Biology of Blood and Marrow Transplantation
Volume 13, Issue 6 , Pages 638-643, June 2007

Stem Cell Transplantation Nephropathy: A Report of Six Cases

  • Sabina Kersting

      Affiliations

    • Corresponding Author InformationCorrespondence and reprint requests: Sabina Kersting, MD, Department of Hematology, B02.226, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
    • ,
  • Leo F. Verdonck

Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

Received 7 November 2006; accepted 22 February 2007. published online 06 April 2007.

Article Outline

Abstract 

Stem cell transplantation (SCT) nephropathy is 1 cause of chronic kidney disease in patients after allogeneic SCT. It is a thrombotic microangiopathic syndrome characterized by raised creatinine, hypertension, and anemia. The difference with thrombotic thrombocytopenic purpura (TTP)-like syndromes is that it occurs later than 3 months after SCT, has marked renal dysfunction, and occurs in the absence of other complications or nephrotoxic medication. Total-body irradiation (TBI) in combination with previous chemotherapy is most likely the cause. We describe 6 cases of SCT nephropathy that occurred in a cohort of 363 patients who received myeloablative allogeneic SCT. All patients had TBI with shielding of the kidneys. We discuss the course of the syndrome, treatment, and outcome of the patients.

Key Words: Stem cell transplantation nephropathy, Chronic kidney disease, Thrombotic microangiopathy, Radiation nephritis, Hemolytic uremic syndrome, Thrombotic thrombocytopenic purpura

 

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Introduction 

One of the causes of chronic kidney disease after stem cell transplantation (SCT) is a thrombotic microangiopathic condition called bone marrow transplantation nephropathy or SCT nephropathy. The syndrome was first described in 1991, and might occur in up to 20% of patients 1 year after allogeneic transplantation. It is characterized by a sudden increase in creatinine, microangiopathic hemolytic anemia, and hypertension occurring typically after 6-12 months. Hereafter, a slower decline in kidney function, leading to end-stage renal disease, but also stabilization can occur [1, 2, 3]. Time of onset, presentation, and histopathologic changes are the same as for radiation nephritis seen previously after radiation for seminomas [4]. Renal shielding during total-body irradiation (TBI) can decrease the chance of developing this syndrome at 2.5 years from around 30% to almost zero [5]. Because this syndrome occurs after a lower dose of irradiation than classical radiation nephritis, other causes might contribute to the pathogenesis [2]. In experimental rat models angiotensin converting enzyme (ACE) inhibitors can treat SCT nephropathy, and treatment with ACE-inhibitors is recommended [6].

Here we describe the clinical course of 6 patients who developed SCT nephropathy in our SCT unit over a period of 11 years and discuss the literature.

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Materials and Methods 

In this retrospective analysis 6 patients with SCT nephropathy could be traced from 363 patients who received myeloablative allogeneic stem cell transplantation from January 1993 to January 2004. SCT nephropathy was defined as the triad of hypertension, disproportionate severe anemia, and sudden rise in serum creatinine with no apparent cause, occuring more than 3 months after transplantation [7].

The charts of the 6 patients were reviewed and hospital course, posttransplant complications, and serum creatinines were noted. Patient characteristics and details of the clinical course are shown in Table 1. Creatinine values at different times are shown in Figure 1.

Table 1. Patient Characteristics of 6 Patients with SCT Nephropathy
Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6
Age at SCT27 years53 years25 years51 years18 years51 years
Sexfemalemalefemalemalemalefemale
DiseaseAML, first remissionCML, chronic phaseAML, first remissionAML, second remissionALL, first remissionALL, first remission
Historynomyocardial infarctionnodiabetes type IInohypertension
Previous treatmentcytarabine, idarubicine, amsacrinehydreacytarabine, idarubicinecyatarabine idarubicine, amsacrine, mitoxantrone, etoposidevincristine, asparaginase, daunorubicine, cytarabine, mercaptopurine, etoposide cyclophosphamidevincristine, asparaginase, daunorubicine, cytarabine, mitoxantrone
Conditioningstandard⁎standardstandardstandardstandardstandard
ATGnonoyesnonoyes
TransplantsiblingsiblingMUDsiblingsiblingMUD
Baseline creatinine53 μmol/L61 μmol/L147 μmol/L75 μmol/L56 μmol/L65 μmol/L
ARFnoyesyesyesyesyes
TTPnonoyesnonono
aGVHDnonononoyesyes
cGVHDnonononoyesyes
Cyclosporine use12 weeks12 weeks12 weeks12 weeks37 weeks14 weeks
Timing SCTnp8 months14 months32 months36 months12 months13 months
Ultrasonographynormalnormalnormalloss of parenchymadecreased right kidneynormal
Kidney biopsyTMAnot donenot donenot doneTMATMA, interstitial nephritis
Proteinuria0.79 g/L1.3 g/L0.90 g/L1.3 g/L0 g/L0.93 g/L
Hematuria+/−+−+/−+/−++
Peak creatinine987 μmol/L276 μmol/L454 μmol/L869 μmol/L861 μmol/L1211 μmol/L
Lowest Hb4.2 mmol/L4.2 mmol/L5.3 mmol/L4.7 mmol/L2.3 mmol/L5.9 mmol/L
Lowest thrombocytes32 × 109/L19 × 109/L63 × 109/L28 × 109/L125 × 109/L128 × 109/L
Highest tension180/110 mmHg220/110 mmHg170/120 mmHg220/130 mmHg170/100 mmHg160/105 mmHg
ACE inhibitoryesnoyesyesyesyes
Last kidney functionperitoneal dialysisGFR 22 mL/min/1.73 m2GFR 19 mL/min/1.73 m2peritoneal dialysis15 mL/min/1.73 m229 mL/min/1.73 m2
Time of death and cause34 months sigmoid perforation15 months multiorgan failurealivealive20 months pneumoniaalive

SCT indicates stem cell transplantation; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; ATG, antithymocyteglobulin; MUD, matched unrelated donor; ARF, acute renal failure defined as doubling of baseline creatinine within 3 months after SCT; TTP, thrombotic thrombocytopenic purpura within 3 months after SCT; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; SCTnp, stem cell transplantation nephropathy; TMA, thrombotic microangiopathy; GFR, glomerular filtration rate, calculated with MDRD equation: GFR = 186.3 × (serum creatinine)−1.154 × age−0.203 × (0.742 for women).

⁎Cyclophosphamide (60 mg/kg/day for 2 days), followed by total-body irradiation (600 cGy/day for 2 days) with partial shielding of the lungs (total lung dose 850 cGy) and partial shielding of the kidneys (500 cGy/day for 2 days).

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Results 

Patient 1 was a 27-year-old woman who received SCT because of acute myelogenous leukemia (AML). She was admitted 8 months after transplantation because of hypertension, raised creatinine, hemolytic anemia with schistocytes, and thrombocytopenia. She received ACE inhibition and a β-blockade. Her creatinine increased despite adequate treatment of hypertension. Because of uremic pericarditis she started peritoneal dialysis 16 months after SCT. She died of multiorgan failure resulting from perforation of the sigmoid 34 months after SCT.

Patient 2 was a 53-year-old man who received SCT because of chronic myelogenous leukemia (CML). Fourteen months after SCT he was admitted because of abdominal pain, hemolytic anemia with schistocytes, hypertension, thrombocytopenia, raised creatinine, and epileptic seizures. Benzodiazepines led to acute respiratory insufficiency and need for mechanical ventilation. Plasma exchange was started to treat suspected thrombotic thrombocytopenic purpura (TTP). Despite this treatment he died of multiorgan failure.

Patient 3 was a 25-year-old woman who received SCT because of AML. Nearly 3 years after transplantation she was admitted because of hypertension, raised creatinine, hemolytic anemia with schistocytes, and thrombocytopenia. Her blood pressure normalized with a β-blockade and ACE inhibition, but creatinine increased slowly. She is now 3 years after transplantation and receives treatment for stage 4 chronic kidney disease with a glomerular filtration rate (GFR) of 19 mL/min/1.73 m2.

Patient 4 was a 51-year-old man who received SCT for AML in second remission. One year after SCT creatinine increased and persistent anemia without an obvious cause developed. Nearly 3 years after SCT hypertension was noted. He was admitted for treatment of hypertension when creatinine was 472 μmol/L 2 years later. ACE inhibition, diuretics, and a β-blockade were started, which led to further rise in creatinine and end-stage renal disease. He started peritoneal dialysis more then 5 years after SCT. Nearly 10 years after SCT he is now in good clinical condition.

Patient 5 was a 18-year-old man who received SCT because of acute lymphoblastic leukemia (ALL). One year after transplantation he developed autoimmune hemolytic anemia with hypertension and creatinine of 400 μmol/L. After starting with ACE inhibition the creatinine stabilized at 250 μmol/L. The hemolytic anemia did not respond to treatment. He died 20 months after SCT because of pneumonia.

Patient 6 was a 51-year-old- woman who received SCT because of ALL. Eight months later a β-blockade was started because of recurrence of hypertension. Five months later ACE inhibition and diuretics were started because of persistence of hypertension, raised creatinine, and anemia, and were discontinued shortly hereafter because of worsening of the kidney function. After an initial decrease her creatinine rose again and liver enzyme abnormalities developed. After discontinuation of valaciclovir and treatment with corticosteroids, creatinine decreased. Hypertension was treated with calcium antagonist, and with this treatment kidney function stabilized at GFR of 28 mL/min/1.73 m2.

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Discussion 

The diagnosis of individual patients with thrombotic microangiopathy and renal dysfunction after allogeneic SCT can be difficult. Different forms of overlapping thrombotic microangiopathic syndromes have been described. A patient with microangiopathic hemolytic anemia after SCT may therefore be given the diagnosis SCT nephropathy [1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18], radiation nephropathy [2, 19, 20, 21, 22], hemolytic uremic syndrome (HUS) [23, 24, 25, 26, 27, 28], or TTP [23, 28, 29, 30]. Pettitt and Clark [26] made a classification of post-SCT thrombotic microangiopathy: (1) multifactorial fulminant thrombotic microangiopathy, (2) cyclosporine nephrotoxicity with microangiopathic hemolytic anemia, (3) cyclosporine neurotoxicity with microangiopathic hemolytic anemia, and (4) conditioning-associated HUS.The first 3 syndromes resemble classical TTP and usually develop within 3 months after SCT. The diagnosis of TTP is uncertain following SCT because of the presence of multiple SCT-associated complications [29], and the absence of generally accepted detailed diagnostic criteria [30]. It is even stated that clinical signs of a systemic infection or graft-versus-host disease (GVHD) mimic TTP, and that TTP is not a specific sequla after SCT [28]. Multifactorial thrombotic microangiopathy or TTP on the background of GVHD, infections, or other complications post-SCT has a high mortality [26]. Plasmapheresis or plasma infusion have shown little efficacy in TTP-like conditions following SCT, in contrast to classical TTP [23, 31]. Treatment of associated complications is recommended [28]. When patients are receiving cyclosporine, this should be discontinued, but this can lead to deterioration of GVHD. Alternative immunosuppression with corticosteroids should be considered [26]. Cyclosporine nephrotoxicity with microangiopathic hemolytic anemia is a form of TTP that is readily reversible on discontinuation of cyclosporine and treatment of hypertension, and thus has a good prognosis [26].

Conditioning-associated HUS, the fourth condition mentioned by Petitt and Clark, is almost similar to SCT nephropathy or radiation nephritis, with predominantly raised creatinine levels and hypertension occuring more than 3 months after SCT, with low mortality but frequent residual renal impairment [26].

The major difference between TTP-like syndromes with renal impairment (multifactorial thrombotic microangiopathy and cyclosporine nephrotoxicity with microangiopathic hemolytic anemia) and SCT nephropathy (radiation nephritis or conditioning-associated HUS) is the time of occurrence, with TTP usually occuring within 3 months after SCT and SCT nephropathy occurring after 3 months. Other differences are that renal impairment and hypertension are a prerequisite for SCT nephropathy [7], but can be less dominant in TTP, and that SCT nephropathy occurs in the absence of active complications or toxic medication [3], whereas TTP often occurs in association with complications like GVHD and infections [28], or cyclosporine [32, 33].

The hallmark of these syndromes is thrombotic microangiopathy. In SCT recipients, multiple insults may lead to the initiation of endothelial cell injury or dysfunction. These can be conditioning regimens with high-dose chemotherapy or TBI, and increased levels of cytokines in association with aGVHD or sinusoidal occlusion syndrome [32]. In addition, cyclosporine may promote procoagulant changes in the endothelium by increasing the release of thromboxane A2 and thromboplastin and increasing ADP, collagen, and adrenaline-induced platelet aggregation and factor VII activity and decreasing the production of prostacycline, thrombomodulin, and protein C [30]. TBI containing conditioning regimens seem to be the major risk factor for SCT nephropathy [34].

In our study SCT nephropathy developed in 6 of 363 patients (1.7%). The incidence of SCT nephropathy after allogeneic SCT in adults varies between 0% and 29% [3, 18, 19, 35, 36], with low incidence if the kidneys are shielded [5]. The low incidence of our cohort confirms the efficacy of renal shielding in reducing the incidence of SCT nephropathy.

The first 3 cases show a condition resembling classical TTP, but it is SCT nephropathy because of the time of occurrence, the marked hypertension, and increase in serum creatinine. The last 3 cases lack the initial event with thrombocytopenia, but are SCT nephropathy because of the combination of anemia, hypertension, and renal impairment in the absence of an obvious cause. In the last 2 patients thrombotic microangiopathy was confirmed by renal biopsies. Previous studies have recognized 3 different courses of SCT nephropathy: acute decline in kidney function (patients 1-3), a more gradual decline in kidney function (patient 4), and an initial decline in kidney function followed by stabilization at a reduced GFR (patients 5 and 6) [7] (Figure 1). SCT nephropathy is a serious condition because it can lead to end-stage renal disease [8], but acute mortality is lower than in complications-associated TTP-like conditions [26]. In our case-series, 2 patients developed end-stage renal disease, 3 patients developed severe kidney disease stage 4 (GFR 15-29 mL/min/1.73m2), and 1 patient died of SCT nephropathy.

Angiotensin converting enzyme inhibition stabilized kidney function in 1 of 5 patients and had no effect in the other 4 patients. These results are not very promising, but because no better treatment is available, ACE inhibition remains the treatment of choice. Plasma exchange therapy showed not to be effective in the 1 patient who received this treatment, as was described in earlier studies [30].

Anemia in SCT nephropathy can be caused by thrombotic microangiopathy or erytropoeitin deficiency in a later phase [1, 3]. Erythropoietin deficiency in patients with SCT nephropathy is more pronounced than observed in patients with an equivalent decrease in GFR by another cause [17]. Therefore, erythropoietin is recommended for treatment of anemia in patients with chronic SCT nephropathy [2]. Our 2 patients with end-stage renal disease received this treatment with successful increase in hemoglobin.

Although nephrotoxic drugs (eg, cyclosporine and amphotericin B) can cause acute renal failure [37, 38], SCT nephropathy seems not influenced by them [39]. There was no direct relationship in use of nephrotoxic drugs and occurrence of SCT nephropathy in our patients, except for the sixth patient, who had a combination of thrombotic microangiopathy and interstitial nephritis because of valaciclovir.

Severe proteinuria is not a sign of SCT nephropathy, and was absent in our patients. Nephrotic syndrome in association with chronic GVHD (cGVHD) is an extremely rare complication after myeloablative SCT, but is now more often recognized after non-myeloablative SCT, even in the absence of cGVHD [40]. Two of our patients had chronic GVHD, but there was no relationship with development of SCT nephropathy.

In summary, SCT nephropathy is 1 of the thrombotic microangiopathic syndromes occuring after SCT. It occurs later than TTP-like syndromes, and is characterized by renal dysfunction, anemia, and hypertension, without an obvious cause. It can lead to an acute decline in kidney function or run a more gradual course. Although acute mortality is not so high, it is a serious condition because it can lead to end-stage renal disease. TBI in conditioning regimens is most likely the cause. ACE inhibition is recommended, but certainly cannot prevent deterioration of kidney function in many patients. Treatment with erythropoietin relieves anemia seen later in these patients.

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PII: S1083-8791(07)00191-7

doi:10.1016/j.bbmt.2007.02.009

Biology of Blood and Marrow Transplantation
Volume 13, Issue 6 , Pages 638-643, June 2007

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