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Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.

Brown tumor is an extreme form of severe hyperparathyroid bone disease in end-stage renal disease patients. The evolution of the tumor after renal transplantation and under conservative treatment is still unclear. Herein, we report a 22-yr-old girl with parathyroid glandular hyperplasia because of an inadequate compliance and control of the mineral metabolism and subsequently developed Brown tumor of the ribs. A gradual improvement in bone and parathyroid gland status was observed within three yr following successful kidney transplantation and treatment with pulses of oral calcitriol. To the best of our knowledge, this is the first case of such severe secondary hyperparathyroidism with successful conservative treatment in the setting of kidney transplantation with no evidence of vascular calcifications and graft failure.

In this publication, we review the activities of the European Uremic Toxin Work Group (EUTox) in the field of uremic toxin research. Founded in 1999 under the umbrella of the European Society of Artificial Organs (ESAO), and active since 2000, this group focuses essentially on questions related to solute retention and removal during chronic kidney disease, and on the deleterious impact of those solutes on biological/biochemical systems. As of January 1, 2009, the group had met 28 times; it organized the third meeting, "Uremic Toxins in Cardiovascular Disease," which took place in October 2008 in Amiens, France. The current group is composed of 25 members belonging to 23 European research institutions. As of November 1, 2008, in total 69 papers had been published to which at least two different research groups belonging to EUTox have contributed in a collaborative effort. Of these, 40 papers were on original research and eight were specific EUTox reviews or position statements. A website (http://www.eutox.info) summarizes all relevant information concerning the work group. EUTox also developed an interactive uremic toxin database, where concentrations of known toxins are displayed, to be used by researchers in the field. In the future, EUTox intends to continue its focus on bench to bedside research with specific consideration of proteomics, metabonomics, secretomics, and genomics. © 2009 Wiley Periodicals, Inc.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial renal disease, occurring in certain regions in 5 countries of the Balkan peninsula. Its etiology is largely unknown, though several hypotheses have been formulated and are discussed in this review. In several cases, etiological hypotheses (e.g., viral, ochratoxin or trace element involvement) are verified only in local endemic areas and can not be confirmed when tested elsewhere. Only certain families in the endemic areas are affected. An exposure of at least 20 years to the unknown factors in the endemic areas seems to be mandatory for the development of the disease, but a genetic predisposition to this disease also seems to be mandatory. Prominent clinical features are severely shrunken kidneys, a more severe anemia relative to the level of renal function, and a slow progression to end-stage renal failure. An international approach to solving the etiological and pathogenetic enigma of BEN is needed in the coming years. It is also time to reevaluate other chronic, slowly progressive tubulointerstitial nephropathies diagnosed elsewhere in the world and to search for possible etiological similarities with BEN.

During the last decades, the prevalence of various types of renal osteodystrophy has been changed from a high to low bone turnover. Besides the established conventional risk factors, the existence of a dynamic bone disease as most prevalent form of renal osteodystrophy nowadays and its reduced ability to handle an exogenous calcium load has implied a higher risk for vascular calcification, morbidity and mortality in the dialysis population. Calcium-based phosphate binders are inexpensive and efficient but their extended and/or inappropriate use, particularly when used in combination with vitamin D analogues, may contribute to the development of adynamic bone disease and promotion of soft-tissue and vascular calcification. It seems reasonable to reduce the number of calcium carbonate/acetate tablets to only 1 g/day in order to increase serum phosphate and decrease serum calcium, which both in turn might positively stimulate the parathyroid hormone secretion. Low calcium dialysate (1.25 mmol/l) was reported to have an impact on the evolution towards markers reflecting higher bone turnover, most probably by prevention of a positive calcium balance, enabling sustained stimulation of parathyroid hormone secretion. Hence, the two reasonable strategies should be employed together in order to prevent consequences related to adynamic bone disease and to contribute to a better long-term quality of life and survival of dialysis patients.

Although medical guidelines generally are graded according to their evidence level, low evidence 'judgement' are generally perceived as much as absolute truth by the medical community as high evidence 'guidelines' are. Being aware of this bias, a workgroup appointed by the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA), the members of which are the authors of the current publication, decided that European nephrology guidelines issued by the Association should be published only as 'guidelines' in the case of high-level evidence; otherwise they should be named 'recommendations' or 'position statements' and be published in a different format. Acknowledging that in nephrology, high levels of evidence are often lacking, it was also decided to rename the responsible body from European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). The present publication reviews the arguments based on which this decision was taken.

Hemodialysis (HD) patients are at increased risk for arterial intimal (AIC) and medial calcification (AMC). In a cross-sectional study on 153 HD patients we evaluated the presence of AIC and AMC using plain radiography of the pelvis and the presence of atherosclerotic lesions using high-resolution B-mode ultrasonography of the common carotid arteries (CCA). The radiography of the pelvis confirmed the frequent presence of AIC (35.3%) and AMC (35.9%) in our HD patients. Arterial calcification was absent (non calcified—NC) in a minority of patients (28.8%). Patients with AIC had significantly higher prevalence of atherosclerotic plaques on CCA (78.6%) compared with both other groups and a higher number of documented atherosclerotic complications, such as cardiovascular (85.2%), cerebrovascular (33.3%) and peripheral arterial disease (38.9%) in comparison with the NC patients. According to the 1-year calculated data from patient records, there were no significant differences in the specific HD risks, such as the dose of prescribed calcium carbonate and vitamin D3, serum levels of calcium, phosphate, calcium-phosphate product and intact parathyroid hormone. All four bone metabolism markers within the range proposed by K/DOQI guidelines were achieved in 9.3%, 14.5% and 20.4% in the AIC, AMC and NC group, respectively. Patients with AIC and AMC are frequently found in the HD population. Screening for arterial calcifications in chronic kidney disease patients is suggested even in the early pre-dialysis period. The highest proportion of patients within the guidelines proposed range for bone and mineral metabolism markers was observed in the NC group. A longer period of data analysis is required in order to evaluate the possible role of some traditional and HD-specific risk factors for the development of arterial calcifications. The achievement of the K/DOQI guidelines is an important issue in the prevention of those conditions.

Abnormal bone in chronic kidney disease (CKD) may adversely affect vascular calcification via disordered calcium and phosphate metabolism. In this context, bone health should be viewed as a prerequisite for the successful prevention/treatment of vascular calcification (VC) along with controlled parathyroid hormone (PTH) secretion, the use of calcium-based phosphate binders and vitamin D therapy. In CKD patients, VC occurs more frequently and progresses more rapidly than in the general population, and is associated with increased cardiovascular disease (CVD) morbidity and mortality. A number of therapies aimed at reducing PTH concentration are associated with an increase of calcaemia and Ca x P product, e.g. calcium-containing phosphate binders or active vitamin D. The introduction of calcium-free phosphate binders has reduced calcium load, attenuating VC and improving trabecular bone content. In addition, a major breakthrough has been achieved through the use of calcimimetics, as first agents which lower PTH without increasing the concentrations of serum calcium and phosphate. Nowadays, it is becoming evident that even early stage CKD is recognised as an independent CVD risk factor. Moreover, the excess of CVD among dialysis patients cannot be explained entirely on the basis of abnormal mineral and bone metabolism. Hence, much controversy has surrounded the cost-effectiveness of treatment with the new phosphate-binding drugs as well as new vitamin D analogs and calcimimetics. Thus, it seems prudent and reasonable that maintaining bone health and mineral homeostasis should rely on some modifications of standard phosphate binding and calcitriol therapy. Hypophosphataemia and hypercalcaemia in adynamic bone disease (ABD) might be treated by reducing the number of calcium carbonate/acetate tablets in order to increase serum phosphate and decrease serum calcium, which, in turn, might positively stimulate PTH secretion. The same rationale is assumed for the use of a low calcium dialysate. On the other hand, secondary hyperparathyroidism with hyperphosphataemia and hypocalcaemia should be treated with a substantial number of calcium carbonate/acetate tablets in combination with calcitriol and low calcium dialysate in order to decrease serum phosphate and maintain the Ca x P product within K/DOQI guidelines (

Discrepancies in reported uremic toxin concentrations were evaluated for 78 retention solutes. For this analysis, 378 publications were screened. Up to eight publications per toxin were retained. The highest and the lowest reported concentrations, as well as the median reported concentration were registered. The ratio between the highest and the lowest (H/L) concentrations and, for some solutes, also the ratio between the highest and the median (H/M) concentrations were calculated. The compounds were arbitrarily subdivided into three groups based on their H/L ratio: group A, H/L3 (n = 33); group B, 3H/L8.5 (n = 20); and group C, H/L8.5 (n = 25). Solutes of groups A and B showed a low to intermediate scatter, suggesting a homogeneity of reported data. Group C showed a more substantial scatter. For at least 10 compounds of group C, extremely divergent concentrations were registered (H/M5.5) using scatter plot analysis. For all solutes of groups A and B, the highest reported concentration could be used as a reference. For some solutes of group C and for the compounds showing a divergent scatter analysis, however, more refined directives should be followed.

The existence of adynamic bone disease (ABD) as most prevalent form of renal osteodystrophy in recent years and its reduced ability to handle an exogenous calcium load has implied a higher risk for vascular and soft-tissue calcifications. The effect of low dialysate calcium (LCD) on parathyroid hormone (PTH) secretion in ABD patients has not yet sufficiently been clarified. This randomized, prospective study aimed to compare the effects of LCD and high calcium dialysate (HCD) on the evolution of bone and mineral parameters related to ABD in dialysis patients.52 out of 60 patients with predialysis intact PTH100 pg/ml completed this study and were equally distributed over LCD (1.25 mmol/l) or HCD (1.75 mmol/l) treatment. The duration of the study was 6 months and the only peroral phosphate binder administered was calcium carbonate. Total and ionised calcium were measured monthly in serum before and after dialysis while serum parameters relevant to bone were measured at the enrollment and at 3-month intervals.There were no differences in predialysis mean phosphate or calcium x phosphorus product (Ca x P). The most common side effects of both treatments were comparable. Hypotension occurred in 16% and 17% and cramps in 6% and 8% of the dialysis sessions, in the HCD and LCD group, respectively. The groups did not differ in the mean tCa before dialysis, but this parameter was significantly higher in the HCD group vs. LCD at the end of dialysis (2.59+/-0.18 vs. 2.44+/-0.19 mmol/l; p0.01). The patients of the HCD group also had a significantly higher mean iCa both before (1.08+/-0.05 vs. 1.04+/-0.06 mmol/l; p=0.02) and at the end of dialysis (1.18+/-0.04 vs. 1.48+/-0.04 mmol/l; p0.01). There were no differences within the LCD group between baseline and end of dialysis treatment values of tCa and iCa. However, the mean tCa and iCa were markedly increased at the end of dialysis in the HDC group [2.40+/-0.21 vs. 2.59+/-0.18 mmol/l (p0.01); 1.08+/-0.05 vs. 1.18+/-0.04 mmol/l (p0.01)]. Mean serum levels of iPTH and total alkaline phosphatase in the LCD group were increased at 3 months and at the end of the study compared with the baseline levels [(38.6+/-22.9 vs. 63.3+/-46.0 vs. 78.6+/-44.7 pg/ml); (59.5+/-18.7 vs. 75.9+/-26.7 vs. 84.0+/-35.4 U/l)], respectively, and bone alkaline phosphatase increased also only after 6 months of treatment (23.4+/-7.3 U/l vs. 35.6+/-22.3). The bone markers in the HCD group did not change. At the end of the study all bone parameters in the LCD group were significantly higher than in the HCD group.There was an evolution towards parameters reflecting higher bone turnover in patients treated with dialysate calcium of 1.25 mmol/l, probably by prevention of a positive calcium balance and enabling sustained stimulation of PTH secretion. Hence, LCD might be considered a valuable therapeutic option for ABD patients.

Background. Lanthanum carbonate (LC) has been proposed as a new phosphate binder. Presented here are the results from one centre that participated in a multicentre trial to assess the effect of treatment with LC and calcium carbonate (CC) on the evolution of renal osteodystrophy in dialysis patients. Bone biopsies were performed at baseline, after 1 year of treatment and after a further 2-year follow-up period to assess the lanthanum concentration in bone and plasma. Methods. Twenty new dialysis patients were randomized to receive LC (median dose 1250 mg) for 1 year (n ¼ 10), followed by 2 years of CC treatment or CC (n ¼ 10) during the whole study period (3 years). Results. After 36 weeks of treatment, steady state was reached with plasma lanthanum levels varying around 0.6 ng/ml. Six weeks after cessation of 1 year of treatment, the plasma lanthanum levels declined to a value of 0.17 � 0.12 ng/ml (P < 0.05) and after 2 years to 0.09 � 0.03 ng/ml. Plasma and bone lanthanum levels did not correlate with the average lanthanum dose at any time point. The mean bone concentration in patients receiving LC increased from 0.05 � 0.03 to 2.3 � 1.6mg/g (P < 0.05) after 1 year and slightly decreased at the end of the study to 1.9 � 1.6mg/g (P < 0.05). Conclusions. Bone deposition after 1 year of treatment with LC is low (highest concentration: 5.5mg/g). There is a slow release of lanthanum from its bone deposits 2 years after the discontinuation of the treatment and no association with aluminium-like bone toxicity.

Background During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. Methods Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. Results HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). Conclusions In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.

Various biochemical markers have been evaluated in dialysis patients for the diagnosis of renal osteodystrophy (ROD). However, their value in predialysis patients with end-stage renal failure (ESRF) is not yet clear.Bone histomorphometric evaluation was performed and biochemical markers of bone turnover were determined in serum of an unselected predialysis ESRF population (N = 84).Significant (P0.005) differences between the five groups with ROD (ie, normal bone [N = 32], adynamic bone [ABD; N = 19], hyperparathyroidism [N = 8], osteomalacia [OM; N = 10], and mixed lesion [N = 15]) were noted for intact parathyroid hormone, total (TAP) and bone alkaline phosphatase (BAP), osteocalcin (OC), and serum calcium levels. Serum creatinine and (deoxy)pyridinoline levels did not differ between groups. For the diagnosis of ABD, an OC level of 41 microg/L or less (or =7.0 nmol/L) had a sensitivity of 83% and specificity of 67%. The positive predictive value (PPV) for the population under study was 47%. The combination of an OC level of 41 ng/L or less (or =7.0 nmol/L) with a BAP level of 23 U/L or less increased the sensitivity, specificity, and PPV to 72%, 89%, and 77%, respectively. ABD and normal bone taken as one group could be detected best by a BAP level of 25 U/L or less and TAP level of 84 U/L or less, showing sensitivities of 72% and 88% and specificities of 76% and 60%, corresponding with PPVs of 89% and 85%, respectively. In the absence of aluminum or strontium exposure, serum calcium level was found to be a useful index for the diagnosis of OM.OC, TAP, BAP, and serum calcium levels are useful in the diagnosis of ABD, normal bone, and OM in predialysis patients with ESRF.

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.

The 8th Congress of the Balkan Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) took place, from 16 to 19 September 2007, in Belgrade, Serbia. After the seven previous successful congresses and this latest one in Belgrade, we are convinced that BANTAO has become firmly established as a professional and cultural phenomenon. Born in Ohrid 1993 and followed by the congresses in Varna (1995), Struga (1997), Belgrade (1998), Izmir (1999), Thessaloniki (2001), Varna (2003) and Ohrid (2005), the Congress in Belgrade showed that the BANTAO idea can be considered as a true marker of our regional communication and collaboration, and as the major forum of Balkan nephrologists, with around 500 participants. Balkan nephrologists have recognized and taken advantage of working in a world without political boundaries; we also have the support of the European Renal Association/European Dialysis and Transplantation Association (ERA/EDTA) and the International Society of Nephrology (ISN), which comes in recognition of our efforts and achievements in attaining the best results for our patients on local and regional levels. The Congress was attended by 456 physicians (nephrologists, nephrology fellows, transplant physicians, cardiologists, internal medicine specialists) from the Balkans, Europe and Asia. In addition to the support of the ERA/EDTA and ISN/COMGAN, the Congress was held under the patronage of their Royal Highnesses Prince Alexander of Serbia and Princess Katherine. In the fields of epidemiology of renal disease, clinical and paediatric nephrology, haemoand peritoneal dialysis, kidney transplantation and apheresis, there were 60 invited guest lecturers and 47 oral and 137 poster presentations. The programme included four educational symposia, two ERA/EDTA courses, three Balkan symposia, six round tables (one ISN/COMGAN) and six keynote lectures; many distinguished nephrologists presented the latest achievements in different fields of nephrology. Importantly, for the

A multicenter study on the affects of lanthanum carbonate (Fosrenol™) and calcium carbonate on renal bone disease in dialysis patients. Background Lanthanum carbonate (LC) (Fosrenol™) is a novel new treatment for hyperphosphatemia. In this phase III, open-label study, we compared the effects of LC and calcium carbonate (CC) on the evolution of renal osteodystrophy (ROD) in dialysis patients. Methods Ninety-eight patients were randomized to LC ( N = 49) or CC ( N = 49). Bone biopsies were taken at baseline and after one year of treatment. Acceptable paired biopsies were available for static and dynamic histomorphometry studies in 33 LC and 30CC patients. Blood samples were taken at regular intervals for biochemical analysis and adverse events were monitored. Results LC was well tolerated and serum phosphate levels were well controlled in both treatment groups. The incidence of hypercalcemia was lower in the LC group (6% vs. 49% for CC). At baseline, subtypes of ROD were similarly distributed in both groups, with mixed ROD being most common. At one-year follow-up in the LC group, 5 of 7 patients with baseline low bone turnover (either adynamic bone or osteomalacia), and 4 of 5 patients with baseline hyperparathyroidism, had evolved toward a normalization of their bone turnover. Only one lanthanum-treated patient evolved toward adynamic bone compared with 6 patients in the CC group. In the LC group, the number of patients having either adynamic bone, osteomalacia, or hyperpara decreased overall from 12 (36%) at baseline to 6 (18%), while in the calcium group, the number of patients with these types of ROD increased from 13 (43%) to 16 (53%). Conclusion LC is a poorly absorbed, well-tolerated, and efficient phosphate binder. LC-treated dialysis patients show almost no evolution toward low bone turnover over one year (unlike CC-treated patients), nor do they experience any aluminum-like effects on bone.

Funding: This article is published as part of a supplement financially supported by the COST Action CA19127-Cognitive Decline in Nephro-Neurology: European Cooperative Target (CONNECT). Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research. publishersversion published