Epidemiology, Treatment Patterns, and Cost Analysis of Immune Thrombocytopenia in Spain between 2014 and 2020: A Population-based Study.

Background Immune thrombocytopenia (ITP) is characterised by low platelet counts and often leads to bleeding, fatigue, and reduced health-related quality of life. Methods This observational, retrospective, population-based study using BIG-PAC® database included Spanish paediatric and adult patients with primary ITP diagnosed in primary care and hospitals between 2014 and 2020 (median follow-up: 4 years). Epidemiology, baseline/clinical characteristics, treatment trends, healthcare resources and costs were analysed. Results The BIG-PAC® database contains records of 1,818,588 patients; 170 adults and 27 children with ITP were included in our analysis. ITP prevalence and annual incidence per 100,000 were estimated in 10.8 (2.8 in chronic ITP [cITP] patients) and 1.5 (0.3 in cITP patients), respectively. Epistaxis was the most common bleeding event, followed by genitourinary and gastrointestinal bleeding; >50%/> 75% of ITP/cITP patients reported fatigue. Chronic patients had lower platelet counts at baseline and required more transfusions. Corticosteroids, immunosuppressants, and thrombopoietin receptor agonists were the most used agents in first-, second- and third-line treatment, respectively. Thirty-five patients, all of them in chronic phase, underwent splenectomy. Patients had on average 13.9, 6.6, and 1.2 visits/year to primary care, haematology/internal medicine, and emergency departments, respectively. More than one-fourth of adult patients took on average 16.3 days of sick leave annually. Mean annual total health care costs were €10,741 (ITP patients) and €19,809 (cITP patients). Conclusion This is the first study to provide an overall perspective on the situation of the Spanish ITP population in terms of epidemiology, treatment trends, health care resources and costs, highlighting unmet patient needs, and direct and indirect costs/resource use between 2014 and 2020.

The hepatocyte growth factor mimetic, ANG-3777, in kidney transplant recipients with delayed graft function: Results from a randomized phase 3 trial.

In kidney transplant recipients, delayed graft function increases the risk of graft failure and mortality. In a phase 3, randomized, double-blind, placebo-controlled trial, we investigated the hepatocyte growth factor mimetic, ANG-3777 (once daily for 3 consecutive days, starting ≤30 hours posttransplant), in 248 patients receiving a first kidney transplant from a deceased donor. At day 360, estimated glomerular filtration rate (primary endpoint) was not significantly different between the ANG-3777 and placebo groups. There were no significant between-group differences in the duration of dialysis through day 30 or in the percentage of patients with an estimated glomerular filtration rate of >30 mL/min/1.73 m2 at day 360. The incidence of both delayed graft function and acute rejection was similar between ANG-3777 and placebo groups (68.5% vs 69.4% and 8.1% vs 6.5%, respectively). ANG-3777 was well tolerated, and there was a numerically lower incidence of graft failure versus placebo (3.2% vs 8.1%). Although there is insufficient evidence to support an indication of ANG-3777 for patients at risk of renal dysfunction after deceased-donor kidney transplantation, these findings indicate potential biological activity that may warrant further investigation.

Efficacy, safety, usability, and acceptability of risankizumab 150 mg formulation administered by prefilled syringe or by an autoinjector for moderate to severe plaque psoriasis.

BACKGROUND: Risankizumab is approved for treatment of moderate to severe plaque psoriasis. Availability of a patient-controlled single self-injection of risankizumab may improve adherence and long-term management of psoriasis. OBJECTIVE: To investigate efficacy, safety, and usability of a new risankizumab 150 mg/mL formulation administered as a single subcutaneous injection via prefilled syringe (PFS) or autoinjector (AI). METHODS: Efficacy, safety, usability, and acceptability of risankizumab 150 mg/mL PFS or AI were investigated in adults with moderate to severe psoriasis in two phase 3 studies. Study 1 was a multicenter, randomized, double-blinded, placebo-controlled study that investigated 150 mg/mL risankizumab PFS; study 2 was a multicenter, single-arm, open-label study that investigated 150 mg/mL risankizumab AI. RESULTS: At week 16, risankizumab 150 mg/mL demonstrated efficacy vs. placebo (Psoriasis Area and Severity Index ≥90% improvement (PASI 90), 62.9% vs. 3.8%; static Physician Global Assessment (sPGA) 0/1, 78.1% vs. 9.6%; both p< .001) in study 1; in study 2, PASI 90 and sPGA 0/1 were 66.7%, and 81.5%, respectively. All patients successfully self-administered study treatments via PFS or AI. Acceptability of self-injection was high in both studies. Efficacy and safety of risankizumab 150 mg/mL were comparable with results from previous risankizumab phase 3 studies using the 90 mg/mL formulation. CONCLUSIONS: The efficacy, safety, and usability of 150 mg/mL risankizumab delivered as a single PFS or AI injection support use of this new formulation in patients with moderate to severe plaque psoriasis. CLINICAL TRIALS: NCT03875482 and NCT0387508.

Efficacy and safety of risankizumab for active psoriatic arthritis: 24-week results from the randomised, double-blind, phase 3 KEEPsAKE 2 trial.

OBJECTIVES: Risankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to ≤2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here. METHODS: Adults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved ≥20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes. RESULTS: A total of 444 patients (median age 53 years, range 23-84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p<0.001) and all secondary endpoints (p<0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively. CONCLUSION: Treatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR. TRIAL REGISTRATION NUMBER: NCT03671148.

A Qualitative Research for Defining Meaningful Attributes for the Treatment of Inflammatory Bowel Disease from the Patient Perspective.

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBD). Each class and type of medication available for the treatment of IBD has distinct characteristics and long-term effects that a patient may consider. We present the results of qualitative research that aimed to develop a descriptive framework that outlines the most relevant disease and/or treatment attributes for IBD treatment decisions and focuses on the patient perspective. METHODS: This research employed a three-step approach: a literature review to identify a broad list of attributes, a focus group meeting including patients and clinicians to assess the relevance of the attributes, and two rounds of voting to name and define each attribute. The literature review was used to develop the initial list of attributes. Although the same attributes were defined for both UC and CD, the relative importance of each attribute to UC or CD was considered. The list of attributes was discussed and evaluated in the focus group meeting, which included eight patient representatives and nine gastroenterologists. Using feedback elicited from the focus group meeting, the research team developed a draft of the descriptive framework that grouped the attributes into domain subsets. All members of the focus group participated in two subsequent rounds of structured, online voting, which was used to refine the wording to name and define each attribute. Additionally, participants ranked all the attributes included in the descriptive framework to suggest which attributes were less relevant and could be omitted. RESULTS: Among 574 publications retrieved from the databases and registries, we identified 32 eligible publications, and an initial list of attributes was developed. This list was refined during the focus group meeting, resulting in a draft descriptive framework of attributes within subsets of domains. The final descriptive framework was developed based on structured rounds of online voting to further refine attribute names and definitions. In the final descriptive framework, a total of ten attributes were identified: abdominal pain, other disease-related pain, bowel urgency, fatigue, risk of cancer and serious infections within the next 10 years, risk of mild to moderate complications, aesthetic complications related to treatment, emotional status, sexual life, and social life and relationships. These attributes were distributed across three domains: efficacy, complications and risk, and health-related quality of life. CONCLUSIONS: Through the identification of the ten most relevant attributes that influence patient decision making for IBD treatments, we developed a descriptive framework that should be considered by physicians when discussing IBD treatment options with their patients. The results of our qualitative research may also be helpful for the development of future IBD clinical studies and quantitative research.

Adalimumab Effectiveness Up to Six Years in Adalimumab-naïve Patients with Crohn's Disease: Results of the PYRAMID Registry.

BACKGROUND: PYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice. METHODS: Adult patients with moderately to severely active Crohn's disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician's Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration. RESULTS: This study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (≥7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low. CONCLUSION: Adalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed.

The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn's disease: a post hoc analysis.

BACKGROUND: In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. AIM: To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. METHODS: Patients 6-17 years old with moderate-to-severe Crohn's disease (n = 192) received weight-based adalimumab induction at baseline and week 2. At week 4, 188 patients were randomised to high-dose or low-dose adalimumab. Patients receiving immunomodulators (investigator's decision) at baseline maintained a stable dose until week 26; patients could then discontinue immunomodulators. Adalimumab serum concentrations were measured at weeks 4, 26 and 52. Safety was evaluated at each study visit. Data were analysed using non-responder imputation (NRI; week 4) or modified NRI (weeks 26; 52). RESULTS: At week 4, patients with (n = 117) and without (n = 71) baseline immunomodulator use had similar response (79%; 87%; P = 0.235) and remission (26%; 30%; P = 0.737) rates. At week 26, patients with and without baseline immunomodulators had no significant difference in response (68%; 55%; P = 0.086) or remission (41%; 30%; P = 0.122). At week 52, patients with (n = 82) and without (n = 106) immunomodulator use had no significant difference in response (56%; 46%; P = 0.189) or remission (38%; 33%; P = 0.539). Adalimumab serum trough concentrations and serious infection rates (7%; 6%) were not significantly different between groups. CONCLUSIONS: Analyses found no statistically significant difference in response or remission between patients receiving adalimumab monotherapy vs immunomodulator and adalimumab combination therapy. Serious and infectious adverse event rates were similar between groups.

Lymphoma Risk and Overall Safety Profile of Adalimumab in Patients With Crohn's Disease With up to 6 Years of Follow-Up in the Pyramid Registry.

OBJECTIVES: Real-world, prospective, long-term studies in Crohn's disease (CD) characterizing adalimumab safety data and lymphoma risk were lacking. We present the final results from the PYRAMID registry, which was designed to rule out a doubling of lymphoma risk in adalimumab-treated patients with CD. METHODS: Patients with moderately to severely active CD newly prescribed or currently receiving adalimumab according to local product labels were followed for up to 6 years and analyzed for adverse events (AEs). The registry exposure-adjusted observed rate of lymphoma was compared with the estimated background lymphoma rate from a sex-matched general population in the Surveillance, Epidemiology, and End Results 17 Registry database adjusted for anticipated prior or concurrent thiopurine use in a CD population. RESULTS: A total of 5025 patients were evaluated (16680.4 PY of adalimumab registry exposure, ≈3 years/patient mean follow-up). Registry treatment-emergent AEs included 4129 serious AEs (n = 1853 [36.9%]; 24.8 E/100 PY), 792 serious infections (n = 556 [11.1%]; 4.7 E/100 PY), and 134 malignancies (n = 116 [2.3%]; 0.8 E/100 PY), including ten lymphomas. The observed lymphoma rate (0.060 E/100 PY) was lower than the estimated background rate (0.084 E/100 PY), and the upper bound of the one-sided 95% CI of the observed rate (0.102 E/100 PY) was lower than double the estimated rate (0.168 E/100 PY). CONCLUSIONS: PYRAMID is the longest prospective adalimumab study in routine clinical practice, with up to 6 years of follow-up. No new safety signals were reported. The pre-specified registry objective of ruling out a doubling of lymphoma risk with adalimumab was met.

Efficacy of Adalimumab for Treatment of Perianal Fistula in Children with Moderately to Severely Active Crohn's Disease: Results from IMAgINE 1 and IMAgINE 2.

BACKGROUND AND AIMS: Adalimumab has been shown to be more effective than placebo in healing fistulae in adults with moderately to severely active Crohn's disease. The efficacy and safety of adalimumab in healing fistulae in children/adolescents with Crohn's disease from the 52-week IMAgINE 1 clinical trial, and its open-label extension IMAgINE 2, are reported. METHODS: Children/adolescents with perianal fistulae at baseline of IMAgINE 1 were assessed for fistula closure and improvement during IMAgINE 1 [Weeks 0-52] and from Week 0 of IMAgINE 2 [Week 52 of IMAgINE 1] through to Week 240 of IMAgINE 2 using non-responder imputation. RESULTS: A total of 36 children/adolescents had fistulae at baseline of IMAgINE 1 and were included in the analysis. Fistula closure and improvement were observed in 44.4% and 52.8%, respectively, at Week 12. Rates of closure and improvement were maintained throughout the analysis period to Week 292. No new safety signals were identified. CONCLUSIONS: In children/adolescents with moderately to severely active, fistulizing Crohn's disease, adalimumab induced perianal fistula closure and improvement within 12 weeks of treatment, with rates that were sustained for more than 5 years. The safety profile of adalimumab in patients with fistulae at baseline was similar to that of the overall population in IMAgINE 1/2. ClinicalTrials.gov identifiers: IMAgINE 1 (NCT00409682); IMAgINE 2 (NCT00686374).

Satisfaction with control of systemic lupus erythematosus and lupus nephritis: physician and patient perspectives.

PURPOSE: Patient satisfaction with disease control of systemic lupus erythematosus (SLE) is an important component of medical management. This analysis evaluated patient and physician satisfaction with disease control of SLE, factors associated with satisfaction/dissatisfaction, and the degree of physician-patient concordance of these parameters. PATIENTS AND METHODS: Data were extracted from the US Adelphi Real World Lupus Disease Specific Programme®, a cross-sectional survey of 50 rheumatologists, 25 nephrologists, and their patients with non-nephritis SLE (NNSLE) or lupus nephritis (LN). RESULTS: Physicians reported moderate or severe disease activity in 25.0% of patients with NNSLE and in 50.5% of patients with LN, and were satisfied with disease control in 78.6% (132/168) and 73.8% (152/206) of patients, respectively. For patients, 75.8% (75/99) with NNSLE were satisfied with their current treatment, compared with 65.5% (74/113) with LN. Physician-patient agreement (70.7%) on the level of satisfaction was "slight" (kappa =0.1445) for NNSLE; patients were more frequently dissatisfied than physicians with regard to joint tenderness, fatigue, anxiety, pain on movement, malar rash, and photosensitivity. Physician-patient agreement (71.4%) on the level of satisfaction was "fair" (kappa =0.3695) for LN; patients expressed greater dissatisfaction than physicians for headache, photosensitivity, and anxiety, whereas physicians were more dissatisfied with regard to joint swelling, kidney function, and blood pressure control. In general, patients with NNSLE or LN who were dissatisfied (or whose physicians were dissatisfied) were more likely to have joint swelling, joint stiffness, malar rash, hair loss, depression, and fatigue, have moderate or severe disease, or to be currently experiencing disease flare. CONCLUSION: These data highlight the patient and physician dissatisfaction with real-world disease control of SLE.

Long-term graft function changes in kidney transplant recipients.

Background. Monitoring changes in glomerular filtration rate (GFR) is the recommended method for assessing the progression of kidney disease. The aim of this study was to assess the decline of graft function defined by the annualized change in GFR and the factors which affect it.Methods. Four thousand four hundred and eighty-eight patients, transplanted during the years 1990, 1994, 1998 and 2002 in 34 centres in Spain with allograft survival of at least 1 year, were included in the study. GFR was estimated using the four-variable equation of the Modification of Diet in Renal Diseases (MDRD) study. Linear mixed effects model was applied to determine the relation between the covariates and the annualized change in GFR after transplantation.Results. The average GFR at 12 months was 51.4 +/- 18.9 mL/min/1.73 m(2); most patients were in stage 3 of chronic kidney disease classification. The average patient slope, calculated in a linear model with varying-intercept and varying-slope without covariates, was -1.12 +/- 0.05 mL/min/year (slope +/- standard error). Some variables were related to both the 12-month GFR (intercept) and the slope: recipient gender, hepatitis C virus (HCV) status, estimated GFR (eGFR) at 3 months and proteinuria at 12 months. Some variables were only related to the slope of eGFR: time on dialysis, primary renal disease and immunosuppression. Others affected only the 12-month GFR: donor age, delayed graft function, acute rejection and systolic blood pressure at 12 months. Higher graft function at 3 months had a negative impact on the GFR slope. Cyclosporine-based immunosuppression had a less favourable effect on the rates of change in allograft function.Conclusions. There was a slow decline in GFR. Poor graft function was not associated with an increased rate of decline of allograft function. Immunosuppression with cyclosporine displayed the worst declining GFR rate.

Sirolimus monotherapy as maintenance immunosuppression: a multicenter experience.

The aim of this study was to retrospectively evaluate safety and feasibility of sirolimus (SRL) monotherapy in kidney transplant recipients. Patients older than 18 years, with monotherapy prescribed for more than 1 month and at least 6 months of follow-up were included. We analysed the data from 138 patients. Mean time period between transplantation and start of monotherapy was 6.5 +/- 4.1 years.The most frequent reason was minimization of immunosuppression followed by malignancy. Acute rejection rate was 1.4% at 12 months (two episodes). Graft and patient survival were 94.2% and 97.1% respectively. Mean follow-up after initiation of monotherapy was 29.4 months. Two patients died as a result of cardiovascular diseases and two because of malignancy. Percentage of withdrawal from monotherapy was 14%. SRL trough levels were 10.2 +/- 2.3 ng/ml at baseline and 9.6 6 +/- 3.3 ng/ml at 12 months. Mean glomerular filtration rate was 48.4 ml/min/1.73 m(2) at baseline and 47.7 ml/min/1.73 m(2) at 12 months. Proteinuria was 499.7 mg/24 h at baseline and 543 +/- 794 mg/24 h at 12 months. No significant changes in lipids, glucose, or hemoglobin occurred, although the percentage of patients treated with statins and Epo increased at the end of the follow-up. SRL monotherapy is suitable as long-term immunosuppression in selected patients with no significantly increased risk of late acute rejection.

Different renal toxicity profiles in the association of cyclosporine and tacrolimus with sirolimus in rats.

BACKGROUND: The association of calcineurin inhibitors (CNIs) with mTOR inhibitors (mTORi) is still a problem in clinical practice and there is substantial interest in better understanding the impact of these associations on kidney toxicity. We aimed to analyse the functional and histological profiles of damage and to define the contribution of inflammatory and pro-fibrotic mediators in the association of cyclosporine (CsA) and/or tacrolimus (Tac) with sirolimus (SRL). METHODS: A well-defined model of nephrotoxicity in salt-depleted male rats was used. Monotherapy groups were distributed as a non-treated control group with saline solution (n = 12), the Tac group (n = 16) (tacrolimus 6 mg/kg/day) and the CsA group (n = 13) (CsA 15 mg/kg/day). The groups with different associations were scattered as the Tac + SRL group (n = 14) (tacrolimus 6 mg/kg/day and rapamycin 3 mg/kg/day) and the CsA + SRL group (n = 7) (CsA 15 mg/kg/day and rapamycin 3 mg/kg/day). Groups were divided into 30 and 70 days of follow-up, but the CsA + SRL group was only studied for 30 days because animals became sick. RESULTS: Rats with the CsA + SRL association were the only ones which showed a significant reduction in body weight, impairment of renal function and severe and diffuse tubular vacuolization and tubular atrophy following a striped distribution, and scarce areas of the kidney were still preserved. The Tac + SRL association did not produce renal function impairment, and mild histological damage including enhanced periglomerular tubular atrophy was observed. This local damage affected the distal convoluted tubule involving macula densa and juxtaglomerular apparatus. Pro-inflammatory mediators paralleled functional and structural data. ED-1 and TNF-alpha were noticeably higher in the CsA + SRL than in the Tac + SRL association. Only in the CsA + SRL association an important increase in alpha-SMA+ cells was seen, mainly found in the areas with tubular atrophy. TGF-beta1 was also markedly enhanced in the CsA + SRL association whilst monotherapy or Tac + SRL groups at 30 days TGF-beta1 did not show any changes. However, at 70 days of treatment TGF-beta1 was significantly increased in the Tac + SRL group. Animals receiving SRL showed a decrease in renal vascular endothelial growth factor (VEGF) expression. This growth factor was significantly down-regulated in both CNI associations than in SRL monotherapy. P-glycoprotein (Pgp) was overexpressed in CsA and CsA + SRL therapy whilst Tac and TAC + SRL showed a middle increase Pgp expression but higher than the control and SRL group. CONCLUSION: We conclude that the association of SRL with high doses of CsA or Tac produces a different functional, histological, inflammatory and pro-fibrogenic pattern. Thus, the addition of SRL to high doses of CsA leads to severe renal injury. Combination with high doses of Tac is clearly less deleterious in the short term. However, there is a low grade of pro-fibrotic inflammatory expression when this association is prolonged.

Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats.

Recent data suggest that the phosphatidylinositol 3-kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway is important in diabetic nephropathy. The effect of mTOR blockade by sirolimus (SRL) in diabetic kidney disease in rats was investigated. Diabetes was induced by streptozotocin in male Sprague-Dawley rats. Sixteen weeks later, diabetic animals were divided into the following groups: diabetes (D; n = 8), diabetes + SRL at 1 mg/kg per d, SRL trough level 2.3 +/- 0.25 ng/ml (D+SRL; n = 7); and diabetes + normoglycemia maintained by insulin implants (D+NG; n = 5). There was an age-matched nondiabetic group (ND; n = 6). All animals were followed for 4 wk. The D group showed glomerular hypertrophy (mean glomerular volume 5.0 +/- 0.4 in D versus 3.3 +/- 0.2 10(6) mu(3) in ND; P < 0.05) without renal hyperplasia (calculated by reverse transcription-PCR of proliferative cell nuclear antigen) and albuminuria (29 +/- 4 in D versus 1.4 +/- 1.5 mg/24 h in ND; P < 0.05). Both D+NG and D+SRL groups had a significant reduction of albuminuria, although glomerular hypertrophy was still present. SRL treatment did not modify the number of infiltrating renal ED1(+) cells. Diabetic animals had greater expression of p-Akt and mTOR, unlike ND rats. NG and SRL treatment reduced p-Akt and normalized mTOR. It is interesting that D+SRL was associated with a significant reduction of renal TGF-beta1 and glomerular connective tissue growth factor. SRL treatment reduced glomerular alpha-smooth muscle actin overexpression and reduced significantly the mesangial matrix accumulation that is characteristic of diabetic nephropathy. In conclusion, mTOR blockade by low-dose SRL has a beneficial effect in diabetic kidney disease, suggesting that the mTOR pathway has an important pathogenic role in diabetic nephropathy.

Resistive index and chronic allograft nephropathy evaluated in protocol biopsies as predictors of graft outcome.

INTRODUCTION: The presence of chronic allograft nephropathy (CAN) in protocol biopsies is negatively associated with graft survival. Although recent studies have indicated that the resistive index (RI) is a predictor of graft failure, it does not correlate with CAN in stable grafts. We therefore studied the relationship between RI and CAN and examined the predictive value of both parameters on graft outcome. METHODS: Included were patients transplanted between 1997 and 2002 and who had protocol biopsies and RI determinations. Renal lesions were blindly evaluated according to Banff 97 criteria. Mean glomerular volume, cortical interstitial volume fraction and intimal arterial volume fraction were estimated using a point counting technique. RI was determined before biopsy in at least two different renal locations. The outcome variable was defined as graft failure or a 30% serum creatinine increase between protocol biopsy and last follow-up. RESULTS: Eighty-seven patients were included. RI correlated with recipient age (R = 0.52, P < 0.0001), diastolic blood pressure (R = -0.36, P = 0.0006), pulse pressure index (R = 0.27, P = 0.009) and g-score for histological glomerulitis (rho = 0.30, P = 0.0054), but there were no correlations between RI and chronic Banff scores or any morphometric parameter. The presence of CAN (relative risk, 3.5; 95% confidence interval 1.2-10.2; P = 0.02) but not RI was associated with the outcome variable. CONCLUSION: RI was associated with surrogate measures of vascular compliance such as recipient age and pulse pressure index but not with chronic allograft damage, even when it was evaluated by histomorphometry. Our results indicate that histology may be superior to RI in predicting graft function deterioration, at least in patients with stable renal function.

Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats.

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy.

Glomerular enlargement assessed by paired donor and early protocol renal allograft biopsies.

The aim of the study was to evaluate the evolution of glomerular volume 4 months after transplantation. Mean glomerular volume (Vg) was estimated according to the Weibel and Gomez method in a donor and a protocol biopsy done at 139 +/- 58 d in 41 stable grafts. Biopsies were also evaluated according to the Banff schema. Vg increased after transplantation from 4.1 +/- 1.4 to 5.1 +/- 2.4 x 10(6) micro3 (p=0.02). In patients with chronic allograft nephropathy in the protocol biopsy (n=14), the Vg enlargement was -0.3 +/-x 10(6) micro3 while in patients without chronic allograft nephropathy (n=27), glomerular enlargement was 1.6 +/- 2.1 x 10(6) micro3 (p=0.01). There was a negative association between glomerular volume in the donor biopsy and glomerular enlargement after transplantation (R=- 0.34, p=0.03). Multivariate regression analysis confirmed that Vg in the donor biopsy and chronic allograft nephropathy in the protocol biopsy were independent predictors of glomerular enlargement after transplantation (R=0.48, p=0.01). Moreover, Vg in the protocol biopsy correlated with creatinine clearance at the time of biopsy (R=0.38, p=0.01). Glomeruli enlarge after transplantation and glomerular volume after 4 months correlates with creatinine clearance, suggesting that glomerular enlargement is a necessary condition for renal adaptation to the recipient. Glomerular enlargement is impaired in patients with chronic allograft nephropathy.