Angiosarcoma of an Arteriovenous Fistula for Hemodialysis in a Kidney Transplant Recipient Affected by Lowe's Syndrome.

Objective/Background. To describe an uncommon, life-threatening condition such as angiosarcoma of a fistula for hemodialysis occurring in a transplant recipient affected by Lowe's syndrome. Summary. We present the case of a 56-year-old male kidney transplant recipient affected by Lowe's syndrome, also known as oculocerebrorenal syndrome, a rare X-linked disorder characterized by congenital cataracts, hypotonia, intellectual disability, and Fanconi-like renal tubular dysfunction, who was diagnosed with angiosarcoma of a functioning arteriovenous fistula for hemodialysis. Conclusion. Angiosarcoma is a rare soft tissue tumor, and only 22 cases of angiosarcoma of arteriovenous fistulae were described so far; although a correlation between Lowe's syndrome and a higher risk of tumor compared to the general population has not been described so far, the mechanisms of disease causation could be an interesting starting point for future studies on a possible connection between the two events.

Advanced age is not an exclusion criterion for kidney transplantation.

INTRODUCTION: Renal transplantation in patients older than 60 years has long been regarded with skepticism owing to the increased risk of complications although, as compared with dialysis treatment, a graft seems to improve not only the quality of life but also long-term patient survival. This study sought to analyze the impact of recipient age older than 60 years on patient and graft outcomes. MATERIALS AND METHODS: We retrospectively investigated the outcomes of 761 kidney transplant recipients from cadaveric donors performed between February 1998 and July 2011. While 69 subjects were at least 60 years of age (group A), 692 were younger than 60 years (group B) at the time of transplantation. RESULT: Mean follow-up was 60.1 ± 38.5 months. Delayed graft function (DGF) requiring dialysis was observed in 36 group A (52.1%) and 205 group B (29.6%) subjects (P = .001). However, there were also significant differences between group A and group B in terms of mean donor age (60.3 vs 44.6 years; P < .001) and mean donor estimated creatinine clearance (57.8 vs 83.4 mL/min; P < .001). There were no significant differences in death-censored graft survival between the two groups, but elderly patients experienced worse survival (P = .0005). The most common causes of patient death were myocardial infarction, other cardiovascular complications, and tumors. CONCLUSION: Kidney transplantation is a good option for elderly recipients with end-stage renal disease, providing long graft survival and a good quality of life, although these patients are more likely to develop cancer or cardiovascular disease. Our findings suggested that older patients should not be excluded a priori from transplantation, but meticulous screening for cancer and heart disease should be always be performed to improve outcomes.

Middle and long-term outcomes of dual kidney transplant: a multicenter experience.

INTRODUCTION: Dual kidney transplantation (DKTx) to reduce the disparity between demand and supply of organs was evaluated in two Italian centers (Bari and Novara). MATERIALS AND METHODS: Between October 2000 and October 2011, we performed 97 DKT (26 ipsilateral/71 bilateral) following routine biopsy of all kidneys obtained from expanded criteria donors by Remuzzi-Karpinsky scores. The reference group was 379 single grafts from donors older than 60 years single kidney transplantation ([SKT] × > 60). RESULTS: Good postoperative renal function was observed in 56 DKTx (57.7%); whereas acute tubular necrosis requiring dialysis was observed in 41 (42.3%) patients. After a mean follow-up of 60 months, DKTx graft survivals were 96%, 93%, and 90% and patient survivals, 96%, 91%, and 91% at 1, 3, and 5 years, respectively. Complications in expanded criteria donor kidney transplantations included a high rate of cytomegalovirus (CMV) disease especially dual kidney cases. DKTx represented the only independent risk factor for CMV disease upon multivariate analysis (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.28-4.2; P = .006). We did not observe any significant difference in graft or patient survival between DKTx and SKTx > 60 years. CONCLUSIONS: We observed good outcomes up to 5 years after transplantation in terms of graft and patient survival despite the use of inferior grafts. Comparing DKTx and SKT > 60, we noted that the mean Karpinski score for SKTx was significantly better than DKTx, although patient and graft survivals were similar. This trend confirms that the use of a biopsy to allocate expanded criteria donor kidneys may be too protective; therefore, the criteria to select DKTx require further refinement.

Allograft nephrectomy: what is the best surgical technique?

BACKGROUND: The objective of this study was to evaluate differences in outcomes of allograft nephrectomies performed by extracapsular versus intracapsular techniques. METHODS: From 1993 to 2010, we performed 89 allograft nephrectomies, including 57 by extracapsular techniques and 32 by intracapsular, chosen according to feasibility at the beginning of the surgery. Fisher exact test and logistic regression were used for statistical analysis. Survival estimates after allograft nephrectomy were calculated according to the Kaplan-Meier method. RESULTS: After a mean graft survival of 49.7 months, the indications for transplant nephrectomy were chronic rejection (39.3%), acute rejection (22.5%), infection/sepsis (19.1%), gross hematuria (6.7%), renal vein thrombosis (6.7%), renal artery thrombosis (3.4%), and graft rupture (2.3%). Mean operative time, blood loss, transfusions, and complications were similar between the extracapsular and intracapsular groups. The only difference in surgical aspects between the 2 groups was the mean hospital stay, which was longer for the extracapsular group (13.8 vs 7.6 days; P = .01), a result that was confirmed by multivariate analysis (odds ratio, 1.05; 95% confidence interval, 1.0-1.1; P = .03). CONCLUSIONS: Our experience showed no significant advantages in favor of the intracapsular technique except for a shorter length of hospital stay than after the extracapsular procedure.

Extended criteria donor kidney transplantation: comparative outcome analysis between single versus double kidney transplantation at 5 years.

INTRODUCTION: Dual 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. MATERIALS AND METHODS: We 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. RESULTS: Delayed 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. CONCLUSIONS: ECD 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.

ID2-VEGF-related pathways in the pathogenesis of Kaposi's sarcoma: a link disrupted by rapamycin.

The Id-proteins are a family of four related proteins implicated in the control of differentiation and cell-cycle progression. Down-regulation of Id-gene expression is essential for the differentiation of several cell types. In addition, deregulated Id2 activity inhibits the Rb tumor suppressor pathway and promotes the expression of vascular endothelial growth factor (VEGF). Several members of VEGF family could be involved in Kaposi's sarcoma (KS) development and progression. Lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) is the first marker of lymphatic endothelial competence during development in the mature vasculature, and is also expressed on KS spindle cells. Rapamycin (RAPA), an immunosuppressive drug, has been shown to reverse KS growth and to reduce tumor angiogenesis. We evaluate, in transplantation-associated KS and in cultured KS-cells the RAPA effect on Id2 and on de novo lymphangiogenesis. Markers of lymphatic-endothelial-cells (VEGFR-3, LYVE-1) and Id2, expressed at low levels within the normal skin, were up-regulated in KS and returned to normal levels after RAPA introduction. The association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and LYVE-1. RAPA inhibition on Id2 expression was confirmed in vitro in KS-cells, both in basal conditions and upon stimulation with VEGF. In conclusion, our data would suggest a novel molecular mechanism for the antineoplastic effects of RAPA in posttransplant KS.

The ratio of epidermal growth factor to monocyte chemotactic peptide-1 in the urine predicts renal prognosis in IgA nephropathy.

The production of cytokines by resident and non-resident renal cells during immunoglobulin A nephropathy (IgAN) plays a key role in the progression of renal damage. The aim of this study was to determine if measurements of urinary epidermal growth factor (EGF) and monocyte chemotactic peptide-1 (MCP-1), at the time of renal biopsy, were a predictor of end-stage renal disease (ESRD) in a cohort of 132 patients with biopsy-proven IgAN. Outcome measures were a doubling of the baseline serum creatinine (sCr) and/or ESRD. Patients with ratios of EGF/MCP-1 in the lowest tertile had a significant decline in renal survival, while patients in the highest tertile maintained 100% renal survival at 48 and 84 months of follow-up. Multivariate Cox's regression analysis showed that the urine EGF/MCP-1 ratio was an independent prognostic factor and indirectly correlated with the combined outcome. The predictive value was also measured by the area under the receiver operating characteristic curve (ROC). The area of the EGF/MCP-1 ratio was significantly higher than that of EGF or MCP-1 alone, histologic grade, creatinine clearance, or proteinuria. Our study suggests that the urinary EGF/MCP-1 ratio may be used as a prognostic marker of ESRD for patients with IgAN.

[Pro and anti-neoplastic effects of immunosuppressive drug in renal transplantation]. / Effetti pro ed anti-neoplastici dei principali farmaci immunosoppressori usati nella pratica clinica trapiantologica.

The increased efficiency of immunosuppressive drugs obtained in the last few years has significantly reduced the incidence of acute rejection, prolonging transplant survival rates. The inevitable trade-off was however an increased rate of post-transplant infections and malignancies. Furthermore, this problem might get more and more serious in the next future due to the increasing incidence of cancer in immunosuppressed transplant recipients; the introduction of new immunosuppressive strategies is expected to extend significantly allograft survival. The inclusion of older recipients in transplant programs will also likely increase this problem. Thus, cancer may represent a serious cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. Nevertheless, effective approaches to deal with malignancies in immunosuppressed patients are still far from the clinical arena. Therefore, once cancer occurs in a transplant recipient, clinicians only have two options: to reduce or withdraw the immunosuppression eventually causing acute or chronic allograft rejection, or to continue the standard immunosuppressive therapy while beginning specific therapy for the malignancy. Several clinical studies suggest that the use of immunosuppressive drugs may result in increased cancer incidence, in transplant as well as autoimmune disease patients. This clinical observation is supported by experimental data showing that these drugs enhance cancer cell growth characteristics and inhibit DNA repair mechanisms, clearly suggesting that the increased incidence of neoplastic disease in patients treated with several immunosuppressive drugs is at least partially independent of their immunosuppressive action. In this scenario it is of particular interest the fact that some immunosuppressive drugs have both an anti-rejection and anti-neoplastic activity. In this review we focus our attention on this potential dual role of immunosuppressive therapy in the development of neoplasia in transplanted patients.

Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection.

The role of hepatitis C virus (HCV) in the production of renal injury has been extensively investigated, though with conflicting results. Laser capture microdissection (LCM) was performed to isolate and collect glomeruli and tubules from 20 consecutive chronically HCV-infected patients, namely 6 with membranoproliferative glomerulonephritis, 4 with membranous glomerulonephritis, 7 with focal segmental glomerulosclerosis and 3 with IgA-nephropathy. RNA for amplification of specific viral sequences was provided by terminal continuation methodology and compared with the expression profile of HCV core protein. For each case two glomeruli and two tubular structures were microdissected and processed. HCV RNA sequences were demonstrated in 26 (65%) of 40 glomeruli, but in only 4 (10%) of the tubules (P < 0.05). HCV core protein was concomitant with viral sequences in the glomeruli and present in 31 of the 40 tubules. HCV RNA and/or HCV core protein was found in all four disease types. The immunohistochemical picture of HCV core protein was compared with the LCM-based immunoassays of the adjacent tissue sections. Immune deposits were detected in 7 (44%) of 16 biopsy samples shown to be positive by extraction methods. The present study indicates that LCM is a reliable method for measuring both HCV RNA genomic sequences and HCV core protein in kidney functional structures from chronically HCV-infected patients with different glomerulopathies and provides a useful baseline estimate to define the role of HCV in the production of renal injury. The different distribution of HCV RNA and HCV-related proteins may reflect a peculiar 'affinity' of kidney microenvironments for HCV and point to distinct pathways of HCV-related damage in glomeruli and tubules.

[HCV+ patients on the waiting list for kidney transplantation. Retrospective analysis of data on the patient population with hepatitis C on the waiting list for kidney transplantation in the setting of the AIRT]. / Pazienti HCV+ in lista d'attesa per trapianto renale. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti affetti da epatite C in lista d'attesa per trapianto di rene in ambito AIRT.

BACKGROUND: HCV infection in hemodialysis is still a matter of debate from an epidemiological and clinical point of view. Evaluation criteria for HCV-infected patients as transplant candidates are still not adequately standardized. Aims of the present study were to investigate: 1. the percentage of HCV positive patients on the waiting list of three Italian regions belonging to the Associazione InterRegionale Trapianti (AIRT); 2. to analyze the clinical approach in the evaluation of these patients in the attempt to define national guidelines for their pre- and post-transplant management. PATIENTS: We evaluated 2045 uremic patients on the waiting lists of four transplant centers (Bari, Bologna, Modena, Novara) belonging to AIRT at 31/12/2002. RESULTS: The overall prevalence of HCV positive patients was 14.2%, with a peak in the Puglia waiting list. The most common screening tests were AST and ALT serum levels and viral load (HCV RNA). Although there is a clear evidence that histological parameters are the main diagnostic and prognostic markers, a liver biopsy was performed in only 9.5% of patients. An even smaller percentage of HCV-infected patients underwent anti-viral therapy. CONCLUSIONS: Our retrospective analysis evidenced the need to improve common clinical strategies in approaching HCV-infected canditates to renal transplantation in the attempt to improve their post-transplant outcome.

[Malignant neoplasia and kidney transplantation. Retrospective analysis of data on the population having kidney transplantation with de novo neoplasia in the setting of the AIRT]. / Trapianto renale e neoplasie. Analisi retrospettiva dei dati relativi alla popolazione dei trapiantati di rene affetti da neoplasie de novo in ambito AIRT.

BACKGROUND: In transplanted patients undergoing immunossuppressive therapy the incidence of malignant neoplasia is 3-4 times higher than in the general population. Aim of the present study was to evaluate the prevalence of different tumours and the links between modulation of immunosuppressive therapy and patient and graft survival. PATIENTS: We evaluated 2029 kidney-transplanted patients from four Transplant Centres (Bari, Bologna, Modena, Novara) belonging to the Associazione InterRegionale Trapianti (AIRT). RESULTS: The incidence of neoplastic disease after transplantation was 3.9% in our population with a median time between transplantation and clinical onset of 23 months. We demonstrated a significant difference in the geographical distribution of different tumours. We did not observe any correlation with specific immunosuppressive drugs. Finally, dramatic reduction of the immunosuppression levels did not modify either the patients' or the graft's survival. CONCLUSIONS: Several factors can influence the post-transplant onset of neoplastic diseases with immunosuppressive therapy playing a pivotal role. The implementation of a National Registry would be the first step in an attempt to optimise immunosuppression in this particular group of patient's.

[Correlation between the onset of early proteinuria and the outcome of renal transplantation. Experience of a single centre]. / Correlazione tra insorgenza di proteinuria precoce e decorso clinico del rene trapiantato. Esperienza di un singolo centro.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. In chronic kidney transplant failure it is associated with poorer graft outcome. MATERIALS AND METHODS: In our Unit 405 renal transplants were performed between April 1992 and December 2001. We analysed 1) the main causes of post-transplant proteinuria and 2) the prognostic significance for graft outcome in patients with a minimum follow-up of 6 months. RESULTS: Early proteinuria was associated with a higher incidence of chronic allograft nephropathy (CAN) and de novo/recurrent nephropathies. Graft outcome was poorer in patients with early persistent proteinuria. CONCLUSIONS: Proteinuria after renal transplantation increases the risk of graft failure. We can, therefore, hypothesize that a graft biopsy is the best way to reveal the causes of proteinuria so that therapeutic interventions, which have been shown to reduce proteinuria, can be applied immediately.

[Herpetic viruses and renal transplantation]. / Virus erpetici e trapianto renale.

Over the last few years emerging evidence indicate the involvement of herpes viruses in the pathogenesis of several medical complications in transplanted patients. Herpes viruses are transmitted via inter-human contact and cause a primary infection, which commonly fails to give clinical signs and may persist even for years in a latent state in healthy subjects. In transplanted patients, herpes viruses may be transmitted through the transplanted organ or may be reactivated because of the use of powerful immunosuppressive drugs. Moreover, the persistence of immunosuppression greatly favours the clinical expression and severity of virus infection. Thus, herpes viruses seem to be involved in both acute and chronic deterioration of graft function, in the pathogenesis of post-transplant lymphoproliferative disorders and Kaposi sarcoma, and even in vessel atherosclerosis. This review will focus on relevant clinical aspects of herpes-virus infection, namely cytomegalovirus, EBV, herpes simplex 1 and 2, varicella zoster virus, HHV-6, HHV-7 and HHV-8, in kidney transplanted patients.

Prospective randomized controlled multicenter trial on steroids plus ramipril in proteinuric IgA nephropathy.

Recent studies have shown that steroids improve renal survival and reduce proteinuria in IgA nephropathy (IgAN) patients with moderate urinary protein excretion and normal renal function. However, this effect seems to diminish over time. Moreover, it has been demonstrated that long-term use of ramipril reduces the risk of end-stage renal disease in proteinuric diabetic and non-diabetic chronic nephropathies. We have planned a long-term unblinded, prospective, centrally randomized, controlled, multicentric trial to assess whether combined treatment of steroids and ramipril is superior to ramipril alone in patients with progressive IgAN disease. A minimum of 134 patients with biopsy-proven IgAN, grade G3 or G4, daily proteinuria > 1.0 g and creatinine clearance > 50 mL/min will be enrolled during a 2-year recruitment period. The patients will be allocated randomly to receive a six-month course of oral prednisone (1.0 mg/Kg/day for 2 months, tapered by 0.2 mg/Kg/day every month) plus ramipril (2.5 mg/day for one month, increased by 1.25 mg/day every month to achieve and maintain a blood pressure less than 120-80 mm Hg and/or to reduce daily proteinuria to 1.0 g or less or by at least 50%) in the experimental group or ramipril alone in the control group. Ramipril will be administered during the whole 5-year follow-up period in both groups. The primary endpoint will be renal survival estimated by 50% increase in baseline serum creatinine; the secondary endpoints will be urinary protein and cytokine excretion and side-effects. Analyses will be done by intention to treat. A p <0.05 will be taken as significant.

Fibrin down-regulates LPS- and PMA-induced tissue factor expression by blood mononuclear cells.

Several studies indicate that fibrin may play a functional role in inflammation by modulating a variety of cellular functions. We investigated the effect of fibrin on tissue factor (TF) production by blood mononuclear cells (MNC). Citrated human blood was recalcified and incubated at 37 degrees C for 1-4 h. The resulting clot was lysed by the addition of tissue plasminogen activator (t-PA) and MNC were isolated by density gradient centrifugation. A control blood sample was processed in the same way but omitting calcium addition and clot formation. Clot- and blood-derived MNC did not express detectable TF activity and antigen whatever the incubation time. Clot-derived MNC, however, generated on average 5 fold less TF (activity and antigen) than control cells, when stimulated with lipopolysaccharide (LPS, I microg/ml) for 3 h at 37 degrees C. A reduced TF response of clot-derived cells was also observed at mRNA level as indicated by RT-PCR and in situ hybridization. The effect was dependent on the incubation time within the clot, could not be reversed by enhancing LPS concentration or by adding serum, and was maintained if LPS was replaced by the tumor promoter PMA. A reduced TF response was also found when washed MNC were incorporated for 1 h at 37 degrees C within purified fibrin but not when the cells were incubated with fibrinogen, thrombin or fibrin split products alone. indicating that contact with fibrin was responsible for the inhibition of TF production. Fibrin-induced down-regulation of TF response to LPS and PMA by MNC may represent a negative feed-back aimed at limiting excessive blood clotting activation in immunoinflammatory diseases.

Clinical relevance of cytokine production in hemodialysis.

Blood-dialyzer interaction in hemodialysis has the potential to activate mononuclear cells leading to the production of inflammatory cytokines. The extent of activation is dependent on the dialyzer material used and is considered an index of biocompatibility. Cytokines, such as interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6, may induce an inflammatory state and are believed to play a significant role in dialysis-related morbidity. The interleukin hypothesis suggests that the release of proinflammatory cytokines acts as an underlying pathophysiologic event in hemodialysis-related acute manifestations, such as fever and hypotension. Nevertheless, a cytokine overproduction may alter sleep pattern in chronic hemodialyzed patients, thus explaining the presence of sleep disorders in these patients. A potential role of cytokines in chronic-related morbidity has also been suggested. High levels of some inflammatory cytokines are often associated with anemia caused by hyporesponsiveness to erythropoietin. Cytokine production may also play a relevant role in bone remodeling by regulating osteoblast/osteoclast cell functions and parathyroid hormone (PTH). Finally, cytokine release may have a long-term deleterious effect on mortality of uremic patients by altering immune response and increasing susceptibility to infections. Bioincompatibility of dialytic membranes may also contribute to malnutrition in dialysis patients by increasing the monocyte release of catabolic cytokines such as TNF-alpha and IL-6. Bioincompatible dialytic treatment may induce an inappropriate monocyte activation and cytokine production, which, in turn, may mediate some of the immune and metabolic dysfunction associated with hemodialysis. The use of biocompatible dialytic membranes appears to reduce the monocyte activation and to improve the survival of hemodialysis patients.

MCP-1 and EGF renal expression and urine excretion in human congenital obstructive nephropathy.

BACKGROUND: Obstructive nephropathy is characterized at the histologic level by tubular atrophy and interstitial monocyte infiltration. The molecular mechanisms underlying these histologic changes are still poorly defined. Epidermal growth factor (EGF) produced by tubular cells seems to play a pivotal role in the modulation of tubular cell growth, while monocyte chemotactic peptide-1 (MCP-1) is a powerful and specific chemotactic and activating factor for monocytes. METHODS: Twenty-four patients with congenital ureteropelvic junction obstruction [UPJO; 10 with recurrent urinary tract infection (UTI) and 10 with no UTI] and 15 healthy children were studied. Diagnosis was made by renal ultrasound, intravenous pielography, and MAG3 scan. Urinary samples were collected before and after surgery. In 10 patients, urine was also collected directly from the affected pelvis at the time of surgery. Urinary EGF and MCP-1 levels were measured by enzyme-linked immunosorbent assay. MCP-1 and EGF gene expression were evaluated by in situ hybridization in 15 biopsies from congenital UPJO and in 10 normal kidneys. RESULTS: In normal kidneys, there was a high expression of EGF mRNA, whereas MCP-1 mRNA was undetectable. MCP-1 gene expression was strikingly increased at the tubulointerstitial level in UPJO biopsies compared with controls and was directly correlated with the extent of monocyte infiltration. In addition, UPJO kidney sections showed a marked reduction in EGF gene expression that was directly correlated with the degree of tubular damage. EGF urine concentration was significantly reduced in UPJO when compared with control and directly correlated with its renal gene expression. On the other hand, the MCP-1 urine concentration was strikingly increased in UPJO patients. It is noteworthy that a significant and inverse correlation was observed between the MCP-1 concentration in the urine collected from the obstructed pelvis and the MAG3 clearance of the obstructed kidney (r = -0.76). The presence of recurrent UTI was associated with a significantly higher MCP-1 excretion and a slight reduction in EGF urine concentration. The surgical correction of UPJO was followed by an improvement of renal function together with a significant reduction in MCP-1 excretion and a marked increase in EGF urine concentrations. Interestingly, EGF urine concentration measured before surgery was significantly correlated with the difference between the MAG3 clearance of the obstructed kidney before and after surgery. CONCLUSIONS: MCP-1 and EGF seem to be involved in the pathogenesis of tubulointerstitial damage in congenital obstructive nephropathy, and their urine excretion may represent a powerful prognostic marker in this form of renal disease.

Renal expression of monocyte chemotactic protein-1 and epidermal growth factor in children with obstructive hydronephrosis.

BACKGROUND/PURPOSE: The authors studied the potential role of ureteropelvic junction obstruction (UPJ-O) in causing progressive renal damage in children through the renal expression of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) mRNA. METHODS: Renal tissues were harvested from 11 children with UPJ-O and from 10 normal kidneys to study the renal expression of EGF and MCP-1 detected by means of in situ hybridization. Five of the patients were found to have a history of urinary tract infection (UTI). RESULTS: Children with UPJ-O had marked reduction of EGF gene expression when compared with controls. Interstitial expression of MCP-1 mRNA was present in all UPJ-O cases. Both EGF and MCP-1 expression did not correlate with age, with differential renal function, and with renal thickness measured through MAG3 renal scan. Children with a history of UTI had a more severe reduction of the renal thickness of the affected kidney compared with those without UTI. MCP-1 expression was higher and EGF more reduced in children with a history of UTI. CONCLUSIONS: Our results suggest a potential role of EGF and MCP-1 in the pathogenesis of renal damage and growth failure in UPJ-O, especially in children with UTI. These important functional changes begin early in life, possibly during fetal life.

Tissue factor, plasminogen activator inhibitor-1, and thrombin receptor expression in human crescentic glomerulonephritis.

Glomerular fibrin deposition is a common histological feature of crescentic glomerulonephritis (CGN). Tissue factor (TF) is the most powerful activator of the coagulation system, whereas plasminogen activator inhibitor (PAI)-1 is a key modulator of the fibrinolytic pathway. Thrombin, released locally as the final step of the coagulation cascade and trapped within the fibrin clots, can induce the activation of glomerular cells, through the interaction with a specific receptor. To investigate the mechanisms underlying coagulation cascade activation and fibrin deposition and the role of this phenomenon in the pathogenesis of human CGN, TF, PAI-1, and thrombin receptor expression were studied in CGN biopsy specimens. Glomerular TF gene and protein expression were strikingly increased in CGN, in particular within the crescents and in the mesangial area, with the same distribution of fibrin deposits. Interestingly, very few infiltrating mononuclear cells were stained in TF immunohistochemistry. To better evaluate the involvement of monocytes in TF expression, TF mRNA and CD68 protein were studied by an in situ hybridization/immunohistochemistry combined technique. Only 16% of the cells expressing TF mRNA were CD68 positive. However, most of the TF signal was localized in the proximity of monocytes, suggesting that soluble mediator(s) released by these cells could induce TF expression. Indeed, interleukin-1 (IL-1), one of the main monocyte-derived cytokines, upregulated TF mRNA levels in cultured human mesangial cells in a time-dependent manner. Moreover, a striking increase in IL-1 expression was present within the cellular crescents in CGN biopsy specimens. Finally, we observed a marked upregulation of both PAI-1 and thrombin receptor mRNA levels in CGN with a pattern resembling TF and fibrin distribution. Surprisingly, thrombin receptor protein expression was strikingly downregulated in CGN, suggesting its continuous activation and degradation. In conclusion, we can hypothesize that TF and PAI-1, mainly expressed by resident cells, may play a pivotal role in the development and preservation of fibrin deposits in CGN. In addition, thrombin, released locally and accumulated within the fibrin clots, may represent a pathogenetic mediator of crescentic lesions.