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Extended Criteria Donor Kidney Transplantation: Comparative Outcome Analysis Between Single versus Double Kidney Transplantation at 5 Years

INTRODUCTIONnDual kidney transplantation (DKT), using extended criteria donor (ECD) grafts not suitable for single kidney transplantation (SKT), has been suggested to expand the kidney donor pool. Herein, we reviewed the long-term outcomes of DKT to assess its results versus a control group of 179 ECD SKTs. The allocation policy was based on a Remuzzi score obtained from a pretransplant biopsy.nnnMATERIALS AND METHODSnWe analyzed SKT in 179 (31.8%) and DKT in 41 (7.3%) of 563 cadaveric transplants from 2000 to 2008. Patients with DKT versus SKT showed mean recipient ages of 54 versus 51 years. We performed 17 ipsilateral and 24 bilateral DKT. The mean score was 2.78 for SKT and 4.3/4.6 for DKT.nnnRESULTSnDelayed graft function requiring dialysis occurred in 23 (56.1%) DKT and 70 (39.1%) SKT recipients. Primary nonfunction was observed in 1 (2.4%) DKT and 7 (3.9%) SKT recipients respectively. One DKT patient underwent monolateral transplantectomy. In the DKT versus SKT group, patient survivals were 92% versus 95%, 89% versus 93%, and 89 versus 91% at 12, 36, and 60 months, respectively (P = .3). Graft survivals were 100% versus 94%, 95% versus 90%, and 89% versus 78% at 12, 36, and 60 months, respectively (P < .001). We observed a lower incidence of chronic allograft nephropathy (P = .01) and a higher incidence of surgical adverse events (P = .04) in DKT.nnnCONCLUSIONSnECD graft survival using DKT provided better results compared with SKT, despite the use of organs from higher-risk donors. At 5 years follow-up, DKT was a safe strategy to face the organ shortage. To optimize the use of available kidneys, the criteria for DKT require further refinement and standardization. Preimplantation evaluation must maximize transplant success and protect recipients from receiving organs at increased risk of premature failure.

Pregnancy in renal transplantation: immunologic evaluation of neonates from mothers with transplanted kidney

The occurrence of pregnancy in young female organ transplant recipients may sustain a high risk for prematurity and low rate of malformations in neonates. Therefore, it is necessary to counsel couples who want a child. In case of pregnancy, strict guidelines must be observed. Continuous exposure to CsA in utero seems to impair T-, B- and NK-cell development and function in neonates. This effect is prolonged throughout the first year of life. In addition, low levels of serum immunoglobulins occur at the same time. This leads to suggest a delayed administration of classical vaccinations (after the first 6 months of life) in view of the potential risks of both sub-optimal immunologic responses, and adverse events after the administration of live, attenuated vaccines in infants born from young female organ transplant recipients.

Low-density lipoproteins enhance transforming growth factor-beta 1 (TGF-β1) and monocyte chemotactic protein-1 (MCP-1) expression induced by cyclosporin in human mesangial cells

Cyclosporin (CsA) is widely used in the treatment of renal disease and transplantation, which are often complicated by alterations of lipid metabolism. Both chronic administration of CsA and hyperlipidaemia have been shown to evoke an early macrophage influx and have progressively led to glomerular and interstitial sclerosis. MCP‐1 is the major monocyte chemoattractant secreted by stimulated mesangial cells and TGF‐β1 is a key mediator of fibrogenesis in chronic progressive renal fibrosis. Thus, the combined effect of CsA and low‐density lipoprotein (LDL) on the gene and protein expression of MCP‐1 and TGF‐β1 in cultured human mesangial cells (HMC) was explored. Both agents induced an early and persistent increase of MCP‐1 and TGF‐β1 mRNA levels and protein release. The simultaneous addition of CsA and LDL did not display any additive effect on target gene expression, but it caused a synergistic effect on MCP‐1 and TGF‐β1 protein secretion into culture medium. On the other hand, CsA and LDL had different effects on cell proliferation: the latter increased DNA synthesis, whereas CsA inhibited both spontaneous and mitogen‐stimulated mesangial cell growth. The study concludes that CsA and LDL display an additive effect on TGF‐β1 and MCP‐1 synthesis and release by HMC, thus possibly co‐operating to induce an early macrophage influx and the subsequent mesangial expansion and increased extracellular matrix deposition. However, in contrast they seem to modulate HMC proliferation differently, which is a further critical event intimately involved in the development of glomerulosclerosis.

For further investigations in IgA nephropathy the approach from phenotype to genotype is welcome

IgA nephropathy (IgAN) is a worldwide disease with unknown aetiology and pathogenesis. There is an increasing body of evidence suggesting that IgAN is characterized by (i) high serum levels of IgA, mainly polymeric IgA1, in more than 50% of patients; (ii) increased numbers of IgA-bearing B lymphocytes and activated Tα helper cells; (iii) overexpression of TGFβ and IL-4 mRNA in CD4 + cells and (iv) increased deposition of IgA in the mesangium. Four systems, namely mucosa, bone marrow, blood and kidney are involved in the disease. During the past 10 years, Feehally’s group have contributed to our understanding of the important role that the mucosa and bone marrow play in IgAN. In this issue of Clinical and Experimental Immunology, Feehally’s group [1] describe the occurrence of a deficiency in γδT cells expressing Vγ3 and Vδ3 in the bone marrow of IgAN patients. In a previous paper, they reported the same deficiency in the duodenal mucosa [2]. Since γδT cells are regulators of the IgA immune response, these results may provide additional information on the pathogenesis of the disease. n nMesangial IgA deposits in the glomeruli are represented mainly by polymeric IgA. For this reason, the deposits were assumed to be of mucosal origin, but now there is good evidence that the bone marrow is the likely source of the deposited polymeric IgA1 [3], and systemic overproduction of pIgA is present in IgAN patients and enhanced by vaccine stimulation [4,5]. n nIgA production is T cell dependent since an increased number of activated Tα helper cells (both Th1 and Th2) occurs in IgAN patients [6]. Recent studies have reported a high number of circulating γδT cells in these patients which increased after systemic antigen challenge [7,8]. The proportion of γδT cells significantly correlated with serum IgA levels as well as with the proportion of surface IgA positive B cells. Since these cells are precursors of IgA-secreting plasma cells, it is evident that γδT cells could participate in the switching to IgA production in naive B cells. Toyabe et al.[7] demonstrated that the removal of γδT cells from the peripheral blood mononuclear cells of IgAN patients diminished the induction of IgA-bearing B cells and IgA synthesis. These γδT cells are represented by different subpopulations distinguished by their restricted TcR V region [9]. There are four Vγ families (Vγ1–4) and six Vδ families (Vδ1–6) which are modulated by specific genes. In fact, during gene rearrangement, each γδT cell selects one Vγ and one Vδ segment to make up its unique γδ TcR. Peripheral blood γδT cells use the Vγ2 and Vδ2 region, while Vγ1, Vδ1 and Vδ3 T cells are dominant in the mucosa. Analysis of the repertoire of the variable region of mucosal and bone marrow γδ T cells shows a decrease in Vγ3 and Vδ3 gene expression in IgAN patients, thus suggesting that this defect may explain the breakdown of oral tolerance in these patients, which manifests itself as an aberrant mucosal and systemic antibody response to antigens [1,2]. Other abnormalities of the cellular immune system have been found in IgAN patients, namely (i) increased numbers of Tα4 cells, which have the capacity to induce the switch from IgM to IgA synthesis, as do γδ T cells [10], and (ii) increased expression of CD40L on IgAN–specific T cells [11] which binds CD40 on B lymphocytes, thus inducing cytokine production which modulates isotype switching. In addition, increased production of transforming growth factor β, which induces the IgA isotype switch, and IL-5, which promotes differentiation of IgA-bearing β lymphocytes, has been observed in IgAN patients and relatives [12]. These data clearly show that different susceptibility genes operate in IgAN patients. n nRecently, recombinant DNA technology has greatly facilitated the search for genetic markers in IgAN and several different polymorphic genes have been investigated using the candidate gene approach [13]. Results from these studies (Table 1) are conflicting, therefore it has been postulated that genetic factors vary among different populations. n n n nTable 1 n nAssociation studies in IgA nephropathy n n n nI believe that molecular genetic profiling should be undertaken using a different methodology which consists of collecting DNA samples from IgAN patients and family members. This allows a set of expression genetic profiles in familial and sporadic IgAN to be obtained. Recently, Gharavi et al.[14] investigated IgAN using genome DNA–wide analysis and they identified a locus on chromosome 6q22–23, which may contain the IgAN1 gene, responsible for the development of the disease. However, in only 58% of studied Italian IgAN families was disease linked with this gene. This means that other genes are responsible for the development of IgAN and probably variable combinations of genes are involved in different areas of the world. For this reason, three familial genetic studies scanning whole genomic DNA for IgAN disease loci are in progress in the USA, Europe (www.health-tech-net.org/IgAN) and Japan, since IgAN is the most prevalent idiopathic glomerulonephritis. Specific regions, within the 22 pairs of human autosomes, that may carry one or more genes responsible for the development of IgAN will be mapped by linkage analysis. n nData from basic and clinical studies are useful because genes responsible for observed immunological phenotypic abnormalities will be searched in those genomic regions of chromosomes suspected of an association with disease susceptibility. Furthermore, the design for testing whether the candidate gene is involved in the development of IgAN may be either the case control study or the cohort study and can be used to study gene–environment interactions. Since tests of linkage for genes of modest effect may not be so powerful, the investigators may use the transmission/disequilibrium test of Spielman [15] using trios (single affected and nonaffected individuals and their parents). This association test can also be performed for pairs of affected and nonaffected siblings (concordant and discordant sib-pairs). This type of association study seems to be more powerful than linkage studies. n nIn conclusion, genomic studies and computational advances will lead to an information revolution concerning the pathogenesis of IgAN. A combination of rich cellular data, genomic profiling, and computational predictions may provide a fuller understanding of this disease. In the future, additional data will be available from DNA chips, mass spectrometry of proteins and large-scale scans of protein–protein interactions thereby expanding this knowledge further.

Role of cytokines in the progression of renal damage in IgA nephropathy

Summary: IgA nephropathy, or Bergers disease (IgAN), is a worldwide disease which is characterized by a slowly progressive loss of renal function accompanied by decreasing kidney size with the development of glomerulosclerosis and interstitial fibrosis. Immunologic and non‐immunologic factors are implicated in the progression of renal damage, since they are potent inducers in stimulating glomerular, tubular and interstitial cells and non‐resident cells to produce free oxygen radicals, cytokines, growth factors, chemokines, etc. Recent data from our laboratory and other groups, synthesized in this review, have demonstrated the remarkable involvement of these humoral factors in the progression of renal damage in IgAN patients. Therefore, prospective therapeutic approaches have been suggested in blocking the inflammatory mediators during the pathophysiologic sequelae of immune and non‐immune mechanisms which may intervene in the outcome of the disease.

Reply: The Importance of Testing Anti-IL-17 Antibodies from Different Suppliers

We thank Yapici et al. (1) for their interest in our study (2). We agree with them that the choice of the antibody is of paramount importance in a study based on immunohistochemistry results. Our choice of the Santa Cruz antibody for the present study was based on the existing literature (3–5) and on our previous work (6). In a recent study performed on graft biopsies of transplant recipients with delayed graft function, we used the same antibody and we did not observe either any epithelial expression or colocalization with CD4 within the interstitial infiltrate (6). Indeed, in this particular set of patients, IL-17 production was mainly localized in infiltrating monocytes and neutrophils (6).

For further investigations on IgA nephropathy the approach from phenotype to genotype is welcome

Recently, the recombinant DNA technology has greatly facilitated the search of genetic markers in IgA nephropathy and several different polymorphic genes have been investigated using the candidate gene approach. Results from these studies are conflicting, therefore it has been postulated that genetic factors vary among different populations. I believe that molecular genetic profiling should be approached using a different methodology which consists in collecting DNA samples from IgA nephropathy patients and family members. Thus, we have the possibility to design a set of expression genetic profiling in familial and sporadic IgA nephropathy. Recently, Gharavi et al. approached IgA nephropathy using genome DNA-wide analysis and they found a locus on chromosome 6q22–23, which may contain the IgA1 gene, responsible for the development of the disease. However, only 58% of studied Italian IgA nephropathy families linked with this gene. This means that other genes develop IgA nephropathy and probably variable combinations of genes are involved in different areas of the world. For this reason three familial genetic studies addressing the scanning of the whole genomic DNA are in progress in the USA, Europe (www.healthtech-net.org, click on IgAN) and Japan since this disease is the most prevalent idiopathic glomerulonephritis. Specific regions, within the 22 pairs of human autosomes that may carry one or more genes responsible for the development of IgA nephropathy will be mapped by linkage analysis. Data from the basic and clinical studies are welcome because genes responsible for observed immunological phenotypic abnormalities will be searched in some genomic regions of chromosomes identified as being suspected of disease. Furthermore, the design for testing whether the candidate gene is involved in the development of IgA nephropathy may be the case control study or cohort study which can be used to study gene–environment interactions. Since tests of linkage for genes of modest effect may be of lower power, investigators may use the transmission/disequilibrium test of Spielman using trios (single affected and non-affected individuals and their parents). This association test can also be performed for pairs of affected and non-affected siblings (concordant and discordant sib-pairs). This type of association study seems to be of a greater power than linkage studies. In conclusion, genomic studies and computational advances will be leading to an information revolution in the pathogenesis of IgA nephropathy. A combination of rich cellular data, genomic profiling, and computational prediction may provide a way out. In the future additional data will be available from DNA chips, mass spectrometry of proteins and large-scale scans of protein–protein interactions.