FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages.

SUMMARY: The hormone fibroblast growth factor 23 (FGF23) is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. In a cohort of 142 patients with CKD stages 2-5D, plasma FGF23 was independently associated with aortic calcification but not with pulse wave velocity or bone mineral density. INTRODUCTION: FGF23 is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. Previous studies related to FGF23 and vascular and bone outcomes have been restricted to dialysis patients. The aim of the present study was to establish whether or not plasma FGF23 is associated with aortic and coronary calcification, arterial stiffness, and bone mineral density in patients with early as well as late stages of CKD. METHODS: In a cohort of 142 patients with CKD stages 2-5D, we made routine biochemistry and intact FGF23 determinations, and assessed aortic and coronary calcification, bone mineral density (BMD), and arterial stiffness by multislice spiral computed tomography and automated pulse wave velocity (PWV). RESULTS: Plasma intact FGF23 levels were elevated in CKD patients; the elevation preceded that of serum phosphate in early-stage CKD. Patients with elevated FGF23 levels had higher aortic and coronary calcification scores than patients with lower FGF23 levels. Multivariate linear regression analysis indicated that only age (p < 0.001) and FGF23 (p = 0.008) were independently associated with aortic calcification score. Plasma FGF23 was neither associated with PWV nor with BMD. CONCLUSION: Our data suggest that plasma FGF23 is an independent biomarker of vascular calcification in patients with various CKD stages including early stages. The association between vascular calcification and FGF23 levels appears to be independent of BMD. It remains to be seen whether this association is independent of bone turnover and bone mass.

Is parathyroid hormone measurement useful for the diagnosis of renal bone disease?

The non-invasive diagnosis of bone turnover in patients with chronic kidney disease (CKD) remains difficult compared with bone histomorphometry as the gold standard. Most clinicians rely on surrogate markers, mainly serum parathyroid hormone and total alkaline phosphatases, in association with serum calcium and phosphorus. Although very high serum PTH levels generally allow the diagnosis of high bone turnover, slight elevations, normal, or low values cannot allow a reliable distinction between normal or low turnover.

Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

The pathogeneses of parathyroid disease in patients with uremia and nonfamilial primary parathyroid hyperplasia are poorly understood. Because of multigland involvement, it has been assumed that these common diseases predominantly involve polyclonal (non-neoplastic) cellular proliferations, but an overall assessment of their clonality has not been done. We examined the clonality of these hyperplastic parathyroid tumors using X-chromosome inactivation analysis with the M27 beta (DXS255) DNA polymorphism and by searching for monoclonal allelic losses at M27 beta and at loci on chromosome band 11q13. Fully 7 of 11 informative hemodialysis patients (64%) with uremic refractory hyperparathyroidism harbored at least one monoclonal parathyroid tumor (with a minimum of 12 of their 19 available glands being monoclonal). Tumor monoclonality was demonstrable in 6 of 16 informative patients (38%) with primary parathyroid hyperplasia. Histopathologic categories of nodular versus generalized hyperplasia were not useful predictors of clonal status. These observations indicate that monoclonal parathyroid neoplasms are common in patients with uremic refractory hyperparathyroidism and also develop in a substantial group of patients with sporadic primary parathyroid hyperplasia, thereby changing our concept of the pathogenesis of these diseases. Neoplastic transformation of preexisting polyclonal hyperplasia, apparently due in large part to genes not yet implicated in parathyroid tumorigenesis and possibly including a novel X-chromosome tumor suppressor gene, is likely to play a central role in these disorders.

Pleiotropic effects of the non-calcium phosphate binder sevelamer.

The number of chronic kidney disease (CKD) patients and related adverse outcomes has dramatically increased worldwide in the past decade. Therefore, numerous experimental and clinical studies have recently addressed the underlying mechanisms, in particular the marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of potentially noxious calcium overload. Sevelamer hydrochloride is a phosphate binder that offers an effective control of hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the clearance of some uremic toxins.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Pathophysiological aspects of vascular calcification in chronic renal failure.

The nephrology community has progressively recognized that vascular calcification in patients with chronic renal failure is a major problem in terms of morbidity and mortality. This type of soft tissue calcification is not only passive, as thought previously, but implies active processes as well. It results from disturbances of the normal balance between calcification inhibitors and promoters, acting both at the systemic and the local level, and from the phenotypic change of smooth muscle cells towards osteoblast-like calcifying cells in the vessel wall. The recognition of the main factors involved will allow in the future a more appropriate prophylactic and therapeutic approach of this clinically important complication of chronic renal failure.

Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients.

Type I collagen represents more than 90% of bone matrix. Quantitative analysis of collagen cross-link molecules such as pyridinoline (PYD) provides valuable information on bone resorption rate. We have studied 37 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Eighteen of them had tetracycline double labeling, allowing to determine dynamic, in addition to static bone parameters. Measurement of serum-free PYD was performed using a new competitive enzyme immunoassay. Serum PYD values were compared with those of three other serum markers of bone metabolism, namely intact PTH (iPTH), bone-specific alkaline phosphatase (bAP), and osteocalcin, for the correlations with bone histomorphometric parameters. Serum PYD levels (mean +/- SD) were significantly higher in dialysis patients than in normal individuals, 90.6 +/- 99.6 nM versus 1.9 +/- 0.4 nM, respectively. Patients with high turnover bone disease had significantly higher serum PYD levels than patients with normal or low bone turnover, 108.8 +/- 108.0 nM versus 34.1 +/- 12.8 nM, respectively. Serum PYD levels were positively correlated with bone resorption parameters including osteoclast surface (r = 0.59, p < 0.0001) and osteoclast number/mm2 (r = 0.61, p < 0.0001), and also with bone formation parameters, osteoblast surface (r = 0.43, p < 0.008), double-labeled surface (r = 0.81, p < 0.001), and BFR (r = 0.91, p < 0.0001). The BFR was better correlated with serum PYD levels than with either serum iPTH or osteocalcin concentrations. However, correlation with serum bAP was comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D receptor as a candidate tumor-suppressor gene in severe hyperparathyroidism of uremia.

Most chronic renal failure patients with severe refractory hyperparathyroidism harbor at least one monoclonal parathyroid tumor, but the specific acquired genetic defects that confer this clonal selective advantage remain poorly understood. Somatic inactivation of the vitamin D receptor (VDR) gene could contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influence of 1,25-dihydroxyvitamin D3. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Therefore, to assess VDR gene inactivation's potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgically resected from uremic patients. First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 genetically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intronic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected to comparative genomic hybridization, and no chromosomal losses in the VDR region (12cen-q12) were observed. These observations suggest that inactivating defects within the VDR gene do not commonly contribute to the primary pathogenesis of severe refractory hyperparathyroidism in uremia.

Measles virus and Guillain-Barré syndrome during long-term hemodialysis.

In a black man, recently receiving long-term hemodialysis, a severe, rapidly progressive polyradiculoneuritis (Guillain-Barre syndrome) developed. Routine virologic study revealed a high antimeasles virus antibody titer (1:1280 by hemagglutination-inhibition) which progressively decreased. There was no clinical evidence of measles. Discussed here is the possible relationship between the Guillain-Barre syndrome and clinically inapparent measles associated with and perhaps modified by the uremic state.

Control of secondary hyperparathyroidism by vitamin D derivatives.

The treatment of the secondary hyperparathyroidism of chronic renal failure patients has greatly improved during the last 2 decades. Significant progress has been made, in particular in the indication of 1alpha-hydroxylated vitamin D derivatives and patient management using these compounds. Treatment and prevention should start early during the development of chronic renal insufficiency. One of the major remaining problems in more advanced stages of renal failure is that control of plasma phosphate often remains extremely difficult. New inert oral phosphate binders are needed. The nephrology community is still waiting for the advent of nonhypercalcemic and nonhyperphosphatemic vitamin D analogs with PTH suppressive activity equal to the parent compound calcitriol or its immediate precursor, alfacalcidol.

Genetic aspects of secondary hyperparathyroidism in uremia.

In addition to the well-known uremia-related factors calcium, phosphate, and vitamin D, genetic polymorphisms and gene mutations appear to have a role as well in modulating parathyroid function. Allelic polymorphisms of the vitamin D receptor gene have been most often examined but to date their precise place is not yet certain in patients with chronic renal failure. The frequent transformation of parathyroid cell proliferation from polyclonal to monoclonal growth in patients with severe secondary hyperparathyroidism must be attributed to mutations or deletions of various tumor-suppressor genes, and probably more rarely also to an activation of tumor-enhancer genes.

Epithelial abnormalities in intestine and kidney of the spontaneously hypertensive rat.

A variety of perturbations of calcium metabolism are reported to occur in the spontaneously hypertensive rat (SHR) compared to its genetic control the Wistar-Kyoto rat (WKY), including significant dysfunction of calcium handling by the proximal renal tubule of the SHR, resulting in impaired active calcium transport in the gut and an apparent renal calcium leak. We explored the intestinal and renal epithelia of 12- to 14-week-old SHR and WKY using electron microscopy. Biochemical comparisons of these transport epithelia included measurements of three vitamin D dependent cellular proteins and one structural protein: alkaline phosphatase, intestinal CaBP9K, renal CaBP28K, and villin expression. Electron microscopy demonstrated a patchy loss in microvilli in the SHR, accounting for approximately 10 to 15% of the total microvillar surface. In the kidney, morphological abnormalities were observed only in the proximal renal tubule. Again, there was patchy loss of microvilli from the brush border membrane. In SHR duodenal alkaline phosphatase activity was significantly reduced compared to the WKY (0.145 +/- 0.002 v 0.186 +/- 0.002 integrated extinction/min/micron 3 X 10(3) brush border (P less than .001). Duodenal CaBP9K and renal CaBP28K were significantly reduced in SHR compared to WKY. There were no differences in villin expression. These data are consistent with the previously characterized disturbances of active calcium transport in the intestine and inappropriate renal calcium leak in the SHR. While a possible link between these disturbances and hypertension remains to be determined, this study provides supportive evidence for a primary disturbance in cell calcium handling and transporting epithelia in this form of genetic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Reoperation for secondary uremic hyperparathyroidism: are technical difficulties influenced by initial surgical procedure?

BACKGROUND: Parathyroid surgery in patients with uremia and secondary hyperparathyroidism is performed either by subtotal parathyroidectomy or total parathyroidectomy with immediate reimplantation. The aim of this study was to compare the results of reoperation for persistent or recurrent hyperparathyroidism after parathyroidectomy according to which initial operative procedure was used. PATIENTS AND METHODS: Eighty-nine patients had reoperation for persistent (28 patients) or recurrent (61 patients) hyperparathyroidism after 53 subtotal parathyroidectomies and 36 total parathyroidectomies with immediate reimplantation. Results of the reoperation were assessed in terms of success rate, morbidity, and operative findings. RESULTS: The success rate of reoperation in patients with persistent hyperparathyroidism was 89% and was independent of the initial type of surgery. Success rates of reoperation for recurrent hyperparathyroidism after initial subtotal parathyroidectomy and total parathyroidectomy with immediate reimplantation were 87% and 70%, respectively (P = .02). Hypertrophy of the parathyroid remnant was the main cause of recurrence after subtotal parathyroidectomy. After total parathyroidectomy with immediate reimplantation, recurrence was located in the graft in half the patients, while hyperplastic tissue was found in the neck or the mediastinum in the other half. CONCLUSIONS: Subtotal parathyroidectomy provides the best conditions for successful reoperation in case of recurrent hyperparathyroidism and should become the surgical treatment of choice for secondary hyperparathyroidism.

Extraskeletal problems and amyloid.

The major clinical manifestations of dialysis-associated A beta 2M amyloidosis are chronic arthralgias, destructive arthropathy and the carpal tunnel syndrome. For dialysis patients who have been maintained on renal replacement therapy for more than 10-15 years, this complication may become a major physical handicap. It may even be life-threatening in some instances due to cervical cord compression. Amyloid deposits in joint areas precede clinical symptoms and signs by several years. Systemic deposits may also occur but their clinical manifestations are infrequent. The diagnosis of dialysis arthropathy associated with beta 2-microglobulin-associated (A beta 2M) amyloidosis mostly relies on indirect clinical and radiological evidence. Histologic proof is rarely obtained in vivo. The pathogenesis of the disease is complex. It includes reduced elimination of beta 2M and potentially also as impaired degradation of A beta 2M as well as enhanced production of A beta 2M amyloid fibrils. Non enzymatic modifications of beta 2M probably play a role, including beta 2M protein modification with advanced glycation end-products (AGE) and advanced oxidation protein products. Modified beta 2M, collagen and proteoglycans appear actively involved in the induction of a local inflammatory response and beta 2M amyloid formation. There is also evidence in favor of treatment-related factors such as the type of hemodialysis membrane and the purity of dialysis water. Hopefully, the translation of our improving knowledge of all the factors involved will lead to a better treatment and eventually to the prevention of this dramatic complication of dialysis.

Role of oxidized low-density lipoprotein in the atherosclerosis of uremia.

Lipoprotein oxidation is involved in the genesis of atherosclerosis. In chronic renal failure (CRF), oxidative stress is enhanced because of an imbalance between pro-oxidant and antioxidant systems. Oxidative modifications of low-density lipoproteins (LDLs) occur not only at the level of lipid moiety, but also of protein moiety. We have shown that oxidation of LDL by hypochlorous acid (HOCl) in vitro, reflecting increased myeloperoxidase activity in vivo, leads to modifications of apoliproteins such that the latter in turn are capable of triggering macrophage nicotinamide adenine dinucleotide phosphate-oxidase activation. These oxidative changes of LDL protein moiety, if shown to occur to a significant extent in uremic patients in vivo, may represent an important alternative pathway in the pathogenesis of atheromatous lesions.

Homocyst(e)ine, oxidative stress, and endothelium function in uremic patients.

Moderate hyperhomocyst(e)inemia and impaired endothelium-dependent vasodilatation are present in uremic patients. However, the precise mechanism(s) underlying the link between moderate hyperhomocyst(e)inemia and endothelium dysfunction in uremic patients remains to be determined. Experimental and clinical evidence have led to the suggestion that moderate hyperhomocyst(e)inemia may predispose to endothelium dysfunction through a mechanism that involves generation of reactive oxygen species and a decrease in nitric oxide bioavailability. Recent preliminary findings in uremic patients provide support for some aspects of this suggestion. These data must be confirmed in additional studies. Moreover, the relative importance of homocysteine-induced oxidant stress versus other potential mechanisms of endothelium dysfunction in these patients remains to be determined.

Decrease of tumor-like calcification in uremia despite aggravation of secondary hyperparathyroidism: a case report.

Extraskeletal pseudotumoral calcifications generally develop in uremic patients with a high calcium x phosphorus (Ca x P) product and severe secondary hyperparathyroidism. In the present case report we describe a chronic hemodialysis patient presenting with a massive calcification of the left shoulder region, severe aluminum (Al) intoxication and moderate hyperparathyroidism. Her initial serum Ca x P product was only slightly elevated: 5.01 mmol2/l2. Under deferoxamine treatment during the subsequent 4 months, Al overload decreased. On the other hand, parathyroid overfunction worsened, as reflected by an increase of the serum immunoreactive parathyroid hormone [1-84] level from initially 690 to 1052 pg/ml (normal, 15-60 pg/ml) and an increase of alkaline phosphatase activity, and plasma calcitriol increased from undetectable to a low-normal value. Predialysis serum total Ca levels decreased rapidly from 2.9 to 2.5 mM but serum P concentrations remained elevated: 1.6-2.5 mM. Unexpectedly, the extent of the periarticular calcification diminished considerably during the same time period. The present observation shows that in a subset of uremic patients with Al overload, pseudotumoral calcifications may regress during Al chelation therapy despite progression of hyperparathyroidism. Since Al may predispose collagen to develop dystrophic or metastatic calcification, it is suggested that this process is reversible by correcting Al intoxication.

Does early anemia correction prevent complications of chronic renal failure?

Anemia is a common complication of chronic renal failure (CRF). With the availability of recombinant human erythropoietin (rhEPO) over the last decade, much progress has been made in the management of anemia in patients with end-stage renal disease (ESRD) [Eschbach 1995, Gimenez and Scheel 1994, Muirhead et al. 1995, Winearls 1995]. The clearest benefit of rhEPO in ESRD is a substantial reduction in transfusion dependency, which reduces the need for hospital admission and the risk of viral transmission. Improvements in hemostasis and a decrease in human leucocyte antigen (HLA) antibodies have also been reported. Beneficial effects of rhEPO on the cardiovascular system in ESRD include regression of left ventricular hypertrophy (LVH), improvement of angina, and a modest increase in aerobic work capacity. Treatment of anemia with rhEPO has also been shown to improve cognitive function, socialization and quality of life in dialysis patients, although this has not led to better vocational rehabilitation or employment status. It has also been reported that a lower hemoglobin (Hb) content is an independent risk factor for increased mortality in hemodialysis patients [Harnett et al. 1995]. Clearly, therefore, treatment of anemia associated with ESRD is required and beneficial. The optimum treatment of anemia prior to dialysis, however, is still a matter for debate.

Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients.

Much progress has been made in recent years in the management of anemia associated with chronic and renal failure with recombinant human erythropoietin (r-Hu EPO). However, there remains much debate surrounding the diagnosis and treatment of iron deficiency. To ensure that full benefit from erythropoietin therapy is received, most patients require iron supplement during treatment. There are, however, few guidelines for the use of iron therapy. Iron deficiency results in an inadequate response to r-Hu EPO and is the main cause of resistance to this treatment. Oral iron therapy is of limited value in patients receiving r-Hu EPO. Thus, intravenous iron supplementation should be administered only in patients who do not tolerate available intravenous iron preparations or who are on continuous ambulatory peritoneal dialysis with no evidence of functional iron deficiency. This article provides guidelines for the diagnosis of absolute or functional iron deficiency in patients with renal anemia and suggests treatment schedules for intravenous iron supplementation. We hope that all dialysis patients will be able on this basis to achieve a satisfactory iron status and benefit fully from r-Hu EPO therapy.

Medical management of secondary hyperparathyroidism in uremia.

The prevention and treatment of the secondary hyperparathyroidism of chronic renal failure by medical means relies on a number of different possible approaches, which should be tailored to each patient's individual needs. Schematically, prevention should start early during the course of chronic renal failure (ie, when plasma intact parathyroid hormone is normal or only slightly elevated). Small calcium supplements prevent the development of a calcium deficit and may prevent parathyroid hormone oversecretion. The various therapeutic options that are available at present include: oral or intravenous vitamin D and vitamin D derivatives, in particular the 1alpha-hydroxylated vitamin D compounds; oral calcium supplements (calcium carbonate and calcium acetate) to avoid calcium depletion and also to bind phosphate in the intestinal lumen; aluminum-containing phosphate binders, the use of which should be restricted; oral magnesium salts (magnesium carbonate and magnesium hydroxide), which often are not well tolerated; general measures, such as dietary restriction of phosphate intake; and, in the case of resistance to all these approaches, the possibility of attempting ultrasound-guided ethanol injection of grossly hyperplastic parathyroid glands. Finally, it is encouraging to know that new drugs are in development, including calcium-free, aluminum-free, nonabsorbable oral phosphate binders, potentially nonhypercalcemic vitamin D derivatives, and calcimimetics. Some of them already have entered the stage of clinical evaluation, and preliminary results are promising.