Lung ultrasound and BNP to detect hidden pulmonary congestion in euvolemic hemodialysis patients: a single centre experience.

BACKGROUND: Dry weight assessment in hemodialysis (HD) remains a challenge. The aim of the study was to investigate the prevalence of subclinical pulmonary congestion using lung ultrasound (LUS) in maintenance HD patients with no clinical or bioimpedance signs of hyperhydration. The correlation between B-lines Score (BLS) and brain natriuretic peptide (BNP) was also evaluated. METHODS: Twenty-four HD patients underwent LUS and BNP dosage at the end of the mid-week HD session, monthly for 6 months . LUS was considered as positive when BLS was >15. Hospitalizations and cardiovascular events were also evaluated in relation to the BLS. RESULTS: LUS+ patients at baseline were 16 (67%), whereas 11 (46%) showed LUS + in at least 50% of the measurements (rLUS+ patients). Only the rLUS+ patients had a higher number of cardiovascular events [p=0.019, OR: 7.4 (CI 95%. 1.32-39.8)] and hospitalizations [p=0.034, OR 5.5 (CI 95% 1.22- 24.89)]. A BNP level of 165 pg/ml was identified as cut-off value for predicting pulmonary congestion, defined by BLS >15. CONCLUSION: Prevalence of pulmonary congestion as assessed by LUS and persistent or recurrent BLS >15 were quite prevalent findings in euvolemic HD patients. In the patients defined as rLUS+, a higher rate of cardiovascular events and hospital admissions was registered. BNP serum levels > 165 pg/ml resulted predictive of pulmonary congestion at LUS. In the dialysis care, regular LUS examination should be reasonably included among the methods useful to detect subclinical lung congestion and to adjust patients' dry weight.

Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy.

AIMS/HYPOTHESIS: The glucosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA1c. We hypothesised that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys. METHODS: This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30-65 years old, with a BMI of 25-35 kg/m2 and stable body weight (±2 kg) over the preceding 3 months, and HbA1c <42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment. RESULTS: Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6 ± 1.1 vs 5.5 ± 0.5 g/6 h; p = 0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (Δ = 1.11 ± 0.72 µmol min-1 kg-1) was significantly lower (p = 0.03) than in the residual native kidney group (Δ = 2.56 ± 0.33 µmol min-1 kg-1). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (r = 0.34, p < 0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. ß-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group. CONCLUSIONS/INTERPRETATION: In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal-hepatic axis). TRIAL REGISTRATION: ClinicalTrials.gov NCT03168295 FUNDING: This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38. Graphical abstract.

Immunotherapy in Underrepresented Populations of Patients with Cancer: Do We Have Enough Evidence at Present? A Focus on Patients with Major Viral Infections and Autoimmune Disorders.

The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as "special populations" or "underrepresented populations." These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. IMPLICATIONS FOR PRACTICE: Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in "underrepresented" patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

Assessment of physical activity, capacity and nutritional status in elderly peritoneal dialysis patients.

BACKGROUND: This study aimed to evaluate the prevalence of sedentarism, and to assess physical capacity and nutritional status in a cohort of older patients on peritoneal dialysis (PD), with respect to age-matched non-dialysis CKD population, using highly accessible, simple methods, namely the Rapid Assessment of Physical activity (RAPA) test and the 30″ Sit-to-stand (STS) test. METHODS: This cross-sectional multicenter study included 151 renal patients older than 60 years; 71 pts. (44 m, age 72 ± 7 yrs) were on PD and 80 pts. (63 m, age 74 ± 7 yrs) were affected by 3-4 stage CKD. RESULTS: The prevalence of sedentary/underactive patients was double of that of the active patients as assessed by RAPA test, both in the PD (65.3%) and in the CKD (67.5%) cohort. The 30"STS test showed a reduced physical performance in both groups: 84.5% of PD patients and 87.5% of CKD patients did not reach the expected number of stands by age and gender. A malnutrition-inflammation score (MIS) ≥ 6 occurred in 37 % of PD patients and in 2.5 % of CKD patients. In PD patients, an independent significant association was observed between 30"STS test and MIS (beta -0.510, p = 0.013), as well as between RAPA and MIS (beta -0.544, p = 003) and phase angle (beta -0.506, p = 0.028). CONCLUSIONS: A high prevalence of low- performance capacity and sedentarism has been detected among elderly patients on PD or with CKD stage 3-4. Apart from age, a condition of malnutrition-inflammation was the major determinant of poor physical activity and capacity in PD patients. Better body composition seems to be positively associated with physical activity in PD and with physical capacity in CKD patients. Routine clinical management should include a close evaluation of nutritional status and evaluation of physical activity and capacity which can be easily assessed by RAPA and 30″STS tests.

Nutritional support in the tertiary care of patients affected by chronic renal insufficiency: report of a step-wise, personalized, pragmatic approach.

BACKGROUND: Dietary treatment is helpful in CKD patients, but nutritional interventions are scarcely implemented. The main concern of the renal diets is its feasibility with regards to daily clinical practice especially in the elderly and co-morbid patients. This study aimed to evaluate the effects of a pragmatic, step-wise, personalized nutritional support in the management of CKD patients on tertiary care. METHODS: This is a case-control study. It included 823 prevalent out-patients affected by CKD stage 3b to 5 not-in-dialysis, followed by tertiary care in nephrology clinics; 305 patients (190 males, aged 70 ± 12 years) received nutritional support (nutritional treatment Group, NTG); 518 patients (281 males, aged 73 ± 13 years) who did not receive any dietary therapy, formed the control group (CG). In the NTG patients the dietary interventions were assigned in order to prevent or correct abnormalities and to maintain a good nutritional status. They included manipulation of sodium, phosphate, energy and protein dietary intakes while paying special attention to each patient's dietary habits. RESULTS: Phosphate and BUN levels were lower in the NTG than in the CG, especially in stage 4 and 5. The prevalence of hyperphosphatemia was lower in the NTG than in CG in stage 5 (13.3 % vs 53.3 %, p < 001, respectively), in stage 4 (4.1 % vs 18.3 % vs, p < 0.001) and stage 3b (2.8 % vs 9.5 % p < 0.05). Serum albumin was higher in NTG than in CG especially in stage 5 . The use of calcium-free intestinal phosphate binders was significantly lower in NTG than in CG (11 % vs 19 % p < 0.01), as well as that of Erythropoiesis stimulating agents (11 % vs 19 %, p < 0.01), and active Vitamin D preparations (13 % vs 21 %, p < 0.01). CONCLUSIONS: This case-control study shows the usefulness of a nutritional support in addition to the pharmacological good practice in CKD patients on tertiary care. Lower phosphate and BUN levels are obtained together with maintenance of serum albumin levels. In addition, a lower need of erythropoiesis stimulating agents, phosphate binders and active Vitamin D preparations was detected in NTG. This study suggests that a nutritional support may be useful in the management of the world-wide growing CKD burden.

"Dietaly": practical issues for the nutritional management of CKD patients in Italy.

Evidence exists that nutritional therapy induces favorable metabolic changes, prevents signs and symptoms of renal insufficiency, and is able to delay the need of dialysis. Currently, the main concern of the renal diets has turned from the efficacy to the feasibility in the daily clinical practice.Herewith we describe some different dietary approaches, developed in Italy in the last decades and applied in the actual clinical practice for the nutritional management of CKD patients.A step-wise approach or simplified dietary regimens are usually prescribed while taking into account not only the residual renal function and progression rate but also socio-economic, psychological and functional aspects.The application of the principles of the Mediterranean diet that covers the recommended daily allowances for nutrients and protein (0.8 g/Kg/day) exert a favorable effect at least in the early stages of CKD. Low protein (0.6 g/kg/day) regimens that include vegan diet and very low-protein (0.3-0.4 g/Kg/day) diet supplemented with essential amino acids and ketoacids, represent more opportunities that should be tailored on the single patient's needs.Rather than a structured dietary plan, a list of basic recommendations to improve compliance with a low-sodium diet in CKD may allow patients to reach the desired salt target in the daily eating.Another approach consists of low protein diets as part of an integrated menu, in which patients can choose the "diet" that best suits their preferences and clinical needs.Lastly, in order to allow efficacy and safety, the importance of monitoring and follow up of a proper nutritional treatment in CKD patients is emphasized.

[Different methods to manage dry weight in hemodialysis patients].

Estimating the euvolemia and dry weight of hemodialysis patients still represents a challenge for the nephrologist, since both dehydration and hyperhydration are associated with intradialytic events and cardiovascular complications in the short and long term. Despite the need for a precise and objective definition of the dry weight for the individual patient on dialysis, this is usually determined on a clinical basis. To obtain greater sensitivity the dosage of natriuretic peptides, Bioelectrical Impedance Analysis (BIA) and, more recently, Lung Ultra-Sound (LUS) can all be used. The BIA allows to estimate the subject's body composition and, in particular, the distribution of body fluids. The presence of hyperhydration, as determined through the BIA, is predictive of an increased mortality in numerous observational studies. In recent years, pulmonary ultrasound has taken on an increasingly important role not only within the cardiology and intensive care units, but also in a nephrology setting, especially in dialysis. The purpose of this article is to analyze the advantages and limitations of the methods that can be used to assess the dry weight of patients undergoing hemodialysis treatment.

Non-Traditional Aspects of Renal Diets: Focus on Fiber, Alkali and Vitamin K1 Intake.

Renal diets for advanced chronic kidney disease (CKD) are structured to achieve a lower protein, phosphate and sodium intake, while supplying adequate energy. The aim of this nutritional intervention is to prevent or correct signs, symptoms and complications of renal insufficiency, delaying the start of dialysis and preserving nutritional status. This paper focuses on three additional aspects of renal diets that can play an important role in the management of CKD patients: the vitamin K1 and fiber content, and the alkalizing potential. We examined the energy and nutrients composition of four types of renal diets according to their protein content: normal diet (ND, 0.8 g protein/kg body weight (bw)), low protein diet (LPD, 0.6 g protein/kg bw), vegan diet (VD, 0.7 g protein/kg bw), very low protein diet (VLPD, 0.3 g protein/kg bw). Fiber content is much higher in the VD and in the VLPD than in the ND or LPD. Vitamin K1 content seems to follow the same trend, but vitamin K2 content, which could not be investigated, might have a different pattern. The net endogenous acid production (NEAP) value decreases from the ND and LPD to the vegetarian diets, namely VD and VLPD; the same finding occurred for the potential renal acid load (PRAL). In conclusion, renal diets may provide additional benefits, and this is the case of vegetarian diets. Namely, VD and VLPD also provide high amounts of fibers and Vitamin K1, with a very low acid load. These features may have favorable effects on Vitamin K1 status, intestinal microbiota and acid-base balance. Hence, we can speculate as to the potential beneficial effects on vascular calcification and bone disease, on protein metabolism, on colonic environment and circulating levels of microbial-derived uremic toxins. In the case of vegetarian diets, attention must be paid to serum potassium levels.

The extra-phosphate intestinal load from medications: is it a real concern?

BACKGROUND AND AIMS: Reduction of intestinal load of phosphorus is important for the prevention and treatment of chronic kidney disease (CKD)-mineral and bone disorder (MBD). However, this strategy is limited by patients' poor adherence to dietary prescription and by the existence of hidden sources of phosphorus. In addition to food containing phosphate-based additives, it was recently claimed that medications may contribute to increase the load of phosphate (P), mainly present as an excipient. To identify medications containing P as an excipient, we performed a systematic screening of medications which could potentially be prescribed for chronic oral therapies in CKD patients. METHODS: We examined 311 active pharmaceutical ingredients (APIs) and 3763 branded or generic medications, identified by the anatomical therapeutic chemical (ATC) international classification system. RESULTS: Sixty APIs (19.3 %) included at least one medication containing P as an excipient. In total, 472 medications (12.5 %) listed P as an excipient. The prevalence of medications containing phosphate as an excipient was highest for oral antidiabetic medications (23.8 %), followed by antidepressant (19.2 %), antihypertensive (17.5 %) and gastro-intestinal tract (16.4 %) medications. All other classes showed a prevalence <10 %. Within each ATC class, the APIs at risk of containing phosphate were identified as well as the prevalence of both branded and generic medications. Calcium hydrogen phosphate was the most prevalent form (77.7 %) of phosphate as an excipient. CONCLUSIONS: Our results suggest that the prevalence of phosphate-containing medications is quite low and it is possible to identify, within each drug category, the medications containing P as an excipient. Calcium phosphate, the most prevalent form, has a lower rate of intestinal absorption than sodium phosphate salts. We did not measure the actual P content, but existing data (measured or estimated) show that it is generally low, except for a few medications that can be easily identified. Thus, the extra-phosphate load from medications may be of concern only in special cases, which could be further limited when correct information and prescriptions are given. The extra-phosphate load from P-containing food and beverages remains the main concern of hidden phosphorus sources in CKD patients.

[Incremental approach to hemodialysis: twice a week, or once weekly hemodialysis combined with low-protein low-phosphorus diet?]. / Approccio incrementale di inizio dialisi: emodialisi bisettimanale, o monosettimanale associata a dieta ipoproteica-ipofosforica?

The start of dialysis treatment is a critical step in the care management of chronic renal failure patients. When hemodialysis is performed three times a week, rapid loss of kidney function and of urine volume output generally occur and this represents an unfavorable prognostic factor. Instead, reducing frequency of hemodialysis sessions, as well as peritoneal dialysis, can contribute to a lesser decrease of residual renal function. Unfortunately, the existing protocols for an incremental hemodialysis approach are not particularly common and they are generally limited to a twice a week hemodialysis schedule. In addition to clinical and economic reasons, an incremental approach to ESRD also contributes to better social and psychological adaptation by the patients to the dramatic change in living conditions linked to the maintenance dialysis treatment. In patients who have attitude for low-protein nutritional therapy, a once weekly dialysis schedule combined with low-protein, low-phosphorus, normal to high energy diet in the remaining six days of the week can be implemented in selected patients. In our experience, this kind of program produced important clinical results and reduction in costs and hospitalization. When compared with a three times a week dialysis schedule, a greater protection of residual renal function and of urine volume output, lower increase in 2 microglobulin, better control of phosphorus and less consumption of phosphate binders and erythropoietin were observed. Careful clinical monitoring and nutrition is essential for the safety and optimization of infrequent hemodialysis. Long-term follow-up analysis shows favorable effects on the overall survival. Furthermore, twice a week hemodialysis is not the only option for an incremental approach of dialysis commencing. In patients who have a good attitude for low-protein nutritional therapy, its arrangement with a program of once weekly dialysis represents a real and effective alternative.

Vitamin D status and cholecalciferol supplementation in chronic kidney disease patients: an Italian cohort report.

This study investigated the factors associated with hypovitaminosis D, in a cohort of 405 prevalent patients with chronic kidney disease (CKD) stages 2-4, living in Italy and followed-up in tertiary care. The effect of cholecalciferol 10,000 IU once-a-week for 12 months was evaluated in a subgroup of 100 consecutive patients with hypovitaminosis D. Vitamin D deficiency was observed in 269 patients (66.4%) whereas vitamin D insufficiency was found in 67 patients (16.5%). In diabetic patients, 25-hydroxyvitamin D deficiency was detected in 80% of cases. In patients older than 65 years, the prevalence of hypovitaminosis D was 89%. In the univariate analysis, 25-hydroxyvitamin D was negatively related to age, parathyroid hormone (PTH), proteinuria, and Charlson index, while a positive relationship has emerged with hemoglobin level. On multiple regression analysis, only age and PTH levels were independently associated with 25-hydroxyvitamin D levels. No relationship emerged between vitamin D deficiency and renal function. Serum levels of 25-hydroxyvitamin D or prevalence of hypovitaminosis D did not differ between patients on a free-choice diet and on a renal diet, including low-protein, low-phosphorus regimens. Twelve-month oral cholecalciferol administration increased 25-hydroxyvitamin D and reduced PTH serum levels. In summary, hypovitaminosis D is very prevalent in CKD patients (83%) in Italy, and it is similar to other locations. PTH serum levels and age, but not renal function, are the major correlates of hypovitaminosis D. Implementation of renal diets is not associated with higher risk of vitamin D depletion. Oral cholecalciferol administration increased 25-hydroxyvitamin D and mildly reduced PTH serum levels. Oral cholecalciferol supplementation should be recommended as a regular practice in CKD patients, also when serum 25-hydroxyvitamin D determination is not available or feasible.

Low-dose synthetic adrenocorticotropic hormone-analog therapy for nephrotic patients: results from a single-center pilot study.

INTRODUCTION: This report describes our experience using a low-dose synthetic adrenocorticotropic hormone (ACTH) analog for patients affected by nephrotic syndrome who had not responded to or had relapsed after steroid and immunosuppressive treatments. PATIENTS AND METHODS: Eighteen adult nephrotic patients with an estimated glomerular filtration rate >30 mL/min were recruited. Histological pictures included ten of membranous nephropathy, three of membranous proliferative glomerulonephritis, three of minimal change, and two of focal segmental glomerular sclerosis. All patients received the synthetic ACTH analog tetracosactide 1 mg intramuscularly once a week for 12 months. Estimated glomerular filtration rate, proteinuria, serum lipids, albumin, glucose, and potassium were determined before and during the treatment. RESULTS: One of the 18 patients discontinued the treatment after 1 month because of severe fluid retention, and two patients were lost at follow-up. Complete remission occurred in six cases, while partial remission occurred in four cases (55.5% responder rate). With respect to baseline, after 12 months proteinuria had decreased from 7.24±0.92 to 2.03±0.65 g/day (P<0.0001), and serum albumin had increased from 2.89±0.14 to 3.66±0.18 g/dL (P<0.0001). Total and low-density lipoprotein cholesterol had decreased from 255±17 to 193±10 mg/dL (P=0.01), and from 168±18 to 114±7 mg/dL (P=0.03), respectively. No cases of severe worsening of renal function, hyperglycemia, or hypokalemia were observed, and no admissions for cardiovascular or infectious events were recorded. CONCLUSION: Tetracosactide administration at the dosage of 1 mg intramuscularly per week for 12 months seems to be an acceptable alternative for nephrotic patients unresponsive or relapsing after steroid-immunosuppressive regimens. Further studies should be planned to assess the effect of this low-dose ACTH regimen also in nephrotic patients not eligible for kidney biopsy or immunosuppressive protocols.

Comparison of sirolimus-based calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation.

INTRODUCTION: This study examines the efficacy and toxicity of sirolimus used as primary immunosuppression in combination with reduced dose tacrolimus (calcineurin inhibitor [CI]-sparing regimen) or mycophenolate mofetil (CI-free regimen) in high-risk cadaveric renal transplantation. METHODS: Seventy subjects were treated in a quadruple sequential protocol in which 41 were treated with a CI-sparing regimen and 29 were treated with a CI-free regimen. The efficacy and toxicity profiles of these regimens were prospectively monitored and compared. RESULTS: The study consisted of African Americans (71%), cadaveric donors (100%), donors aged more than 50 years (30%), and patients with delayed graft function (47%). At 1 year, patient survival, graft survival, and incidence of biopsy-proven acute rejection were 98%, 80%, and 10%, respectively, in the CI-sparing group and 100%, 89%, and 7%, respectively, in the CI-free group. Three-month protocol biopsies were performed in 41% (17/41) and 67% (20/29) of the subjects in the CI-sparing and CI-free groups, respectively. Subclinical rejection was detected in 6% (1/17) and 15% (3/20) of the subjects in the CI-sparing and CI-free groups, respectively. Histologic evidence of chronic allograft nephropathy was more prevalent in the CI-sparing group. At 1 year, the mean estimated creatinine clearance was higher in the CI-free group than in the CI-sparing group (72.4 +/-20.0 mL/min vs. 50.5 +/-20.8 mL/min, P <0.01). The two regimens had similar toxicity profiles (hospital readmission, infection, wound complications, and metabolic complications). CONCLUSIONS: Both sirolimus-based CI-sparing and CI-free regimens are safe and effective in a population with high immunologic risk. The CI-free regimen is associated with better renal function at 1 year post-transplant. Long-term follow-up will aid in determining the risk and benefit ratio of these regimens.

Nephrolithiasis and hypertension: possible links and clinical implications.

A definite epidemiological association exists between kidney stone disease and arterial hypertension, but the pathophysiological mechanisms are still not fully understood. Hypercalciuria or inflammation and oxidative stress have been proposed as possible links. However, there is more convincing evidence that the association between nephrolithiasis and hypertension may be considered as a part of the association between kidney stone disease, metabolic syndrome and atherosclerosis. From a clinical point of view, this association represents a crucial aspect of the clinical management of patients affected by kidney stone disease. In order to implement early prevention and treatment of cardiovascular and/or renal damage physicians should be encouraged to assess individual cardiovascular risk factors in any adult with kidney stones. Consequently, patients with kidney stones need a comprehensive approach rather than an intervention limited to the urinary tract and focused on stone resolution and recurrence prevention. It is time to view kidney stone disease as a systemic disorder, associated to or predictive of hypertension, chronic kidney disease, bone and cardiovascular damage. All these conditions negatively affect patient prognosis. This multi-systemic approach could increase the clinical impact of the kidney stone clinic.

Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation.

BACKGROUND: Balancing the risk of acute rejection (AR) with drug-induced toxicities complicates the selection of the optimal immunosuppressive regimen, especially in the high-risk renal transplant recipient. This study was designed to determine the optimal dosage combinations of tacrolimus and sirolimus in a high-risk cadaveric renal transplant population. METHODS: Primary cadaveric renal transplant recipients were randomly assigned to receive either standard tacrolimus (trough levels of 10-15 ng/mL) plus reduced sirolimus (trough levels of 5-10 ng,mL) (Group I) or to receive reduced tacrolimus (trough levels of 5-10 ng,mL) plus standard sirolimus (trough levels of 10-15 ng/mL) (Group II). All patients received Thymoglobulin induction and steroids. RESULTS: Thirty-nine (16 in Group I and 23 in Group II) high-risk renal transplant recipients (100% cadaveric donors, 79% African-American recipients, and 59% delayed graft function) are the subjects of this report. At 6 months, the patient survival rate was 94 and 100% and the graft survival rate was 94 and 83% in Groups I and II, respectively. The incidence of biopsy-proven AR was 6 and 5% in Groups I and II, respectively. Eight patients (50%) in Group I required discontinuation of tacrolimus, seven because of biopsy-proven tacrolimus nephrotoxicity and one secondarily to interstitial pneumonitis. Wound complications were the most frequent adverse event reported in both groups. CONCLUSIONS: The combination of tacrolimus and sirolimus was associated with a low risk of AR in this cohort of high-risk renal transplant recipients. However, 50% of patients who received standard tacrolimus and reduced sirolimus combination had to be discontinued from the regimen because of biopsy-proven nephrotoxicity. These preliminary results provide evidence that sirolimus should not be added to tacrolimus without dosage adjustments. We have discontinued recruitment of patients to the standard tacrolimus and reduced sirolimus combination and we have tightened our criteria for selection of marginal donor kidneys with our high-risk renal transplant recipients.