Agalsidase therapy in patients with Fabry disease on renal replacement therapy: a nationwide study in Italy.

BACKGROUND: In Fabry disease, end-stage renal disease (ESRD) and severe neurologic and cardiac complications represent the leading causes of late morbidity and mortality. A comprehensive Italian nationwide survey study was conducted to explore changes in cardiac status and renal allograft function in Fabry patients on renal replacement therapy (RRT) and enzyme replacement therapy (ERT). METHODS: This study was designed as a cross-sectional survey study with prospective follow-up. Of the 34 patients identified via searches in registries, 31 males and 2 females who received RRT and ERT (agalsidase beta in 30 patients, agalsidase alpha in 3) were included. Left ventricular mass index (LVMI), interventricular septal thickness at end diastole (IVSD), left ventricular posterior wall thickness (LVPWT) and renal allograft function were assessed at ERT baseline and subsequently at yearly intervals. RESULTS: The patients in the dialysis and transplant groups had been started on dialysis at age 42.0 and 37.1 years (mean), respectively, and patients in the transplant group received their renal allograft at age 39.8 years (mean). The mean age at the start of ERT was similar, 44.1 and 44.6 years, respectively. The mean RRT follow-up was 61.1 and 110.6 months for dialysis and transplant patients, respectively, whereas the ERT duration was 45.1 and 48.4 months, respectively. Cardiac parameters increased in dialysis patients. In transplant patients, mean LVMI seemed to plateau during agalsidase therapy at a lower level as compared to baseline. Decline in renal allograft function was relatively mild (-1.92 ml/min/year). Agalsidase therapy was well tolerated. Serious ERT-unrelated events occurred more often in the dialysis group. CONCLUSIONS: Kidney transplantation should be the standard of care for Fabry patients progressing towards ESRD. Transplanted Fabry patients on ERT may do better than patients remaining on maintenance dialysis. Larger, controlled studies in Fabry patients with ESRD will have to demonstrate if ERT is able to change the trajectory of cardiac disease and can preserve graft renal function.     

Isolated hydatid disease of the native kidney in a renal transplant recipient.

A 43-year-old male renal allograft recipient was admitted tothe hospital for annual check-up. He received a cadaveric renaltransplant 2 years previously. On admission his physical examinationdid not show any abnormalities. Abdominal ultrasonography ofthe patient revealed     

Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function

Abstract:  Recurrence of focal segmental glomerular sclerosis (FSGS) in the allograft following renal transplantation can be graft threatening. To assess risk factors associated with FSGS recurrence, we analyzed 22 patients with FSGS who underwent transplantation between 1996 and 2004. Five patients (Group I, 23%) developed FSGS post-transplantation. Of these patients, 60% had undergone bilateral nephrectomy (BN) for progressive disease compared with none of the patients that were free of recurrence (Group II) (p = 0.0006). Other factors linked with recurrent FSGS were time to first dialysis (Group I: 3.1 ± 1.1 yr vs. Group II: 11.9 ± 1.9 yr; p = 0.03), pre-transplant proteinuria (Group I: 7.0 ± 1.8 g/d vs. Group II: 2.5 ± 0.7 g/d; p = 0.02), young age at transplantation (p = 0.09) and female sex (Group I: 80% vs. Group II: 24%; p = 0.021). Eighty percent of Group I patients received a living related transplant vs. 24% in Group II (p = 0.021). All grafts continue to function at last follow-up with comparable serum creatinines. Overall, post-transplant FSGS recurrence may be associated with BN, severity of pre-transplant FSGS, female gender, and living donation. These patients should be monitored closely for early recurrence and may benefit from early plasmapheresis to restore and facilitate long-term graft function.     

11个Fabry病家系的α-半乳糖苷酶A活性及GLA基因检测

目的 建立Fabry病α-半乳糖苷酶A（α-gal A）酶活性及基因检测体系,并对基因型临床表型进行分析。方法 检测11个Fabry病家系先证者及家系成员外周血粒细胞α-gal A活性及GLA基因。酶活性检测采用底物荧光法,基因检测采用PCR直接测序法,并进行临床评估。结果 在11个Fabry病家系中检出9种GAL基因突变,包括5个错义突变（R301Q、I91T、G132R、F273L、D165Y）,2个无义突变（W236X、R342X）,1个单碱基缺失（1082delG）和1个大片段缺失（44 bp nt．1077）,其中4种为新突变（D165Y、F273L、1082delG、44 bp nt．1077）。11个家系中通过基因及酶活性检测,确诊男性半合子13例,女性杂合子12例。男性半合子α-gal A酶活性显著下降,女性杂合子α-gal A酶活性部分下降,1/4女性杂合子的α-gal A酶活性处于正常范围内。结论 确诊了11个Fabry病家系的GLA基因突变类型,并筛出所有家系中先证者以外的患者14例。外周血粒细胞α-gal A酶活性和GAL基因检测是筛查和诊断Fabry病的有效手段。     

Fatigue in kidney transplant recipients

Fatigue is still present in approximately 40%‐50% of kidney transplant recipients (KTR), rates comparable to that of the hemodialysis population. Correlates of fatigue include inflammation, symptoms of depression, sleep disorders, and obesity. Fatigue in KTR determines a significant severe functional impairment, either when globally considered or when analyzed at the level of the single domains such as sleep and rest, homemaking, mobility, social interaction, ambulation, leisure activities, alertness behavior, and work limitations. In addition, fatigue in KTR is significantly associated with a severe deterioration of quality of life. Fatigue is very common among KTR poorly adherent to immunosuppressive therapy. Unfortunately, there is no evidence of studies about the treatments of this symptom in KTR. Efforts to detect and treat fatigue should be a priority in order to improve quality of life of KTR.     

Fabry Disease in a Renal Allograft

Incidental findings of rare diseases in organ donors can be seen in allograft biopsies that may have profound implications for the recipient and for the donor and their family. Fabry disease is an X-linked recessive lipid storage disease with cardiovascular, renal and lenticular abnormalities. Phenotypic expression in female heterozygote carriers depends on lyonization. Minimal data exists on outcomes of transplanted kidneys from carriers of Fabry disease. We report a patient with ESRD secondary to focal sclerosis who received a HLA-identical transplant from her sister whose pretransplant donor work up was completely negative. Post-transplant, while pregnant, the recipient developed increasing proteinuria and was biopsied. The biopsy showed extensive myelin figures consistent with Fabry disease. Subsequent genetic, enzymatic and pedigree analysis confirmed the diagnosis in the recipient, the donor and the donor's son. Two years post-transplant the patient continues to have non-nephrotic range proteinuria with normal serum creatinine.     

Pregnancy outcomes in simultaneous pancreas and kidney transplant recipients: a national French survey study

Simultaneous pancreas and kidney transplantation (SPK) is currently the best therapeutic option for patients with type 1 diabetes and terminal renal failure. Renal transplantation restores fertility enabling women to pursue pregnancies. However, scarcity of available data on pregnancy outcomes in SPK impedes fair medical counseling. Medical files of all pregnancies that lasted ≥3 months among recipients of functional SPK performed between 1990 and 2015 in France were retrospectively analyzed. Twenty‐six pregnancies in 22 SPK recipients were identified. Main maternal complications included gestational hypertension (53.8%) and infections (50%). Cesarean section was performed in 73% of cases. Overall fetal survival was 92.6% with a mean gestational age of 34.2 ± 3 weeks. Four children (16.7% of live births) had a birth weight <10th percentile. Endocrine pancreas graft function remained stable during pregnancy. An acute kidney rejection occurred in two patients, one of which resulting in graft loss. Kidney and pancreas graft survival was, respectively, 96% and 100% at 1 year postconception and did not differ from controls. Pregnancy in SPK is feasible, but patients should be informed of the risks for the fetus, the mother, and the grafts. Planning of pregnancy in SPK women is key to allow a personalized multidisciplinary monitoring, which represents the most straightforward approach to optimize outcomes.     

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation

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Graft outcomes following diagnosis of post‐transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study

Data related to graft outcomes following post‐transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow‐up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED‐PTLD‐2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet‐PHL C1. In four patients, donor‐specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody‐mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range‐based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B‐cell‐depleting therapy of PTLD with rituximab.     

Sexual and reproductive function in end-stage renal disease and effect of kidney transplantation

Advanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage. Semen analysis typically shows a decreased volume of ejaculate, oligo-or complete azoospermia, and a low percentage of motile sperm. Erectile dysfunction （ED） is also common in patients with chronic renal failure （CRF） and is observed in excess of 50% of these patients. There have been ongoing improvements in survival and quality of life after renal transplantation. One of the most impressive aspects of successful renal transplantation in the young people is the ability of the male patient to father a child. In this article we first review pathophysiology of reproductive failure in end-stage renal disease （ESRD）, then ED in ESRD and its management are discussed, finally sexual function in renal transplant patients and management of ED in these patients are reviewed.     

Significance of screening for Fabry disease among male dialysis patients

Background Fabry disease is an X-linked disorder resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A(α-Gal A). Renal insufficiency is a very important manifestation and affects the prognosis of patients. Recently, a renal variant type that is characterized by low plasma α-Gal A activity and a milder phenotype, but which progresses to end-stage renal failure, has been reported. In this study, we clarified the incidence of this atypical variant of Fabry disease in hemodialysis patients. Methods We measured plasma α-Gal A activity in 450 male dialysis patients who had never been diagnosed with Fabry disease. Results The mean of the α-Gal A activity of the patients was 9.75 ± 3.20 nmol/h/ml, while the controls with classical Fabry (n = 3) were 0.52–1.04 nmol/h/ml. Among the patients, one patient was found to exhibit low α-Gal A activity in plasma (3.18 nmol/h/ml) and in leukocytes (0.639 nmol/h/mg). This patient was a 43-year-old Japanese man who had been on regular dialysis since the age of 23. He did not present typical clinical signs of classical Fabry, such as acroparesthesias or hypohidrosis, but did present renal insufficiency and severe left ventricular hypertrophy which had developed only recently, suggesting a variant form of Fabry disease. Sequencing of the DNA of this patient revealed a deletion of a single amino acid of valine in 10252. Conclusions A case of an atypical variant of Fabry among 450 male dialysis patients (0.22%) was found in the survey. This indicates the potential for undiagnosed Fabry disease among dialysis patients. The results of this study indicate the significance of screening for Fabry disease among male dialysis patients.     

Screening for Fabry disease in male patients with end-stage renal disease in western France

ContextFabry disease is a rare X-linked genetic disease due to pathogenic variants in the GLA gene. Classic Fabry disease is characterized by glycosphingolipids accumulation in all organs including the kidney, resulting in end-stage renal disease in a subset of male patients. Fabry disease should therefore be considered in the differential diagnosis of patients with unexplained end-stage renal disease.ObjectiveWe performed a prospective screening study in Western France to determine the prevalence of Fabry disease in a large population of dialyzed and transplanted patients.Patients and methodsPatients meeting the inclusion criteria (males, 18-70 years with end-stage renal disease of unknown or vascular origin) were selected from the REIN® registry and the CRISTAL® database. Screening on filter papers was performed after patient consent was obtained during either a dialysis session or a transplantation follow-up visit.ResultsOne thousand five hundred and sixty-one end-stage renal disease male patients were screened and 819 consented (dialysis: n = 242; transplant: n = 577). One single patient was found with decreased alpha-galactosidase levels <25%. GLA sequencing identified the p.Phe113Leu variant in favor of an unknown superimposed kidney disease responsible for end-stage renal disease since this GLA pathogenic variant is associated with a later-onset cardiac form of Fabry disease with minimal kidney involvement. Family cascade genotyping revealed a previously undiagnosed affected brother.ConclusionThe prevalence of Fabry disease in end-stage renal disease patients was 0.12%, questioning the efficacy of this screening strategy with respect to the low prevalence. However, beside the benefit for the patient and his family, the increased awareness of Fabry disease among participating nephrologists may be of interest for future patients.     

Effect of anaemia on mortality, cardiovascular hospitalizations and end-stage renal disease among patients with chronic kidney disease

Objective:   To determine whether an independent association exists between anaemia and chronic kidney disease (CKD) outcomes in a quasi-incidence cohort when patients' most recent laboratory values are considered.
Methods:   We conducted a dynamic, retrospective cohort study among patients with incident CKD in a large health maintenance organization administrative data set. CKD was defined by two estimated glomerular filtration rates (eGFR). We measured the absolute rates for all-cause mortality, cardiovascular hospitalizations and end-stage renal disease.
Results:   Our completed cases Cox regression model followed 5885 patients with both CKD and haemoglobin measures. For patients with the most severe anaemia (haemoglobin <10.5 g/dL), we estimated an increased rate of mortality (hazard ratio (HR) = 5.27, CI 4.37–6.35), cardiovascular hospitalizations (HR = 2.18, CI 1.76–2.70) and end-stage renal disease (HR = 5.46, CI 3.38–8.82) when compared with patients who were not anaemic; the HR reflect time-varying haemoglobins and eGFR.
Conclusion:   Anaemia is a predictor of excess mortality, excess cardiovascular hospitalizations and excess end-stage renal disease even when the progression of CKD is considered by controlling for time-varying eGFR values.     

Hypertension in kidney transplant recipients

Arterial hypertension is frequently observed in renal transplant recipients. Its pathogenesis is multifactorial in most cases. Calcineurin inhibitors (CNI) can increase peripheral vascular resistance by inducing arteriolar vasoconstriction and can cause extracellular fluid expansion by reducing the glomerular filtration rate (GFR), activating the renin–angiotensin system (RAS), and by inactivating the atrial natriuretic peptide. Glucocorticoids can impair urinary water and salt excretion. Poor graft function can lead to increased extracellular volume and inappropriate production of renin. Native kidneys, older age of the donor and transplant renal artery stenosis (TRAS) may also contribute to the development of hypertension. Arterial hypertension not only can increases the risk for cardiovascular events but can also deteriorate renal allograft function. A number of studies have shown that the higher the levels of blood pressure are, the higher is the risk of graft failure. On the other hand, a good control of blood pressure may prevent many cardiovascular and renal complications. Appropriate lifestyle modification is the first step for treating hypertension. Calcium channel blockers (CCB) and renin–angiotensin system (RAS) inhibitors are the most frequently used antihypertensive agents, but in many cases, a combination of these and other drugs is required to obtain good control of hypertension.     

Cytomegalovirus disease among renal transplant recipients in India

SUMMARY: There is a paucity of data on cytomegalovirus (CMV) disease in renal transplant recipients from India. We have encountered this problem with increasing frequency at our centre, and document our experience in this paper. Case records of 514 recipients of renal transplants performed between 1980 and 1997, including 96 autopsies, were reviewed. Diagnosis was made by demonstration of classic cytomegaly and intranuclear inclusions on histology, and/or detection of CMV pp-65 antigen in the peripheral blood leucocytes. Cytomegalovirus disease was documented in 21 cases (11 at autopsy, six by antigen detection, and four by a combination of histological demonstration and antigenemia detection). the incidence of this infection rose from 0.6% in 1980–1991 (pre-cyclosporin era) to 5.5% (4.4% lethal) during 1992–1997 (postcyclosporin era). At autopsy, the lung was the most frequently involved organ followed by the gastrointestinal tract. Ninety-five per cent of patients had co-infection with other organisms, and fungi were isolated in 80% of all patients with co-infection. Graft dysfunction was present in 17 cases (81%). We conclude that there has been a four fold increase in the incidence of lethal CMV disease in renal transplant recipients after the introduction of cyclosporin immunosuppression. There is a high incidence of co-infection with other organisms, with fungi being the commonest offenders in tropical environment. This, along with allograft dysfunction, could account for the high mortality seen with CMV disease.     

Comparing aortic stiffness in kidney transplant recipients, hemodialysis patients, and patients with chronic renal failure

Pan CR, Schmaderer C, Roos M, von Eynatten M, Sollinger D, Lutz J, Heemann U, Baumann M. Comparing aortic stiffness in kidney transplant recipients, hemodialysis patients, and patients with chronic renal failure.
Clin Transplant 2011: 25: E463–E468. © 2011 John Wiley & Sons A/S. Abstract: Background: The poor cardiovascular survival of patients with renal insufficiency is improved by transplantation. Carotid‐femoral pulse wave velocity (PWV) is able to predict independently overall and cardiovascular mortality. PWV is elevated in renal insufficiency. Consequently, PWV may change according to the improvement in renal function after kidney transplantation. Methods: In a cross‐sectional setting, PWV was determined in 40 renal transplant recipients (RTx) and compared to the PWV of 40 age‐ and gender‐matched patients with comparable renal insufficiency (CKD) and 40 age‐ and gender‐matched hemodialysis patients (HD). Results: RTx and CKD patients had comparable eGFR (RTx: 42.9 ± 18.4, CKD: 48.3 ± 29.1 mL/min/1.73 m²) and protein/creatinine ratio (RTx: median 172.5, 25th percentile 97.75, 75th percentile 344.5, CKD: median 183.272, 25th percentile 100.00, 75th percentile 470.00 mg/g creatinine). There was no significant difference in PWV between RTx 3–12 months post‐transplant and CKD or HD patients (RTx: 9.65 ± 1.57, CKD: 9.98 ± 3.91, HD: 10.27 ± 2.89 m/s; n = 20 pairs). Similarly, PWV in transplant patients >12‐month post‐transplant was similar to that of CKD and HD patients (RTx: 9.71 ± 2.23, CKD: 9.36 ± 2.74, HD: 9.84 ± 3.41 m/s; n = 20 pairs). Discussion: We could not detect significant differences in PWV comparing RTx with age‐ and gender‐matched CKD patients.     

Renal cell carcinoma of native kidney in renal transplant recipients

OBJECTIVE: To evaluate the prevalence, prognosis and possible risk factors of renal cell carcinoma (RCC) of the native kidney in renal transplant recipients. PATIENTS AND METHODS: We retrospectively re-examined the follow-up data of 373 consecutive renal transplant recipients at our institution between August 1993 and September 2004. We collected the data of all de novo RCC of the native kidney in the current analysis. RESULTS: Of the 373 patients examined, 12 tumours of the native kidney were diagnosed in 10 individuals. The mean ages at transplantation and diagnosis were 33 and 45.8 years, respectively. Thirteen malignancies were discovered fortuitously. Among the renal ultrasonograms there were two false-negative results. The mean tumour size was 21 mm. Nephrectomy was performed in all cases. Among the 12 kidney malignancies, there were five conventional RCCs and seven papillary RCCs. Half of all tumours were Furhman Grade 3 lesions, and pT1aN0M0 tumours also accounted for all malignancies in the current cohort. One of the 10 patients died, from progression of metastases 6 years after diagnosis. One patient had a local recurrence 2 years after diagnosis. The other eight patients were alive with no evidence of disease at the time of the current report. No significant relationship was detected between RCC occurrence and clinical patient characteristics. CONCLUSIONS: There appears to be a greater risk of RCC of the native kidney in patients with end-stage renal disease. The present results suggest that an annual examination of the native kidney before and after renal transplantation is essential.