Bone morphogenic proteins-2, -4, -6 and 7 in non-muscle invasive bladder cancer.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-ß (TGF-ß) family and may play an important role in the regulation of malignant cells in bladder cancer. The aim of the present study was to investigate BMP expression in non-muscle invasive bladder cancer. Tumor tissue samples from 71 patients treated with transurethral resection and 10 samples of normal bladder tissue were stained using immunohistochemistry for BMP-2, -4, -6 and -7. The levels of BMP were correlated with the number and size of tumors in the bladder, the pathohistological findings as well as with tumor recurrence and progression. The results of the present study demonstrated that BMP-2 and -7 are highly expressed in normal bladder tissue, but significantly downregulated in cancer samples. This reduction correlates with a faster rate of tumor recurrence as well as with an increase in the number of recurrent tumors. There was no evident interrelation between BMP-2 and -7 reduction and changes in tumor grade and stage. In conclusion, BMP-2 and -7 are potential prognostic factors for tumor recurrence and further studies on BMP and bladder cancer are needed to confirm these results.

Differences in CVVH vs. CVVHDF in the management of sepsis-induced acute kidney injury in critically ill patients.

We hypothesized that patients with sepsis and AKI, especially patients without preserved renal function, and treated with continuous veno-venous hemodiafiltration (CVVHDF), have lower risk for mortality than patients treated with continuous veno-venous hemofiltration (CVVH). Patients were included if they fulfilled the diagnosis of severe sepsis or septic shock, suffered AKI and received continuous renal replacement therapy (CRRT) in intensive care unit. There were 62 patients treated by CVVH and 75 treated by CVVHDF. Mean survival time was longer in CVVHDF group with oliguric/anuric patients than in CVVH group. CVVH, and not classic risk factors, was associated with higher overall mortality in oliguric/anuric patients. In the linear regression model, hourly urine output was the strongest and positive predictor of longer survival. CVVHDF is according to our results a CRRT modality of choice for the treatment and lower mortality of septic patients with AKI where renal function is no longer preserved. CRRT has been associated with improved renal recovery, but it should be started earlier in AKI evolution with still preserved hourly urine output which is the most sensitive and prognostic marker of survival in septic patients with AKI.

Membrane therapeutic plasma exchange with and without heparin anticoagulation.

BACKGROUND: Administration of an anticoagulant during therapeutic plasma exchange (TPE) is necessary to avoid circuit clotting and impaired treatment effectiveness. Citrate is the preferred anticoagulant for apheresis worldwide, and unfractionated heparin (UH) is the second most preferred, yet there are only a few published studies regarding the use of UH during TPE. There are even fewer studies regarding the use of low-molecular-weight heparin (LMWH) and TPE performed without anticoagulation. MATERIALS AND METHODS: We retrospectively analyzed the database of the Department of Nephrology at Zagreb University Hospital Center from 1982 to 2014 to test the safety of various heparin anticoagulation in TPE. We grouped procedures according to anticoagulation type (UH, LMWH, and no anticoagulation) and compared differences in the use of anticoagulants during our study period, patient populations, replacement fluids, and complications. RESULTS: Complications were recorded during 11.1% of the 9,501 procedures. The incidence of any recorded complication was significantly higher in the LMWH group (21.2%) compared to the group with no anticoagulation (16.3%) and the UH group (9.5%) (P < 0.001). Similarly, the blood clotting in the extracorporeal circuit was most common in the LMWH group (LMWH, 12.0%; no anticoagulation, 6.3%; UH, 2.4%; P < 0.001). Incidents of bleeding complications were very low and occurred during or after 13 TPE sessions (0.1% of all procedures). CONCLUSIONS: Our findings indicate that TPE procedures can be conducted safely with UH and, when necessary, without anticoagulation. The use of LMWH was associated with more complications when compared with use of UH and to TPE done without anticoagulation. Further studies are necessary to study its use during TPE procedures.

Continuous Veno-Venous Hemofiltration Improves Survival of Patients With Congestive Heart Failure and Cardiorenal Syndrome Compared to Slow Continuous Ultrafiltration.

Continuous veno-venous hemofiltration (CVVH) could modulate the inflammatory response by removal of circulating cytokines and therefore improve cardiac function in patients with heart failure (HF). We hypothesized that patients with developed cardiorenal syndrome and treated with CVVH have lower risk for mortality than other patients treated with slow continuous ultrafiltration (SCUF). This was a prospective, longitudinal follow-up study for 24 months duration. In total, 120 patients were recruited from the intensive care units. Only patients with cardiorenal syndrome type 1 and 2 were enrolled. 54 CVVH and 23 SCUF patients survived. Mean survival time was longer in CVVH group with cardiomyopathy than in the SCUF group. When we compared patients with cardiomyopathy and hourly urine output <10 mL/h, mean survival time was significantly longer in patients treated with CVVH. This is the first study to analyze the impact of different CRRT modalities (CVVH vs. SCUF) on survival of patients with HF and who developed cardiorenal syndrome. Better survival in patients treated with CVVH, which is mostly pronounced in patients with cardiomyopathy, is a consequence of a better preserved hourly urine output. Longer survival in patients with cardiomyopathy is most probably related to cytokine removal by CVVH with smaller UF rates and longer duration of each treatment. Slow continuous ultrafiltration remains the method of choice in patients with HF and preserved renal function but in cases of developed cardiorenal syndrome is much inferior to CVVH.

Expression of BMP-2 in Vascular Endothelial Cells of Recipient May Predict Delayed Graft Function After Renal Transplantation.

BACKGROUND/AIMS: Delayed graft function (DGF) is associated with adverse outcomes after renal transplantation. Bone morphogenetic protein-2 (BMP-2) is involved in both endothelial function and immunological events. We compared expression of BMP-2 in epigastric artery of renal transplant recipients with immediate graft function (IGF) and DGF. METHODS: 79 patients were included in this prospective study. Patients were divided in IGF group (64 patients) and DGF group (15 patients). BMP-2 expression in intima media (BMP2m) and endothelium (BMP2e) of epigastric artery was assessed by immunohistochemistry. RESULTS: Lower intensity of BMP2e staining was recorded in DGF compared to IGF. In DGF patients, 93% had no expression of BMP2e and 7% had 1st grade expression, compared to 45% and 41% in IGF group, respectively (P=0.001) (P<0.001 for no expression and P = 0.015 for 1st grade expression). Patients who had BMP2e staining positive had lower odds for DGF (OR 0.059 [0.007, 0.477]) and this remained significant even after adjustment for donor and recipient variables, cold ischemia time, and immunological matching (OR 0.038 [0.003, 0.492]). CONCLUSIONS: Our results demonstrate that BMP-2 expression in endothelial cells of epigastric arteries may predict development of DGF.

A randomized crossover study comparing membrane and centrifugal therapeutic plasma exchange procedures.

BACKGROUND: Therapeutic plasma exchange (TPE) can be performed either on a membrane-based system (mTPE) or on a device that separates blood components by centrifugation (cTPE). The number of studies in this field is limited. This randomized study is the first that offers data on the membrane-based Diapact device (B. Braun Medical, Inc.) for TPE procedures and compares it to the centrifuge-based Spectra Optia (Terumo BCT, Inc.). STUDY DESIGN AND METHODS: Twenty-seven patients were enrolled in this randomized prospective head-to-head study comparing the mTPE and cTPE systems. Procedures on both devices were standardized and the plasma removal efficiency (PRE); total procedure time (including setup and priming time); and removal efficiencies of blood cells, immunoglobulin (Ig)G, and fibrinogen for all procedures were analyzed. RESULTS: While both systems removed similar amounts of plasma, it took the cTPE device a mean of 101.5 ± 24.6 minutes to finalize a procedure that was one-third less than procedures on the mTPE device (157 ± 26.2 min; p < 0.0001), due to a difference in PRE between the Spectra Optia (83.0% ± 4.9%) and the Diapact (53.2% ± 6.6%; p < 0.0001). The difference in removal efficiencies of IgG and blood cells were not significantly different but the Spectra Optia was more efficient in removing the larger fibrinogen protein than the Diapact (72.3% ± 8.5% vs. 62.9% ± 16.1%, respectively; p < 0.02). CONCLUSION: This study shows that, although both systems perform adequate and safe TPE procedures, those on the Spectra Optia in comparison to the Diapact are more efficient in terms of plasma removal and significantly shorter.

Therapeutic Plasma Exchange-Does Age Matter? A Single-Center Study.

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique designed for the removal of substances with large molecular weight from the plasma. However, it is not commonly performed in children and the elderly because of concern of potential complications. The Department of Nephrology at Zagreb University Hospital Centre's database (8335 procedures, 981 patients) was retrospectively analyzed from 1982 to 2011 to record indications, applications, and safety of TPE use in children (≤18 years), adults (>18 and <65 years), and elderly patients (≥65 years). Indications, blood access, replacement fluid, and anticoagulation during TPE differed among age groups. Significantly more complications were recorded in the youngest and eldest patients compared with the adults (12.2% and 12.7% vs. 9.9%, respectively), while the severity of complications did not differ significantly among the age groups. Our results indicate that TPE may be performed relatively safely in all age groups when the patients' differences are acknowledged prior to prescribing the procedure.

[[GUIDELINES FOR THE PREVENTION, MONITORING AND THERAPY OF CHRONIC KIDNEY DISEASE-METABOLIC BONE DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE].]

Chronic kidney disease (CKD) is a systemic disease with numerous complications associated with increased morbidity and mortality. Chronic kidney disease-metabolic bone disease (CKD-MBD) starts at early stages of CKD with phosphorus accumulation and consequent initiation of numerous events that result with the development of secondary hyperparathyroidism with changes on bones and extraskeletal tissues. The most important and clinically most relevant consequences of CKD-MBD are vascular calcifications which contribute to cardiovascular mortality. Patients with the increased risk for the development of CKD-MBD should be recognized and treated. Prevention is the most important therapeutic option. The first step should be nutritional counseling with vitamin supplementation if necessary and correction of mineral status. Progression of CKD requires more intensive medicamentous treatment with the additional correction of metabolic acidosis and anemia. Renal replacement therapy should be timely initiated, with the adequate dose of dislaysis. Ideally, preemptive renal transplantion should be offered in individuals without contraindication for immunosuppressive therapy.

SIGNIFICANCE OF FIBROBLAST GROWTH FACTOR 23 IN ACUTE KIDNEY INJURY.

Acute kidney injury is a clinical syndrome associated with increased patient morbidity and mortality, as well as serious short-term and long-term consequences, especially in the perioperative period. Yet, patients having suffering from temporary acute kidney injury and achieving full recovery of kidney function usually complain of poor quality of life associated with loss of energy and limited physical activity. Therefore, there is a necessity for a novel biomarker of acute kidney injury with better features than currently used serum creatinine and urine output. So far, several investigations have demonstrated that the fibroblast growth factor 23 could be that desperately searched novel biomarker of acute kidney injury. It cannot only detect kidney dysfunction at the time but also before the injury process begins. Moreover, serum levels of the fibroblast growth factor 23 can predict adverse progression of the kidney injury. However, the role of the fibroblast growth factor 23 in the acute but also in chronic kidney dysfunction is still a riddle that requires additional research to clarify it.

The Effect of Preserved Residual Renal Function on Left Ventricular Structure in Non-Anuric Peritoneal Dialysis Patients.

BACKGROUND/AIMS: Residual renal function (RRF) has been shown to influence survival of peritoneal dialysis (PD) patients. This study examined the relations between RRF and left ventricular hypertrophy (LVH) before switching on dialysis treatment and observed during 18 months on PD treatment. METHODS: A prospective longitudinal study was performed in 50 non-anuric (defined as >200 mL urine output in a 24-hour period) PD patients. Echocardiography, RRF and other known risk factors for the increase of LV mass index (LVMi) were determined at study baseline and the end of follow-up. RESULTS: There was 78% patients with LVH in end-stage renal disease (ESRD) baseline and 60% at the end of follow-up. RRF at the start of the study showed no significant difference between patients with normal and increased LVMi, as well as in daily collection of urine. After 18 months, patients with decreased LVMi had better RRF, lower CRP and better Kt/V compared to patients with increased LVMi (p < 0.001). Patients with better preserved RRF not only had significantly higher total Kt/V, but were less anemic and hypoproteinemic and lesser presence of LVH. CONCLUSIONS: PD in non-anuric ESRD patients the first 18 months has a positive effect on the preservation of RRF and partial regression of left ventricular remodeling.

Cardiovascular surgery after renal transplantation--indications, complications and outcome.

UNLABELLED: Cardiovascular diseases are the major cause of morbidity and mortality in renal transplant recipients. We report our experience in the treatment of patients with renal allograft who required cardiovascular surgery. METHODS: Indications for cardiovascular surgery, postoperative complications, and outcome were recorded in a cohort of renal transplant recipients. RESULTS: Thirteen patients, five female and eight male, aged from 46 to 75 years underwent cardiac surgery after renal transplantation at University Hospital Centre Zagreb. Isolated coronary artery bypass grafting (CABG) was performed in five patients, valve replacement in six patients, reconstruction of ascending aorta, and aortic arch in one patient as well as the extraction of tumor formation from the heart. Three patients had simultaneous CABG and valve replacement. Four patients (31%) required acute hemodialysis after the surgery and two of them continued with dialysis after discharge. Postoperative course was complicated with infections of the lower respiratory tract in two patients, pericardial tamponade, unstable sternum with bleeding from the wound, increased drainage from the chest demanding additional hemostasis, and in-stent restenosis in the previously placed stents, in one patient each. Fatal outcome occurred in two patients who underwent simultaneous valvular replacement and CABG within one month from the surgery. CONCLUSION: In patients with functional renal allograft cardiovascular, surgery procedures are safe, but associated with increased incidence of perioperative complications, with majority of patients maintaining their graft function.

BMP-7 PROTEIN EXPRESSION IS DOWNREGULATED IN HUMAN DIABETIC NEPHROPATHY.

Bone morphogenetic protein-7 (BMP-7) is expressed in all parts of the normal kidney parenchyma, being highest in the epithelium of proximal tubules. It protects kidney against acute and chronic injury, inflammation and fibrosis. Diabetic nephropathy is the leading cause of chronic kidney disease, and is characterized by decreased expression of BMP-7. The aim of our study was to analyze whether the expression of BMP-7 is significantly changed in advanced stages of human diabetic nephropathy. Immunohistochemical analysis of the expression of BMP-7 was performed on archival material of 30 patients that underwent renal biopsy and had confirmed diagnosis of diabetic nephropathy. Results showed that BMP-7 was differently expressed in the cytoplasm of epithelial cells of proximal tubules and podocytes among all stages of diabetic nephropathy. At early stages of diabetic nephropathy, BMP-7 was strongly positive in proximal tubules and podocytes, while low expression was recorded in the majority of samples at advanced stages. In conclusion, increased expression of BMP-7 at initial stages of diabetic nephropathy with subsequent decrease at advanced stage highlights the role of BMP-7 in the protection of kidney structure and function. Further investigations should be focused on disturbances of BMP-7 receptors and signaling pathways in patients with diabetic nephropathy.

The novella about diabetic nephropathy.

Diabetic nephropathy is a common complication in patients with diabetes mellitus and one of the major reasons for renal replacement therapy in Croatia, Europe and the United States. It is characterized by proteinuria, decline in glomerular filtration, hypertension, and high risk of cardiovascular morbidity and mortality. Deterioration of renal function in diabetic nephropathy develops through five clinical stages characterized by the respective histologic description. Genetic susceptibility, hyperglycemia, high blood pressure and duration of diabetes mellitus definitely play a role in the pathogenetic sequence. Early diagnosis, appropriate patient follow up and treatment are essential to improve the outcomes. Interdisciplinary approach and close collaboration of nephrologists and diabetologists are essential for timely detection of disease progression. Tight glycemic control under the supervision of diabetologists, screening of patients, and once a year report of albuminuria and glomerular filtration allow for detection of renal damage in the early stages and timely referral to a nephrologist. The points of interest given in this overview are description of clinical staging in relation to pathologic classification, repetition of basic causal features, and brief analysis of treatment.

Expression of bone morphogenetic proteins 4, 6 and 7 is downregulated in kidney allografts with interstitial fibrosis and tubular atrophy.

PURPOSE: Bone morphogenetic proteins (BMPs) are pleiotropic growth factors. This paper investigates the connection between the expression pattern of BMPs in kidney allograft tissue versus the cause of allograft dysfunction. METHODS: The expression pattern of BMP2, BMP4, BMP6 and BMP7 in 50 kidney allografts obtained by transplant nephrectomy is investigated. Immunohistochemical staining is semiquantitatively evaluated for intensity to identify the expression pattern of BMPs in normal and allograft kidney tissues. RESULTS: The expression of BMP4 is unique between different tubular cell types in grafts without signs of fibrosis. This effect is not found in specimens with high grades of interstitial fibrosis and tubular atrophy (IFTA). In samples with IFTA grades II and III, the BMP7 expression is reduced in a significant fraction of specimens relative to those without signs of IFTA. The expression pattern of BMP6 indicates that its activation may be triggered by the act of transplantation and subsequent reperfusion injury. The expression of BMP2 is strong in all types of tubular epithelial cells and does not differ between the compared allografts and control kidney specimens. CONCLUSION: The intensity and expression pattern of BMP4, BMP6 and BMP7 in transplanted kidney tissue are found to be dependent upon the length of the transplanted period, the clinical indication for transplant nephrectomy and signs of IFTA in kidney tissue.

[Croatian guidelines for screening, prevention and treatment of protein-energy wasting in chronic kidney disease patients]. / Preporuke za pracenje, prevenciju i lijecenje proteinsko-energijske pothranjenosti u bolesnika s kronicnom bubrezom bolesti.

There is a high incidence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) and malnutrition is a powerful predictor of cardiovascular morbidity and mortality in this population of patients. A multitude of factors related to CKD and renal replacement therapy can affect the nutritional status of CKD patients and lead to the development of malnutrition. In patients with CKD, protein energy wasting (PEW) is a condition that is distinct from undernutrition and is associated with inflammation, increased resting energy expenditure, low serum levels of albumin and prealbumin, sarcopenia, weight loss and poor clinical outcomes. Nutritional and metabolic derangements are implicated for the development of PEW in CKD and leading to the development of chronic catabolic state with muscle and fat loss. Prevention is the best way in treating PEW. Appropriate management of CKD patients at risk for PEW requires a comprehensive combination of strategies to diminish protein and energy depletion, and to institute therapies that will avoid further losses. The mainstay of nutritional treatment in MHD patients is nutritional counselling and provision of an adequate amount of protein and energy, using oral supplementation as needed. Intradialytic parenteral nutrition and total enteral nutrition should be attempted in CKD patients who cannot use the gastrointestinal tract efficiently. Other strategies such as anemia correction, treatment of secondary hyperparathyroidism and acidosis, delivering adequate dialysis dose can be considered as complementary therapies in CKD patients. Multidisciplinary work of nephrologists, gastroenterologist and dietician is needed to achieve best therapeutic goals in treating CKD patients with PEW.

METABOLIC ACIDOSIS--AN UNDERESTIMATED PROBLEM AFTER KIDNEY TRANSPLANTATION?.

Despite prolonged survival and better quality of life as compared to dialysis, kidney transplantation frequently presents with a complex set of medical issues that require intensive management to protect graft function. Metabolic acidosis has an impact on several metabolic complications such as mineral and muscle metabolism, nutritional status and anemia. It may also have an effect on graft function, possibly through the stimulation of adaptive mechanisms aimed at maintaining acid-base homeostasis. We investigated current practice in the evaluation of metabolic acidosis at one of the largest transplant centers in the Eurotransplant region. Adult renal transplant recipients having received allograft from January 2011 to August 2012 were included in the investigation. We recorded the frequency of measuring the parameters of venous blood gas analysis, as well as creatinine and urea levels, creatinine clearance, proteinuria, calcium, phosphate and potassium blood levels, body mass index and the time spent on dialysis prior to kidney transplantation. Out of 203 patients who had received renal allograft at our institution during the observed period, 191 (124 males and 67 females, age range from 18 to 77 years) were enrolled in the study. Of these, only 92 (48.167%) patients had parameters of venous blood gas analysis measured at some time after kidney transplantation. Acid-base status was determined more often in males (77 males vs. 22 females, p = 0.001). Patients with pH/blood gas analysis performed were found to have significantly higher creatinine and urea levels and significantly lower creatinine clearance (p < 0.001 both). Serum calcium levels were also significantly lower in this group of patients (p < 0.001). Metabolic acidosis is a very important clinical issue that needs to be monitored in every transplant recipient. Its effects on graft function, nutritional status, anemia and bone mass are complex but can be successfully managed. Our study showed metabolic acidosis to be linked with significantly higher creatinine and urea levels, decreased creatinine clearance and lower calcium levels. Nevertheless, metabolic acidosis still stays a highly underestimated problem among nephrologists dealing with transplant recipients. We suggest regular determination of the acid-base status in renal transplant recipients.

[Renal transplantation in patients with lupus nephritis]. / Transplantacija bubrega u bolesnika s lupusnim nefritisom.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), associated with high morbidity and mortality. Up to 60% of SLE patients develop LN, and despite novel and potent therapeutic regimens, 5 to 22% develop end-stage renal disease within 15 years of diagnosis. While LN primarily affects younger individuals, it is important to choose optimal method of renal replacement therapy for those who develop end-stage renal disease. Numerous studies were carried out trying to solve problems of treatment of patients with LN. Increased risk of infections, disease recurrence in renal allograft, undefined criteria for follow-up of disease activity after transplantation, as well as higher inci- dence of rejection episodes and thrombotic events are well known risks which have postponed and restricted access to transplantation for patients with LN for long-time. However, numerous studies have demonstrated similar long-term survival in patients treated with haemodialysis or peritoneal dialysis, with clear superiority of renal transplantation regarding the prolonged survival and better quality of life for SLE patients. Many questions are still waiting for answers. Close cooperation between nephrologists and immunologists provides the best treatment for SLE patients with end-stage renal disease.

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal transplant recipients or comparing sirolimus versus everolimus impact on bone, so only general conclusions could be drawn. Hence, the use of mTORi might be useful in patients with PRO due to their possible potential to inhibit osteoclast activity which might lead to a decreased rate of bone resorption. In addition, it should be also emphasized that they might inhibit osteoblast activity which may lead to a decreased bone formation and adynamic bone disease. Further studies are urgently needed to solve these important clinical dilemmas.