IVIg for treatment; however, therapy is mostly supportive—treating the underlying infection, reduction in immunosuppression (RI), and consideration for the use of pulse steroids and plasma exchange.