Bone Marrow Transplant Nephropathy Research Articles

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long‐term immunosuppression for many years, suggesting permanent donor‐specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Complications rénales au décours de la greffe de cellules souches hématopoïétiques

Hematopoietic stem cell transplantation is a widely used therapeutic modality for many, mainly malignant, diseases. Toxicities of this procedure include acute and chronic renal dysfunction. Acute renal failure, generally reversible is due to acute tubular necrosis (tumor lysis syndrome, marrow-infusion toxicity, sepsis, nephrotoxins), hepatic veno-occlusive disease or acute graft-versus-host disease. Chronic renal failure is often multifactorial, caused by conditioning-associated endothelial cell toxicity (bone marrow transplant nephropathy) and calcineurin inhibitors toxicity. Renal pathologic findings are somewhat similar to thrombotic microangiopathy, with sometimes systemic disease. Rare cases of nephrotic syndrome have been described after hematopoietic stem cell transplantation, mainly membranous nephropathy, associated with graft-versus-host disease. Therapeutic options for renal dysfunction after hematopoietic stem cell transplantation are limited but kidney transplantation is possible in case of end-stage renal disease.

Kidney Complications of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) exposes a patient's kidneys to a unique combination of challenges, including high-dose radiation, anemia, chemotherapeutic agents, graft-versus-host disease, opportunistic infections, attenuated and altered immunologic responses, fluid and electrolyte imbalances, and extensive courses of antimicrobial agents. Since the inception of HSCT in the 1950s, there has been increasing interest in defining, determining, and managing the kidney complications that accompany this procedure. In this article, we review the common causes of acute kidney injury and chronic kidney disease that occur with HSCT, including HSCT-associated thrombotic microangiopathy, a distinct cause of chronic kidney disease with a multifactorial cause previously known as bone marrow transplant nephropathy or radiation nephropathy. Additionally, we review other kidney complications, including calcineurin inhibitor nephrotoxicity and chronic graft-versus-host disease-associated glomerulonephritis, that develop post-HSCT. Critically, due to its grave prognosis, it is important to identify HSCT-associated thrombotic microangiopathy early, as well as distinguish it from the other causes of chronic kidney disease.

Radiation-Associated Kidney Injury

The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy-associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients.

Renal Transplantation for End-Stage Renal Disease Following Bone Marrow Transplantation: A 10-Year Outcomes Review.

Abstract 4294 BackgroundThe incidence of hematopoietic stem cell transplantations (HSCTs) in the US is increasing dramatically each year. Nephrotoxic agents used in these patients often lead to kidney injury that can be severe and progress to end-stage renal disease (ESRD) requiring long term dialysis or kidney transplant. Kidney transplantation is the best method of renal replacement therapy and maintenance immunosuppression is the mainstay to prevent graft rejection. Immune tolerance is of substantial interest because it obviates the need for long-term immunosuppression. MethodsWe performed a retrospective analysis of nine patients that developed ESRD after HSCT at the Medical College of Wisconsin. Chart review was performed to obtain demographic information and details of the transplants, patient and transplant outcomes, and various renal and HSCT related parameters. ResultsA total of nine patients were reviewed. Patient age at the time of HSCT ranged from 25-40 years. ESRD was caused by bone marrow transplant nephropathy (BMT-Np) in seven patients, HUS/TTP in one patient, and anti-TBM nephritis in one patient. Six patients received their kidney from a living related donor (LRD), whereas two patients received living unrelated renal transplants (LURRTx), and one recipient received a deceased donor transplant. Three of the six LRD recipients had same-donor renal and hematopoietic stem cell (HSC) transplants and did not require post-transplant maintenance immunosuppression. Of the two LURRTx recipients, no maintenance immunosuppression was required for the patient receiving same-donor organs. The deceased donor transplant recipient continues to be on immunosuppression. Follow-up ranges from 12-23 years post HSCT and 3-12 years post-renal transplant. Seven of the nine patients have functioning bone marrow and kidney transplants. Their serum creatinine ranges from 0.77 to 1.7 mg/dL. One patient died 24 months post-renal transplant from metastatic vaginal squamous cell cancer and had a functioning bone marrow and kidney at the time of death. Another patient was lost to follow-up and died of unknown cause, although her renal function 34 months post transplant was excellent off maintenance immunosupression. ConclusionsBased on our case series, we conclude that the long-term outcome of renal allografts in patients who have received a renal transplant after HSCT is excellent. The overall requirement for immunosuppressive medications in this population is reduced. Disclosures:No relevant conflicts of interest to declare.

A 5-Year-Old Girl With Impaired Renal Function After Autologous Bone Marrow Transplantation

ONE MARROW TRANSPLANTATION(BMT) increasingly is used for the treatmentof patients with hematologic malignancies, somemetabolic and immunologic diseases, and de-pressed bone marrow after cancer treatment. Renalinsufficiency after BMT is common and related tomanycauses.Wepresentthecaseofagirlwhohadrenalinsufficiency4monthsafterautologousBMT.

Bone marrow transplant nephropathy successfully treated with angiotensin-converting enzyme inhibitor

We report a patient who developed chronic renal failure 11 months after an allogeneic hematopoietic stem-cell transplantation (HSCT) for Ph1(+) acute lymphocytic leukemia. Renal biopsy showed typical pathological findings compatible with a bone marrow transplant nephropathy (BMT nephropathy). The general course of BMT nephropathy is slowly progressive, eventually reaching endstage renal failure. Intervention therapy with an angiotensin-converting enzyme inhibitor (ACE-I), temocapril, was started for this patient, based on several experimental reports showing the protective effects of ACE-Is on BMT nephropathy. After the induction of ACE-I in this patient, the rate of regression of renal function was significantly reduced and his serum creatinine was maintained at almost the same level for 18 months. Although the course of observation in this patient was short, we clearly showed the effects of an ACE-I on preventing BMT nephropathy from progressing to endstage renal failure in a human rather than in an experimental model.

Renal involvement in bone marrow transplantation

Bone marrow transplantation (BMT) is an effective therapeutic strategy for leukaemic malignancies and depressed bone marrow following cancer. However, its side effects on kidneys have been reported. Some drugs and irradiation are also suggested to be nephrotoxic. It is well known that haemolytic uraemic syndrome (HUS) after BMT develops as late-onset BMT nephropathy. Cyclosporine A (CsA) is a possible cause. Radiation nephropathy shows changes that are similar to the histology of HUS. These findings suggest that endothelial damage is closely associated with the pathogenesis of post-BMT nephropathy. Recently, some patients have developed glomerulonephritis accompanied by graft-versus-host disease (GVHD) after BMT. In these patients immune deposits are found mainly in subepithelium and mesangium equal to those of secondary membranous glomerulonephritis. A murine experimental model of GVHD manifests similar symptoms and histological changes to those of actual patients and may suggest the pathogenesis of glomerulonephritis.

Retinoic acid may increase the risk of bone marrow transplant nephropathy

Bone marrow transplant nephropathy (BMTN) classically presents more than 100 days after transplantation as an acute nephritis with hypertension, azotaemia and anemia that usually results in end stage renal failure (ESRF). The risk of developing BMTN may be greater with the use of more intensive chemotherapy and higher total body and tumor bed irradiation. Cis-retinoic acid (RA) may further increase the risk of developing BMTN. Here, we report the cases of two children who developed typical clinical and biochemical features of BMTN. They were both treated for stage IV neuroblastoma with chemotherapy, bone marrow transplant (BMT) conditioning that included total body irradiation and RA therapy after BMT, although the patient in case 1 had established renal insufficiency prior to the commencement of RA. Renal biopsy of these children showed classical BMTN histology, and the renal manifestations progressed quickly; the patient in case 1 became dialysis dependent by 1 year post-bone marrow transplant. Recently, RA has been added to the post-BMT therapy in children with stage IV neuroblastoma. The occurrence of BMTN in two children treated with RA in our unit is unlikely to be coincidental. Although RA has been shown to confer a significant survival advantage in this disease, animal studies and a previous case report have suggested it could increase the toxic effects of chemotherapy and renal irradiation. It is likely that RA contributed to the deterioration in renal function in these patients.

Pathologic quiz case: renal impairment after bone marrow transplantation. Bone marrow transplant nephropathy.

Pathologic quiz case: renal impairment after bone marrow transplantation. Bone marrow transplant nephropathy.

Renal function following hematological stem cell transplantation in childhood.

Renal function greatly influences mortality rates in the early phase following hematological stem cell transplantation (HSCT) in childhood, as well as the quality of life in long-term survivors. Nevertheless, the number of studies in pediatric populations is limited and some important aspects of kidney function after HSCT have only been elucidated in adults. The incidence of acute renal failure (ARF) immediately after HSCT in pediatric patients is between 25% and 50%, with 5%-10% of children requiring renal replacement therapy. Doubling of serum creatinine is associated with a twofold increase in mortality. However, the need for dialysis leads to a further increase in mortality rates to 80%-90%. Specific renal syndromes appear at different times following HSCT, revealing a similar pattern in children and adult patients. In both children and adults, impaired renal function associated with liver impairment (hepatorenal syndrome) is the most important cause for ARF. Therapeutic approaches have not been able to reduce the frequency or to improve outcome so far. In adults surviving long term, bone marrow transplant (BMT) nephropathy is the most frequent renal complication, although a considerable variation in incidence (up to 70%) has been published, partly due to various definitions and manifestations. Little is known about the long-term outcome of renal function in patients treated with HSCT in childhood. However, chronic renal failure has been reported in 0%-28%, but no end-stage renal failure has been published so far. Tubular function following HSCT is rarely investigated, although its impact on long-term survivors of BMT in childhood might be of some importance, especially for growth and bone metabolism.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Membranoproliferative glomerulonephritis develops in a child with autologous stem cell transplant

Bone marrow transplant nephropathy is a known complication of bone marrow transplantation. Bone marrow transplantation can cause various rare kidney diseases such as membranous nephropathy and focal segmental glomerulosclerosis. Idiopathic membranoproliferative glomerulonephritis is rare in children. Here the authors report on a 5-year-old pediatric autologous stem cell recipient, in whom type I membranoproliferative glomerulonephritis developed 111 days after bone marrow transplantation and presented with hematuria, hypertension, proteinuria, and renal failure. Am J Kidney Dis 40:E19. © 2002 by the National Kidney Foundation, Inc.

Brief Pharmacological Intervention in Experimental Radiation Nephropathy

Brief postirradiation treatment with an angiotensin-converting enzyme (ACE) inhibitor has been shown to be effective in reducing the severity of radiation nephropathy in rats. The efficacy of brief treatment with an ACE inhibitor was shown to be greatest when the animals were young when irradiated and when the treatment was given 4 to 10 weeks after bone marrow transplantation (BMT). In further studies with a BMT nephropathy model, we have shown that brief treatment with an angiotensin II type I receptor antagonist (AII blocker) is even more effective than brief treatment with an ACE inhibitor. We have also shown that an NO synthase inhibitor, which exacerbated radiation nephropathy when given continuously, has no effect when given during the postirradiation interval when ACE inhibitors and AII blockers were most effective. Studies also showed that the loss of efficacy of brief treatment with increased age at irradiation parallels the decrease in radiosensitivity that occurs with increasing age at irradiation, but that this decrease in radiosensitivity is not sufficient to explain the loss of efficacy of brief treatment. These data indicate that the renin-angiotensin system is important in the expression of renal radiation injury, particularly between 4 and 10 weeks after irradiation.

Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy

Purpose: Angiotensin-converting enzyme (ACE) inhibitors are effective in the prophylaxis of radiation-induced renal and lung injury. Studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than blocking AII synthesis with ACE inhibitors, would also be effective. Materials and methods : Rats received total body irradiation (TBI) followed by bone marrow transplantation (BMT), and were randomized to: an ACE inhibitor (captopril); an AII type 1 (AT1) receptor antagonist (L-158,809); or no treatment. Drug therapy began 9 days prior to BMT and continued for the duration of the study. Results : Analysis of renal function, histopathology and animal survival showed that the AII blocker was more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. Further studies have shown that the AII blocker is as effective as captopril in the treatment of established radiation nephropathy, and that the AII blocker is at least as effective as captopril in the prophylaxis of lung injury induced by chemo-radiation therapy. Conclusions : These studies indicate that blockage of the AT1 receptor by itself is sufficient for the treatment of radiationinduced renal and lung injury, hence the renin-angiotensin system is fundamentally involved in the pathogenesis of these injuries. These studies provide further evidence that there is more to late radiation injuries than delayed mitotic cell death.

Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy after BMT. In previous BMT nephropathy studies, ACE inhibitor therapy was started pre-BMT and continued indefinitely. In preparation for clinical trials, studies were designed to determine whether effective prophylaxis could be achieved if ACE inhibitor therapy was started after engraftment, and to determine whether ACE inhibitors needed to be given indefinitely. The present studies in our rat syngeneic BMT model showed that captopril therapy started 25 days post-BMT was as effective as therapy started prior to BMT. When ACE inhibitor therapy was discontinued 28 weeks after BMT, the protective effect was not lost if adequate control of azotemia had been maintained for 26 weeks. If adequate control of azotemia was not maintained for 26 weeks, BMT nephropathy progressed rapidly when ACE inhibitor therapy ended, and slowly when it was continued. Failure to control azotemia was a better predictor of renal failure than failure to control hypertension or proteinuria. Based on these preclinical studies, it would appear that ACE inhibitor therapy will be effective in the prophylaxis of BMT nephropathy even if begun after engraftment, and that ACE inhibitors may not need to be given indefinitely.

Age Dependence of Radiation Nephropathy in the Rat

A higher incidence of radiation nephropathy is reported in pediatric than in adult patients. Preliminary experiments showed that juvenile rats had lower renal tolerance than adult rats. The experiments reported here were designed to determine the age at which tolerance changes and the magnitude of the change. Five- to 25-week-old rats were given bilateral kidney irradiation with 15-29 Gy X rays given in five fractions. Renal function was assessed 4 and 6 months after irradiation. Isoeffect doses for renal dysfunction were 15.5-17.5 Gy for rats irradiated at 5-8 weeks of age and 20.2-25.2 Gy for rats irradiated at 12+ weeks of age. At 23 Gy, rats irradiated at 5.5 weeks of age developed renal failure after 16 weeks; this increased to 21 weeks for irradiation at 7.5 weeks of age and to 27+ weeks for irradiation at 12-27 weeks of age. Renal tolerance increased steadily for irradiation at ages between 5-10 weeks, and maximum tolerance was reached by 12-15 weeks of age; a similar dependence on age at irradiation was found for bone marrow transplant nephropathy. The decrease in renal radiosensitivity with age may partially explain the increased incidence of radiation nephropathy in pediatric populations.

Angiotensin II Receptor Antagonists in the Prevention of Radiation Nephropathy

Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy. Current studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than preventing the creation of AII, would be effective in the prophylaxis of radiation nephropathy. Rats received 17 Gy total-body irradiation (TBI) in six fractions followed by syngeneic bone marrow transplantation (BMT). Prior to TBI the rats were randomized to groups receiving an ACE inhibitor (captopril), an AII type 1 (AT1) receptor antagonist (L-158,809) or no treatment. Renal function was assessed over 40 weeks, and a subset of animals were sacrificed for histopathology at 33 weeks. Renal function deteriorated progressively in animals receiving TBI alone, leading to renal failure by 34 weeks. Renal function was significantly better in animals receiving either captopril or L-158,809, and none of these animals had progressed to renal failure by 43 weeks. Analysis of both renal function and histopathology shows that the AII receptor antagonist is more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. This indicates that a reduction of activation of the AT1 receptor by AII, by itself, is sufficient for the prophylaxis of radiation nephropathy.

Late Onset Bone Marrow Transplant Nephropathy.

We report a patient who exhibited proteinuria and renal failure 93 months after receiving an allogeneic bone marrow transplantation (BMT) from his HLA-identical brother. A renal biopsy specimen revealed segmental sclerosis, mesangiolysis, subendothelial lucency in the glomeruli, fibrosis and small round cell infiltration in the interstitium, and hyaline droplets in the intimal spaces of arterioles and small arteries. These histological findings were consistent with late onset BMT nephropathy. This nephropathy may represent a more serious problem in the near future in Japan, since the number of BMT performed has been increasing with the establishment of a bone marrow bank.

Bone marrow transplant nephropathy: radiation nephritis revisited.

Late-onset renal failure occurs in up to 20% of survivors of bone marrow transplantation. Total body irradiation is a major factor in this syndrome, so-called bone marrow transplant nephropathy (BMT NP), which is defined by disproportionate anemia, hypertension, and azotemia. Previous or concurrent chemotherapy may potentiate the effect of radiation on the kidney. Kidney function may decline acutely or more gradually, with eventual long-term stabilization. Patient survival is associated with control of the blood pressure. BMT NP is a recognized complication of bone marrow transplantation, which will require ongoing attention.