Renal Involvement in Primary Sj?gren's Syndrome: A Clinicopathologic Study

Background & objectives: Renal pathology and clinical outcomes in patients with primary Sjögren''s syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported.Design, setting, participants, & measurements: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted.Results: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment.Conclusions: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.Primary Sjögren''s syndrome (pSS) is a progressive autoimmune disorder involving the exocrine glands (1), typically presenting with keratoconjunctivitis and xerostomia (2). It is characterized pathologically by a predominant lymphocytic infiltrate around epithelial ducts of exocrine glands on salivary gland biopsy (3). Extraglandular manifestations of pSS, once thought to be uncommon, occur in up to 25% of patients. Patients can be afflicted by severe interstitial lung disease (4), cutaneous vasculitis (5), peripheral neuropathy (6), and hematologic complications such as lymphoma (7). They are also at increased risk for celiac sprue (8) and complications from Helicobacter pylori infection (9) such as mucosa-associated lymphatic tissue (MALT)-type lymphoma.Much of our understanding of the clinical presentation of renal involvement in pSS is based on case reports (10–26) and small retrospective cohorts (27–29). Tubulointerstitial nephritis (TIN) remains the most common presentation of renal involvement in pSS and CD4/CD8 T cell subsets are reported to predominate (27,30). This is often characterized by a distal (type I) renal tubular acidosis (RTA) and less commonly proximal (type II) RTA (Fanconi syndrome) (11,31–33). GN is thought to be a rare occurrence, with only case reports available in the literature (10,12–23), and tends to be a late development (34) in the course of the disease.We examined the renal pathologic findings and clinical trends of all patients with pSS who underwent kidney biopsy (KB) at Mayo Clinic since 1967 and assembled a case series of patients with pSS with renal pathologic disease evaluated by renal biopsy at a single center in the United States. This case series aimed to describe the common clinical presentations of renal disease in pSS, the array of pathologic findings of renal involvement in pSS, and trends during follow-up and treatment.     

Outcomes Associated with Serum Calcium Level in Men with Non-Dialysis-Dependent Chronic Kidney Disease

Background and objectives: Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in non-dialysis-dependent (NDD) chronic kidney disease (CKD). Outcomes associated with low serum calcium are also not well-characterized.Design, setting, participants, & measurements: We examined associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in a historic prospective cohort of 1243 men with moderate and advanced NDD CKD by using Cox models.Results: The association of serum calcium with mortality varied according to the applied statistical models. Higher baseline calcium and time-averaged calcium were associated with higher mortality (multivariable adjusted hazard ratio (95% confidence interval): 1.31 (1.13, 1.53); P < 0.001 for a baseline calcium 1 mg/dl higher). However, in time-varying analyses, lower calcium levels were associated with increased mortality.Conclusions: Higher serum calcium is associated with increased long-term mortality (as reflected by the baseline and time-averaged models), and lower serum calcium is associated with increased short-term mortality (as reflected by the time-varying models) in patients with NDD CKD. Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in these patients.Mineral and bone disorders in chronic kidney disease (CKD) (1) have emerged as novel mortality risk factors in dialysis patients (2–8). Some of these abnormalities (such as serum phosphorus and parathyroid hormone (PTH) levels) have also been implicated in similar ways in patients with non-dialysis-dependent (NDD) CKD (9–12). Serum calcium''s effect on outcomes has been the focus of attention mainly in dialysis patients, where calcium metabolism is significantly distorted (13–19). The use of calcium-containing phosphate binders further complicates the picture because these medications could be involved in the etiology of vascular calcification (20,21), and their roles as therapeutic agents have been intensely debated (22). Supporting the potential role for calcium in cardiovascular disease were epidemiologic studies showing an association between higher calcium and increased mortality (2–8). Some of the same studies have also suggested that extremely low calcium levels may themselves be deleterious (2,3), which has ultimately resulted in recommendations to attain a low-normal serum calcium level in dialysis patients (23). Studies examining the role of calcium in NDD CKD patients are fewer and failed to unequivocally show an association between abnormal calcium levels and vascular calcification (24–27). No study has yet examined the association of calcium levels with mortality in NDD CKD.We examined the association of serum calcium levels with all-cause mortality in a large number of male US veterans with moderate and advanced NDD CKD at a single medical institution.     

Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Background and objectives: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS.Design, setting, participants, & measurements: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy.Results: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN-α for hepatitis C virus infection (n = 5) or malignant melanoma (n = 1), three were receiving IFN-β for multiple sclerosis, and two were treated with IFN-γ for idiopathic pulmonary fibrosis. After a mean and median duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit.Conclusions: Collapsing FSGS may occur after treatment with IFN-α, -β, or -γ and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN.FSGS is the most common cause of idiopathic nephrotic syndrome in black patients and may be the most frequent cause of nephrotic syndrome in the general population (1–6). The spectrum of FSGS includes primary forms mediated by a putative circulating or permeability factor and a number of secondary forms caused by such diverse insults as hereditable mutations in podocyte genes, drugs, viral infections, and adaptive responses to reduced renal mass or other hemodynamic stress (1). A variety of histologic variants of FSGS have been identified and can be applied to both primary and secondary forms (7–9). Many secondary forms tend to manifest as particular morphologic subtypes (1).The collapsing variant of FSGS is defined by implosive wrinkling and “collapse” of the glomerular basement membrane associated with hypertrophy and hyperplasia of overlying podocytes (10–12). Collapsing FSGS was mainly described in patients with HIV-associated nephropathy (HIVAN) (13) but also was recognized as a variant of idiopathic FSGS (11,12). Both idiopathic collapsing FSGS and HIVAN are most commonly seen in young black patients (8–12,14). Compared with the usual, most common form of FSGS with discrete segmental scars (FSGS not otherwise specified [FSGS NOS]), collapsing FSGS is distinguished by more severe nephrotic syndrome and renal insufficiency at presentation and a more rapid course to renal failure (8–12,14). Central to the morphogenesis of the collapsing variant is podocyte injury that leads to podocyte dedifferentiation, apoptosis, and proliferation, in part through dysregulation of cell cycle–related proteins (15–19). Podocyte precursor cells from the parietal cell layer may contribute to the glomerular epithelial cell proliferation (20).HIVAN is not the only established secondary cause of collapsing FSGS. Collapsing FSGS has been reported in the setting of Parvovirus B19 infection (21) and in patients with hemophagocytic syndrome (with or without underlying lymphoma) (22). Collapsing FSGS also may follow treatment with pamidronate (23), with 15 cases reported in the medical literature (23,24). In contrast, FSGS NOS has been reported to result from treatment with lithium (25), sirolimus (26), and more recently anabolic steroids (27). Although rare cases of collapsing FSGS also have been reported after treatment with IFN-α (28–30), this therapeutic agent is more commonly associated with minimal-change disease (MCD) (31–38) and FSGS NOS (39–47). We report 11 additional cases of collapsing FSGS that developed during treatment with IFN, including six IFN-α (for hepatitis C virus [HCV] infection or melanoma), three IFN-β (for multiple sclerosis [MS]), and two IFN-γ (for idiopathic pulmonary fibrosis).     

Phosphoinositides and SNARE chaperones synergistically assemble and remodel SNARE complexes for membrane fusion

Yeast vacuole fusion requires 4 SNAREs, 2 SNARE chaperone systems (Sec17p/Sec18p/ATP and the HOPS complex), and 2 phosphoinositides, phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. By reconstituting proteoliposomal fusion with purified components, we now show that phosphoinositides have 4 distinct roles: PI(3)P is recognized by the PX domain of the SNARE Vam7p; PI(3)P enhances the capacity of membrane-bound SNAREs to drive fusion in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ can activate SNARE chaperones for the recruitment of Vam7p into fusion-competent SNARE complexes; and either PI(3)P or PI(4,5)P₂ strikingly promotes synergistic SNARE complex remodeling by Sec17p/Sec18p/ATP and HOPS. This ternary synergy of phosphoinositides and 2 SNARE chaperone systems is required for rapid fusion.Intracellular membrane fusion is a conserved reaction, vital for vesicle trafficking, hormone secretion, and neurotransmission. Fusion is regulated by NSF (N-ethylmaleimide-sensitive factor)/Sec18p, αSNAP (soluble NSF attachment protein)/Sec17p, SNAREs (SNAP receptors), Sec1p/Munc18–1p family (SM) proteins, Rab GTPases, and Rab:GTP-binding proteins, termed “Rab effectors” (1–3). Lipids, including phosphoinositides, sterols, diacylglycerol (DAG), and phosphatidic acid (PA), have specific roles in fusion (4–14). Proteins and lipids cooperate for their enrichment in membrane fusion microdomains (6, 8, 15, 16).SNARE proteins are integral or peripheral membrane proteins required for membrane fusion. SNAREs have either a Q or R residue at the center of their SNARE domain and associate in 4-helical QabcR complexes in cis (anchored to one membrane) or in trans (anchored to apposed membranes), where a, b, and c are families of related Q-SNAREs (2, 17, 18). Reconstituted proteoliposomes (RPLs) bearing Q-SNAREs fuse with RPLs bearing an R-SNARE through trans-SNARE-complex assembly (19, 20). This fusion has slow kinetics, requires nonphysiologically high SNARE densities, and causes substantial leakage of luminal contents of the RPLs (21–24).We study membrane fusion with yeast vacuoles (lysosomes). Vacuole fusion (25) requires 3 Q-SNAREs (Vam3p, Vti1p, and Vam7p) and 1R-SNARE (Nyv1p) (26, 27), two SNARE chaperone systems, Sec17p/Sec18p/ATP (28), and the HOPS (homotypic fusion and vacuole protein sorting)/Vps Class C complex (29, 30), the Rab-GTPase Ypt7p (31), and chemically minor but functionally vital “regulatory lipids”: ergosterol (ERG), DAG, PI(3)P, and PI(4,5)P₂ (8). Inactive 4SNARE cis-complexes on isolated organelles are disassembled by Sec17p/Sec18p/ATP (27). The heterohexameric HOPS complex, containing the SM protein Vps33p as a subunit, promotes and proofreads SNARE-complex assembly (32–34). HOPS can physically interact with the Q-SNAREs [Vam7p (35) and Vam3p (36, 37)], 4SNARE cis-complexes (32), GTP-bound Ypt7p (29), and phosphoinositides (35). PI(3)P supports the membrane association of the Qc-SNARE Vam7p, which has no transmembrane domain, through binding its PX domain (38). SNAREs, HOPS, Ypt7p, and regulatory lipids assemble in an interdependent fashion to form a fusion-competent membrane microdomain, the “vertex ring” (8, 16, 39). Trans-SNARE complexes are essential for fusion (26), yet fusion can be accelerated by SNARE-associating factors such as HOPS (14, 35) and by cycles of SNARE complex disassembly and reassembly, termed “remodeling” (40).Membrane fusion has been reconstituted with all purified yeast vacuolar components, including 4SNAREs, vacuolar lipids, 2 SNARE chaperone systems, and phosphoinositides (14). We now show distinct functions of phosphoinositides in RPL fusion: the PX-domain of the SNARE Vam7p recognizes PI(3)P, as reported (38); PI(3)P activates the 3Q-SNAREs to be more fusogenic in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ accelerates fusion by promoting the synergy between Sec17p/Sec18p and HOPS, although this synergy is not a function of the membrane recruitments of these SNARE chaperones. This ternary synergy between phosphoinositides and SNARE chaperones is essential for the assembly and remodeling of SNARE complexes.     

Hypophosphatemic Effect of Niacin in Patients without Renal Failure: A Randomized Trial

Background and objectives: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease.Design, setting, participants, & measurements: We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268).Results: Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of −0.13 mmol/L (−0.15 to −0.13 mmol/L; −0.41 mg/dl [−0.46 to −0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or ≥60 ml/min per 1.73 m², a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus ≤1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use.Conclusions: We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to ≥90 ml/min per 1.73 m² (i.e., stages 1 through 3 chronic kidney disease).Abnormalities in calcium-phosphorus homeostasis, including significant elevations in serum phosphorus concentrations, are thought to contribute to arterial stiffening, hypertension, and cardiovascular disease (CVD) risk in patients with advanced chronic kidney disease and ESRD that requires maintenance dialysis (1–6). Observational data from population-based studies suggested that even serum phosphorus concentrations within the normative range are linearly associated with measures of subclinical arteriosclerosis and the development of incident CVD outcomes (7–12). Two cross-sectional studies from patients who underwent cardiac catheterization have further indicated that serum phosphorus concentrations, primarily within the normative range, were directly associated with both the presence and the severity of angiographic coronary artery disease (13,14). Moreover, a graded, independent association between serum phosphorus concentrations (again, within the normative range) and recurrent CVD events was reported among a large clinical trial cohort of patients with a previous myocardial infarction (15).Supplementation of calcium salts, despite their efficacy and tolerability as a phosphorus-lowering treatment in ESRD, may enhance coronary artery and aortic valve calcification (16,17). This observation highlights the need for hyperphosphatemia treatment protocols to balance potential benefits and adverse effects (18–22). Phosphorus-lowering drugs that target other cardiovascular risk factors in chronic kidney disease (CKD), simultaneously, including, for example, dyslipidemia (23), might have additive or synergistic benefits. These findings may also be relevant to populations with less advanced CKD or normal renal function.Preliminary studies suggested that niacin administration (as niacinamide, niceritrol, or nicotinic acid) could be a useful primary or adjunctive treatment for the marked hyperphosphatemia that is characteristic of ESRD (24–30). Several reports from clinical trials of extended-release niacin (ERN) that was given to patients who had dyslipidemia and were free of clinical renal disease and hyperphosphatemia have contained limited additional data noting up to 10% reductions in the serum phosphorus concentrations of actively treated patients (31–34). These repeated clinical observations (24–34) are most plausibly explained by the direct inhibitory effect of niacin compounds on active transport-mediated phosphorus absorption in the mammalian small intestine (35–39).Published studies of patient populations who had dyslipidemia and were receiving ERN that included phosphorus data may have failed to provide information on baseline phosphorus values (33,34), and none (31–34) performed repeated measures analyses to examine the potential effects of niacin treatment on serum phosphorus and calcium concentrations, as well as the calcium-phosphorus products.Focused reexamination of the large, placebo-controlled clinical trial data set assembled by Maccubbin et al. (34) afforded us a unique opportunity to elucidate these and other unresolved issues regarding the impact of niacin given as the fixed-dose combination of ERN and laropiprant (ERN-L), a selective prostaglandin D2 receptor subtype 1 inhibitor that reduces niacin-induced flushing (34) or ERN alone on serum phosphorus and calcium concentrations and calcium-phosphorus products. We further evaluated whether there was evidence for significant effect modification by estimated GFR (eGFR), baseline serum phosphorus concentration, the presence of diabetes, or concurrent hepatic hydroxymethyl glutaryl–CoA reductase inhibitor (statin) use when assessing the potential impact of niacin on these routine clinical measures of calcium-phosphorus homeostasis.     

Coronary Calcification in Patients with Chronic Kidney Disease and Coronary Artery Disease

Background and objectives: A close linkage between chronic kidney disease (CKD) and cardiovascular disease (CVD) has been demonstrated. Coronary artery calcification (CAC) is considered to be the causal link connecting them. The aim of the study is to determine the relationship between level of kidney function and the prevalence of CAC.Design, setting, participants, & measurements: Autopsy subjects known to have coronary artery disease and a wide range of kidney function were studied. Patients without CKD were classified into five groups depending on estimated GFR (eGFR) and proteinuria: eGFR ≥60 ml/min/1.73 m² without proteinuria; CKD1/2: eGFR ≥60 ml/min/1.73 m² with proteinuria; CKD3: 60 ml/min/1.73 m² >eGFR ≥30 ml/min/1.73 m²; CKD4/5: eGFR <30 ml/min/1.73 m²; and CKD5D: on hemodialysis. Intimal and medial calcification of the coronary arteries was evaluated. Risk factors for CVD and uremia were identified as relevant to CAC using logistic regression analysis.Results: Intimal calcification of plaques was present in all groups, but was most frequent and severe in the CKD5D group and less so in the CKD4/5 and CKD3 groups. Risk factors included luminal stenosis, age, smoking, diabetes, calcium-phosphorus product, inflammation, and kidney function. Medial calcification was seen in a small number of CKD4/5 and CKD5D groups. Risk factors were use of calcium-containing phosphate binders, hemodialysis treatment, and duration.Conclusions: It was concluded that CAC was present in the intimal plaque of both nonrenal and renal patients. Renal function and traditional risks were linked to initimal calcification. Medial calcification occurred only in CKD patients.Cardiovascular disease (CVD) is the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD) (1,2) or chronic kidney disease (CKD) (3–7). The mechanisms underlying this increased cardiovascular risk are not clearly understood. In the general population, traditional risk factors for CVD have been well characterized (8), and these are also present in CKD (3–6,9). The mechanisms involved in the connection between CKD and CVD are probably numerous (3–6). Vascular calcification, such as coronary artery calcification (CAC) (10,11), is considered to be the causal link between them.Vascular calcification is common in physiologic and pathologic conditions such as aging, diabetes, dyslipidemia, genetic diseases, and diseases with disturbances of calcium metabolism (12–14). In CKD patients, vascular calcification is even more common, developing early and contributing to the markedly increased cardiovascular risk. Pathomorphologically, atherosclerosis (plaque-forming degenerative changes of the aorta and of large elastic arteries) and arteriosclerosis (concentric medial thickening and hyalinosis of muscular arteries) can be distinguished. Increased knowledge about the mechanisms of calcification together with improved imaging techniques have provided evidence that vascular calcification should be divided into two distinct entities according to the specific site of calcification within the vascular wall: plaque calcification, involving patchy calcification of the intima in the vicinity of lipid or cholesterol deposits, and calcification of the media in the absence of such lipid or cholesterol deposits, known as Mönckeberg-type atherosclerosis (12–14). These two types of calcification may vary in terms of the type of vessel affected, the location along the arterial tree (proximal versus distal), clinical presentation, and treatment and prognosis (12–14). In the general population and in patients with CKD, electron-beam computed tomography (EBCT) has proven CAC as a potent predictor of cardiac events (15–18). Both the prevalence and intensity of CAC are increased in patients with CKD (19–27). Several studies have been undertaken to investigate whether calcification occurs in the intima or media of the coronaries and whether the morphologic details of calcified plaques differ between renal and nonrenal patients (12–14,24). Causal elements for either type of CAC have not been definitively determined (12–14).Autopsy studies are limited in terms of patient selection, but have a major advantage in terms of being able to distinguish intimal from medial calcification. Therefore, our primary goal is to determine whether, among autopsy subjects known to have CAD, there exists a direct relationship between level of kidney function and the prevalence of intimal or medial calcification.     

Training of Surgeons in Peritoneal Dialysis Catheter Placement in the United States: A National Survey

Background and objectives: Peritoneal dialysis (PD) depends on timely and skilled placement of a PD catheter (PDC). Most PDCs are placed surgically, but little is known about the residency training of surgeons in this procedure. Inadequate residency training could limit surgical expertise in PDCs, resulting in high complication rates that discourage PD use. This study assessed surgical PDC training in the United States to explore this issue.Design, setting, participants, & measurements: A survey was sent to program directors of 248 U.S. surgery residency programs regarding the amount of PDC training, attitudes toward PDCs, and barriers to PDC training. Results were compared between academic and private centers.Results: Ninety-three surgery programs (38%) responded: 82% provided training in PDC and 69% were academic centers. Most surgeons placed 2 to ≤5 catheters during residency. Forty-eight percent of program directors felt that PDC training was important, 61% felt PDC training affected outcomes and increased the likelihood surgeons would place PDCs in practice, and 62% of programs expressed willingness to provide more PDC training. Lack of referrals from nephrology was the most frequently cited barrier to PDC training.Conclusions: Although many U.S. surgery residency programs provide PDC training, this training appears inadequate. Low PD use and lack of referrals limits surgical training at most centers. Nephrologists need to develop initiatives with surgeons to improve PDC training and outcomes.The use of peritoneal dialysis (PD) in the United States is declining. Despite comparable efficacy, improving outcomes, and cost savings compared with hemodialysis (HD), only 6% of incident and 7.2% of prevalent dialysis patients are treated with PD (1–4). Although many factors determine success on PD, a well functioning PD catheter (PDC) is absolutely necessary. Placement of a PDC by an experienced operator is strongly recommended to reduce complications (5–9). Little attention has been given to the potential effect of surgical PDC training on PD use and outcomes (1–2,10). Conversely, considerable focus has been placed on improving surgical training and outcomes for HD access (11–15).Problems with PDC placement and malfunction can disrupt efforts to grow and develop a PD program (5,9,16–18). PDC problems frustrate patients, nurses, and nephrologists alike, leading to dissatisfaction with PD and an early switch to HD (18). PDC malfunction is second only to infection as the cause of technique failure in PD (19,20). Surgeons insert most PD catheters in the United States because most nephrologists are not trained in PDC placement (5,21–23). Unfortunately, there is a shortage of surgeons interested and skilled in performing this procedure (5).Surgical outcomes correlate strongly with training during residency (24). Reluctance by surgeons to place PDCs and suboptimal PDC outcomes might stem from inadequate residency training. Unfortunately, little is known about the training surgeons undergo in this outwardly simple, yet critical procedure. We sought to investigate PDC training in U.S. surgery residency programs and explore surgical program directors'' attitudes toward this procedure.     

A state-mutating genetic algorithm to design ion-channel models

Realistic computational models of single neurons require component ion channels that reproduce experimental findings. Here, a topology-mutating genetic algorithm that searches for the best state diagram and transition-rate parameters to model macroscopic ion-channel behavior is described. Important features of the algorithm include a topology-altering strategy, automatic satisfaction of equilibrium constraints (microscopic reversibility), and multiple-protocol fitting using sequential goal programming rather than explicit weighting. Application of this genetic algorithm to design a sodium-channel model exhibiting both fast and prolonged inactivation yields a six-state model that produces realistic activity-dependent attenuation of action-potential backpropagation in current-clamp simulations of a CA1 pyramidal neuron.The importance of modeling ion channels has been understood since Hodgkin and Huxley''s seminal work with the squid giant axon (1). Subsequently, the development of the patch-clamp method (2) enabled the characterization of the properties of a wide range of channels, and intensive efforts followed to produce quantitative models that could predict and explain specific ion-channel behavior (3–7). Such efforts have led to two broad classes of models: those describing single-channel and gating currents, and those describing macroscopic currents.Models of single-channel and gating currents can be used to analyze properties such as open-channel probabilities, dwell times, and activation kinetics; they therefore facilitate an improved understanding of channel biophysics (3–5, 7–9). By contrast, models of macroscopic currents are usually intended as empirical tools as part of larger compartmental models of neurons. Such a macroscopic model may not necessarily describe the actual molecular state changes of the channel; the goal is rather for it to function as a “black-box” that reproduces the mean behavior of a population of channels. Hodgkin and Huxley''s (1) original formulation of sodium- and potassium-channel models is a prime example of this case, and its basic formalism continues to be widely used to generate empirical ion-channel models.An alternative to the Hodgkin–Huxley formalism is the state-dependent modeling approach (3). In reality, state-dependent models subsume Hodgkin–Huxley models because the latter can be recast as the former (3). State-dependent models are more general, however, because they can describe certain behaviors more easily than Hodgkin–Huxley type models, such as having widely different transition rates into and out of a given state (10). In general, the gold standard for the use of state-dependent models is single-channel recording (3, 5, 11), but the state-dependent formalism is also often employed in models of macroscopic currents (12–15) because of the generality and flexibility it affords.Methods to make empirical state-dependent models conform to data have been studied extensively and have involved a multitude of techniques such as hand fitting (12–14, 16), principal-axis fitting (17), maximum-likelihood estimation (5, 7, 17, 18), and genetic algorithms (15), among others. Here, we present a new fitting technique based on a topology-mutating genetic algorithm. Genetic algorithms have a number of useful characteristics: First, they have been shown to explore a large area of parameter space with relatively quick convergence, especially for problems with many parameters (19). Second, they are easily parallelizable. Third, they have been successfully applied to neuronal modeling, both for Hodgkin–Huxley-type ion-channel parameters and for compartmental neuronal models with voltage-activated conductances (15). Here we show that if the ion-channel model is formulated properly, genetic algorithms provide a natural way to incorporate changes in model topology as mutations.The algorithm presented here has several key features. Most notably, whereas other published optimization algorithms fix the model topology and optimize the rate constants, our algorithm searches over the space of model topologies and the space of rate parameters simultaneously. In order to design such an algorithm appropriate for state-dependent ion-channel models, we formulated an automated, computationally efficient method to satisfy the principle of microscopic reversibility, an equilibrium condition that imposes constraints on topologies with loops (20, 21). Finally, our algorithm uses a sequential approach, also known as goal programming (22), to optimize multiple protocols without the need to assign weights to each of the objective functions. The ability of this genetic algorithm to select and examine topologies not previously explored demonstrates its flexibility in developing working empirical models.We applied this genetic algorithm to devise a sodium-channel model that exhibits both fast and slow inactivation. Fast inactivation refers to a nonconducting channel state that follows quickly after depolarization and activation (within milliseconds) and from which channels recover quickly when the voltage is restored to resting levels (1). In response to either sustained depolarization (23, 24) or a train of depolarizing pulses (16, 25), however, the fraction of sodium channels available for activation also decreases rapidly, but in this case recovery occurs much more slowly, on the order of seconds rather than milliseconds. This form of inactivation has therefore been called “prolonged” or “slow” (16, 25). The presence of such widely disparate time scales makes the creation of state-dependent models of these channels a challenge. At the same time, the effect of prolonged inactivation on processes such as action-potential backpropagation (26, 27), transitions from bursting to spiking (28), and dendritic spiking (29, 30) makes the development of accurate models of prolonged inactivation important for computational simulations of neuronal function.     

Incidence of Contrast-Induced Nephropathy after Contrast-Enhanced Computed Tomography in the Outpatient Setting

Background and objectives: No prospective study has reported the incidence of contrast-induced nephropathy (CIN) or the associated morbidity and mortality after contrast-enhanced computed tomography (CECT) in the outpatient setting.Design, setting, participants, & measurements: We enrolled and followed a prospective, consecutive cohort (June 2007 through January 2009) of patients who received intravenous contrast for CECT in the emergency department of a large, academic, tertiary care center. Outcomes measured were as follows (1) CIN: An increase in serum creatinine ≥0.5 mg/dl or ≥25% 2 to 7 d after contrast administration; (2) severe renal failure: An increase in serum creatinine to ≥3.0 mg/dl or the need for dialysis at 45 d; and (3) renal failure as a contributing cause of death (consensus of three independent physicians) at 45 d.Results: The incidence of CIN was 11% (70 of 633) among the 633 patients enrolled. Fifteen (2%) patients died within 45 d, including six deaths after study-defined CIN. Seven (1%) patients developed severe renal failure, six of whom had study-defined CIN. Of the six patients with CIN and severe renal failure, four died, and adjudicators determined that renal failure significantly contributed to all four deaths. Thus, CIN was associated with an increased risk for severe renal failure and death from renal failure.Conclusions: CIN occurs in >10% of patients who undergo CECT in the outpatient setting and is associated with a significant risk for severe renal failure and death.Contrast-induced nephropathy (CIN) is a known complication of intravenous, iodinated contrast; is a common cause of renal failure in the inpatient setting (1–5); and is associated with both short- and long-term adverse outcomes (6,7). Previous reports indicated that CIN occurs in 4 to 20% of patients after intra-arterial administration after coronary angiography (5–9). In the outpatient setting, the use of intravenous contrast to enhance (contrast-enhanced computed tomography [CECT]) imaging has increased sharply in recent years. Despite that >6% of all emergency department (ED) patients undergo CECT in the United States (10), no prospective data allow clinicians to estimate the rate of CIN or the associated morbidity and mortality after CECT in the outpatient setting in a heterogeneous population. Previous, retrospective work in outpatients who underwent CECT found the prevalence of CIN to be 5 to 13% (11–14) and indicates that patients without baseline renal insufficiency or chronic kidney disease may still be at risk for CIN in this population (11); however, these studies were limited by retrospective design and selection bias related to inclusion of inpatients with existing kidney disease (11–14). Thus, the absence of predicate literature required to estimate both the incidence and the clinical significance of CIN after CECT provided rationale for this work.In this study, we sought to define prospectively the incidence of CIN in an unselected, consecutive, heterogeneous population of ED patients who received low-osmolar, nonionic contrast for a CECT study of any body region. We tested the hypothesis that the incidence of CIN in the ED population exceeds 4% and that CIN is associated with a high rate of severe renal failure and death (5–9,11).     

Prevalence of Atrial Fibrillation and Its Predictors in Nondialysis Patients with Chronic Kidney Disease

Background and objectives: Chronic kidney disease (CKD) increases systemic inflammation, which is implicated in development and maintenance of atrial fibrillation (AF); therefore, we hypothesized that the prevalence of AF would be increased among nondialysis patients with CKD. This study also reports independent predictors of the presence of AF in this population.Design, setting, participants, & measurements: A retrospective, cross-sectional analysis of 1010 consecutive nondialysis patients with CKD from two community-based hospitals was conducted. Estimated GFRs (eGFRs) were calculated using the Modification of Diet in Renal Disease (MDRD) equation. Multivariate logistic regression was used to determine independent predictors.Results: Of 1010 nondialysis patients with CKD, 214 (21.2%) had AF. Patients with AF were older than patients without AF (76 ± 11 versus 63 ± 15 yr). The prevalence of AF among white patients (42.7%) was higher than among black patients (12.7%) or other races (5.7%). In multivariate analyses, age, white race, increasing left atrial diameter, lower systolic BP, and congestive heart failure were identified as independent predictors of the presence of AF. Although serum high-sensitivity C-reactive protein levels were elevated in our population (5.2 ± 7.4 mg/L), levels did not correlate with the presence of AF or with eGFR. Finally, eGFR did not correlate with the presence of AF in our population.Conclusions: The prevalence of AF was increased in our population, and independent predictors were age, white race, increasing left atrial diameter, lower systolic BP, and congestive heart failure.Atrial fibrillation (AF) is the most common arrhythmia in clinical practice (1). Cardiac comorbidities that are associated with AF include hypertension, coronary artery disease (CAD), valvular heart disease (VHD), congestive heart failure (CHF), cardiomyopathy, pericarditis, congenital heart disease (CHD), and cardiac surgery (2–9). Noncardiac comorbidities that are associated with AF include acute pulmonary embolism, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, hyperthyroidism, and obesity (10–14).Evidence suggests that inflammation is involved in the pathogenesis of AF (15–20). For example, AF after cardiac surgery is associated with proinflammatory cytokine and complement activation (16,19). Moreover, patients with refractory lone AF have inflammatory infiltrates, myocyte necrosis, and fibrosis on biopsy (18). Several studies also reported elevated serum high-sensitivity C-reactive protein (hsCRP) levels in patients with AF (15–17,20).Evidence suggests that inflammation is associated with renal dysfunction (21–24). Proposed mechanisms include decreased proinflammatory cytokine clearance, endotoxemia, oxidative stress, and reduced antioxidant levels (23,24). Moreover, hsCRP levels are higher among elderly patients with renal insufficiency (24). In hemodialysis (HD) patients with ESRD, hsCRP, IL-6, and fibrinogen levels are elevated (21,22).HD patients with ESRD have an increased prevalence of AF; however, prevalence among nondialysis patients with CKD has not been investigated (25–30). Because CKD promotes inflammation, which promotes AF, we hypothesized the prevalence of AF would be increased among nondialysis patients with CKD. This study reports the prevalence and independent predictors of the presence of AF in a nondialysis population with CKD.     

Recent assembly of the Cerrado,a neotropical plant diversity hotspot,by in situ evolution of adaptations to fire

The relative importance of local ecological and larger-scale historical processes in causing differences in species richness across the globe remains keenly debated. To gain insight into these questions, we investigated the assembly of plant diversity in the Cerrado in South America, the world''s most species-rich tropical savanna. Time-calibrated phylogenies suggest that Cerrado lineages started to diversify less than 10 Mya, with most lineages diversifying at 4 Mya or less, coinciding with the rise to dominance of flammable C4 grasses and expansion of the savanna biome worldwide. These plant phylogenies show that Cerrado lineages are strongly associated with adaptations to fire and have sister groups in largely fire-free nearby wet forest, seasonally dry forest, subtropical grassland, or wetland vegetation. These findings imply that the Cerrado formed in situ via recent and frequent adaptive shifts to resist fire, rather than via dispersal of lineages already adapted to fire. The location of the Cerrado surrounded by a diverse array of species-rich biomes, and the apparently modest adaptive barrier posed by fire, are likely to have contributed to its striking species richness. These findings add to growing evidence that the origins and historical assembly of species-rich biomes have been idiosyncratic, driven in large part by unique features of regional- and continental-scale geohistory and that different historical processes can lead to similar levels of modern species richness.The uneven distribution of species diversity across the globe and the occurrence of biodiversity hotspots with high concentrations of species are well established (1–3). However, the underlying causes of differences in species diversity and composition among biomes and the processes that have prompted accumulation of high species diversity in some areas remain poorly understood (4–6). Correlations between species richness and annual energy input, water supply, and physiographic complexity suggest that climatic and other environmental factors are major determinants of species diversity (7). Indeed, it has been shown that these factors can accurately predict the locations of most global diversity hotspots and account for the latitudinal gradient of species richness (7). However, such insights contribute little to our understanding of the historical assembly of species-rich biomes and the larger-scale evolutionary processes that have generated global patterns of diversity (4, 8, 9). Little is known about the historical and geographical assembly of species-rich biomes (5), in terms of when, how quickly, and from where the species and lineages that make up different biomes have been recruited and how they subsequently evolved in situ. This lack of data on geographical and temporal patterns of species diversification, especially in the tropics where most diversity resides, makes it difficult to assess why there are so many species in these areas, to what extent variation in diversity can be attributed to regional and continental-scale historical contingencies (4, 10, 11), and to compare patterns among different species-rich biomes (9, 12).Recent discussion has highlighted the potential role of phylogenetic niche conservatism in shaping regional species pools (8, 13) and explaining diversity gradients (11). Prominent examples of large-scale niche or biome conservatism have been documented for the tropical–temperate biotas (11), mangroves (14), southern hemisphere extratropical biomes (13), Andean grasslands (8, 15), and seasonally dry tropical forests (16–18). However, the extent to which this tendency to retain ancestral ecology across lineages has influenced species composition in the most species-rich tropical biomes is unknown.Recent insights into the historical assembly of species diversity and biomes have come from time-calibrated phylogenies for biome-specific lineages (5, 9, 19–23). Phylogenies have potential for reconstructing transitions from precursor to modern biotas and identifying the underlying factors that drive these processes (4, 11, 24). However, the sparse sampling of lineages and species in such studies (5, 24) has limited these insights to a few well-studied areas such as the Cape Floristic Region (12, 20).     

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.Patients with diabetic kidney disease (DKD) are at increased risk for cardiovascular complications and early mortality. Those who survive long enough tend to progress to ESRD requiring dialysis or transplantation. Although advances in therapy with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor type II blockers (ARBs) have attenuated the incident rate of ESRD (1), disease progression remains common (2–4) and diabetes continues to be the leading cause for initiation of dialysis in the United States (1).Connective tissue growth factor (CTGF) is a 349-amino-acid secreted pleiotropic protein belonging to the cysteine-rich CCN (CTGF/Cyr61/Cef10/NOVH) family. Numerous glomerular, tubulointerstitial, and vascular cells types can produce CTGF, and many factors associated with the diabetic condition can stimulate CTGF expression, including hypertension, hyperglycemia, and hyperlipidemia (5–24).CTGF is a critical mediator of extracellular matrix accumulation and coordinates a final common pathway of fibrosis (5,25,26). CTGF has been shown to amplify the fibrogenic activity of TGFβ (27) and IGF-1 (17) and to inhibit the action of antifibrotic and regenerative factors bone morphogenic protein-7 (27,28) and vascular endothelial growth factor (29,30).In type 1 diabetes, plasma and urine CTGF levels correlate with the level of albuminuria and the stage of progressive renal insufficiency (31–34), and the plasma CTGF level is an independent predictor of vascular disease as assessed by intimal medial thickness (35) and of mortality and progression to ESRD (36). In renal biopsy specimens from patients with diabetes, elevated levels of CTGF mRNA are associated with chronic tubulointerstitial damage, albuminuria, and progression of renal insufficiency (37–39).FG-3019 is a recombinant human anti-CTGF monoclonal IgG₁ antibody that has shown activity in rodent models of kidney dysfunction associated with type 1 and 2 diabetes (40–42). Here, we report results of an open-label dose-escalation trial of FG-3019 infusions administered biweekly over 56 days in patients with DKD, the first study designed to evaluate safety and potential therapeutic effect of FG-3019 in this patient population.     

Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.Amyotrophic lateral sclerosis (ALS) refers to a heterogeneous group of adult onset human diseases, in which progressive neurodegeneration affecting both the upper and lower motor neuron systems causes advancing weakness and muscle atrophy, and culminates in paralysis and death. Approximately 5 to 10% of ALS cases are familial; the rest appear to be sporadic (1–3). Mutations in SOD1 account for ≈20% of the familial ALS cases and 1 to 5% of the cases of sporadic ALS (1–4); >120 different SOD1 mutations have been identified in ALS patients (http://alsod.iop.kcl.ac.uk/Als/index.aspx). Elucidation of mechanisms underlying ALS has been hampered by a paucity of biological material from affected individuals in early stages of the disease (5). To our knowledge, there are no previous reports of spontaneously occurring animal models of ALS. Thus, ALS research has relied heavily on transgenic rodents expressing mutant human SOD1 (hSOD1^m) to produce a motor neuron disease, which recapitulates many features of ALS (5–7). In contrast, nullizygous SOD1 knockout mice develop normally (8), suggesting that the neurodegeneration in hSOD1^m mice and in ALS patients results from a toxic gain of function (1, 5–8). Although the nature of the toxin is unclear, several experiments suggest that the neurodegeneration occurs because conformational changes in the mutant superoxide dismutase 1 protein (SOD1) alter the biological activity and/or promote the formation of intracellular SOD1 aggregates (1, 4, 9, 10).Canine degenerative myelopathy (DM) has been recognized for >35 years as a spontaneously occurring, adult-onset spinal cord disorder of dogs (11). When pelvic limb hyporeflexia and nerve root involvement were observed, the disease was termed chronic degenerative radiculomyelopathy (12). Initially thought to be specific to German Shepherds, it has also been called German Shepherd dog myelopathy (13). Since these early reports, DM has been diagnosed in several other breeds. The disease is common in certain breeds including the Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, and Chesapeake Bay retriever (14).With DM, there is no sex predilection. Most dogs are at least 8 years old before the onset of clinical signs (11–18). The initial clinical sign is a spastic and general proprioceptive ataxia in the pelvic limbs. At this stage of the disease, the presence of spinal reflexes indicates an upper motor neuron paresis (11). The asymmetric weakness frequently reported at disease onset progresses to paraplegia (11, 12, 14, 16, 18). Hyporeflexia of the myotatic and withdrawal reflexes occur in the latter disease stage (11, 12, 14, 16, 18). The disease duration can exceed 3 years; however, dog owners usually elect euthanasia within a year of diagnosis when their dogs become paraplegic. If the disease is allowed to progress, clinical signs will ascend to affect the thoracic limbs (11, 14, 16). Because various common acquired compressive spinal cord diseases can mimic DM by compromising the upper motor neuron and general proprioceptive pathways, a definitive diagnosis of DM can only be accomplished postmortem by the histopathologic observation of axonal and myelin degeneration, which can occur at all levels of the spinal cord (16–18) and in all spinal cord funiculi, but are consistently most severe in the dorsal portion of the lateral funiculus within the middle to caudal thoracic region (11, 13–18).     

Associations between Serum Leptin Level and Bone Turnover in Kidney Transplant Recipients

Background and objectives: Obesity is associated with increased parathyroid hormone (PTH) in the general population and in patients with chronic kidney disease (CKD). A direct effect of adipose tissue on bone turnover through leptin production has been suggested, but such an association has not been explored in kidney transplant recipients.Design, setting, participants, & measurements: This study examined associations of serum leptin with PTH and with biomarkers of bone turnover (serum beta crosslaps [CTX, a marker of bone resorption] and osteocalcin [OC, a marker of bone formation]) in 978 kidney transplant recipients. Associations were examined in multivariable regression models. Path analyses were used to determine if the association of leptin with bone turnover is independent of PTH.Results: Higher leptin levels were associated with higher PTH and lower vitamin D levels, and adjustment for vitamin D attenuated the association between leptin and PTH. However, higher leptin was also significantly associated with lower levels of the bone turnover markers: 1 SD higher leptin was associated with 0.13 lower log-OC (−0.17, −0.08, P < 0.001) and 0.030 lower log-CTX (−0.045, −0.016, P < 0.001) after multivariable adjustments. Path analysis indicated that the association of leptin with PTH was mostly mediated through vitamin D, and that the association between leptin and bone turnover was independent of PTH and vitamin D.Conclusions: Elevated leptin level is associated with lower bone turnover independent of its effects on serum PTH in kidney transplant recipients.Secondary hyperparathyroidism (SHPT) develops early in the course of chronic kidney disease (CKD) (1), and it has been associated with higher cardiovascular morbidity (2) and mortality (3) in hemodialysis patients and with higher mortality in patients with nondialysis-dependent CKD (4). In addition to factors directly related to worsening kidney function (e.g., abnormalities in calcium, phosphorus, vitamin D, and FGF23 metabolism) (1,5–8), PTH levels are also affected by demographic (9,10) and co-morbidity characteristics (11) in CKD. There is mounting evidence that obesity is also associated with higher PTH levels in the general population (12–16) and in patients with CKD (17,18). Furthermore, measurements of body composition suggest that the higher PTH associated with elevated body mass index (BMI) is directly related to the higher adiposity of these individuals (16). There have been speculations that obesity and adiposity indirectly cause elevated PTH levels by affecting vitamin D metabolism (15,19). This would logically imply a consequent increase in bone turnover mediated by PTH. More recently it has been suggested that adipose tissue may also exert a direct effect on bone tissue, possibly mediated through leptin secretion (20), providing an explanation for the decrease in bone turnover reported by some studies in obese individuals, despite relatively higher PTH levels (12). Earlier studies in dialysis patients reported an inverse association between leptin level and bone turnover (21,22). It is unclear if similar associations are present in kidney transplant recipients, a population that is also characterized by distinct changes in bone metabolism (23–26).The gold standard of determining bone turnover is bone histology, but this method is not feasible for application in large groups of patients. Possible alternatives to bone histology are biochemical markers of bone turnover such as serum beta crosslaps (CTX)—the C-terminal telopeptide fragments of type I collagen, a marker of bone resorption (27), or serum osteocalcin (OC) and serum alkaline phosphatase (ALP), markers of bone formation (28,29). To test the hypothesis that leptin may be directly associated with bone metabolism rather than through its effects on PTH, we examined the association of serum leptin with serum PTH level and with biochemical markers of bone resorption and formation in a large prevalent cohort of kidney transplant recipients.