Bilateral Renal Angiomyolipomas and Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex: a Case Report and Review of The Literature.

Tuberous sclerosis complex (TSC) is an autosomal-dominant multi system disorder. The genetic basis of the disorder is mutations in the TSC1 or TSC2 gene, which leads to over activation of the mammalian target of rapamycin (mTOR) protein complex and results in development of benign tumors in different body systems such as brain, skin, lungs and kidney. The mTOR inhibitors are presently the main treatment option for patients with TSC. We here report a 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of largest AML decreased by ~24.0% in the longest diameter. A reduction of the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episode associated with skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well.

Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Kidney transplantation in emerging countries: do we know all issues?

Although it seems that end stage renal disease (ESRD) therapies gradually become more accessible in the developing world, yet, the vast majority of people living in those areas do not have access to dialysis and especially transplantation because of the economic and technological inequality as compared with the developed world. Despite the great advantage in survival and considerable socioeconomic advantages of transplantation vs. dialysis, there is a widespread recognition that the growing gap between organ supply and demand will continue into the foreseeable future. Several reasons might be considered in this regard as: insufficient data on the topic in the public domain, inadequate governmental financial resources, lack of public awareness, education and motivation for organ donation as well as the low number of organized teams of transplant surgeons and nephrologists, and lack of organizational infrastructure, i.e. coordinators. The defined priorities for the future in terms of improving living donor transplantation, composition of the official waiting lists and registries of transplant recipients and living donors and the role of transplant professionals have been discussed. In conclusion, whatever the governmental support is, as professionals, we should just reinforce our efforts to help our patients as best as we can in the current situation.

Brain natriuretic peptide between traditional and nontraditional risk factors in hemodialysis patients: analysis of cardiovascular mortality in a two-year follow-up.

BACKGROUND: The ability of brain natriuretic peptide (BNP) together with other traditional and nontraditional risk factors to predict cardiovascular (CV) mortality in hemodialysis (HD) patients has not been well established. The aim of this prospective study was to determine the predictive cutoff values of baseline measurement of BNP along with the known CV disease risk factors to predict all-cause and CV mortality in HD patients. METHODS: BNP concentration before HD was measured in 125 prevalent HD patients (age 53.0 ± 13.5 years, HD vintage 75.2 ± 61.0 months). In addition, several traditional CV risk factors (blood pressure, dyslipidemia, diabetes mellitus, body mass index, left ventricular hypertrophy) and uremia/dialysis-related CV risk factors (anemia, calcium and phosphate impairment, malnutrition, inflammation, ultrafiltration, HD duration, Kt/V) were examined. RESULTS: During the 2-year follow-up, we lost 28 out of 125 patients (22.5%), with CV disease (65.7%) being the main cause of mortality. The cutoff point for BNP, as predictor of the clinical outcome, according to the ROC curve was 1,194 pg/ml for CV mortality with sensitivity and specificity of 63 and 65%, respectively (AUC 0.61 and confidence interval (CI) 95% 0.47-0.75). Kaplan-Meier analysis showed that all-cause (log-rank, p = 0.002) and CV mortality (log-rank, p = 0.001) were the cause of a significantly lower survival in patients with a mean BNP >1,200 pg/ml. The univariate Cox regression analysis found the following factors to be predictors of all-cause mortality: hemoglobin (<110 g/l), phosphorus (>1.78 mmol/l), albumin (<40 g/l), C-reactive protein (CRP ≥ 10 mg/l), BNP (>1,200 pg/ml) and cardiac ejection fraction (≤ 55%). The multivariate Cox regression analyses demonstrated that only CRP ≥ 10 mg/l with a hazard ratio (HR) 6.82 (CI 95% 1.86-24.9, p = 0.004) and BNP >1,200 pg/ml with HR 5.79 (CI 95% 1.58-21.3, p = 0.004) were predictors of all-cause mortality. BNP >1,200 pg/ml with HR 13.52 (CI 95% 1.68-108.9, p = 0.014) was found to be an even stronger predictor of CV mortality than CRP ≥ 10 mg/l with HR 6.53 (CI 95% 1.35-31.6, p = 0.020). CONCLUSIONS: Our study pointed out that BNP >1,200 pg/ml as a marker of cardiac dysfunction and CRP ≥ 10 mg/l as a marker of inflammation identify HD patients at increased risk of CV mortality.

Strategies to manage low-bone turnover.

A change in paradigm occurred lately whereby not hypocalcemia but hypercalcemia and positive calcium balance were considered negative factors. Namely, the use of calcium- based binders in combination with vitamin D analogues, has been shown to lead to an over-suppression of parathyroid hormone (PTH) and development of low-bone turnover adynamic bone disease (ABD). The changing prevalence of various types of bone diseases from a high to low-bone turnover goes in line with the presence of increased risk for vascular calcification (VC), morbidity and mortality in the dialysis population. The attenuation of the previous great expectations in calcium-based phosphate binders and vitamin D-analogues entailed a new treatment strategy to preserve bone and vascular health. Hence, a new evidence for treatment of ABD with various types of non calcium based binders and low calcium dialysate is presented. Sevelamer treatment has reduced calcium concentration and increased PTH levels, resulting in the improvement of markers of bone turnover, increased bone formation and improved trabecular architecture, providing a slower progression of VC. Data on lanthanum beneficial effect on ABD histology have been demonstrated in long-term clinical studies. Although there is a slow release of lanthanum from its bone deposits after discontinuation of the treatment and no association with aluminium- like bone toxicity, there is still an ongoing scientific debate about its long-term toxic potential. Finally, reducing the number of calcium based binders and low calcium dialysate (1.25 mmol/l) has been reported to have an impact on the evolution towards markers reflecting higher bone turnover. Then, adoption of the non calcium-based binders should be reserved to high risk patients with ABD and progression of vascular calcifications associated with increased morbidity and mortality.

Calcimimetics versus parathyroidectomy: What is preferable?

Secondary hyperparathyroidism (SHPT) is common among patients with end-stage renal disease (ESRD). SHPT is associated with high-turnover bone disease, interstitial and vascular calcifications, cardiovascular morbidity and mortality. The pharmacological management of SHPT has progressed in recent years. The introduction of targeted therapies, such as selective vitamin D receptors activators and calcium-sensing receptor modulators, offers an increased opportunity to adequately control elevated parathyroid hormone (PTH), especially in patients with chronic kidney disease under dialysis treatment. Calcimimetic medications such as cinacalcet negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation. However, there are no randomised, prospective data that demonstrate improved quality of life, improvement in anemia, reduction in phosphate binders, reduction in use of vitamin D analogs, or reduction in mortality. Literature supports cinacalcet therapy to improve patient outcomes, especially with regard to vascular calcifications and presumably the very lethal condition of calciphylaxis. However, cinacalcet is administered orally and has been associated with gastrointestinal intolerance along with hypocalcemia. In addition, poor adherence has been observed among dialysis patients self-administering oral cinacalcet. On the other hand, successful surgical parathyroidectomy (sPTX) can yield a dramatic reduction in PTH level and clinical symptoms. The advanced pharmacological treatments of SHPT often obviate parathyroidectomy; however, some researchers have reported that sPTX may be more cost-effective than cinacalcet in some patients with ESRD and suffering uncontrolled SHPT.

Do we have to treat subclinical rejections in early protocol renal allograft biopsies?

The aim of the present study was to evaluate whether treatment of subclinical, borderline rejections (SR/BR) or histological findings of chronic allograft nephropathy (CAN) in protocol biopsies in the first month posttransplantation after living related kidney transplantation has a beneficial effect on graft histology and renal function at 6 months. Among the 40 paired biopsies, only 6/80 showed no histological lesions. BR was found in 13/40 and 12/40, and SR in 15/40 and 21/40 of patients on the 1- and 6-month biopsies, respectively. The mean histological index/total sum of scores for acute and chronic changes (HI) increased at 6-month biopsy: 5.3 +/- 2.9 vs 7.8 +/- 3.6 (P < .001). Similarly, the mean sum of histological markers for chronicity (CAN score) of 2.1 +/- 1.5 increased to 4.6 +/- 2.3 (P < .001) on the 6-month biopsy. When divided according to whether there was treatment of BR and SR, the treated BR/SR group on 1-month biopsy had a mean HI score of 7.11 +/- 1.9, which remained almost the same (7.11 +/- 2.32) at 6 months. Among the untreated BR/SR group it increased from 4.95 +/- 1.99 to 8.16 +/- 4.30. However, there was no difference in graft function between the groups from 1 to 6 months. In conclusion, a protocol 1-month biopsy may be valuable to establish the prevalence of BR/SR in stable allografts. The presence of an untreated BR/SR upon a 1-month biopsy showed greater susceptibility for histological deterioration on the 6-month biopsy due to an accelerated CAN process.

First two AB-incompatible living kidney transplantations in the Balkans--should it be a procedure of choice in a developing country?

Kidney transplantation is the best available medical intervention for the treatment of end-stage renal failure. However, as a consequence of the growing gap between organ supply and demand, many patients die waiting for an organ each year. In order to increase the number of organs, living donor (LD) transplantation from unrelated and ABO-incompatible (ABOi) donors have been introduced over the last few decades. While in the past ABOi transplantation resulted in hyperacute or acute antibody-mediated rejection, the tremendous progress in this area in recent years has shown that it can be overcome by careful patient management, including protocols to remove or lower antibodies, along with stronger immunosuppression and intensive monitoring. The organ shortage problem is even more prominent in regions such as the Balkans where cadaver transplantation has not been well developed. In addition to the introduction of expanded criteria for living donation (elderly and marginal donors), we performed the first two ABOi/LD transplantations in the Balkans in the last 2 years using an already established preconditioning regimen and maintenance therapy with cyclosporine, mofetil mycophenolate and prednisolon. We report our modest experience of a case in which the patient developed lymphadenopathy, sarcomatosis and died after one year; and a second case with accelerated acute rejection and hemorrhagic necrosis with explantation of the graft after a month. Taking into account the high cost of the desensitization procedure and induction therapy as well as the need for intensive monitoring throughout the standardized procedures and facilities, we might reconsider whether ABOi living kidney transplantation should be a procedure of choice in developing countries.

Living-unrelated (paid) renal transplantation--ten years later.

Due to the increase of organ shortage and still inadequate development of cadaver transplantation, many end-stage patients from the Balkan region travel mostly to India to buy a kidney. Despite all the ethical dilemmas and discussions, organ sales is present nowdays in Third-World countries. Sixteen patients (13 from Macedonia and 3 from Kosovo, SCG) were observed clinically during a period of 10 years. Recipients of mean age 36.5 years (range 10 to 58) displayed the following underlying diseases: chronic glomerulonephritis (n = 5), urethral valves with reflux (n = 2), ADPKD (n = 1), hypertensive nephropathy (n = 4), lithiasis (n = 1), and unknown cause of ESRD (n = 3). The donor population was young (22 to 29 years). Most patient records did not include data on HLA, cross-match, MLC, kind of surgery, or usual pretransplant workup. The immunosuppressive protocol included CyA, PRED, and AZA or MMF. All transplanted patients were followed on an outpatient basis in our department; patients with complications were hospitalized. The 1, 3, 5, and 10 year Kaplan Meier graft survival rates were 78.6%, 50.2%, 33.3%, and 18.8%, respectively. Seven patients were lost (43.7%), two during the first month after transplantation, two at the end of the first year, and three at 5, 6, and 8 years thereafter. The main reasons for death were severe pulmonary infections with sepsis, hepatitis B with liver cirrhosis, Kala Azar, CMV, and cancer of the colon. Five grafts were lost due to repeated rejection episodes and chronic graft nephropathy. The last three cases remained with good renal function and actual serum creatinine values of 135 +/- 9. In view of this experience, the authors cannot recommend this type of transplantation, not only from the ethical point of view, but also from frequent medical and surgical complications which are sometimes life threatening.

Protocol biopsies in kidney transplant recipients: histologic findings as prognostic markers for graft function and outcome.

The aim of the present study was to identify subclinical and borderline rejections as well as histological markers of chronic allograft nephropathy (CAN) among protocol biopsies performed at 1 and 6 months after living related kidney transplantation to assess their possible implications for graft function. Twenty paired allograft biopsies performed at 1 and 6 months were reviewed according to the Banff scoring scheme. The mean ages of donors and recipients were 59.6 +/- 13.8 and 34.4 +/- 8.7 years, respectively. Among all biopsies only 10% (4/40) showed no histopathological lesions. At the first month borderline rejection was shown in 35% and subclinical rejection in 10% of patients. At 6 months the proportion of findings was even higher, namely, 40% and 30%, respectively. When divided according to donor age, donors above 55 years showed a mean CAN score of 2.33 +/- 1.56 which increased to 5.0 +/- 2.26 on the 6 month biopsy (214.3%). Unexpectedly, the proportion of these changes in the younger donor group also increased by 173.3%, which might have been explained by the greater number of borderline and subclinical rejections in the younger donor group at the 1 month biopsy. In conclusion, 1 month biopsy may be valuable to determine borderline and subclinical rejection and to prognosticate the outcome of renal allograft function. Our findings suggest a greater susceptibility of histological deterioration among the older donor population. However, the presence of an untreated rejection in the younger donor pool leads to a rapid impairment of the graft function accelerating the process of chronic allograft nephropathy.

Meeting Report: International nephrology days - In honor of the 75(th) anniversary of acad. Momir Polenakovic and 50 years of scientific work, 26-27 September 2014.

The International Nephrology Days in honor of the 75(th) anniversary of Academician Momir Polenakovic and 50 years of his scientific work were held in the Macedonian Academy of Sciences and Arts (MASA) on 26 and 27 September 2014. Organizers of the meeting were the Macedonian Academy of Sciences and Arts and the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO). The days were programmed with the VII Macedonian-Croatian Nephrology Meeting and the Continuing Medical Education (CME) Course on "Renal Replacement Therapy - when & how - update on the outcome and cost-efficacy" organized by the MSNDTAO in cooperation with the European Renal Association (ERA-EDTA). Prominent academicians, researchers and nephrologists from Europe and neighboring countries contributed with their lectures and discussion at this scientific event. On September 26, 2014 the opening talk was given by Acad. V. Kambovski, President of the MASA, about the Life and Work of Academician Momir Polenakovic. In honor of his anniversary and valuable scientific opus, during the meeting Acad. Momir Polenakovic was awarded with Certificate of the European Renal Association (ERA-EDTA) for his significant role in the development of nephrology in the Balkan region and couple of other diplomas and acknowledgement. Prof. Polenakovic is founder of the MSNDTAO and his lifetime honorary president.

Epoetin omega for treatment of anemia in maintenance hemodialysis patients.

After the synthesis of epoetins alpha and -beta, a third molecule of recombinant human erythropoietin (rHuEPO) was synthesized and was named epoetin-omega. The molecule of epoetin-omega is a sialoglycoprotein with smaller amounts of O-bound sugars, less acidic and with different hydrophylity than the other 2 epoetins. The purpose of the study was to assess the efficacy, safety and clinical tolerance of epoetin-omega for treatment of renal anemia. In an open-label, uncontrolled prospective clinical study, 22 end-stage renal disease patients (9 male and 13 female) were followed for 6 months. They all had a hemoglobin (Hb) value below 85 g/l, and were on regular hemodialysis therapy 3 times a week, 4 hours per session. The initial weekly dose of epoetin-omega was 90 units per kg of body weight (b.w.) divided in 3 equal portions and administered subcutaneously after each dialysis session. After correction of the hemoglobin, the dose of rHuEPO was individualized to keep Hb within target limits of 100-120 g/l. To follow efficacy and safety, a number of clinical and laboratory parameters were monitored. All patients responded well to the therapy with corrected hemoglobin after the 10th week of the study. The mean dose of epoetin-omega during the correction period never exceeded 100 U/kg b.w. per week. The average maintenance dose of rHuEPO was 50-60 U/kg b.w. per week. Iron was, where needed, supplied intravenously. We noted no change in serum urea. creatinine, phosphorus, and heparin dose per dialysis session. The prothrombin time improved during the study. Serum albumin increased. No change was observed in urea reduction ratio (URR), body weight and mean arterial pressure. One serious adverse event was noted: worsening of hypertension in 1 patient, with the development of hypertensive encephalopathy and severe headache. rHuEPO treatment was stopped. The blood pressure was effectively controlled by reducting her body weight by 5%. Thereafter, rHuEPO therapy was resumed with good blood pressure control. We could conclude that recombinant human erythropoietin-omega was an efficient and safe therapeutic agent for the treatment of renal anemia.

Living related renal transplantation--the use of advanced age donors.

AIM: Efforts to increase the donor pool and available organs included some unconventional kidney transplantation. One of these was including elderly donors for both, living and cadaver kidney transplantation. The aim of the study was to review our single centre experience with living donor transplants from elderly advanced age donors. PATIENTS AND METHODS: During a period of 7 years, 71 living related renal transplantations were performed. Twenty-six of them were over 65 (mean 69+/-4, range 65 to 81), but 10 were over 70 years of age. The survival rate was compared with 45 transplants from younger donors (mean age 51+/-6, range 24 to 59). The cold and warm ischemia time, the preservation procedure and blood vessels anastomosis time were comparable in both donor groups. The immunosuppression included sequental quadruple protocol with ATG, PRED, AZA and CyA replacing ATG after 7 days. The triple drug (AZA, PRED, CyA) maintenance therapy was applied to all recipients. RESULTS: Kaplan-Meier 1-, 3- and 5-year graft survival was 88.0%, 79.2% and 68%, respectively, for advanced donor age group and 90.2%, 82.4% and 74%, respectively, for younger donor group. The difference was slightly statistically significant (p < 0.05). In 6 patients who received graft from elderly donors, a delayed graft function was observed, whereas only in one in the younger donor group. CONCLUSION: Despite the worse results in the elderly donors' transplants, we consider the advanced age donors as an important source of kidneys contributing to solving the actual organ shortage, especially in our region.

Bone biopsy as a diagnostic tool in the assessment of renal osteodystrophy.

When renal disease develops, mineral and vitamin D homeostasis is disrupted, resulting in diverse modifications in bone cells, bone structure and the rate of bone turnover. In end stage renal failure (ESRF) when patients require chronic maintenance dialysis, nearly all of them have abnormal bone histology known as renal osteodystrophy (ROD). Moreover, survival rates of patients on dialysis have increased because of therapeutic improvement and the resultant increase in duration of dialysis has led to a further rise in renal osteodystrophy. Because metabolic bone disease can produce fractures, bone pain, and deformities late in the course of the disease, prevention and early treatment are essential. Serum PTH and various bone markers are commonly used to assess bone changes in ESRF patients, but the diagnosis of underlying bone disease is still rather uncertain. To date, bone biopsy is the most powerful and informative diagnostic tool to provide precise information on the type and severity of renal osteodystrophy, and on the presence and amount of aluminum and strontium deposited in the bone. Bone biopsy is not only useful in clinical settings but also in research to assess the effects of therapies on bone. Although considered an invasive procedure, bone biopsy has been proven to be safe and free from major complications, but the operator's experience and skill is important in further minimizing morbidity. Alternatives to bone biopsy continue to be sought, but the non-invasive bone markers have not been proven to be sufficient in diagnostic performance related to bone turnover, mineralization process and bone cell abnormality. Hence, transiliac bone biopsy remains the gold standard for the diagnosis of renal osteodystrophy.

[Kidney transplantation using living donors over age 65]. / Transplantation rénale utilisant des donneurs vivants de plus de 65 ans.

Efforts to increase the donor pool of available organs have resulted in some unconventional kidney transplantation procedures. One of these is the use of elderly donors for both living and cadaver kidney transplantations. The aim of this study was to review our experience with kidney transplants from living elderly donors. During a period of 10 years, 70 living renal transplantations were performed. In 32 transplants the age of the donor was above 65 years (mean 69 +/- 4 years, range: 65 to 81 years) and in 10 of these 32 transplants the age of the donor was over 70 years. The survival rate was compared with that of 38 transplants from younger donors (mean age 51 +/- 6 years, range: 24 to 59 years). The time to cold and warm ischemia, the preservation procedure and time to anastomosis of blood vessels were comparable in both groups of donors. Immunosuppression included a sequential quadruple protocol, using thymoglobulin (ATG), prednisolone (PRED), azathioprin (AZA) and cyclosporin A (CsA), which replaced ATG/PRED after day seven. A triple drug maintenance therapy (AZA, PRED, CsA) was used in all recipients. Kaplan-Meier survival curves at 1, 3 and 5 years showed that graft survival was 88%, 79% and 64% respectively for grafts from the advanced age donor group and 92%, 82% and 68% respectively for grafts from the younger donor group. The difference was slightly statistically significant (p < 0.05). Functioning of the graft was delayed in six patients who had received grafts from elderly donors and in one patient who had received a graft from a young donor. Despite worse results in transplantation with grafts from elderly donors, we consider this population as an important source of kidneys, which might help solve the present organ shortage, especially in our region.

[Cancer after kidney transplantation and immunosuppression]. / Cancer après transplantation rénale et immunosuppression.

Between 1977-1998 we followed up 115 patients with renal allograft. Seventy patients had received a graft from a living donor, while 45 had received a graft from a cadaver donor. The immunosuppressive therapy included azathioprin (AZA), prednisolone (PRED) and cyclosporin A (CyA) in 90 patients and AZA and PRED in 25 patients. Nine patients showed skin malignancies (7.3%), three of these patients had Kaposi's sarcoma and the other six patients squamous or basal cell carcinoma. All cases were clinically and histologically confirmed. Squamous or basal cell carcinoma occurred mostly on the head and was radiosensitive, though recurrences might be observed. Kaposi's sarcoma was localized on either the lower extremities or the face. The condition of two patients treated by radiotherapy only partially improved. Due to chronic renal allograft rejection immunosuppressive therapy was withdrawn in two patients and dialysis was restarted without any other recurrence of the sarcoma. The rate of cancer occurrence in patients with renal allograft is consistent with the findings of other authors. Reduction or withdrawal of immunosuppressive therapy may have a beneficial effect on malignancy, but incurs the risk of losing the allograft.

Biopsy of the transplanted kidney--role of protocol biopsies.

Traditionally, renal allograft biopsies were performed mainly in the setting of acute graft dysfunction. Recently, there has been a change of paradigms. Several reports suggested that acute rejection of the graft and chronic allograft nephropathy are often subclinical without any deterioration in the graft function. This raises the issue of biopsies in functionally stable allografts (e.g. protocol biopsies) and the clinically useful information they provide. Namely, recent reports provide evidence in favour of treating biopsy-proven subclinical rejections. Moreover, by early identification of chronic histological lesions, protocol biopsies give an opportunity for individualized immunosuppressive regimen and use of targeted therapeutic strategies, in order to prevent chronic allograft dysfunction and improve long-term graft outcome. In this review, diagnostic, therapeutic and research benefit information on protocol biopsies performed in stable kidney recipients are described.

Efficacy and tolerability of hyaluronic acid, tea tree oil and methyl-sulfonyl-methane in a new gel medical device for treatment of haemorrhoids in a double-blind, placebo-controlled clinical trial.

Topical formulations are widely used in anti-haemorrhoidal treatment, but often lacking controlled clinical trials. Here, we report the results from a controlled clinical trial performed with a new gel medical device (Proctoial) containing hyaluronic acid with tea tree oil and methyl-sulfonyl-methane as major components. The total number of 36 haemorrhoidal patients (grade 1-3) was enrolled in a double-blind, placebo-controlled clinical trial and divided into 2 equal parallel groups. The anal pain, pain during defecation, visible bleeding, pruritus and irritation/inflammation were recorded before and after 14-day treatment using a visual analogue scale both by the investigators and by the patients. Safety and tolerability of the treatments were also recorded. The new gel medical device statistically significantly reduced all the symptoms after the treatment compared to placebo. The results indicated also a very good tolerability and safety of the treatments.

Achievements in CKD-MBD guidelines targets: is there a progress in the implementation practice?

BACKGROUND: Guidelines should help the practicing nephrologists to reduce the variability in diagnostic and treatment strategies, and achieve the best possible patients' outcomes. The aim of our study was to look at the treatment strategies and the shortcomings in the implementation of the chronic kidney disease mineral and bone disorder (CKD-MBD) KDOQI guidelines in dialysis units across the Republic of Macedonia in 2009, and to analyze trends with regard to our previous analysis from 2005. METHODS: A questionnaire was sent in 2009 to all dialysis units in our country for data concerning CKD-MBD in dialysis patients. This study included 742 patients, comparable with the reply we got on the same our 2005 survey, with a total of 588 patients. We collected the last 6 months mean values of biochemical parameters [calcium (Ca), phosphate (P), and intact parathyroid hormone (iPTH)], as well as treatment data including dialysate Ca concentration, phosphate binding agents, and vitamin D doses. RESULTS: The majority of patients in both surveys had values within the target ranges for all parameters, except for iPTH, which was <150 pg/ml in most patients, in both reports. Compared to the 2005 study, in 2009 we found a significantly improved control of all four biochemical parameters, but a greater proportion of patients within guidelines targets was found only for serum Ca (79 vs. 67.4%, P<0.05). Treatment with low Ca dialysate concentration of 1.25 mmol/L continued to be an underused option (3.7 vs. 6.1%), while the 1.75 mmol/L was still the standard dialysate in the majority of patients (57.7 vs. 64.2%). The dose of calcium carbonate was significantly reduced (2.77±1.71 vs. 3.06±1.54, P<0.01) in 2009 compared to 2005. The mean of the achieved targets increased significantly in 2009 (2.33±1.05 vs. 2.13±1.03, P<0.01). CONCLUSION: There was an improved control of all bone and mineral parameters in our dialysis units, following the publication of the CKD-MBD KDOQI guidelines. In order to improve the iPTH values, a more frequent use of low Ca dialysate (1.25 mmol/L) and of non-calcium-based phosphate binders in this small subset of patients should be implemented, as recommended by the guidelines. Individualization of the CKD-MBD management may be successful, even when newer treatment options are not available. Finally, the guidelines implementation process should be a continuous and self-monitored process, with the help of periodic surveys.

Unusual clinical presentation of brown tumor in hemodialysis patients: two case reports.

Brown tumor or osteoclastoma is a lytic bone tumor, which is common in secondary hyperparathyroidism (1.5-13%) in chronic dialysis patients, mainly in those with untreated renal osteodystrophy. Brown tumor appears as a result from excess osteoclast activity and consists of collections of osteoclasts intermixed with fibrous tissue and poorly mineralized woven bone. It can be manifested as a single or multiple bone lesions. Although invasive, it has no malignant potential and should be distinguished from giant cell tumors of the bone. Two unusual cases of brown tumor in dialysis patients are reported. We present a first patient with five subtotal parathyroidectomies between 2002 and 2009 and a tendency toward recurrence of secondary hyperparathyroidism (sHPTH). The double MRI check up could not reveal any ectopic parathyroid gland. Although the patient had permanently high PTH values, serum calcium level was never above the normal range. However, the brown tumor in the cervical spine was destructing the cervical vertebrae and required surgical intervention. Despite the conservative treatment with calcium and non-calcium-based binders and various forms of vitamin D, the patient's clinical and biochemical condition improved only after the use of cinacalcet. The second patient, a 58-years-old female on chronic hemodialysis since 1998, was found with high PTH serum levels in 2009. The development of sHPTH was scintigraphically confirmed and surgically treated. During the late 2008, she started feeling pain, numbness and swelling of the 3rd right hand finger, prior to the full clinical manifestation of the tumor. The CT scan of the right hand showed osteolytic changes and soft tissue destruction of the middle phalanx of the 3rd right hand finger. This formation corresponded to an unusual presentation of brown tumor associated with sHPTH. As expected, after the parathyroidectomy, there was no marked change in the destructed bone of the 3rd right hand finger middle phalanx, but only a gradual improvement in the subjective clinical condition of the patient. Based on these two reports, we would recommend that in cases of severe or recurrent sHPTH either total parathyroidectomy or early administration of calcimimetics should be considered. Furthermore, the implementation of regular checkup and treatment according to the KDIGO guidelines should be advised and clinical appearance of any bone tumor immediately checked for an association with sHPTH, which is a rather common entity in dialysis patients.