The use of eculizumab in renal transplantation

The complement system plays a vital role in mediating disease processes within renal allografts. Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC). It has been used primarily within renal transplantation to treat atypical hemolytic‐uremic syndrome (aHUS) and antibody‐mediated rejection (AMR) post‐transplant, and also as prophylaxis in transplants at high risk for these conditions. Eculizumab appears to be effective in protecting renal allografts when post‐transplant aHUS or AMR occur, although the published cases report relatively short follow‐up. It is unclear how long treatment should continue (a particularly important issue given the expense of the drug), or whether eculizumab contributes to the development of accommodation in humans. When used for prophylaxis, eculizumab also appears to be effective. Some highly sensitized patients have developed either acute AMR or features of chronic AMR despite administration of the drug – this suggests that complement activation is not the only mechanism responsible for AMR. All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Clinical trials, predominantly in antibody‐incompatible renal transplantation, are ongoing to determine the optimal use of C5 inhibition.     

Rituximab in renal transplantation

Rituximab is a chimeric anti‐CD20 monoclonal antibody that leads to B cell depletion. It is not licensed for use in renal transplantation but is in widespread use in ABO blood group incompatible transplantation. It is an effective treatment for post‐transplant lymphoproliferative disorder, and is also used in both HLA antibody incompatible renal transplantation and the treatment of acute rejection. Recent evidence suggests rituximab may prevent the development of chronic antibody mediated rejection. The mechanisms underlying its effects are likely to relate both to long‐term effects on plasma cell development and to the impact on B cell modulation of T cell responses. Rituximab (in multiple doses or in combination with other monoclonal antibodies and/or other immunosuppressants) may lead to an increase in infectious complications, although the evidence is not clear. Rarely, the drug can cause a cytokine release syndrome, thrombocytopenia and neutropenia. It has been related to an increased risk of progressive multifocal leucoencephalopathy and, recently, deaths from cardiovascular causes. Trials examining the effects of rituximab in induction therapy for compatible renal transplantation and the treatment of chronic antibody mediated rejection are ongoing. These trials should aid greater understanding of the role of B‐cells in the alloresponse to renal transplantation.     

Pathology after eculizumab in dense deposit disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.     

Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock

Studies have shown that active hepatocellular function is depressed early after trauma-hemorrhage and persists despite resuscitation with two or three times (x) the volume of maximum bleedout (MB) with lactated Ringer's solution (LR). However, it is not known if a larger volume of fluid resuscitation corrects this dysfunction. To study this, rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the MB volume was returned in the form of LR, and then resuscitated with 4x or 5x the volume of MB with LR. Three doses of indocyanine green (ICG) were given intravenously and [ICG] measured in vivo using an in-vivo hemoreflectometer. The initial velocity of the clearance of ICG was calculated. Maximal velocity of the clearance (Vmax: the number of functional ICG receptors) and kinetic constant (Km: the efficiency of the active transport) were determined from the Lineweaver-Burk plot. Vmax decreased during hemorrhage, was restored to control levels at 0-4 hours after resuscitation, but decreased at 4-8 hours after resuscitation despite restoration of cardiac output following resuscitation with 5x LR. This could be the result of increased TNF release. The Km also decreased during hemorrhage, but increased at 0-1.5 hours and remained at control levels even 4-8 hours after resuscitation. Thus the failure of Vmax to remain at control levels following adequate fluid resuscitation may form the basis of cellular dysfunction and multiple organ failure after severe hemorrhagic shock.     

美罗华在肾脏病和肾移植中的应用

美罗华,CD20单克隆抗体,最早用于治疗非霍奇金淋巴瘤.近年来,美罗华用于治疗特发性膜性肾病、局灶性节段性肾小球硬化、狼疮性肾炎、原发性血管炎等肾脏病,同也应用于肾移植领域:治疗抗体介导性排异、移植后淋巴增生性障碍,处理高度致敏受者和ABO-不相容移植.很多小样本研究表明美罗华在治疗这疾病中起了重要作用.     

Residual renal function assessment with cystatin C

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/V_urea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/V_urea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters.     

Chronic endothelin antagonism restores cerebrovascular function in diabetes

OBJECTIVE: Diabetes profoundly alters vascular function and is a risk factor for cerebrovascular disease. Diabetes increases myogenic tone and decreases responsiveness to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channel openers and endothelium-dependent vasodilators. The mechanism(s) by which diabetes impairs cerebrovascular function remain obscure. In the present study, the effects of the potent vasoactive peptide endothelin-1 on myogenic tone and endothelium-dependent and potassium channel-mediated vasodilation in middle cerebral arteries from diabetic and nondiabetic rats were investigated. METHODS: Twenty-eight Wistar rats were divided into four experimental groups (n = 7 per group): control (C), control treated with bosentan (an endothelin A/B receptor antagonist) (CB), diabetic (D), and diabetic bosentan-treated (DB). Diabetes was induced with streptozotocin (D and DB groups), after which chronic bosentan treatment was initiated (CB and DB groups). Middle cerebral arteries were mounted in a pressure myograph, and myogenic responses were recorded. In addition, endothelium-dependent and -independent responses and the effects of the K(ATP) channel opener pinacidil were examined. RESULTS: Cerebral arteries from the diabetic and nondiabetic rats constricted in response to graded pressure increases. Maximum myogenic responses (percent constriction at 60 mm Hg) were significantly greater in the D group (38 +/- 3% versus 25 +/- 3% in C; P < 0.02). The enhanced myogenic tone in the D group was completely prevented by bosentan treatment (DB, 23 +/- 5% versus D; P < 0.003) without an effect on the CB group. In addition, bosentan treatment improved endothelium-dependent vasomotion and improved K(ATP)-mediated vasodilation in the DB group (P < 0.001). CONCLUSION: These data describe, for the first time, the interaction between endothelin-1, myogenic tone, and endothelial function in diabetes. Chronic endothelin antagonism restores cerebrovascular function in this model of diabetes and has global implications for the management of cerebrovascular disease in diabetes.     

Assessment of renal function in renal transplant patients using cystatin C. A comparison to other renal function markers and estimates

To date, little evidence is available to define the role of cystatin C in patients with renal transplants. Thus, to assess, whether cystatin C (CysC) provides better information on renal function than other markers, CysC, creatinine clearance (CrCl), serum creatinine (SCr), beta2-microglobulin (beta2-M), and 125I-Iothalamate clearance were determined in 30 patients. Correlation and ROC curves were obtained and characteristics like sensitivity and specificity were calculated. Further, to evaluate the usefulness of these markers for monitoring, intraindividual coefficients of variation for CysC and SCr measurements were compared in 85 renal transplant patients. CysC correlated best with GFR, whereas SCr, CrCl and beta2-M all had lower correlation coefficients. CysC was superior to SCr, even when renal function equations of were used. The diagnostic accuracy of CysC was significantly better than SCr. but did not differ significantly from CrCl and beta2-M. Together, our data show that in patients with renal transplants, CysC has a similar diagnostic value as CrCl. However, it is superior to determinations of SCr. The intraindividual variation of CysC is significantly greater than that of SCr. This might be due to better ability of CysC to reflect temporary changes especially in mildly impaired GFR, most critical for early detection of rejection and other function impairment. In conclusion, CysC allows for easy and accurate assessment of renal function (GFR) in steady state renal transplant patients and is clearly superior to the commonly used serum creatinine.     

Rituximab therapy for mixed cryoglobulinemia in seven renal transplant patients

Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have been achieved in hepatitis C virus-positive immunocompetent patients with rituximab, a human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen. Thus, this provides a rationale for the use of rituximab for type III cryoglobulin-related graft dysfunction in renal-transplant patients. Seven patients, of whom five were hepatitis C positive, developed renal function impairment long after transplantation, as well as de novo nephrotic syndrome (n = 5), severe hypertension (n = 5), nephritic syndrome (n = 1), and increased serum creatinine (n = 1). This type III cryoglobulinemia was associated with membranoproliferative glomerulonephritis and with thrombi within the glomeruli in one case. In addition to their baseline standard immunosuppressive medications, the patients were given weekly rituximab infusions: 375 mg/m(2) for 2 weeks in four cases, for 3 weeks in one case, and for 4 weeks in two cases. This treatment resulted in a dramatic improvement in all renal parameters, particularly a sustained remission of nephrotic syndrome in three cases, the disappearance of nephritic syndrome in one patient, and improved nephrotic syndrome in two cases, as well as a sustained clearance of cryoglobulins in six cases. However, it also resulted in severe infectious complications in two cases. We concluded that rituximab therapy is effective in cryoglobulin-related renal dysfunction in renal transplant patients but, due to chronic immunosuppression, this may be achieved at the expense of infectious complications.     

血清半胱氨酸蛋白酶抑制剂C在肾病患者肾功能评估中的应用

临床上常用的评估肾小球滤过率(GFR)的BUN和Scr并不是理想的指标。研究发现,半胱氨酸蛋白酶抑制剂C(CysC)是一种比Scr更好反映肾小球滤过功能的理想指标,且已推导出GFR公式:GFR(ml／min)=99．19×CysC- 1．713(女性×0．823)。为此,我们分别用CysC-GFR公式、Cockcroft-Gault公式计算GFR值并与实测GFR值相比较。一、对象与方法     

Mycophenolate mofetil restores renal function and spares steroids during idiopathic nephrotic syndrome in children. A cohort study

Renal function evolution during idiopathic nephrotic syndrome depends on treatment toxicity. Cyclosporin is effective as a steroid-sparing agent but patients are dependant on this drug, which can lead to renal toxicity. Mycophenolate mofetil, a widely used drug in organ transplantation, has short-term beneficial effects in glomerular diseases, including idiopathic nephrotic syndrome. Little is known about mycophenolate mofetil in children and long-term evolution. We analysed a cohort of 12 children with steroid-dependant nephrotic syndrome due to minimal change disease in remission with cyclosporine therapy. They were switched to mycophenolate mofetil, when renal toxicity was diagnosed. We evaluated the number of relapses, tolerance of this new treatment, renal function and body mass index under mycophenolate. After a follow-up of 31.25 months, mycophenolate mofetil alone was effective in preventing relapses in eight patients, without side effects. Renal function significantly improved and the final body mass index decreased. Three patients relapsed on discontinuation of mycophenolate mofetil. The results suggest that mycophenolate mofetil is effective and safe in preventing relapses in steroid-dependant nephrotic syndrome. Furthermore, switching from cyclosporine to mycophenolate mofetil restores renal function. Therefore, mycophenolate mofetil might be considered as an alternative to cyclosporine, to preserve renal function and spare steroids during idiopathic nephrotic syndrome in children.     

Glomerular C3 receptors in human renal disease

The relationship between glomerular C3 receptor activity and intraglomerular C3 deposition was studied in 73 cases of various forms of renal disease. C3 receptor activity was measured by enumeration of complement-coated sheep red blood cells (IgM EAC) that adhered to glomeruli in frozen sections and expressed as a percentage of the mean number present in control kidneys. Adjacent sections were studied for the presence and distribution of C3 deposits. The precise location of corresponding dense deposits was determined through 1-mu sections or electron micrographs. Marked depression of C3 receptor activity was found in most cases in which there was accumulation of C3 along the glomerular basement membrane, irrespective of whether the deposits were in a subepithelial, intramembranous, or subendothelial location. In contrast, when C3 was not detectable or was found exclusively in the mesangium, C3 receptor activity was affected only moderately, if at all. These data are consistent with the hypothesis that the interaction of C3 with podocytes is a major determinant in the loss of C3 receptor activity in glomerular disease, but do not exclude the possibility that interaction with mesangial or endothelial cells may also influence C3 receptor activity.     

动态监测血清胱抑素 C 评价肾移植术后肾功能的改变

目的 监测肾移植受者血清胱抑素C(Cys C)浓度以评估移植肾功能的改变. 方法 监测58例肾移植成功受者术前及术后不同时间的血清Cys C、肌酐(SCr)、β2-微球蛋白(β2-MG)和尿素氮(BUN)水平;并于术后第7天使用99mTc-DTPA测定受者肾小球虑过滤(GFR),比较其与上述四项指标的相关性.以GFR=1.5 ml/s为临界值,绘制ROC曲线,比较各项检测指标鉴别轻度与中重度肾功能损伤的诊断性能.计算受者不同时间段血清Cys C及SCr变异系数及其比值(R值). 结果 Cys C于术后第1天下降达48.1%,明显大于其他指标的下降幅度.血清Cys C、SCr、β2-MG和BUN与GFR相关系数依次为0.876、0.691、0.589和0.516.血清Cys C、SCr、β2-MG和BUN的诊断性能:敏感性分别为91.3%、87.2%、82.6%和87.0%;特异性分别为80.0%、69.2%、71.4%和42.9%;阳性预期值分别为82.0%、73.7%、74.3%和60.4%;阳性似然比分别为4.81、2.83、2.87和1.53;ROC曲线下面积(AUC)分别为0.914、0.828、0.803和0.765.SCr的变异系数显著小于Cys C(P＜0.01),Cys C＜2 mg/L的受者R值大多＜1,Cys C＞2 mg/L的受者,伴随Cys C水平升高,R值趋近于1. 结论 Cys C与GFR相关性最好;Cys C的诊断性能及准确性均优于其他指标,即使肾功能有微小损伤,Cys C也会有显著改变.因此,肾移植术后动态监测Cys C对于及时判断移植肾存活及肾微小损伤时肾功能的改变优于其他指标.     

Renal function and 1 alpha-hydroxyvitamin D3 in rabbits with normal renal function and renal insufficiency

The effect of 1 alpha-hydroxyvitamin D3 (1 alpha OHD3) on the renal clearance of creatinine was investigated in groups of rabbits with stable renal insufficiency and normal controls. Urine was collected in the two groups for two one-week periods during placebo treatment. Then, 1 alpha OHD3, 0.02 micrograms/kg BW/day, was administered orally and urine was collected during the next two weeks. Weekly blood samples were obtained. The treatment had no significant effect on the serum concentrations of calcium and phosphate in either group. Creatinine clearance decreased significantly in both groups during the 1 alpha OHD3 treatment (p less than 0.05), mainly due to a decreased urinary excretion of creatinine. It is suggested that changes in the renal tubular handling of creatinine caused by 1 alpha OHD3 may be the explanation of the observed effect.     

Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement

BACKGROUND: It is well known that serum creatinine may be used as a marker of renal function only if taking into account factors that influence creatinine production, such as age, gender, and weight. Serum cystatin C has been proposed as a potentially superior marker than serum creatinine, because serum cystatin C level is believed to be produced at a constant rate and not to be affected by such factors. However, there are limited data on factors that may influence serum cystatin C levels, and there are limited data comparing cystatin C-based estimates of renal function with creatinine-based estimates that adjust for such factors, especially in individuals with normal, or mildly reduced, renal function. METHODS: This was a cross-sectional study of 8058 inhabitants of the city of Groningen, The Netherlands, 28 to 75 years of age. Serum cystatin C and serum creatinine levels were measured, and creatinine clearance was determined from the average of two separate 24-hour urine collections. We performed multivariate analyses to identify factors independently associated with serum cystatin C levels after adjusting for creatinine clearance. Then, partial Spearman correlations were obtained after adjusting for factors that may influence serum cystatin C and creatinine levels. We also compared the goodness-of-fit (R(2)) of different multivariate linear regression models including serum cystatin C level and serum creatinine level for the outcome of creatinine clearance. RESULTS: Older age, male gender, greater weight, greater height, current cigarette smoking, and higher serum C-reactive protein (CRP) levels were independently associated with higher serum cystatin C levels after adjusting for creatinine clearance. After adjusting for age, weight, and gender, the partial Spearman correlations between creatinine and, respectively, serum cystatin C level and serum creatinine level were -0.29 (P < 0.001) and -0.42 (P < 0.001), respectively. The R(2) values for serum cystatin C level and serum creatinine level adjusted for age, weight, and gender were 0.38 and 0.42, respectively. The addition of cigarette smoking and serum CRP levels did not improve the R(2) value for the multivariate serum cystatin C-based model. CONCLUSION: Serum cystatin C appears to be influenced by factors other than renal function alone. In addition, we found no evidence that multivariate serum cystatin C-based estimates of renal function are superior to multivariate serum creatinine-based estimates.     

Rituximab therapy for de novo mixed cryoglobulinemia in renal transplant patients

BACKGROUND: Type II or III cryoglobulins are fairly prevalent in renal-transplant (RT) patients, and are often related to chronic hepatitis C virus (HCV) infection. However, they rarely result in graft dysfunction. They are sustained by proliferation of oligoclonal B-cells. Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have been achieved in HCV-positive immunocompetent patients with a human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (i.e., rituximab). Thus, this provides the rationale to use rituximab for cryoglobulin-related graft dysfunction in RT patients. METHODS: Three RT patients, of whom one was HCV-positive, developed renal-function impairment long after transplantation, as well as de novo nephrotic syndrome (n=2) and severe hypertension (n=2). This latter case was related to type III cryoglobulinemia and was associated with membranoproliferative glomerulonephritis. In addition to their baseline standard immunosuppression, the patients were given weekly rituximab infusions of 375 mg/m (two infusions in patient and four infusions for the other two cases). RESULTS: This treatment resulted in a dramatic improvement in renal parameters, particularly in a sustained remittence of nephrotic syndrome, a sustained clearance of cryoglobulins in two cases, but also in severe infectious complications in two cases. CONCLUSION: We conclude that rituximab therapy is highly effective in cryoglobulin-related renal dysfunction in RT patients; however, due to chronic immunosuppression, this is at the expense of infectious complications.