Angiotensin-II receptor antagonist losartan reduces microalbuminuria in hypertensive renal transplant recipients

In recent years, it has been demonstrated that losartan lowers macroproteinuria in diabetic or non-diabetic renal transplant recipients (RTx) similar to angiotensin converting enzyme (ACE) inhibitors. Microalbuminuria (MAU) may reflect subclinical hyperfiltration damage of the glomerulus. It could be a marker of kidney dysfunction in renal transplantation. The aim of the study was to assess the efficacy of losartan in hypertensive RTx with MAU. This study was conducted in 17 (M/F: 4/13) stable RTx. No change was made in the medical treatment of the patients. All cases received 50 mg/day losartan therapy for 12 wk. Renal functions and MAU were determined 12 and 6 wk and just before the treatment as well as sixth and twelfth week of the treatment in all patients. Losartan satisfactorily lowered systemic blood pressure. A significant reduction in MAU was observed from 103 +/- 53 microg/min at the beginning to 59 +/- 25 microg/min in the sixth week and 47 +/- 24 microg/min in the twelfth week (p=0.0007 and 0.0005, respectively). From the sixth week of the treatment, the therapy significantly decreased hemoglobin, hematocrit and erythrocyte levels but did not change mean leukocyte and platelet counts, urea, creatinine levels and creatinine clearances. No serious side-effect was observed during the study. In conclusion, we found that losartan decreased MAU in hypertensive RTx. For that reason, it might be considered as the first choise antihypertensive agent for the renoprotection in selected patients.     

羟苯磺酸钙在肾移植术后移植肾功能不全患者中应用的临床观察

探讨羟苯磺酸钙治疗肾移植术后移植肾功能不全的有效性和安全性.方法 回顾性分析2009年9月至2012年2月期间,在解放军总医院泌尿外科进行随访的移植肾功能不全患者,共150例.患者均排除急性排斥反应.所有患者被告知其治疗目的,均取得患者同意.患者均给予羟苯磺酸钙1 000 mg/d,分两次于每日早晚餐间口服,服用1~24个月(中位时间18个月).观察患者羟苯磺酸钙治疗前、治疗后各时间点移植肾功能的变化情况,主要指标包括血清肌酐(Scr)、估算肾小球滤过率(estimated glomerular filtration rate,eGFR)、血尿素氮(BUN)及血清尿酸等.记录不良反应的发生情况,主要指标包括丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、空腹血糖、总胆固醇及甘油三酯等.结果 服药期间,4例因出现明显的胃肠道反应停药退出研究;2例死亡,死亡原因分别为肺癌转移和猝死.使用羟苯磺酸钙治疗后,移植肾功能基本保持原有水平或比治疗前好转,与治疗前比较,治疗后各时间点的Scr明显降低,eGFR明显升高(P<0.05或P<0.01).羟苯磺酸钙的主要不良反应为胃肠道反应,大部分患者对治疗能耐受.与治疗前比较,治疗后各时间点的肝功能、血糖、血脂无明显变化.结论 羟苯磺酸钙治疗肾移植术后移植肾功能不全是有效和安全的.     

Effects of the prostacyclin analogue iloprost on cyclosporin-induced renal hypoperfusion in stable renal transplant recipients

BACKGROUND.: The synthetic prostacyclin analogues have been proposed to protectagainst cyclosporin A (CsA) nephrotoxicity. The present studyinvestigated the effect of infusion of the prostacyclin analogueiloprost on the acute CsA-induced renal hypoperfusion and hypofiltrationin stable renal-transplant recipients. METHODS.: The study included 10 stable renal-transplant recipients withgood graft function (s-creatinine 90–170 umol/1). Renalfunction and the acute renal haemodynamic and tubular responseto an oral CsA-dose (Sandimmun Neoral, 3 mg.kg^–1) wereinvestigated with an infusion of iloprost (1 ng.kg^–1.min^–1)or placebo on 2 separate days. After an overnight fast, seven30-min renal clearance periods were performed, two before infusion,three during infusion, and two recovery periods. An additionalcontrol clearance study without CsA intake or iloprost/placeboinfusion was done in eight of the patients. RESULTS.: CsA ingestion decreased ERPF and GFR significantly with a maximumdecline at the end of the clearance study. Iloprost infusionabolished the CsAinduced decrease in ERPF, but had no effecton the CsA-induced decrease in GFR, leading to a significantdecline in FF. Renal clearance of lithium (CLi), used as anindex of proximal tubular outflow, decreased in parallel withGFR after CsA intake, with no additional effects of iloprost.Iloprost infusion decreased blood pressure and increased heartrate. CONCLUSION.: Infusion of iloprost causes systemic and renal vasodilatation,but has no effect on the CsA-induced decrease in GFR and C_Liin stable renal transplant recipients.     

Validation of plasma clearance of 51Cr-EDTA in adult renal transplant recipients: comparison with inulin renal clearance

Plasma clearance of ⁵¹Cr-EDTA (⁵¹Cr-EDTA-Cl) is an alternative method to evaluate glomerular filtration rate (GFR). This study aimed to investigate the concordance between ⁵¹Cr-EDTA-Cl and renal inulin clearance (In-Cl) in renal transplant recipients as well to determine the repeatability of ⁵¹Cr-EDTA-Cl in kidney donors. Forty four kidney recipients and 22 kidney donors were enrolled. Simultaneous measurements of ⁵¹Cr-EDTA-Cl and In-Cl were performed. A single dose of 3.7MBq of ⁵¹Cr-EDTA was injected and the plasma disappearance curve was created by taking blood samples at 2, 4, 6 and 8 h after injection. Bland and Altman statistical approach was used to quantify the agreement between In-Cl and ⁵¹Cr-EDTA-Cl and to determine the better concordance between all possibilities of measure for the ⁵¹Cr-EDTA-Cl. The mean of In-Cl was 44.5 ± 17.9 ml/min/1.73 m². There was a positive correlation between In-Cl and all possible measurements of ⁵¹Cr-EDTA-Cl. ⁵¹Cr-EDTA-Cl with two samples taken at 4 and 8 h or at 4 and 6 h presenting the narrow limits of agreement and a difference (bias) of 2.8 and 2.7 ml/min, respectively. Two plasma sampling for ⁵¹Cr-EDTA-Cl was a reliable method to measure GFR compared with In-Cl and comprises a suitable method to be used in kidney transplanted patients.     

Urinary kallikrein excretion is related to renal function change and inflammatory status in chronic kidney disease patients receiving angiotensin II receptor blocker treatment

Aim: This study was to evaluate the correlation of urinary kallikrein to renal function, proteinuria and urinary cytokines in chronic kidney disease patients in a longitudinal follow up. Method: We measured urinary kallikrein and cytokines in 50 patients who were followed up for 12 months. Results: Using regression model we found that the kallikrein excretion (estimated by log kallikrein/creatinine) was positively correlated to log estimated glomerular filtration rate in the beginning and the end of follow up (P = 0.049 and 0.006, respectively). No correlation existed between kallikrein excretion and proteinuria. The kallikrein excretion decreased after 12 months of follow up, which was also associated with the decrease of log estimated glomerular filtration rate. There was a significant positive correlation between the log urinary kallikrein and monocyte chemoattractant protein‐1 (MCP‐1) concentration (correlation coefficient = 0.277; P = 0.049). Urinary kallikrein excretion was also positively correlated with serum MCP‐1 level (correlation coefficient = 0.431; P = 0.002). No correlation existed between urinary kallikrein and transforming growth factor β‐1 or tumour necrosis factor‐α concentration. Conclusion: Urinary kallikrein excretion is positively correlated to renal function, serum and urinary inflammatory mediator MCP‐1 in chronic kidney disease patients. These findings indicate that urinary kallikrein excretion may reflect the change of renal function and kidney inflammatory status.     

Prevalence and staging of chronic kidney disease in renal transplant recipients

Abstract: Introduction: Diagnosis and staging of chronic kidney disease (CKD) is important for management and prevention of renal disease progression. It is unclear whether K/DOQI guidelines of the National Kidney Foundation are applicable to diagnosis of CKD in renal transplant recipients (RTRs) and which method is most appropriate for estimating glomerular filtration. Objectives: To determine the prevalence and staging of CKD in RTRs, according to K/DOQI guidelines, and the prevalence of complications of CKD. Subjects and methods: This cross‐sectional study included RTRs at least six months post‐transplantation followed at a single out‐patient service. The glomerular filtration rate (GFR) was estimated with two different equations: the MDRD equation (Modification of Diet in Renal Disease) with four variables (age, creatinine level, gender, and race) and the Cockcroft–Gault (CG) formula. Patients with GFR more than 60 mL/min/1.73 m² were diagnosed with CKD only in the presence of renal damage (hematuria, proteinuria, or evidence of injury in renal biopsy). CKD staging was compared to the two equations and the prevalence of complications was determined. Results: The study evaluated 241 RTRs (average age: 40.6 ± 12.5 yr, 62.2% male; 4.5% black, 50.6% from cadaveric donors). Average follow‐up time was 6.8 ± 6.1 yr and the average baseline creatinine level was 1.48 ± 0.72 mg/dL. CKD was diagnosed in 70.5% of RTRs, of whom 52.9% (MDRD)/47.6% (CG) were classified as Stage III (GFR: 30–59 mL/min/1.73 m²). The agreement between the two methods was very close with regard to CKD diagnosis (κ = 0.92) and close for stage‐dependent prevalence (κ = 0.68). The prevalence of anemia, hypocalcemia, hyperphosphatemia (HF), hyperuricemia (HU), and systemic arterial hypertension (SAH) was 10.6%, 7.6%, 10.3%, 54%, and 73.4% for patients with CKD. Significant differences were observed for HU, HF and SAH in patients without CKD. Anemia, HU and SAH were associated with CKD stage (p < 0.001). Conclusion: The prevalence of CKD in the study population was high (70.5%). The two equations tested correlated closely when used for GFR estimation. Routine CKD staging in RTRs would provide patients with safer and more appropriate management.     

The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA.

BACKGROUND: The angiotensin II (AT II) type I receptor antagonist losartan has been reported to increase urinary uric acid and potassium excretion. These effects might be beneficial in cyclosporin (CsA)-treated renal transplant recipients, who frequently suffer from hyperuricaemia and hyperkalaemia. METHODS: In this prospective, open, randomized, two-way cross-over study we included 13 hypertensive CsA-treated patients after renal transplantation and administered either the angiotensin-converting enzyme (ACE) inhibitors enalapril or losartan. Laboratory parameters, 24-h urinary protein excretion, and mean 24-h arterial blood pressure (MAP) were checked after 3 weeks treatment with enalapril, after a wash-out period of 2 weeks, and before and after a 3-week treatment course with losartan. RESULTS: Both drugs slightly reduced MAP (losartan from 97+/-6 to 94+/-9 and enalapril to 93+/-8 mmHg). Serum potassium levels significantly increased during enalapril therapy (from 4.3+/-0.5 to 4.8+/-0.4 mmol/l, P<0.05), as did, although not significantly, uric acid concentrations (from 7.8+/-1.9 to 8.2+/-1.8 mg/dl, P=0.5). Losartan, on the contrary, only mildly affected serum potassium (4.3+/-0.5 vs 4.5+/-0.5 mmol/l, P=0.25) and serum uric acid decreased (from 7.8+/-2.4 to 7.3+/-1.8 mg/dl, P=0.6). Serum aldosterone and urinary aldosterone excretion were significantly reduced only during ACE inhibitor treatment, which might explain the variable effects on potassium homeostasis. CONCLUSION: Losartan may be a useful agent to reduce blood pressure and serum uric acid levels in renal transplant recipients treated with CSA: Furthermore, in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril.     

Correlations with six‐month protocol biopsy findings in pediatric transplant recipients on low‐ and regular‐dose CNI regimens

Protocol biopsies (PB) are seldom performed after pediatric kidney transplantation (KTx), and factors influencing PB results have not previously been investigated. We performed PB in 79 children six months after KTx and evaluated the results using Banff 2007 criteria. Complications such as bleeding or infections were not detected. The influence of different variables on PB results was evaluated by covariance analysis. Children treated with a low‐dose calcineurin inhibitor (CNI) together with an mTOR inhibitor exhibited decreased subclinical rejection (0% vs. 19%, p = 0.001) and decreased interstitial fibrosis and tubular atrophy (IF/TA) (15% vs. 42%, p = 0.013) compared with patients treated with a conventional regimen consisting of normal‐dose CNI and mycophenolate mofetil. Children with IF/TA had a lower GFR four wk after Tx (83 ± 22 vs. 62 ± 20 mL/min/1.73 m², p = 0.001). Cold ischemia time, living‐related donors, pre‐emptive KTx, and donor age did not influence PB results. Treatment with low‐dose CNI and mTOR inhibitor and high GFR directly after Tx are the main factors associated with less inflammation and fibrosis in PB and might therefore lead to better long‐term graft function.     

Analysis of urinary donor-derived DNA in renal transplant recipients with acute rejection

Abstract: In renal transplantation we usually diagnose an acute rejection by based on the results of a needle biopsy; however, this takes time and findings in some cases are not definite. We analysed the urine of renal recipients for the presence of donor DNA in an attempt to establish a diagnostic means of acute rejection. Sixty-four renal transplant recipients were examined. Thirty-seven patients had no trouble after transplantation and 22 patients developed acute rejection, diagnosed based on serum creatinine levels and/or needle biopsy findings of the graft. Five patients had drug-induced renal dysfunction. In female recipients with a male graft we examined urine for the presence of Y-chromosome (SRY and DYZ-1) and in recipients receiving a HLA mismatched graft we investigated the HLA-DR gene (DRB1) by the polymerase chain reaction (PCR) method. Among female recipients with a male graft there were 14 patients with stable renal function and SRY and DYZ-1 on Y-chromosome were negative in 13 (93%) and positive in one, whereas SRY and DYZ-1 of urine were positive in the four female patients with acute rejection and these DNA fragments disappeared in three after rejection therapy. One patient was subjected to haemodialysis. Among 23 recipients of a graft from HLA mismatched donors with stable renal function, DRB1 was negative in 21(91%). Among 18 patients with acute rejection DRB1 was positive in 16 (93%) and negative in two. These DNA fragments disappeared in 13 patients after rejection therapy. In all patients with drug-induced renal dysfunction donor-derived DNA was negative. Presence of donor-specific DNA in the urine of the recipient is associated strongly with acute rejection and analysis of DNA derived from donor cells in urine might be an effective and accurate method for the diagnosis of acute rejection of a renal transplant.     

The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study.

BACKGROUND: Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis. METHODS: We used data from the Prevention of REnal and Vascular ENd-stage Disease Intervention trial (PREVEND-IT) and the PREVEND cohort study. The PREVEND-IT subjects (788 with a UAE 15-300 mg/day) received pravastatin 40 mg/day vs placebo and/or fosinopril 20 mg/day vs placebo in a 2x2 factorial-RCT design. Of the 3440 cohort subjects, 469 used statins during the 4-year follow-up period. Multivariate-regression adjusted for confounding factors and the propensity score was used to estimate the relation between statin use and UAE and GFR. RESULTS: In the RCT, pravastatin did not change UAE or GFR, neither in fosinopril yes/no subgroups. In the observational cohort, statin use was associated with a rise in UAE (+12.1%), compared with statin non-use (+3.6%, P<0.001). This rise was most pronounced in those on statins prior to the first screening [+24.8% (95% CI: 11.9-39.2)], those using statins>3 years [+18.5% (7.3-30.8)] and those with >1 or >2 defined daily doses (+15.7 and +17.3%, respectively). These differences remained significant after adjustment for relevant variables and propensity score. The rise in UAE could not be attributed to a higher dose or a specific statin. GFR fell in 4 years in both statin users and non-users (4.6+/-13.5 and 2.4+/-11.2, respectively). The fall in GFR between groups was not different after adjustment (P=0.11). CONCLUSIONS: We conclude from the RCT data that statins do not lower UAE in subjects selected because of an elevated UAE instead of hyperlipidaemia. In the observational cohort study, the use of statins similarly was not associated with a fall in UAE; UAE instead increased. Statin treatment was not associated with a significant change in GFR in these subjects with only modestly impaired GFR.     

术前合并肾功能不全对心脏移植受者预后的影响分析

目的  评估心脏移植术前合并肾功能不全对围手术期死亡和并发症发生及长期生存的影响,并比较术前血清肌酐（Scr）和估测肾小球滤过率（eGFR）在术前风险评估中的差异。方法  回顾性分析1 095例心脏移植受者的临床资料,根据术前Scr分为Scr < 133 μmol/L组（980例）、Scr 133~176 μmol/L组（83例）和Scr≥177 μmol/L组（32例）;根据术前eGFR分为eGFR≥90 mL/（min·1.73 m²）组（436例）、eGFR 60~89 mL/（min·1.73 m²）组（418例）和eGFR < 60 mL/（min·1.73 m²）组（241例）。分析不同分组受者术后肾功能的转归情况及围手术期和远期结局。评价eGFR和Scr对心脏移植术后肾功能损伤和远期生存的影响。结果  随着术前Scr升高,受者术后使用连续性肾脏替代治疗（CRRT）的比例增加,术后机械循环辅助的比例增加,术后并发症发生率增加,机械通气时间和重症监护室（ICU）入住时间延长,院内病死率增加,3组间差异均有统计学意义（均为P < 0.05）。随着术前eGFR的下降,受者术后使用CRRT辅助的比例增加,术后使用主动脉内球囊反搏（IABP）的比例增加,机械通气时间和ICU入住时间延长,院内病死率增加,3组间差异均有统计学意义（均为P < 0.05）。Scr≥177 μmol/L是受者术后死亡的独立危险因素[校正风险比（HR）3.64,95%可信区间（CI）1.89~6.99,P < 0.01]。以Scr及以eGFR为指标的分组中,3组间的术后肾功能损伤累积发生率和远期生存率差异均有统计学意义（均为P < 0.05）。术前Scr < 133 μmol/L的受者中,术后远期肾功能损伤随时间的累积发生率随术前eGFR降低而升高（P < 0.01）,而不同eGFR分层的患者术后远期生存率差异无统计学意义（P > 0.05）。结论  心脏移植术前合并肾功能不全与围手术期和远期预后不良相关。心脏移植术前Scr和eGFR均是术后肾功能损伤发生的独立危险因素。Scr对于术前肾功能评估的灵敏度较低,但预测围手术期死亡风险的准确性更高。eGFR是术前评估肾功能更为敏感的指标,可以早期发现肾功能异常,早期采取有效措施从而减少对预后的不良影响。     

Renal haemodynamic characteristics and their correlation with renal pathology in patients with systemic lupus erythematosus

SUMMARY: To clarify the characteristics of renal haemodynamics and their correlation with renal pathology in patients with systemic lupus erythematosus (SLE), renal function and renal biopsy findings from 101 SLE patients were analysed retrospectively. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were examined simultaneously. Filtration fraction (FF) was calculated from the values obtained for GFR and RPF (GFR/RPF). The GFR was low in one-third and within normal limits in two-thirds of class IV patients with lupus nephritis (LN). In contrast, high RPF was observed in half of class IV patients. As a result, over 70% of class IV patients possessed a very low FF (less than 15%). The sensitivity of very low FF for class IV LN was significantly higher than that of low GFR. In conclusion, low FF was frequently recognized, especially in patients with diffuse proliferative LN. Decreased FF was a highly sensitive indicator of diffuse proliferative LN. Thus, determination of renal haemodynamics, including FF, may be a useful clinical parameter for evaluating renal involvement in patients with SLE.     

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation

Abstract:  Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.     

The beneficial effects of oral nifedipine on cyclosporin-treated renal transplant recipients — a randomised prospective study

The aim of this study was to test the hypothesis that nifedipine will improve graft survival in cyclosporin A (CyA)-treated renal transplant recipients. One hundred and forty-seven patients were randomised to one of three regimens. Group A received CyA, 7 mg/kg per day, and prednisolone; group B followed the same regimen as group A plus oral nifedipine and group C received CyA, 4 mg/kg per day, prednisolone and azathioprine. Calcium channel blockers were avoided in groups A and C. The crude 2-year (P=0.0223) and 4-year (P=0.0181) graft survival was significantly better in group B (86% and 81%, respectively) than in group A (75% and 63%, respectively). Delayed initial function was seen least frequently in group B (10.2%) compared to groups A (31%) and C (28%; P<0.01). Group B also experienced fewer rejection episodes than groups A and C (P<0.05). We conclude that the combination of oral nifedipine and CyA significantly improves initial graft function, rejection frequency and long term graft survival.     

Effect of mycophenolate mofetil on hematological side effects incidence in renal transplant recipients

Mycophenolate mofetil (MMF), an immunosuppressant administered after solid organ transplantation, is generally well tolerated; however, it frequently causes hematological toxicity. In this study, we aimed to assess the relation between the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA] and 7‐O‐MPA glucuronide [MPAG]) and the adverse effects on the hematopoietic system in renal transplant recipients. The four‐h pharmacokinetic profiles of MPA and MPAG were determined using the HPLC method for MMF‐treated patients (n = 61) among 106 renal transplant recipients (during the late post‐transplant period) participating in the study. Anemia was more frequently observed in the study group compared with the control group (30.7% vs. 20.0%) and although the difference was insignificant, plasma iron concentrations were significantly higher in patients treated with MMF (32.9 ± 9.4 μmol/L vs. 28.7 ± 9.4 μmol/L; p = 0.032). Iron supplementation was more frequently applied to patients with anemia (48.2%) compared with patients with hemoglobin within the norm (20.3%; p = 0.005). As all MPAG pharmacokinetic parameters correlated negatively with hemoglobin and hematocrit, and MPAG pharmacokinetic parameters were higher in patients with anemia, MPAG may be the predicting factor of MMF side effects. In renal transplant recipients, especially with deteriorated renal function, extensive iron supplementation may be ineffective as anemia was associated with declined renal function and was not caused by low iron concentration.     

Follow-up of renal function and urinary protein excretion in childhood IgA nephropathy

Renal haemodynamics and urinary protein excretion (UPE) were investigated in 36 patients with IgA nephropathy more than 3 years after renal biopsy (mean interval 6.3±0.5 years). At follow-up, 39% of patients had a reduced glornerular filtration rate (GFR) and 11% end-stage renal failure. Twenty-five percent had albuminuria, and a further 25% microalbuminuria. All albuminuric patients had GFRs below the mean, and 78% of the albuminurics had a reduced GFR. However, non-albuminurics also had decreased GFRs and GFR tended to fall with the duration of the disease in this group of patients. On comparing the histological changes in the biopsies with haemodynamic and UPE studies performed 6 years later, we found significant correlations between the extent of segmental glomerular sclerosis and GFR, effective renal plasma flow, urinary albumin and IgG excretion, respectively. Histological grading correlated with the same variables. Of the 4 uraemic patients, 2 were nephrotic at presentation, while the other 2 had a nephritic onset of disease and later developed heavy proteinuria. Three of their biopsies showed 10% segmental glomerulosclerosis. Juvenile IgA nephropathy is not a harmless disease. Our results indicate that these children should be carefully monitored with adequate GFR measurements and urine protein analyses.