Long-Term Outcomes of Kidney Transplants from Older/Marginal Donors: A Cohort Study.

INTRODUCTION: To safely expand the donor pool, we introduced a strategy of biopsy-guided selection and allocation to single or dual transplantation of kidneys from donors >60 years old or with hypertension, diabetes, and/or proteinuria (older/marginal donors). Here, we evaluated the long-term performance of this approach in everyday clinical practice. METHODS: In this single-center cohort study, we compared outcomes of 98 patients who received one or two biopsy-evaluated grafts from older/marginal donors ("recipients") and 198 patients who received nonhistologically assessed single graft from ideal donors ("reference-recipients") from October 2004 to December 2015 at the Bergamo Transplant Center (Italy). RESULTS: Older/marginal donors and their recipients were 27.9 and 19.3 years older than ideal donors and their reference-recipients, respectively. KDPI/KDRI and donor serum creatinine were higher and cold ischemia time longer in the recipient group. During a median follow-up of 51.9 (interquartile range 23.1-88.6) months, 11.2% of recipients died, 7.1% lost their graft, and 16.3% had biopsy-proven acute rejection (BPAR) versus 3.5, 7.6, and 17.7%, respectively, of reference-recipients. Overall death-censored graft failure (rate ratio 0.78 [95% CI 0.33-2.08]), 5-year death-censored graft survival (94.3% [87.8-100.0] vs. 94.2% [90.5-98.0]), BPAR incidence (rate ratio 0.87 [0.49-1.62]), and yearly measured glomerular filtration rate decline (1.18 ± 3.27 vs. 0.68 ± 2.42 mL/min/1.73 m2, p = 0.37) were similar between recipients and reference-recipients, respectively. CONCLUSIONS: Biopsy-guided selection and allocation of kidneys from older/marginal donors can safely increase transplant activity in clinical practice without affecting long-term outcomes. This may help manage the growing gap between organ demand and supply without affecting long-term recipient and graft outcomes.

Data on the assessment of LV mechanics by speckle tracking echocardiography in ADPKD patients.

In this article, we report anthropometric, clinical and laboratory data from Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients with mild to moderate renal dysfunction and normal LV ejection fraction and from age- and sex-matched healthy controls and renal controls. Factors influencing LV untwisting rate in the group of ADPKD patients are also reported. For further interpretation and discussion please refer to the research article "Left ventricular dysfunction in ADPKD and effects of Octreotide-LAR: a cross-sectional and longitudinal sub study of the ALADIN trial" (Spinelli et al., 2018) [1].

Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients.

BACKGROUND/AIMS: Transplant physicians and patients are often reluctant to change to generic versions of immunosuppressive drugs with a narrow therapeutic index, such as ciclosporin (CsA). Thus, in routine follow-up for kidney transplant patients receiving CsA maintenance immunosuppressive therapy in our center, we evaluated the exchangeability of the brand name, Neoral, and the recently approved CsA generic formulation, Ciqorin. METHODS: We assessed the complete 12-h CsA pharmacokinetic profile and direct measurement of glomerular filtration rate (mGFR) of 10 patients receiving stable doses of Neoral (138 ± 43 mg/day), at least 6 months after kidney transplantation (Neoral 1). The same evaluations were repeated 10 days after conversion to Ciqorin on a milligram-to-milligram basis and 10 days after reinstituting Neoral (Neoral 2). RESULTS: The mean CsA area under the concentration-time curve increased slightly after switching from Neoral to Ciqorin (p = 0.03), but did not change significantly after Neoral was reintroduced (Neoral 1: 2,234 ± 783, Ciqorin: 2,452 ± 767, Neoral 2: 2,472 ± 784 ng × h/mL). There were no appreciable differences between the 2 CsA formulations in trough levels, maximum concentrations, or time to reach maximum concentrations. In all patients, renal function remained stable throughout the monitoring period (mGFR, Neoral 1: 52.0 ± 16.2; Ciqorin: 55.0 ± 19.0; Neoral 2: 55.8 ± 18.9 mL/min/1.73 m2), as did urinary and hematochemical parameters. CONCLUSIONS: In stable kidney transplant recipients, switching from Neoral to Ciqorin resulted in similar pharmacokinetic parameters and did not change renal allograft function, reassuring physicians and patients regarding the exchangeability of reference and generic CsA formulations.

Low-dose RATG with or without basiliximab in renal transplantation: a matched-cohort observational study.

BACKGROUND/AIMS: In renal transplantation, peri-operative low-dose rabbit-antithymocyte-globulin (RATG) plus basiliximab induction prevented acute allograft rejection more effectively than post-operative RATG plus basiliximab induction. We investigated the specific antirejection contribution of basiliximab in this context. METHODS: This single-center, observational, matched-cohort study evaluated allograft rejections (primary outcome), steroid exposure and side effects, GFR (iohexol plasma clearance) and treatment costs in 16 deceased-donor renal transplant recipients induced with RATG (0.5 mg/kg/day) and 32 age-, gender- and treatment-matched reference-patients given RATG plus basiliximab (20 mg on days 0 and 4). RESULTS: Induction was well tolerated. At 18 months, 8 patients (50%) vs. 3 reference-patients (9.4%) rejected the graft [HR (95% CI): 6.53 (1.73-24.70), p = 0.006]. Difference was significant (p < 0.01) even after adjusting for recipient/donor age and gender, cold ischemia time and HLA mismatches. There were 1 antibody-mediated rejection and 2 moderate cellular rejections in patients vs. none in reference-patients (p = 0.032). The median (interquartile range) prednisone cumulative dose was remarkably higher in patients than reference-patients [4.78 (1.12-6.10) vs. 0.19 (0.18-3.81) grams, p = 0.002]. Three patients vs. 24 reference-patients were off-steroid at study end (p < 0.001). Three patients vs. no reference-patient developed new-onset diabetes (p = 0.003). Both inductions similarly depleted B-cells. Outcomes of AZA- vs. MMF-treated participants were similar. GFR was similar in all groups. Compared to MMF, AZA therapy saved ≈ EUR 2,500/year and by month 14.3 post-transplant compensated basiliximab costs. CONCLUSION: In renal transplantation, basiliximab plus peri-operative low-dose RATG more efficiently prevented allograft rejection than RATG monotherapy, and minimized steroid exposure and toxicity. AZA- vs MMF-based maintenance immunosuppression largely compensated the extra costs of basiliximab.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Successes and disappointments with clinical islet transplantation.

Transplantation of pancreatic islets is considered a therapeutic option for patients with type 1 diabetes mellitus who have life-threatening hypoglycaemic episodes. After the procedure, a decrease in the frequency and severity of hypoglycaemic episodes and sustained graft function as indicated by detectable levels of C-peptide can be seen in the majority of patients. However, true insulin independence, if achieved, usually lasts for at most a few years. Apart from the low insulin independence rates, reasons for concern regarding this procedure are the side effects of the immunosuppressive therapy, allo-immunization, and the high costs. Moreover, whether islet transplantation prevents the progression of diabetic micro- and macrovascular complications is largely unknown. Areas of current research include the development of less toxic immunosuppressive regimens, the control of the inflammatory reaction immediately after transplantation, the identification of the optimal anatomical site for islet infusion, and the possibility to encapsulate transplanted islets to protect them from the allo-immune response. At present, pancreatic islet transplantation is still an experimental procedure, which is only indicated for a highly selected group of type 1 diabetic patients with life-threatening hypoglycaemic episodes.

Cost-effectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy: influence of the ACE insertion/deletion polymorphism.

INTRODUCTION: End-stage renal disease is associated with high health-care costs and low quality of life compared with chronic kidney disease. The renoprotective effectiveness of angiotensin-converting enzyme inhibitors (ACEi) is largely determined by the ACE insertion/deletion (I/D) polymorphism. We determined the cost-effectiveness of ACEi therapy in nondiabetic nephropathy for the ACE II/ID and for the ACE DD genotype separately. Furthermore, we considered a selective screen-and-treat strategy in which patients are prescribed alternative, more effective, therapy based on their ACE (I/D) polymorphism. METHODS: Time-dependent Markov models were constructed; cohorts of 1000 patients were followed for 10 years. Data were mainly gathered from the Ramipril Efficacy In Nephropathy trial. Both univariate and probabilistic sensitivity analyses were performed. RESULTS: ACEi therapy dominated placebo in both the ACE II/ID group (euro15 826, and 0.091 quality-adjusted life years gained per patient) and the ACE DD group (euro105 104 and 0.553 quality-adjusted life years gained). Sensitivity analyses showed 30.2% probability of ACEi being not cost-effective in the ACE II/ID group, against an almost 100% probability of cost-effectiveness in the ACE DD group. A selective screen-and-treat strategy should incorporate an alternative therapy for patients with the ACE II/ID genotype with an at least 9.1% increase in survival time compared with ACEi therapy to be cost-effective. Sensitivity analyses show that higher effectiveness and lower costs of the alternative therapy improve the cost-effectiveness of a screening strategy. CONCLUSION: ACEi therapy is a cost-saving treatment compared with placebo in nondiabetic nephropathy, irrespective of ACE (I/D) genotype. However, ACEi therapy saved more costs and more health gains were achieved in the ACE DD genotype than in the ACE II/ID genotype. An alternative treatment featuring a modest increase in effectiveness compared with ACEi therapy for patients with the ACE II/ID genotype can be incorporated in a cost-effective or even cost-saving screen-and-treat strategy.

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease.

The renin-angiotensin-aldosterone system (RAAS) is a well known regulator of blood pressure (BP) and determinant of target-organ damage. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and Kidneys. Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor effect predominantly on the postglomerular arterioles, thereby increasing the glomerular hydraulic pressure and the ultrafiltration of plasma proteins, effects that may contribute to the onset and progression of chronic renal damage. AII may also directly contribute to accelerate renal damage by sustaining cell growth, inflammation, and fibrosis. Interventions that inhibit the activity of the RAAS are renoprotective and may slow or even halt the progression of chronic nephropathies. ACE inhibitors and angiotensin II receptor antagonists can be used in combination to maximize RAAS inhibition and more effectively reduce proteinuria and GFR decline in diabetic and nondiabetic renal disease. Recent evidence suggests that add-on therapy with an aldosterone antagonist may further increase renoprotection, but may also enhance the risk hyperkalemia. Maximized RAAS inhibition, combined with intensified blood pressure control (and metabolic control in diabetics) and amelioration of dyslipidemia in a multimodal approach including lifestyle modifications (Remission Clinic), may achieve remission of proteinuria and renal function stabilization in a substantial proportion of patients with proteinuric renal disease. Ongoing studies will tell whether novel drugs inhibiting the RAAS, such as the renin inhibitors or the vasopeptidase inhibitors, may offer additional benefits to those who do not respond, or only partially respond, to this multimodal regimen.

Strategies for national health care systems in emerging countries: the case of screening and prevention of renal disease progression in Bolivia.

There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. In 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled "El Proyecto de Enfermedades Renales en Bolivia" (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center "Aldo e Cele Dacco" of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled "First Clinical and Epidemiological Program of Renal Diseases"-under the auspices of the Renal Sister Center Program of the International Society of Nephrology-was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted by 21 clinical centers. Apparently healthy patients (14,082) were enrolled over a period of 7 months. Urinary abnormalities were found on first screening in 4261 patients, but only 1019 patients (23.9%) were available for follow-up. At second urinalysis, 35% of patients had no abnormalities. In the remaining positive group of patients, further investigations disclosed the following abnormalities: urinary tract infection (48.4%), isolated hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%), and other diagnoses 4.3% (kidney stones, 1.3%; diabetic nephropathy, 1%; polycystic kidney diseases, 1.9%). The experience gained from this initial screening program formed the basis for a second study aimed to prevent renal disease progression in a selected Bolivian population with high altitude polycythemia. In conclusion, our studies show that mass screening of the population for renal disease is feasible in developing countries and can provide useful information on frequency of renal diseases. Also, in patients with altitude polycythemia, long-term treatment with low doses of enalapril safely prevents increase in arterial blood pressure and progressively reduces hematocrit and proteinuria. Aside from its scientific value, this last study can be taken as an example of how, by rationalizing resources and investing in research programs, renal disease progression and cardiovascular risk may eventually improve, which ultimately should translate into less demand for dialysis, and thus provide alternatives to costly RRT. The transformation of the Bolivian pilot model into a systematic program applicable to most emerging countries may be seen as a task of national nephrology societies, along with methodologic and economic support of international bodies.

Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results.

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.

Chronic nephropathies: individual risk for progression to end-stage renal failure as predicted by an integrated probabilistic model.

BACKGROUND/AIMS: To predict risk of end-stage renal disease (ESRD) in individual patients with chronic nephropathy. METHODS: Sequential use of univariate analyses and Cox regression to identify risk factors, artificial neural network to quantify their relative importance and Bayesian analysis to address uncertainty of relationships and incorporate ESRD prevalence information in 344 patients with chronic nephropathy enrolled in the Ramipril Efficacy In Nephropathy study. RESULTS: Serum creatinine (SC), 24-hour urinary protein excretion (UPE) and calcium-phosphorus (Ca*P) product were, in this order, the strongest time-adjusted ESRD predictors. Individual risk of ESRD ranged from near zero when SC and UPE were <1.66 mg/dl and <3 g/24 h, to 69% when SC, UPE and Ca*P were > or =2.41 mg/dl, > or =3 g/24 h and > or =32.64 mg2/dl2, respectively. Receiver operating characteristic curves showed that within lowest, middle and highest tertiles of basal SC (0.90-1.65, 1.66-2.40 and 2.41-6.30 mg/dl, respectively) the model accurately predicted ESRD (AUC = 0.80, 0.72 and 0.65; p = 0.0003, 0.0001 and 0.0022, respectively), quality of life or treatment costs. CONCLUSION: Integrated use of regression analysis and probabilistic models allows computation of individual risk of progression to ESRD and related utilities. This may help in optimizing care and costs in nephrology and other medical areas and designing trials in high-risk patients.