Recurrent IgA nephropathy after renal transplantation and steroid withdrawal.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis; the reported recurrence rate of IgAN after renal transplantation is as high as 13%-50%. The impact of immunosuppressive therapy and steroid withdrawal on the risk of recurrence of IgAN is still under debate. We performed a retrospective single-center study, selecting 123 kidney transplants (rtx) in 120 patients, between January 1995 and December 2012, with IgAN on the native kidney. In 51 of 123 transplants, at least one post-transplantation biopsy for clinical indication was performed; in 28 of 51 transplants, IgAN recurrence (IgANr) was demonstrated. This group (G1; N = 28) was compared with a group without IgANr (G2; N = 23). In our study, clinically evident IgANr rate was 54.9% (28/51) on biopsied patients. At discharge, the use of the immunosuppressant drugs (tacrolimus, cyclosporine A, mycophenolate mofetil, azathioprine, mTor inhibitors) was not associated with an increased risk of IgANr (P = NS). At discharge, all patients were steroid treated. Neither the use of tacrolimus, mycophenolate mofetil, nor mTor inhibitors (mTori) at biopsy time were associated with IgANr. However, IgANr was significantly higher in patients who experienced steroid withdrawal at any post-transplantation time (OR 7.7 P = .03). The median time to recurrence after steroid withdrawal was 59 months (min 4.18, max 113.2).

Treatment protocol with pulse and oral steroids for IgA Nephropathy after kidney transplantation.

BACKGROUND: No specific treatment for IgA nephropathy (IgAN) after kidney transplantation is currently available. METHODS: We conducted a retrospective single-center study on 29 patients with biopsy-proven de novo and recurrent IgAN after kidney transplantation, divided into two groups. Group 1 (n = 16) received intravenous methylprednisolone 500 mg per day for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for 6 months. The control group (n = 13, Group 2) received supportive therapies. RESULTS: The two groups were comparable for serum creatinine (sCr) and proteinuria at the time of renal biopsy, but differed significantly at the end of follow-up. sCr was 1.8 ± 0.4 mg/dl in Group 1 vs. 2.7 ± 0.9 in Group 2 (p = 0.002), and proteinuria was 0.9 g/day in Group 1 vs. 1.9 in Group 2 (p = 0.04). The composite outcome of death-censored graft loss or doubling of sCr displayed 2 events in Group 1 (12.5 % of the entire group) and 5 events in Group 2 (38.5 % of the entire group), p = 0.19, odds ratio (OR) 4.4 [95 % confidence interval (CI) 0.7-27.8]. CONCLUSIONS: In the absence of therapeutic guidelines for de novo or recurrent IgAN after kidney transplantation, our study reports that therapy with pulse and oral steroids for 6 months is associated with an improved renal function. Nevertheless, further randomized controlled studies in larger patient cohorts are necessary to establish the gold standard treatment.

Lymphatic disorders after renal transplantation: new insights for an old complication.

In renal transplanted patients, lymphoceles and lymphorrhea are well-known lymphatic complications. Surgical damage of the lymphatics of the graft during the procurement and of the lymphatic around the iliac vessels of the recipients has been associated with development of lymphatic complications. However, lymphatic complications may be related to medical factors such as diabetes, obesity, blood coagulation abnormalities, anticoagulation prophylaxis, high dose of diuretics, delay in graft function and immunosuppressive drugs. Consistently, immunosuppression regimens based on the use of mTOR inhibitors, especially in association with steroids and immediately after transplantation, has been associated with a high risk to develop lymphocele or lymphorrhea. In addition, several studies have demonstrated the association between rejection episodes and lymphatic complications. However, before the discovery of reliable markers of lymphatic vessels, the pathogenic mechanisms underlining the development of lymphatic complications during rejection and the influence of mTOR inhibitors remained not fully understood. The recent findings on the lymphatic systems of either native or transplanted kidneys together with the advances achieved on lymphangiogenesis shared some lights on the pathogenesis of lymphatic complications after renal transplantation. In this review, we describe the surgical and medical causes of lymphatic complications focusing on the rejection and immunosuppressive drugs as causes of lymphatic complications.

Neutrophil Gelatinase Associated Lipocalin Is an Early and Accurate Biomarker of Graft Function and Tissue Regeneration in Kidney Transplantation from Extended Criteria Donors.

BACKGROUND: Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD. METHODS: We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction. RESULTS: Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio). CONCLUSIONS: NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.

Relationship among C1q-fixing de novo donor specific antibodies, C4d deposition and renal outcome in transplant glomerulopathy.

BACKGROUND: The C1q-binding properties of donor specific antibodies (DSA) may be related to antibody-mediated rejection and poor outcome. METHODS: We retrospectively studied 35 kidney transplant recipients with transplant glomerulopathy (TG) and de novo DSA (dnDSA). C1q dnDSA were measured in the serum stored at renal biopsy and the association among C1q-fixing dnDSA, C4d deposition and graft loss was examined. RESULTS: Of the 35 patients with dnDSA and TG, 15 (42.9%) had C1q-positive dnDSA and 20 (57.1%) had C1q-negative dnDSA. Ten out of 15 patients with C1q-positive dnDSA (66.6%) and 5 with C1q-negative dnDSA (25%) had C4d positive staining renal biopsies (P=0.02), being the C1q-negative dnDSA/C4d-negative TG 42.9% of the total. The C1q-positive dnDSA group has significantly higher IgG DSA Class II MFI than the C1q-negative dnDSA group (P=0.004). Patients with C4d deposits have significantly higher IgG DSA MFI for both Class I and Class II than those without C4d deposits (P=0.02). We found a trend toward higher graft loss in the C1q-positive dnDSA group (60%) versus the C1q-negative dnDSA group (40%) without a statistical significance (P=0.31). CONCLUSION: Our study provides further characterization of TG associated with dnDSA. The major part of dnDSA-associated TG was C1q-negative and the presence of C1q-fixing dnDSA did not significantly correlate with graft outcome.

Mitochondrial neurogastrointestinal encephalomyopathy treated with peritoneal dialysis and bone marrow transplantation.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disease caused by thymidine phosphorylase deficiency which leads to toxic accumulations of thymidine (dThd) and deoxyuridine (dUrd). It lacks an established treatment and the prognosis is traditionally poor. We report a case of a young female patient with normal renal function and MNGIE treated by peritoneal dialysis (PD) and allogeneic bone marrow transplantation (BMT). PD was effective in reducing dThd and dUrd plasma levels and in improving clinical symptoms. To our knowledge, this is the first report on the beneficial effects of PD regarding MNGIE neurological symptoms. PD, therefore, should be considered especially in medically compromised patients as a supportive treatment to improve clinical conditions before BMT.

Pulmonary toxicity in a renal transplant recipient treated with amiodarone and everolimus: a case of hypothetical synergy and a proposal for a screening protocol.

Pneumotoxic drugs like amiodarone and m-TOR inhibitors (m-TORi) may be administered contemporaneously in therapy for patients who had renal transplants. We present a case of amiodarone pulmonary toxicity (APT) in a patient treated with amiodarone and everolimus. A 57-year-old Caucasian male, under treatment with both everolimus (for 3 years) and amiodarone (for 2 months), presented with fever, dyspnoea and a negative chest X-ray after his second kidney transplant with suboptimal serum creatinine (3 mg/dl). A non-contrastive high-resolution CT scan showed bilateral interstitial lung disease with an associated reduction in carbon monoxide diffusing capacity. Bronchoalveolar lavage (BAL) was negative for an infection, but BAL cytology was suitable for APT (50% of 'foamy' macrophages). A complete recovery was achieved after amiodarone interruption and an oral steroid therapy increase. Everolimus was continued. His kidney function remained unchanged in the upcoming months. In conclusion, we suggest a possible synergistic effect between m-TORi and amiodarone. Furthermore, we propose a diagnostic algorithm that can be used as a surveillance tool to identify a potential initial lung damage in patients treated with 1 or more pneumotoxic drugs.

Phosphodiesterase type 5 inhibitor treatment for erectile dysfunction in patients with end-stage renal disease receiving dialysis or after renal transplantation.

INTRODUCTION: The phosphodiesterase type 5 (PDE5) inhibitors are generally well tolerated and effective for treating erectile dysfunction (ED), including in patients with significant comorbidity. Because of this benign safety profile, investigators have used PDE5 inhibitors to treat patients with ED and severe renal disease or those who have received renal transplants. AIM: To assess safety and efficacy of PDE5 inhibitors in patients receiving dialysis or renal transplants. MAIN OUTCOME MEASURES: Erectile function as assessed by the International Index of Erectile Function (IIEF) and Global Assessment Questions; adverse events (AEs). METHODS: We reviewed published studies of PDE5 inhibitors in patients receiving dialysis or renal transplants. RESULTS: In double-blind, placebo-controlled studies in patients receiving dialysis or renal transplants, sildenafil significantly improved erectile function as assessed by the IIEF, and 75-85% of patients reported improved erectile function on Global Assessment Questions; efficacy was more variable in less well-controlled studies. In >260 patients undergoing dialysis who received sildenafil in clinical studies, there were only six reported discontinuations because of AEs (headache [N=3], headache and nausea [N=1], gastrointestinal [N=1], and symptomatic blood pressure decrease [N=1]). In approximately 400 patients with renal transplants who received sildenafil, only three patients discontinued because of AEs. Vardenafil improved IIEF scores of up to 82% of renal transplant recipients in randomized, controlled studies (N=59, total), with no reported discontinuations because of AEs. Limited data also suggest benefit with tadalafil. CONCLUSIONS: ED is common in patients undergoing renal dialysis or postrenal transplant and substantially affects patient quality of life. Sildenafil and vardenafil appear to be efficacious and well tolerated in patients receiving renal dialysis or transplant.

Different regulatory and cytotoxic CD4+ T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function.

Comparative analysis of the different subsets of CD4(+) T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed peripheral regulatory CD4(+) T cells (Tregs) and CD4(+) cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4(+)CD25(high) T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4(+)CD25(high) Foxp3(+) cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4(+)CD25(high) T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4(+)CD25(high) and CD4(+)Foxp3(+) T cells in the LTKT in respect to the other transplant groups. CD4(+)CD25(high)CD45RO(+) and CD4(+)Foxp3(+)CD45RO(+) regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4(+)CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4(+)CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4(+)CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development of immunologic events in kidney transplantation.

Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009.

To assess incidence and risk factors for de novo cancers (DNCs) after kidney transplant (KT), we carried out a cohort investigation in 15 Italian KT centres. Seven thousand two-hundred seventeen KT recipients (64.2% men), transplanted between 1997 and 2007 and followed-up until 2009, represented the study group. Person years (PY) were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis or to study closure. The number of observed DNCs was compared to that expected in the general population of Italy through standardised incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed. Three-hundred ninety five DNCs were diagnosed during 39.598PYs, with Kaposi's sarcoma (KS), post-transplant lymphoproliferative disorders (PTLD), particularly non-Hodgkin' lymphoma (NHL), lung, kidney and prostate as the most common types. The overall IR was 9.98/1.000PY, with a 1.7-fold augmented SIR (95% CI: 1.6-1.9). SIRs were particularly elevated for KS (135), lip (9.4), kidney carcinoma (4.9), NHL (4.5) and mesothelioma (4.2). KT recipients born in Southern Italy were at reduced risk of kidney cancer and solid tumors, though at a higher KS risk, than those born in Northern Italy. Use of mTOR inhibitors (mTORi) exerted, for all cancers combined, a 46% significantly reduced risk (95% CI: 0.4-0.7). Our study findings confirmed, in Italy, the increased risks for cancer following KT, and they also suggested a possible protective effect of mTORi in reducing the frequency of post transplant cancers.

A case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits after kidney transplant treated with plasmapheresis.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare and recently identified disease with a poor prognosis irrespective of the treatment. Recently, the possibility of recurrent or de novo PGNMID after kidney transplantation has been reported, which is associated with a better prognosis compared to PGNMID on native kidneys. Nevertheless, at present, due to the very few cases of recurrent PGNMID diagnosed, there is no proven effective treatment. Here, we report a case of recurrent PGNMID successfully treated with plasmapheresis, steroids and mycophenolate mofetil. Our report suggests that plasmapheresis might be a valid therapeutic option to treat recurrent PGNMID.

[Immunosuppressive treatment after kidney transplant: the frontier of chronic antibody-mediated rejection]. / Terapia immunosoppressiva nel trapianto renale: la frontiera del rigetto cronico anticorpo-mediato.

The recognition of antibody-mediated rejection as an important factor in the reduction of long-term renal graft survival represents a new challenge to the immunosuppressive strategies of recent years, which have been quite successful in reducing the acute rejection rates as well as the side effects of pharmacological immunosuppression. The search for an effective treatment of chronic anti-donor antibody disease has been pursued mostly through limited single-center experiences and therefore in a dispersed fashion, without leading to the definition of a consolidated approach. The most frequently used pharmacological approaches stem from the experience of antibody-mediated acute rejection. In this review we will critically analyze the results reported so far of various intervention strategies and we will discuss future pharmacological novelties targeting the humoral immune response.

Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets.

The efficacy of islet transplantation is limited by poor graft vascularization. We herein demonstrated that microvesicles (MVs) released from endothelial progenitor cells (EPCs) enhanced human islet vascularization. After incorporation into islet endothelium and ß-cells, EPC-derived MVs favored insulin secretion, survival, and revascularization of islets transplanted in SCID mice. MVs induced in vitro islet endothelial cell proliferation, migration, resistance to apoptosis, and organization in vessel-like structures. Moreover, MVs partially overcame the antiangiogenic effect of rapamycin and inhibited endothelial-leukocyte interaction via L-selectin and CD40. MVs were previously shown to contain defined patterns of mRNAs. Here we demonstrated that MVs carried the proangiogenic miR-126 and miR-296 microRNAs (miRNAs). MVs pretreated with RNase or derived from Dicer knocked-down EPCs showed a reduced angiogenic effect. In addition, MVs overcame the antiangiogenic effect of the specific antagomiRs of miR-126 and miR-296, suggesting a relevant contribution of miRNAs delivered by MVs to islet endothelium. Microarray analysis of MV-stimulated islet endothelium indicated the upregulation of mRNAs coding for factors involved in endothelial proliferation, differentiation, and angiogenesis. In addition, MVs induced the activation of the PI3K-Akt and eNOS signaling pathways in islet endothelium. These results suggest that MVs activate an angiogenic program in islet endothelium that may sustain revascularization and ß-cell function.

Anidulafungin treatment in a kidney transplant recipient with hepatic damage.

A 50-year old female was treated with anidulafungin after fluconazole treatment, for a complex clinical picture and immunosuppression. Anidulafungin was chosen when liver function test was abnormal in a setting of multiple causes of liver toxicity.

Skin cancers and other cutaneous diseases in renal transplant recipients: a single Italian center observational study.

Kidney transplant recipients frequently suffer from skin infections and malignancies, due to the effects of long-term immunosuppressive therapy. Herein, a dermatological screening was performed to evaluate the relationship between risk factors, cutaneous tumours and other skin diseases in a group of 282 kidney transplant patients. Infectious diseases (16.7%) were the most frequent dermatological disorders, whereas cutaneous inflammatory and autoimmune diseases were relatively rare, probably due to an indirect therapeutic role of immunosuppressive regimens. Thirty patients experienced cutaneous side effects from immunosuppressants, mainly when receiving corticosteroids (p = 0.0372). We identified 99 patients (35.1%) who developed cutaneous tumours after transplantation. Cumulative tumour incidence was observed during long-term immunosuppressive therapy; no relationships were identified between skin cancer risk and single class of drug or combination regimens. When we evaluated the eventual relevance of other risk factors for skin cancers, we demonstrated a statistical significance in univariate analysis for male gender, more advanced age at transplantation, long duration of immunosuppressive regimens, no sunscreen usage, outdoor job, absence of cherry angiomas and presence of actinic keratoses (AKs). Age at transplantation (p = 0.0174), presence of AKs (p = 0.0005) and duration of immunosuppression (p = 0.0011) also confirmed their significance in multivariate analysis.

[Lymphomatous renal involvement]. / Il coinvolgimento renale nei linfomi.

The incidence of lymphomas, especially non-Hodgkin's lymphoma (NHL), has shown a steady increase over the last decades. At the same time, the prognosis has improved. Given the longer survival of lymphoma patients, pathological manifestations related to malignancy might become more frequent. In this setting, the kidney is one of the most important solid organs affected by direct or indirect lymphomatous involvement. Kidney involvement can be related to obstruction or treatment-induced toxicity, but more intriguing are 1) direct infiltration (NHL); 2) renal malignancies in patients affected by Hodgkin's disease or NHL; 3) associated glomerular diseases. Primary infiltration is rarely seen, while secondary infiltration is described most frequently in autopsy series, even in the absence of renal failure. These alterations may mimic glomerular and/or interstitial disease. The association with kidney malignancies, mostly renal cell carcinoma but also urothelial tumors in Hodgkin''s disease, is higher in lymphoma patients than in the general population: the relative risk at 10 years is about 1.5. Glomerulonephritis is described in patients with Hodgkin's disease or NHL; in the former minimal change disease is most frequent, in the latter the glomerular pattern varies widely. Glomerulonephritis can precede, be concurrent with, or follow lymphoma manifestations. Renal biopsy is often needed in this setting.

Protective effect of resin adsorption on septic plasma-induced tubular injury.

INTRODUCTION: A pro-apoptotic effect of circulating mediators on renal tubular epithelial cells has been involved in the pathogenesis of sepsis-associated acute kidney injury (AKI). Adsorption techniques have been showed to efficiently remove inflammatory cytokines from plasma. The aim of this study was to evaluate the efficiency of the hydrophobic resin Amberchrom CG161 M to adsorb from septic plasma soluble mediators involved in tubular injury. METHODS: We enrolled in the study 10 critically ill patients with sepsis-associated AKI and we evaluated the effects of their plasma on granulocyte adhesion, apoptosis and functional alterations of cultured human kidney tubular epithelial cells. We established an in vitro model of plasma adsorption and we studied the protective effect of unselective removal of soluble mediators by the Amberchrom CG161 M resin on septic plasma-induced tubular cell injury. RESULTS: Plasma from septic patients induced granulocyte adhesion, apoptosis and altered polarity in tubular cells. Plasma adsorption significantly decreased these effects and abated the concentrations of several soluble mediators. The inhibition of granulocyte adhesion to tubular cells was associated with the down-regulation of ICAM-1 and CD40. Resin adsorption inhibited tubular cell apoptosis induced by septic plasma by down-regulating the activation of caspase-3, 8, 9 and of Fas/death receptor-mediated signalling pathways. The alteration of cell polarity, morphogenesis, protein reabsorption and the down-regulation of the tight junction molecule ZO-1, of the sodium transporter NHE3, of the glucose transporter GLUT-2 and of the endocytic receptor megalin all induced by septic plasma were significantly reduced by resin adsorption. CONCLUSIONS: Septic plasma induced a direct injury of tubular cells by favouring granulocyte adhesion, by inducing cell apoptosis and by altering cell polarity and function. All these biological effects are related to the presence of circulating inflammatory mediators that can be efficiently removed by resin adsorption with a consequent limitation of tubular cell injury.

'Bench' MRI before transplant on harvested kidneys: a possible tool for diagnosis of acute pyelonephritis.

We present the first case in which magnetic resonance imaging (MRI) has been utilized to rule out lesions compatible with acute pyelonephritis in kidneys from a cadaveric organ donor before transplanting them. A 40-year-old female underwent diagnosis of brain death following a septic shock. The ecotomography of the kidneys showed areas compatible with micro-abscesses raising the hypothesis of acute pyelonephritis. Our radiologist proposed to perform a bench-MRI (maintaining kidneys within the sterile preservation bags constantly on ice); this did not show lesions except little cysts not relevant by the clinical point of view. We transplanted kidneys without infective complications and results were very good.

B cell positive cross-match not due to anti-HLA Class I antibodies and first kidney graft outcome.

The effect of B cell cross-match (XM) was investigated in 680 first deceased-donor kidney transplants in a single centre from 1990 to 1999: 74 transplants presented a B-positive XM (Group 1) 606 had a B-negative XM (Group 2). The absence in Group 1 of weak/low-titre anti-HLA Class I antibodies was assured blocking anti-Class I reactivity by treating B cells with non-cytotoxic anti-beta2 microglobulin (alphabeta2 M) serum before XM. Graft survivals up to 5 years were not significantly different; some differences were nevertheless observed: HLA-A,B,DR mismatches influenced graft outcome in Group 1: patients with 0-2 mismatches had better survival than patients with 3-4. When analysed according DR mismatch, patients with 1 mismatch had worse graft survival than well matched patients (p<0.05). No significant difference depending on HLA match was observed in Group 2. Early acute rejection rate was similar in the Groups except the rejection episodes after one year: Group 1 had significantly more. 61/74 patients of Group 1 were retrospectively analysed for anti-HLA-DR,DQ reactivity: only 11/61 had anti-HLA-DR or DQ antibodies (3/11 were donor specific); graft survival and rejections were not significantly different in the patients with and without anti-HLA Class II antibodies. Anti-donor B cell reactivity, at XM, once excluded the presence of weak/low-titre anti-HLA Class I antibodies, did not influence first kidney graft survival.

Macrophage stimulating protein may promote tubular regeneration after acute injury.

Macrophage-stimulating protein (MSP) exerts proliferative and antiapoptotic effects, suggesting that it may play a role in tubular regeneration after acute kidney injury. In this study, elevated plasma levels of MSP were found both in critically ill patients with acute renal failure and in recipients of renal allografts during the first week after transplantation. In addition, MSP and its receptor, RON, were markedly upregulated in the regenerative phase after glycerol-induced tubular injury in mice. In vitro, MSP stimulated tubular epithelial cell proliferation and conferred resistance to cisplatin-induced apoptosis by inhibiting caspase activation and modulating Fas, mitochondrial proteins, Akt, and extracellular signal-regulated kinase. MSP also enhanced migration, scattering, branching morphogenesis, tubulogenesis, and mesenchymal de-differentiation of surviving tubular cells. In addition, MSP induced an embryonic phenotype characterized by Pax-2 expression. In conclusion, MSP is upregulated during the regeneration of injured tubular cells, and it exerts multiple biologic effects that may aid recovery from acute kidney injury.