The Nephrologist's Role in the Collaborative Multi-Specialist Network Taking Care of Patients with Diabetes on Maintenance Hemodialysis: An Overview.

Diabetes mellitus is the leading cause of renal failure in incident dialysis patients in several countries around the world. The quality of life for patients with diabetes in maintenance hemodialysis (HD) treatment is in general poor due to disease complications. Nephrologists have to cope with all these problems because of the "total care model" and strive to improve their patients' outcome. In this review, an updated overview of the aspects the nephrologist must face in the management of these patients is reported. The conventional marker of glycemic control, hemoglobin A1c (HbA1c), is unreliable. HD itself may be responsible for dangerous hypoglycemic events. New methods of glucose control could be used even during dialysis, such as a continuous glucose monitoring (CGM) device. The pharmacological control of diabetes is another complex topic. Because of the risk of hypoglycemia, insulin and other medications used to treat diabetes may need dose adjustment. The new class of antidiabetic drugs dipeptidyl peptidase 4 (DPP-4) inhibitors can safely be used in non-insulin-dependent end-stage renal disease (ESRD) patients. Nephrologists should take care to improve the hemodynamic tolerance to HD treatment, frequently compromised by the high level of ultrafiltration needed to counter high interdialytic weight gain. Kidney and pancreas transplantation, in selected patients with diabetes, is the best therapy and is the only approach able to free patients from both dialysis and insulin therapy.

Acute Kidney Ischemic Injury in a Rat Model Treated by Human Omental Mesenchymal Stem Cells.

BACKGROUND: Mesenchymal stem cells (MSCs) may provide a novel clinical approach for acute kidney injury (AKI), which represents a severe health care condition. The human omentum is an important source of MSCs. We investigated the effects of human omental mesenchymal stem cells (HO-MSCs) after induction of ischemic AKI in a rat model. METHODS: The ischemic-reperfusion injury (IRI) was induced at reperfusion following a 45-minute clamping of renal vessels. Twenty animals were used in this study. Each rat was randomly assigned to 1 of 2 groups: G1 (control, n = 10; IRI infusion of phosphate buffer solution) or G2 (HO-MSCs, n = 10; IRI infusion of HO-MSCs). The infusions were performed in the parenchyma at reperfusion. Renal function at 1, 3, 5, and 7 days was assessed. At sacrifice, histologic samples were analyzed by light, and renal injury was graded. RESULTS: HO-MSCs induced an accelerated renal exocrine functional recovery, demonstrated by biochemical parameters and confirmed by histology showing that histopathological alterations associated with ischemic injury were less severe in cell-treated kidneys as compared with control groups (P < .05). The renal damage degree was significantly less in the animals of the HO-MSC group (P < .0001). CONCLUSIONS: These results suggest that HO-MSCs could be useful in the treatment of AKI in a rat model with possible potential implication in clinical setting.

Partial Portal Vein Arterialization to Treat Toxic Acute Liver Failure in Elderly Rats.

INTRODUCTION: Toxic acute liver failure can be fatal even after liver transplantation. Since there are data only in young rats, the aim of our study was to verify the effectiveness of the increase of oxygen to the liver by partial portal vein arterialization (PPVA) in elderly rats with acute liver failure induced by carbon tetrachloride (CCl4) intoxication. METHODS: Twenty elderly (30 months) Sprague-Dawley rats underwent a CCl4 intoxication (5 mL/kg). Animals were divided after 24 hours (n = 10 per group) to either undergo PPVA (G1, treated group) or be untreated (G2, control group). PPVA consisted of a shunt between the left renal artery and splenic vein after nephrectomy and spelnectomy. The G2 group animals underwent nephrectomy and splenectomy only. The 10-day survival was evaluated. Before euthanasia, blood samples from the portal vein were detected for blood gas analysis. Liver injury was evaluated by the serum alanine aminotransferase (ALT) and prothrombin time levels. Histology was done to evaluate the liver necrosis. Hepatocyte regeneration was assessed by the mitotic index at immunohistochemistry. RESULTS: The PPVA has resulted in a significant increase in the oxygen partial pressure and saturation in portal blood. A survival improvement at 10 days was registered in the PPVA-treated rats (90% vs 30%; P = .0065). After 24 hours from intoxication, ALT was high in both groups. A rapid decrease of ALT was observed in G1 as compared to G2. At the same time, livers showed a severe centrolobular necrosis. In the suviving G2 rats, a moderate necrosis was present, while only a mild necrosis was observed in the G1 rats. An higher mitotic index was detected in rats treated with PPVA. CONCLUSIONS: In our experimental study, the presence of oxygenated blood in the portal venous system following the PPVA procedure had positive effects on liver regeneration and rats' survival. The PPVA treatment had beneficial effects in elderly rats.

Post-operative outcomes and predictors of mortality after colorectal cancer surgery in the very elderly patients.

BACKGROUND: The frailty of the very elderly patients who undergo surgery for colorectal cancer negatively influences postoperative mortality. This study aimed to identify risk factors for postoperative mortality in octogenarian and nonagenarian patients who underwent surgical treatment for colorectal cancer. METHODS: This is a single institution retrospective study. The primary outcomes were risk factors for postoperative mortality. The variables of the octogenarians and nonagenarians were compared by using t-test, chi-square test, and Fisher exact test. A multivariate logistic regression analysis was carried out on the combined cohorts. RESULTS: we identified 319 octogenarians and 43 nonagenarians (N = 362) who underwent surgery for colorectal cancer at the Sant'Orsola-Malpighi university hospital in Bologna between 2011 and 2015. The 30-day post-operative mortality was 6% (N = 18) among octogenarians and 21% (N = 9) for the nonagenarians.The groups significantly differed in the type of surgery (elective vs. urgent surgery, p < 0.0001), ASA score (p = 0.0003) and rates of 30-day postoperative mortality (6% vs. 21%, p = 0.0003).In the multivariate analysis ASA > III (OR 2.37, 95% CI [1.43-3.93], p < 0,001), and urgent surgery (OR 2.17, 95% CI [1.17-4.04], p = 0.014) were associated to post-operative mortality. On the contrary, pre-operative albumin≥3.4 g/dL (OR 0.14, 95% CI [0.05-0.52], p = 0.001) was associated with a protective effect on postoperative mortality. CONCLUSIONS: In the very elderly affected by colorectal cancer, preoperative nutritional status and pre-existing comorbidities, rather than age itself, should be considered as selection criteria for surgery. Preoperative improvement of nutritional status and ASA risk assessment may be beneficial for stratification of patients and ultimately for optimizing outcomes.

[Choice and management of anticoagulation during CRRT].

Continuous renal replacement therapies (CRRT) are widely used in the treatment of acute kidney injury. Several causes, related to the treatment itself or to the patient's condition, determine the coagulation of the extracorporeal circuit. These interruptions (or down-time) have a negative impact on the effectiveness of the treatment in terms of solute clearance and fluid balance. Historically, the choice of anticoagulant has fallen on unfractionated heparin because it is cheap and easy to use. Today, the use of citrate is recommended in most instances because of its high efficacy and safety. Several studies demonstrate the superiority of citrate in terms of filter survival. The reduction of down-time results in a reduction of the delta between the prescribed dialysis dose and the dose that is actually administered (ml/Kg/hour of collected effluent). The literature also agrees that there is a reduction in the incidence of major bleeding events when citrate is used instead of heparin, although there is no impact on mortality rates. Some technical and clinical complexities, secondary to citrate action both as anticoagulant and buffer, still exist in the use of regional citrate anticoagulation. However, complications due to citrate use, such as acid-base balance disorders and hypocalcaemia, are rare and easily reversible. There is not much data about the costs and benefits of using citrate instead of heparin; according to the experience within our own Unit, we have observed a reduction in costs when the data is normalized for 35 ml of effluent administered. Appropriate protocols, accurate surveillance and the automated management of regional citrate anticoagulation thanks to dedicated software make this technique safe and effective.

How Safe is Performing Cholecystectomy in the Oldest Old? A 15-year Retrospective Study from a Single Institution.

BACKGROUND: Globally, the number of people aged 80 years or over, the "oldest old," is the fastest growing population group. Because of the strong association between age and gallstone disease, both prevalence and incidence of this disease are increasing. The feasibility of the cholecystectomy in octogenarians has been evaluated in several studies that confirmed the safety of the operation. However, the safety of this procedure in nonagenarians is still controversial. The aim of this study was to evaluate the safety of cholecystectomies in nonagenarians and identify related predictors for postoperative hospital length of stay (LOS) and in-hospital mortality up to 30 days postoperatively. METHODS: More than 500 cholecystectomies, both open and laparoscopic, were performed between January 2000 and September 2015 at our institution in patients 80 years and older. These statistics include both elective and emergent admissions. A retrospective review of charts over the last 15 years was conducted to compare mortality and length of postoperative stay among two patient groups: 319 octogenarians and 36 nonagenarians. Parameters evaluated include demographics, surgical presentation, American Society of Anesthesiologists (ASA) score, main diagnosis, comorbidities, type of surgery performed, LOS and in-hospital mortality. All data were analyzed with STATA (v.13) software, using a multivariate logistic regression after determining the statistically significant variables through a stepwise regression. CONCLUSIONS: We found out that being nonagenarian, compared to octogenarian, is not a significant risk factor in terms of LOS and in-hospital mortality within 30 days postoperatively. Despite that, the mortality rate among nonagenarians is still remarkably high as almost every patient was admitted in an emergent setting. The most remarkable predictor for mortality among the two groups was an "afternoon/night emergency" surgical presentation (OR 25.5, CI 1.53-42.35, p = 0.02). Thus, the surgical emergency management for gallbladder disease at our institution should be critically reevaluated. Performing the procedure in laparoscopy predicted a significant reduction (-5 days, CI -8.5 to -1.4, p = 0.006) of LOS, while presenting with "gallbladder and bile duct stones" (+6.3 days, CI 1.5-11.1, p = 0.01) or "acalculous cholecystitis" (+4.7 days, CI 0.4-9.2, p = 0.03) had the opposite effect. Despite the remarkable mortality rate of our series, being nonagenarian should not be considered as a reason to avoid gallbladder surgery in case of need. Our study suggests that nonagenarians are more suitable surgical candidates than may have previously expected.

Dialyzability of Oxycodone and Its Metabolites in Chronic Noncancer Pain Patients with End-Stage Renal Disease.

OBJECTIVES: Opioids are the preferred analgesic drugs to treat severe chronic pain conditions among dialysis patients; however, knowledge about their dialyzability features is limited. Oxycodone is increasingly used for the treatment of chronic pain conditions as oral controlled release (CR) tablets; however, evidence about this drug and its metabolites' dialyzability is lacking. METHODS: We assessed, during 4-hour dialysis sessions, the effect of standard hemodialysis (HD) and online hemodiafiltration (HDF) methods on the plasma concentration of oxycodone and its metabolites in n = 20 chronic pain patients with end-stage renal disease who were stably treated with oral CR oxycodone. Chromatographic techniques were used to evaluate the studied compounds' plasma concentrations at three different time points during dialysis. RESULTS: Mean plasma concentrations of oxycodone and noroxycodone in the sample showed an overall reduction trend over time, but it was less enhanced for noroxycodone. Mean reduction in oxycodone and noroxycodone arterial concentrations was significant and higher with HDF (54% and 27%, respectively) than with HD (22% and 17%, respectively). Analysis of the regression of these compounds' clearance on their increasing arterial concentration showed a more stable and linear clearance prediction with HDF (roughly 85 mL/min); with HD, for increasing arterial concentration, clearance of oxycodone decreased while noroxycodone clearance increased. DISCUSSION: While no oxymorphone or noroxymorphone metabolites were detected, limited dialyzability of oxycodone and noroxycodone was documented along with insignificant postdialysis pain increment. This evidence will contribute toward considerations as to the safety of the use of oxycodone in dialysis patients in the future.

Liver resection for metastases from colorectal cancer in very elderly patients: New surgical horizons.

INTRODUCTION AND AIM: Patients with colorectal cancer (CRC) may develop liver metastases. Surgical resection remains the best treatment of choice for colorectal liver metastases (CRLM) according to resectability criteria, with a long-term survival of 25% up to 41% after 5 years. Advanced age is associated with a higher incidence and co-morbidity, particularly cardiovascular disease, as well as deteriorating physiological reserves. The aim of this study was to analyse the overall and disease-free survival for patients with CRLM according to their chronological age. METHODS: Patients with CRLM were enrolled in the study. Data on gender, age, co-morbidity, metastasis characteristics (number, size and total metastatic volume (TMV)), use of perioperative chemotherapy and operative and post-operative complications were collected. Then, according to recent World Health Organization (WHO) guidelines, the patients were grouped by age. Statistical analysis was performed using the software R (ver. 2.14.1). RESULTS: Hepatic resection was performed in 149 patients (21 patients in the very elderly group, 79 in the elderly group and 49 in the younger group). The three groups were comparable in terms of operative duration, transfusion rate, length of high-dependency unit (HDU) stay and post-operative hospital stay. The very elderly group showed a non-significant increase in post-operative morbidity. The 30-day and 60-day/inpatient mortality rates increased with age without any significant statistically difference between the three groups (very elderly group 4.8% and 4.8%; elderly group: 2.5% and 3.8%; and younger group 0% and 2%). At 5 years, the overall survival was 28.6% for very elderly patients (≥75 years), 33.3% for elderly patients (≥65 to <75 years) and 43.5% for younger patients (≤65 years). The 1-, 3- and 5-year disease-free survival was similar across the groups. CONCLUSIONS: Liver resection for CRLM in carefully selected patients above the age of 75 can be performed with acceptable morbidity and mortality rates, similar to those in younger patients. Moreover, the severity of CRLM in elderly patients is proven to be lesser than in younger patients. Thus, we can conclude that advanced chronological age cannot be considered a contraindication to hepatic resection for CRLM.

Resection of hepatocellular carcinoma in elderly patients and the role of energy balance.

INTRODUCTION: Progressive functional impairment with age has a significant impact on perioperative risk management. Chronic liver diseases induce a strong oxidative stress; in the elderly, in particular, impaired elimination of free radicals leads to insufficient DNA repair. The events associated with a weak response to growth factors after hepatectomy leads to a decline in liver regeneration. Hypercholesterolemia is highly prevalent in the elderly, which may alter the coenzyme Q10 (CoQ) levels and in turn the cellular energy balance. This condition is commonly treated with statins. The aim of this study is to investigate the role of preoperative cellular energy balance in predicting hepatocellular carcinoma (HCC) postresection outcomes. MATERIALS AND METHODS: In a 5-year period (2009-2013), elderly patients with hypercholesterolemia, cardiovascular disease, and diabetes mellitus, undergoing HCC resection, were recruited and grouped by age (<75 and ≥ 75 years old). All patients were previously treated with statins. The risk factors associated with hospital morbidity/mortality and prolonged length of stay (LOS) were evaluated. RESULTS: Forty-five elderly patients were recruited and grouped according to their treatment: Group 1 (n = 23) was treated with statins alone (control group), whereas Group 2 (n = 22) was treated with statins and a CoQ analogue, 3 weeks from the surgery and at least a month later (experimental group). The majority of our patients were treated with atorvastatin [n = 28 (53.84%)] and the minority with simvastatin [n = 17 (32.69%)], 20 mg/day, for at least 3 years before the surgery. Perioperative mortality was observed in one patient of Group 1 (4.3%). Morbidities were noted in 13 patients of Group 1 (56.5%) and four patients of Group 2 (18.2%). The control group showed delayed functional recovery, muscle weakness, increased infection rate, and pleural effusion due to prolonged bed rest (hospital stay 13 days (7-19) vs. 8.5 days (5-12)), compared with the experimental group. The overall survival at 5 years was similar for both groups (n = 10 patients (43%) in Group 1 vs. n = 10 patients (45%) in Group 2). CONCLUSION: In the elderly population, survival is closely linked to postoperative morbidity and mortality. In our study, prolonged LOS was found to be related to delayed bioenergetic recovery. When limited, risk factors such as infections, neutropenia, and red blood cell transfusions could lower LOS and mortality of elderly patients with HCC. Higher age was associated with greater postoperative morbidity and successful hospital stay.

Portal blood arterialization with an extracorporeal device to treat toxic acute hepatic failure in a swine model.

PURPOSE: This study aimed to determine whether a controlled portal blood arterialization by a liver extracorporeal device (L.E.O2 NARDO) is effective in treating acute hepatic failure (AHF) induced through CCl4 administration in a swine model. METHODS: 20 swine with AHF induced by intraperitoneal injection of carbon tetrachloride (CCl4) in oil solution, were randomly divided into two groups: animals receiving L.E.O2 NARDO treatment 48 h after the intoxication (study group); animals sham operated 48 h after the intoxication (control group). Blood was withdrawn from the iliac artery and reversed in the portal venous system by an interposed extracorporeal device. Each treatment lasted 6 h. The survival was assessed at 5 days after L.E.O2 NARDO treatment or sham operation. In both groups blood samples were collected for biochemical analysis at different time points and liver biopsies were collected 48 h after intoxication and at sacrifice. RESULTS: We observed decreased transaminases levels and a more rapid INR recovery in the study group, as compared to the control group. Eight animals of the study group vs. two animals of the control group survived at five days after surgery with a statistically significant difference (p<0.05). Liver biopsies performed at sacrifice showed a reduction of the damaged hepatic areas in the study group as compared to the control group. CONCLUSIONS: Arterial blood supply in the portal system through the L.E.O2 NARDO device is easily applicable, efficacious, and safe in a swine model of AHF induced by CCl4 intoxication.

Partial portal vein arterialization in acute liver failure.

Experimental studies have shown that increasing the oxygen supply to the liver through partial portal vein arterialization (PPVA) enhances liver regeneration after extensive liver resection or drug intoxication. In the last two decades, several PPVA procedures were performed in humans with the aim to prevent or treat acute liver failure (ALF) following major hepatobiliary surgery or other etiology. The aim of this review was to analyze literature data on PPVA and report our experimental and clinical experience of this procedure. In this setting, we report our positive experience in the realization and clinical application of an extracorporeal device able to increase the oxygenated blood delivered to the liver through the umbilical vein and to support liver function in a man subjected to an extended liver resection. PPVA procedure has shown promising results in the treatment of ALF following major hepatobiliary surgery or from other etiology. Moreover, less invasive approaches to PPVA demonstrated to be safe and efficacy. It is clear that further investigations must be done to fully understand the potentiality of PPVA as a strategy to treat ALF.

Effect of colic vein ligature in rats with loperamide-induced constipation.

INTRODUCTION: Medical treatment in chronic constipation is not always successful. Surgery is indicated in unresponsive selected severe cases. This study presents the distal venous colic ligation in rat as a novel surgical approach. MATERIALS AND METHODS: 16 rats (study group) were evaluated in 3 phases of 6 days each: A (normal conditions), B (loperamide-induced constipation), and C (colic vein legation) and compared with rats treated in phase C with PEG 4,000 (control group). Blood biochemical and physiological parameters, daily fecal water content (FWC), and histological analysis were performed in all study phases. RESULTS: No biochemical and physiological parameters changes were observed. FWC decreased in phase B and increased in phase C in both groups with a grow up to 2.3-fold in study group compared to control (P < 0.0001). Moreover, in study group, a high number of colonic goblet cells were detected (phase C versus phase B: P < 0.001) while no differences were registered in control. CONCLUSION: By ligature of the colic vein in constipated rats, an increase in FWC and goblet cells higher than in PEG treated rats was detected. The described surgical procedure appeared effective, simple, and safe; further studies in animal models, however, are necessary to assess its clinical applicability.

Mesenchymal stem cells and islet cotransplantation in diabetic rats: improved islet graft revascularization and function by human adipose tissue-derived stem cells preconditioned with natural molecules.

Hypoxia plays an important role in limiting the engraftment, survival, and function of intrahepatically transplanted islets. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection but also to promote revascularization. Among different possible origins, adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose tissue-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs (hMSCs). Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF) as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

Aortoiliac surgery concomitant with kidney transplantation: a single center experience.

INTRODUCTION: Aortoiliac pathology in kidney allograft recipients is not rare but treatment timing is controversial. As most publications on this topic are case reports its difficult to evaluate long-term outcomes of those clinical challenges. Herein we report long-term results of these procedures. METHODS: From 1970 to 2006, 1544 kidney transplants were performed in our center. Thirty patients underwent aortoiliac surgery simultaneously with kidney transplantation. We analyzed their clinical records to come up with outcomes of these complex clinical challenges. RESULTS: Vascular pathology was distributed as following: 19 stenoses treated with endarterectomy (15), aortoiliac bypass (two), aorto-bi-iliac bypass (one) and aorto-bifemoral bypass (one); and 11 aneurysms treated with arterioplasty (four), aorto-bi-iliac bypass (four) and iliac-iliac bypass (three). In 24 cases (80%) the necessity of vascular surgery was established intraoperatively as vessels conditions did not permit safe anastomoses and jeopardized graft survival. Mean follow-up was 59 months (12-125). Five (16.7%) grafts were lost and three (10%) patients died in the first postoperative month: acute myocardial infarction (two) and non-viable kidney (one). Three patients died six, seven and 10 yr after the procedure. Nineteen patients are currently well with functioning grafts. CONCLUSIONS: Surgical correction of aortoiliac pathology may be performed simultaneously with kidney transplantation with acceptable outcome. This complex surgery can be performed in centers with experienced vascular surgeons. Specific vascular imaging should be performed regularly on patient at risk of aortoiliac disease before insertion and while on waiting list.

Radical surgical treatment of recurrent hepatic hydatidosis.

BACKGROUND/AIMS: The treatment of relapsing hydatidosis must aim at the reduction of both morbidity and mortality rates and the risk of new recurrences. METHODOLOGY: Thirty-three patients with recurrence of hepatic ecchinococcosis were observed between January 1975 and May 2001. All selected patients received a first conservative surgical treatment, and recurrences developed in a period ranging from 1 to 46 years from the therapy. All patients with secondary hydatidosis were then submitted to radical surgical treatment. Ultrasound examinations, the first after 3 months from surgery, were performed to evaluate disease recurrence. Intraoperative morbidity and mortality were also evaluated. RESULTS: No intraoperative mortality was encountered. Intraoperative and postoperative morbidity were 6% and 12% respectively. During follow-up, (mean duration 53 months) no recurrences were recorded. CONCLUSIONS: Radical surgical approach is the best treatment of recurrent hydatid cysts as it represents a valid compromise between the need of a surgical radicality and a low intraoperative and postoperative morbidity.