Prospective study of pulmonary function for cyclomegalovirus infection after renal transplantation

Abstract Pulmonary involvement remains the main complication of cytomegalovirus (CMV) infection in renal transplantation (RT). Early diagnosis is required for the best management of patients, and preemptive therapy could be a successful approach. In order to define the predictive value of lung alveolocapillary abnormalities. We prospectively studied 26 renal transplant recipients for their diffusing capacity of carbon monoxide (DLCO) and their pulmonary clearance of a ^99mTc-DTPA aerosol. Patients were studied before transplantation and then every 2 weeks up to the end of the 3rd month following RT. Viral blood cultures and serological determinations were performed every week during these first 3 months. Bronchoalveolar lavage (BAL) was done in case of CMV disease. Statistic analysis was done using Student's t -test and Pearson's chi-quare test. During the 3-month follow-up, 13 patients remained free of CMV infection. Three non-infected and 8 infected patients showed DTPA clearance abnormalities (P < 0.05). Six non-infected and 7 infected patients showed DLCO disturbance (P > 0.50). DTPA clearance were significantly modified on days 45 and 60 in the infected group. Serial DTPA scanning, in association with viral blood cultures, could be a useful test to avoid unnecessary BAL in a preemptive therapy strategy.     

Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children

We have prospectively studied the occurrence of monoclonal serum immunoglobulins in 38 recipients of BMT. Patients were young children with primary immunodeficiencies (n = 31), other inherited diseases (n = 4), leukemia (n = 2), or aplastic anemia (n = 1). Twenty-nine received an HLA-nonidentical marrow and nine an HLA-identical marrow. Serum monoclonal immunoglobulins were detected by the immunofixation method. Monoclonal immunoglobulins were found in 26 patients. Monoclonal components were more frequently detected in patients with primary severe T cell deficiencies (21/25) rather than in the other patients (6/13). In 7 of 29 recipients of HLA-nonidentical transplants, versus 0 out of 9 recipients of HLA-identical transplants, serum monoclonal immunoglobulins were found associated with a B lymphocyte proliferation syndrome due to an Epstein-Barr virus infection. In this group, monoclonal immunoglobulins were detected early, prior to the onset of the clinical syndrome. The simultaneous occurrence of several monoclonal immunoglobulins was more frequent in these patients, while monoclonal immunoglobulin concentrations increased faster, especially those of IgM isotype. These characteristics may allow in patients at risk (recipients with primary T cell immunodeficiencies and receiving HLA-nonidentical transplantation) an earlier diagnosis of B lymphocyte proliferative syndrome that may eventually lead to early and more efficient therapy.     

Tolerance in renal transplantation after allogeneic bone marrow transplantation-6-year follow-up.

Despite significant advancements in clinical transplantation, very few reports describe the long-term acceptance of transplanted solid organs without indefinite immunosuppression. The immunosuppressive agents used are nonspecific and have serious potential side effects. We present a patient who received a living-donor renal allograft from the same person who had donated bone marrow to her several years earlier. Tolerance was expected based on previous acceptance of full-thickness skin grafts from the donor. Indeed, there has been no evidence of rejection during a 6-year follow-up period, and no induction or maintenance immunosuppression has been given. All noninvasive parameters of graft function remain normal. This and similar reports prove that genetically disparate solid organs can coexist without pharmacological immunosuppression.     

Diagnostic open-lung biopsy after bone marrow transplantation

The development of pulmonary infiltrates is an ominous sign in the immunocompromised host (ICH). Selection of the best diagnostic and therapeutic approach is often difficult, and in part depends on the risk-to-benefit ratio of various diagnostic modalities, such as bronchoscopy, bronchioalveolar lavage, percutaneous needle biopsy, and open-lung biopsy (OLB). We reviewed our experience with OLB and bronchoscopy in a predominantly pediatric bone marrow transplantation population, and attempted to assess the frequency with which OLB results directed a therapeutic change, as well as the clinical results of any such therapeutic alteration. A retrospective chart review was conducted of 87 bone marrow transplantation recipients undergoing diagnostic OLB from 1975 to 1986. Bronchoscopic and OLB cultures, histopathologic studies, serological data, and autopsy results were all carefully examined. An assessment of therapeutic alteration as a result of OLB was made, and clinical changes attributable to an OLB-directed therapeutic alteration were sought. Ninety-four OLBs and 37 bronchoscopic examinations were performed in 87 patients. All patients had undergone bone marrow transplantation, most often for leukemia (58/87) or aplastic anemia (13/87). The mean interval from bone marrow transplantation to OLB was 106 days. There were no intraoperative complications, but minor postoperative surgical complications were frequent (incidence, 21%). Postoperative mortality, defined as a death occurring within 30 days of surgery, was 45% (39/87). Seventy-four percent of the patients (64/87) died during the course of the study, at a mean of 43 days after OLB. Most OLBs (60%) yielded a specific diagnosis, defined as the establishment of a precise cause for the infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infections after bone marrow transplantation using cyclosporine

The incidence of infection in 86 consecutive patients having bone marrow transplantation for acute or chronic myeloid leukemia, in a protocol in which cyclosporine was the main immunosuppressant, was low. Severe bacterial infections were infrequent and mostly caused by gram-positive cocci but early bacterial infection was often associated with severe graft-versus-host disease. Fungal infections were prevented by nystatin and amphotericin thus avoiding the difficult combination of cyclosporine and ketaconazole. Viral infections were no more common than in other series but, in patients with mismatched grafts, they tended to be associated with neurological complications clinically diagnosed as encephalitis.     

Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient’s pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.     

Diffuse proliferative glomerulonephritis after bone marrow transplantation

A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.     

Aseptic bone necrosis after renal transplantation

Osteonecrosis is a common complication of renal transplantation and is an obstacle to rehabilitation. While prednisone has long been implicated as causative, the sporadic nature of aseptic necrosis (ASN) is poorly understood. Four hundred forty-four patients received kidney transplants (TX) between January 1978 and December 1984. Fifty-two patients (16%) have developed ASN. This retrospective study was developed in an attempt to define potential etiologic factors. Age, sex, donor, source, primary renal disease, duration of dialysis, and pre-TX parathyroidectomy did not correlate with ASN. Prednisone administration and duration of use prior to transplantation was equally common in ASN and control patients. Black recipients had a twofold frequency of ASN, although this association did not quite reach significance (p = 0.07). Pretransplant x-ray evidence of either osteopenia or renal osteodystrophy was significant (p less than 0.01) and apparent in 23 of 52 patients (44%). ASN was associated with a history of early acute rejection (p less than 0.02), higher final serum creatinine (p = 0.07), and greater mean prednisone (p less than 0.0001). The mean linear trend of daily prednisone dose was also significant (p less than 0.03). This study suggests that ASN is three times more likely to occur if radiographic evidence is apparent before TX. Rejection and higher daily steroid dosage correlate with a greater incidence of ASN, and blacks appear to be at greater risk.     

粒细胞集落刺激因子减轻小鼠混合骨髓移植后移植物抗宿主病的实验研究

目的探讨同基因骨髓混合一定比例粒细胞集落刺激因子(G-CSF)动员的异基因骨髓移植能否减轻急性移植物抗宿主病(aGVHD).方法将BALB/c与BCF1(BALB/c×C57BL/6)小鼠或与G-CSF动员BCF1小鼠脾细胞按一定比例混合,腹腔注入BALB/c幼鼠,制备新生小鼠GVHD模型,结果以脾指数表示.成年雌性BALB/c小鼠接受60Co全身照射8.5Gy后进行移植,移植物为BALB/c与雄性BCF1或与G-CSF动员BCF.小鼠骨髓细胞按一定比例的混合,移植细胞总数60×105个/只.观察移植小鼠aGVHD典型症状、病理表现及存活率.ELISA法测定细胞因子含量,流式细胞术分析T细胞亚群变化.结果(1)注射BALB/c与BCF1小鼠脾细胞混合比例为21、11及异基因BCF1小鼠脾细胞的新生小鼠均发生GVHD;但G-CSF动员与否,GVHD发生程度差异有统计学意义.(2)21及11混合骨髓移植(MBMT)组小鼠有中到重度GVHD表现;经G-CSF动员的MBMT组小鼠8周存活率较未动员组明显提高(P＜0.05).(3)G-CSF动员供鼠后L3T4+细胞下降显著,L3T4+/Lyt2+比值明显低于未动员组(P＜0.01).(4)G-CSF动员供鼠后混合淋巴细胞反应(MLR)细胞培养上清中,IL-2、IFN-γ水平降低,IL-4水平升高.结论同基因骨髓混合一定量H-2半相合异基因骨髓移植可减轻GVHD的发生;G-CSF动员供鼠可进一步减轻MBMT后GVHD的发生.其机理可能与IL-2、IFN-γ下降、IL-4升高有关.     

A longitudinal study of bone disease after successful renal transplantation.

A retrospective study of 100 patients followed for 1-4 years after successful renal transplantation was undertaken to assess the amelioration of previously present metabolic bone disease and to determine the risk factors associated with the development of osteonecrosis. 42% of patients showed some evidence of bony abnormality. Following transplantation, there was slow but progressive resolution in the X-ray changes of hyperparathyroidism but not of osteoporosis. 14% of patients developed osteonecrosis in the posttransplant period with the femoral head the most common site involved (72% of patients). Osteonecrosis could not be related to average steroid dose, number of steroid pulses, or the preexistence of metabolic bone disease.     

Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients

To assess the incidence, risk factors, and course of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 272 patients receiving transplants at the Fred Hutchinson Cancer Research Center during 1986 was undertaken. The patients were divided into three groups: group 1, hemodialysis requiring ARF; group 2, mild renal insufficiency (doubling of serum creatinine, Scr, but no dialysis); group 3, relatively normal post-BMT renal function (no doubling of Scr). Fifty-three percent of patients at least doubled their Scr (Groups 1 and 2), and 24% required dialysis. The degree of renal functional impairment had a dramatic impact on patient mortality rates (84%, 37%, and 17% in groups 1, 2, and 3, respectively). Jaundice (bilirubin greater than or equal to 2.0 mg/dL), weight gain (greater than or equal to 2.0 kg), amphotericin B use, and a pretransplant Scr greater than or equal to 0.7 mg/dL were independently associated with the subsequent development of dialysis-requiring ARF (P less than 0.001; relative risks, 3.0 to 7.7). Neither aminoglycoside/vancomycin/cyclosporine A use nor acute graft v host disease correlated with the development of ARF. A mismatched graft was a significant risk factor for ARF by univariate but not by multivariate analysis. Within 48 hours before doubling the Scr, 63% of group 1 patients had positive blood cultures and 39% developed hypotension. Of the 26 group 1 patients who had urine Na concentrations measured, 85% had values less than or equal to 40 mEq/L. Autopsy kidney specimens provided no clear explanation for ARF in the vast majority of patients in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

The fate of bone after renal transplantation

Post-transplantation bone disease is a multifactorial, complex condition. It derives in a significant part from pre-existing renal osteodystrophy, but it is aggravated by factors emerging after renal transplantation. Among the latter factors, the key pathophysiological contributor to bone disease is immunosuppressive agent application (especially glucocorticoids (GC)). Post-transplantation bone disease is detectable even years after renal transplantation in the vast majority of patients, and potentially it never resolves completely. Due to post-transplantation bone disease, a rapid reduction of bone mineral density (BMD) develops that can exceed 10% in the first 12 months. Subsequently, the bone loss slows down or even a secondary increase occurs. Post-transplantation bone disease results in a significantly elevated fracture risk, which largely contributes to the increased morbidity in transplant patients. Currently, vitamin D metabolites and bisphosphonates are the most extensively tested therapeutic agents against this accelerated bone loss. Both substances have proven effective. However, it is yet unproven that they reduce the fracture risk. In patients with adynamic bone disease, bisphosphonate usage cannot be recommended, since this group of drugs could oversuppress bone metabolism.     

Lung transplantation for bronchiolitis obliterans after allogenic bone marrow transplantation

Introduction

Bronchiolitis obliterans (BO) occurring after allogeneic bone marrow transplant (ABMT) may be an expression of lung damage of multifactorial origins. At present, it is not a usual condition for lung transplant (LT), accounting for <1% of all indications in the international registry. We sought, to describe the clinical features and outcomes of patients undergoing LT for BO after ABMT in our group.

Patients and Methods

We undertook a cross-sectional study of patients with an indication for LT due to BO after ABMT from the beginning of our program. We recorded the type of transplant, patient age, clinical course, functional outcome, and survival.

Results

Among 313 LT, 13 cases (4.2%) were due to BO, including 3 after ABMT (0.96%). ABMT was indicated after bone marrow aplasia in 2 cases and acute myeloid leukemia in the other patient. The patients were 2 men (both 35 years old) and 1 woman, aged 25 years. All subjects received double elective LT at 24, 20, and 9 years post ABMT. At the time of LT, all displayed severe obstructive ventilatory defects with a forced expiratory volume in 1 second (FEV₁) <30% and partial respiratory insufficiency. The initial immunosuppression was cyclosporine, mycophenolate mofetil, and steroids in all cases. Two of the subjects required changes in the immunosuppressive regimen: 1 due to chronic graft rejection with subsequent functional recovery and the other due to hematologic and neurologic toxicity. After 96, 37, and 9 months, all the patients were alive with baseline dyspnea of functional class 0 and a FEV₁ of about 68%.

Conclusion

LT is an effective therapy in terms of lung function and survival for patients with respiratory failure secondary to the development of BO after ABMT.     

Avascular necrosis of bone after renal transplantation

Summary: Avascular necrosis (AVN) of bone is the most debilitating musculoskeletal complication that can follow renal transplantation, and has been reported in 3-41% of patients. In this unit 351 renal transplants have been done on 285 recipients. Five (1.8%) of these patients (mean age 41.6 years; range 22-57 years; four female; all cadaveric kidneys) developed AVN which affected both hip joints. the mean duration of renal failure before dialysis was 18.2 months (range 5-36). All five were on dialysis for a mean of 16.2 months (range 4-29) pre-transplant. No patient had radiological evidence of renal osteodystrophy prior to transplantation. the first 116 patients were immunosuppressed with prednisone/azathioprine and four (3.5%) developed AVN. the subsequent 169 patients were treated with prednisone/azathioprine/ cyclosporine and one (0.6%) developed AVN. Only two of the five patients needed treatment for acute rejection (methylprednisolone 3 g and 6 g). the mean time from transplantation to onset of joint pain was 45.4 months (range 6-108). Total hip replacement (THR) was undertaken on all 10 joints with the first side being operated on after a mean of 73.2 months (range 23-124) from transplantation and the contralateral side after 88.4 months (range 24–144). Total hip replacement resulted in relief of pain in all joints: three surgical revisions were required, two for dislocation and one for a fractured prosthesis. This study has shown a low prevalence of AVN after renal transplantation. Possible explanations include careful control of renal osteodystrophy while on dialysis and the use of low dose prednisone in the immunosuppressive regimen.