Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study

DeSoi C.A., Umans J.G.

Phosphate clearance by polysulfone (PS) and cuprophane (CU) membranes and the relationship of peridialytic changes in serum phosphate with those of serum-ionized calcium, parathyroid hormone (PTH), and insulin were studied in six stable patients undergoing chronic hemodialysis (HD). Dietary phosphate intake was 25.7 mmol/day, and total dose of elemental calcium was 3.2 g/day. Patients were dialyzed for 2 to 4 h, once with each membrane. Serum phosphate levels fell precipitously during the first hour of HD with both dialyzers, from 1.42 and 1.49 mM to nadirs of 0.53 and 0.69 mM for PS and CU, respectively. Phosphate levels began to increase either late in HD or at the end of HD and, by 4 h post-HD, did not differ from predialysis values. Total mass transfer of phosphate was greater during the first hour (3.4 and 3.2 mmol for PS and CU, respectively) than during the remainder of HD (2.4 and 2.6 mmol/h). There were no significant differences in intradialytic serum phosphate changes, postdialytic phosphate rebound, or total phosphate removal between the two dialyzers. Ionized calcium increased by 0.11 mM, and PTH was suppressed to 40 to 50% of baseline values during dialysis with either membrane. Although phosphate removal continued for the duration of dialysis, serum phosphate did not continue to decrease, either reaching an apparent steady state or beginning to rebound, even during dialysis. This suggests active phosphate mobilization from a pool other than the extracellular fluid and demonstrates the inadequacy of a one-compartment model to explain these data. Further, these data do not support the regulation of intradialytic phosphate mobilization by serum PTH or insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Daugirdas J.T.

The original formula proposed to estimate variable-volume single-pool (VVSP) Kt/V was Kt/V = -In(R - 0.008 * t - f * UF/W), where in the Kt/V range of 0.7 to 1.3, f = 1.0 (* denotes multiplication). This formula tends to overestimate Kt/V as the Kt/V increases above 1.3. Because higher Kt/V values are now commonly delivered, the validity of both the urea generation term (0.008 * f) and correction for UF/W were explored by solving VVSP equations for simulated hemodialysis situations, with Kt/V ranging from 0.6 to 2.6. The analysis led to the development of a second-generation formula, namely: Kt/V = -In(R - 0.008 * t) + (4-3.5 * R) * UF/W. The first and second generation formulas were then used to estimate the modeled VVSP Kt/V in 500 modeling sessions in which the Kt/V ranged widely from 0.7 to 2.1. An analysis of error showed that this second-generation formula eliminated the overestimation of Kt/V in the high ranges found with the first-generation formula. Also, total error (absolute value percent error + 2 SD) was reduced with the second-generation formula. These results led to the proposal of a new formula that can be used for a very wide range of delivered Kt/V.

GANESH S.K., STACK A.G., LEVIN N.W., HULBERT-SHEARON T., PORT F.K.

. Hyperphosphatemia is highly prevalent among patients with end-stage renal disease (ESRD) and is associated with increased mortality risk in hemodialysis (HD) patients. The mechanism through which this mortality risk is mediated is unclear. Data from two national random samples of HD patients ( n = 12,833) was used to test the hypothesis that elevated serum PO 4 contributes mainly to cardiac causes of death. During a 2-yr follow-up, the cause-specific relative risk (RR) of death for patients was analyzed separately for several categories of cause of death, including coronary artery disease (CAD), sudden death, and other cardiac causes, cerebrovascular and infection. Cox regression models were fit for each of the eight cause of death categories, adjusting for patient demographics and non-cardiovascular comorbid conditions. Time at risk for each cause-specific model was censored at death that resulted from any of the other causes. Higher mortality risk was seen for patients in the high PO 4 group (>6.5mg/dl) compared with the lower PO 4 group (≤6.5mg/dl) for death resulting from CAD (RR 1.41; P < 0.0005), sudden death (RR 1.20; P < 0.01), infection (RR 1.20; P < 0.05), and unknown causes (RR 1.25; P < 0.05). Patients in the high PO 4 group also had non-significantly increased RR of death from other cardiac and cerebrovascular causes of death. The RR of sudden death was also strongly associated with elevated Ca × PO 4 product (RR 1.07 per 10 mg 2 /dl 2 ; P < 0.005) and serum parathyroid hormone levels greater than 495 pg/ml (RR 1.25; P < 0.05). This study identifies strong relationships between elevated serum PO 4 , Ca × PO 4 product, and parathyroid hormone and cardiac causes of death in HD patients, especially deaths resulting from CAD and sudden death. More vigorous measures to reduce the prevalence of these factors in HD patients may result in improved survival.

Blacher J., Guerin A.P., Pannier B., Marchais S.J., London G.M.

To test the predictive values of and independent contributions to cardiovascular and all-cause mortality of various arterial parameters exploring characteristics of the arterial wall at different sites, we studied prospectively 110 stable end-stage renal disease patients on hemodialysis. These parameters involved carotid diameter, carotid intima-media thickness, carotid compliance, carotid distensibility, carotid incremental elastic modulus, aortic diameter, aortic pulse wave velocity, and the presence of arterial calcifications measured at the sites of the carotid artery, abdominal aorta, iliofemoral axis, and legs. The presence of calcifications was analyzed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. During a follow-up of 53±21 months (mean±SD), 25 cardiovascular and 14 noncardiovascular deaths occurred. In univariate analysis, the carotid incremental elastic modulus was the most closely related to prognosis. Risk of death increased with the number of vascular sites involved by calcifications. Moreover, information (in terms of prediction) given by carotid elastic incremental modulus was additive to the presence and extent of vascular calcification-related prediction value. Adjusted hazard ratios of all-cause and cardiovascular mortality for an increase of 1 unit in calcification score were 1.9 (95% confidence interval [CI], 1.4 to 2.6) and 2.6 (95% CI, 1.5 to 4.4), respectively ( P <0.001 for both). Adjusted hazard ratios of all-cause and cardiovascular mortality for a 1-SD increase in carotid incremental elastic modulus were 1.6 (95% CI, 1.2 to 2.2) and 1.7 (95% CI, 1.2 to 2.4), respectively ( P <0.01 for both). The results of this study showed that the presence and extent of vascular calcifications were strong predictors of cardiovascular and all-cause mortality. Carotid incremental elastic modulus gave additional predictive value.

Unruh M.L., Evans I.V., Fink N.E., Powe N.R., Meyer K.B.

Skipping hemodialysis treatments and failing to adhere to prescribed diets are thought to injure hemodialysis patients.We examined predictors of hemodialysis skipping and laboratory measures of nonadherence and then examined the association of dialysis skipping and serum potassium and phosphate levels with survival.Of 739 patients, 67 were classified as skippers because they were absent for greater than 3% of scheduled treatments. Black race (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.30 to 3.92), current smoking (OR, 1.79; 95% CI, 1.02 to 3.13), and use of illicit drugs (OR, 3.96; 95% CI, 2.16 to 7.24) were associated with skipping. White race, increased serum phosphate level, greater creatinine level, and lower body mass index increased the likelihood of a serum potassium level greater than 5.0 mEq/L (mmol/L); younger age, greater serum potassium level, and greater serum creatinine level were associated with a serum phosphate level greater than 5.5 mg/dL (>1.78 mmol/L). Skipping was associated with an increased risk for death (hazard ratio [HR], 1.69; 95% CI, 1.24 to 2.31), as were phosphate level greater than 5.5 mg/dL (HR, 1.59; 95% CI, 1.16 to 2.17) and potassium level greater than 5.0 mEq/L (HR, 1.50; 95% CI, 1.10 to 2.06). Skipping was associated with a lower likelihood of kidney transplantation in those younger than 65 years (OR, 0.41; 95% CI, 0.18 to 0.93).These findings show that hemodialysis patients of black race and those with current tobacco or illicit drug use are at risk for skipping dialysis treatments. Skipping treatments and markers of poor dietary adherence are strongly associated with greater risk for death. Targeting high-risk patients to understand reasons for nonadherence and to intervene could prevent premature death.

Slinin Y., Foley R.N., Collins A.J.

Animal studies suggest that calcium-phosphorus homeostatic abnormalities cause cardiovascular disease in uremia; few observational studies in humans have explored this. Associations in the retrospective United States Renal Data System Waves 1, 3, and 4 Study of 14,829 patients who were on hemodialysis on December 31, 1993, were examined. Mean age and duration of renal replacement therapy were 60.0 and 3.2 yr, respectively; 40.7% had diabetes. Quintiles (Q(1) to Q(5)) of (albumin-adjusted) calcium were 10.2 mg/dl; phosphorus, 7.5 mg/dl; calcium-phosphorus product, 71.0 mg(2)/dl(2); and parathyroid hormone (PTH), 480 pg/ml. Higher calcium levels were associated with fatal or nonfatal cardiovascular events (adjusted hazards ratio, 1.08 for Q(5), versus Q(1)) and all-cause mortality (Q(2), 1.07; Q(4), 1.11; Q(5), 1.14). Phosphorus levels were associated with cardiovascular events (Q(2), 1.06; Q(3), 1.13; Q(4), 1.14; Q(5), 1.25) and mortality (Q(4), 1.10; Q(5), 1.19), calcium-phosphorus product was associated with cardiovascular events (Q(3), 1.09; Q(4), 1.14; Q(5), 1.24) and mortality (Q(4), 1.09; Q(5), 1.19), and PTH levels were associated with cardiovascular events (Q(5), 1.12) and mortality (Q(5), 1.17). Despite limitations (including retrospective design; noncurrent study era; and lack of serial calcium, phosphorus, and PTH measurements), this study suggests that disorders of calcium homeostasis are associated with fatal and nonfatal cardiovascular events and all-cause mortality in hemodialysis patients.

Teng M., Wolf M., Ofsthun M.N., Lazarus J.M., Hernán M.A., Camargo C.A., Thadhani R.

Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non–vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.

Kestenbaum B., Andress D.L., Schwartz S.M., Gillen D.L., Seliger S.L., Jadav P.R., Sherrard D.J., Stehman-Breen C.

Secondary hyperparathyroidism (SHPTH) is highly prevalent among persons with end-stage renal disease (ESRD). SHPTH has been linked to uremic bone disease, vascular calcification, and a higher risk of death. Parathyroidectomy (PTX) can dramatically reduce parathyroid hormone (PTH) and phosphate levels; however, the relationship between PTX and survival is not known.We conducted an observational matched cohort study utilizing data from the United States Renal Database System (USRDS) in which 4558 patients undergoing a first PTX while on hemodialysis or peritoneal dialysis were individually matched by age, race, gender, cause of ESRD, dialysis duration, prior transplantation status, and dialysis modality to 4558 control patients who did not undergo PTX. Patients were followed from the date of PTX until they died or were lost to follow-up.The 30-day postoperative mortality rate following PTX was 3.1%. Long-term relative risks of death among patients undergoing PTX were estimated to be 10% to 15% lower than those of matched control patients not undergoing surgery. Survival curves between the 2 groups crossed 587 days following PTX. Median survival was 53.4 months (95% CI: 51.2-56.4) in the PTX group, and 46.8 months (95% CI: 44.7-48.9) in the control group.PTX was associated with higher short-term, and lower long-term, mortality rates among U.S. patients receiving chronic dialysis. Measures to attenuate SHPTH may play an important role in reducing mortality among patients with end-stage renal disease.

Longenecker J.C., Coresh J., Powe N.R., Levey A.S., Fink N.E., Martin A., Klag M.J.

Although atherosclerotic cardiovascular disease (ASCVD) risk in end-stage renal disease (ESRD) is 5 to 30 times that of the general population, few data exist comparing ASCVD risk factors among new dialysis patients to the general population. This cross-sectional study of 1041 dialysis patients describes the prevalence of ASCVD risk factors at the beginning of ESRD compared with estimates of ASCVD risk factors in the adult US population derived from the Third National Health and Nutrition Examination (NHANES III). CHOICE Study participants had a high prevalence of diabetes (54%), hypertension (96%), left ventricular hypertrophy by electrocardiogram (EKG) criteria (22%), low physical activity (80%), hypertriglyceridemia (36%), and low HDL cholesterol (33%). CHOICE participants were more likely to be older, black, and male than NHANES III participants. After adjustment for age, race, gender, and ASCVD (defined as myocardial infarction, revascularization procedure, stroke, carotid endarterectomy, and amputation in CHOICE; and as myocardial infarction and stroke in NHANES III), the prevalence of diabetes, hypertension, left ventricular hypertrophy by EKG, low physical activity, low HDL cholesterol, and hypertriglyceridemia were still more common in CHOICE participants. Smoking, obesity, hypercholesterolemia, and high LDL cholesterol, however, were less common in CHOICE than NHANES III participants. The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants (13%) than in the NHANES III participants (6%). In summary, many ASCVD risk factors are more prevalent in ESRD than in the general population and may explain some, but probably not all, of the increased ASCVD risk in ESRD.

Moe S.M., Chen N.X.

Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor α-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present. In cultured vascular smooth muscle cells, the addition of pooled serum from dialysis patients (versus normal healthy controls) accelerated mineralization and increased expression of Cbfa1, osteopontin, and alkaline phosphatase to a similar magnitude as does β-glycerophosphate alone. However, a lack of inhibitors of calcification may also be important. Dialysis patients with low levels of serum fetuin-A, a circulating inhibitor of mineralization, have increased coronary artery calcification and fetuin-A can inhibit mineralization of vascular smooth muscle cells in vitro. These data support that elevated levels of phosphorus and/or other potential uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce a matrix of bone collagen and noncollagenous proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors.

Block G.A.

Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

London G.M.

Arterial calcification (AC) is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex, including disturbances of mineral metabolism and active expression of various mineral-regulating proteins. An inverse relationship between AC and bone density has been documented in uremic patients. In the study presented here, which included 58 patients with ESRD on hemodialysis (HD), bone-histomorphometry characteristics were compared with the AC scores (0 to 4) determined according to the number of arterial sites with calcifications. Patients with AC scores of 0 (no calcifications), or 1 or 2 (mild calcifications) had similar serum parathyroid hormone levels and bone histomorphometry, with larger osteoclast resorption, higher osteoclast numbers, and larger osteoblastic and double tertracycline-labeled surfaces. In contrast, patients with high AC scores (3 and 4) were characterized by lower serum parathyroid hormone, low osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces, and high percentages of aluminum-stained surfaces. According to multivariate analysis, AC score was positively associated with age (P < 0.0001), daily dose of calcium-containing phosphate binders (P = 0.009), and bone aluminum-stained surfaces (P = 0.037), and an inverse correlation was observed with osteoblastic surfaces (P = 0.001). A high AC score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. These findings suggest that therapeutic interventions associated with excessive lowering of parathyroid activity (parathyroidectomy, excessive calcium or aluminum load) favor lower bone turnover and adynamic bone disease, which could influence the development and progression of AC.

Stevens L.A.

Current literature suggests associations between abnormal mineral metabolism (MM) to cardiovascular disease in dialysis populations, with conflicting results. MM physiology is complex; therefore, it was hypothesized that constellations of MM parameters, reflecting this complexity, would be predictive of mortality and that this effect would be modified by dialysis duration (DD). Prevalent dialysis patients in British Columbia, Canada, who had measurements of calcium (Ca), phosphate (Pi), and parathyroid hormone (iPTH) between January and March 2000 were followed prospectively until December 2002. Statistical analysis included Cox proportional hazard models with Ca, Pi, and iPTH alone and in combination as explanatory variables; analyses were stratified by DD. The 515 patients included in this analysis represent British Columbia and Canadian dialysis populations: 69% were on hemodialysis, mean age was 60 +/- 17 yr, 40% were female, and 34% had diabetes. Mean Ca and Pi values were 2.32 +/- 0.22 mmol/L and 1.68 +/- 0.59 mmol/L, respectively, and median iPTH was 15.8 pmol/L (25th to 75th percentile: 6.9 to 37.3 pmol/L). Serum Pi, after adjusting for demographic, dialysis type and adequacy, hemoglobin, and albumin, independently predicted mortality (risk ratio [RR], 1.56 per 1 mmol/L; 95% confidence interval [CI], 1.15 to 2.12; P = 0.004). When combinations of parameters were modeled (overall P = 0.003), the combinations of high serum Pi and Ca with high iPTH (RR, 3.71; 95% CI, 1.53 to 9.03; P = 0.004) and low iPTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < 0.001) had highest risks for mortality as compared with the combination of high iPTH with normal serum Ca and Pi that had the lowest mortality and was used as index category. These effects varied across different strata of DD. This analysis demonstrates the importance of examining combinations of MM parameters as opposed to single variables alone and the effect of DD. In so doing, the complex interaction of time and MM can begin to be understand. Further exploration is required.

Miskulin D.C.

A valid and practical measure of comorbid illness burden in dialysis populations is greatly needed to enable unbiased comparisons of clinical outcomes. We compare the discriminatory accuracy of 1 year mortality predictions derived from four comorbidity instruments in a large representative US dialysis population.Comorbidity information was collected using the Index of Coexistent Diseases (ICED) in 1779 haemodialysis patients of a national dialysis provider between 1997 and 2000. Comorbidity was also scored according to the Charlson Comorbidity Index (CCI), Wright-Khan and Davies indices. Relationships of instrument scores with 1 year mortality were assessed in separate logistic regression analyses. Discriminatory ability was compared using the area under the receiver-operating characteristics curve (AUC), based on predictions of each regression model.When mortality was predicted using comorbidity and age, the ICED better discriminated between survivors and those who died (AUC 0.72) as compared with the CCI (0.67), Wright-Khan (0.68) and Davies (0.68) indices. Upon addition of race and serum albumin, predictive accuracy of each model improved further (AUCs of the ICED, 0.77; CCI, 0.75; Wright-Khan Index, 0.75; Davies Index, 0.74).The ICED had greater discriminatory ability than the CCI, Davies and Wright-Khan indices, when age and a comorbidity index were used alone to predict 1 year mortality; however, the differences among instruments diminished once serum albumin, race and the cause of ESRD were accounted for. None of the currently available comorbidity instruments tested in this study discriminated mortality outcomes particularly well. Assessing comorbidity using the ICED takes significantly more time. Identifying the key prognostic comorbid conditions and weighting these according to outcomes in a dialysis population should increase accuracy and, with restriction to a finite number of items, provide a practical means for widespread comorbidity assessment.

Saleh F.

A relation between left ventricular hypertrophy and parathyroid hormone (PTH) has been described in patients with end stage renal disease and secondary hyperparathyroidism. In vitro studies indicate a hypertrophic effect of PTH on cardiomyocytes. The purpose of this study was to examine the relation between PTH and left ventricular hypertrophy in a general population.The fourth Tromsø study (1994-1995) included 27159 subjects. 2700 had serum PTH measurement and left ventricular mass by height (LVMH) estimated with M-mode echocardiography. Among these, 980 males and 1060 females were without known cardiovascular disease or valvular heart disease and did not use blood pressure medication. In this group, using a multiple linear regression model, body mass index (BMI), followed by systolic blood pressure, were found to be the strongest predictors of LVMH. In males older than 59 years and females younger than 60 years, PTH was a significant and positive predictor of LVMH (P

Cui H., Bai X., Yang H., He Y.

Luo C., Bian X., Ji C., Wang H., Ma J., Zhong C., Yu Q.

To examine the relationship between serum intact parathyroid hormone (iPTH) levels and survival in maintenance dialysis patients. We retrospectively reviewed the data of patients who began and continued dialysis from January 2013 to December 2022. Patients were categorized based on their baseline and time-averaged (TA) iPTH levels into three groups: low (iPTH < 150 pg/ml), medium (150 ≤ iPTH < 300 pg/ml), and high (iPTH ≥ 300 pg/ml). We utilized the Kaplan–Meier method to assess survival differences, the Cox proportional hazards regression model to identify risk factors impacting adverse outcomes and the restricted cubic spline model to evaluate the association between iPTH levels and the all-cause mortality. We included a total of 1023 participants, comprising 524 hemodialysis and 499 peritoneal dialysis. Kaplan–Meier analysis showed that high baseline group had higher survival and low baseline group had poorer survival, compared with medium baseline group, respectively (χ2 = 44.974, P < 0.001). The three TA groups showed similar results (χ2 = 67.316, P < 0.001). Multivariate COX regression analysis showed that low TA iPTH was an independent risk factor for all-cause death (hazard ratio [HR] = 1.655, 95% CI 1.159–2.365, P = 0.006). The restricted cubic spline model revealed an L-shaped connection between TA iPTH level and the all-cause mortality with an inflection point of 193 pg/ml. The survival for maintenance dialysis patients varies significantly based on their baseline and time-averaged iPTH levels, with time-averaged iPTH emerges as an independent risk factor for all-cause death in these patients.

Suzuki K., Soeda K., Komaba H.

The kidneys play an important role in the regulation of phosphate and calcium balance and serum concentrations, coordinated by fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D). In patients with chronic kidney disease (CKD), this regulation is impaired, leading to CKD-mineral and bone disorder (CKD-MBD), characterized by decreased 1,25D, elevated FGF23, secondary hyperparathyroidism, hyperphosphatemia, bone abnormalities, and vascular and soft-tissue calcification. While bone abnormalities associated with CKD-MBD, known as renal osteodystrophy, have been recognized as the most typical interaction between the kidney and bone, a number of other kidney–bone interactions have been identified, for which our knowledge of the pathogenesis of CKD-MBD has played an important role. This article summarizes recent findings on CKD-MBD and explores the crosstalk between the kidney and bone from the perspective of CKD-MBD.

Rojas-Campos E., Ruvalcaba-Contreras N., Campos-Mariz A., Aguilar-Campos A., Andrade-Sierra J., Cerrillos-Gutiérrez J.I., Medina-Pérez M., Evangelista-Carrillo L., Banda A., Cueto-Manzano A.M.

Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is associated with clinical outcomes. It is necessary to identify the phenotype to make clinical decisions that optimize resources and follow-up. To determine the frequency of the CKD-MBD phenotype in dialysis patients and the associated factors. Cross-sectional study in 440 patients, evaluated for CKD-MBD. Phenotypes show frequency of high, low or on target levels of PTH, vitamin D and phosphorus. The most common phenotype was used for comparisons. Age was 37.5 ± 15.8 years, 53% male, 28% were diabetic, 60% on peritoneal dialysis (PD), dialysis vintage was 12.0 months (IQR 3.0–34.3). High PTH was 58%, low vitamin D 82%, high phosphorus 39%, low calcium 50%, and vascular calcification 55%. The combination of high PTH and low vitamin D and high on-target phosphorus was 39%. Those with high PTH and low vitamin D were more likely to use PD (71 vs 51%; p

Li J., Zhang W., Wang X., Sun N., Li L., Chang W.

ABSTRACTBackgroundDialytic phosphate removal is a cornerstone of the management of hyperphosphatemia in peritoneal dialysis (PD) patients, but the influencing factors on peritoneal phosphate clearance (PPC) are incompletely understood. Our objective was to explore clinically relevant factors associated with PPC in patients with different PD modality and peritoneal transport status and the association of PPC with mortality.MethodsThis is a cross‐sectional and prospective observational study. Four hundred eighty‐five PD patients were enrolled and divided into 2 groups according to PPC. All‐cause mortality was evaluated after followed‐up for at least 3 months.ResultsHigh PPC group showed lower mortality compared with Low PPC group by Kaplan–Meier analysis and log‐rank test. Both multivariate linear regression and multivariate logistic regression revealed that high transport status, total effluent dialysate volume per day, continuous ambulatory PD (CAPD), and protein in total effluent dialysate volume appeared to be positively correlated with PPC; body mass index (BMI) and the normalized protein equivalent of total nitrogen appearance (nPNA) were negatively correlated with PPC. Besides PD modality and membrane transport status, total effluent dialysate volume showed a strong relationship with PPC, but the correlation differed among PD modalities.ConclusionsHigher PPC was associated with lower all‐cause mortality risk in PD patients. Higher PPC correlated with CAPD modality, fast transport status, higher effluent dialysate volume and protein content, and with lower BMI and nPNA.

Shen Y., Xia J., Yi C., Li T., Wang P., Dai L., Shi J., Wang K., Sun C., Ye H.

The relationship between circulating 25-hydroxyvitamin D [25(OH)D] and pancreatic cancer has been well studied but remains unclear. The purpose of this study was to elucidate the association between circulating 25(OH)D and pancreatic cancer by using a meta-analytic approach. PubMed, Embase, and Wed of Science databases were searched through October 15, 2022. A random or fixed-effects model was used to estimate the pooled odds ratio (OR), risk ratio (RR), hazard ratio (HR) and their 95% confidence intervals (CIs). A total of 16 studies including 529,917 participants met the inclusion criteria, of which 10 reported incidence and 6 reported mortality. For the highest versus lowest categories of circulating 25(OH)D, the pooled OR of pancreatic cancer incidence in case–control studies was 0.98 (95% CI 0.69–1.27), and the pooled HRs of pancreatic cancer mortality in cohort and case–control studies were 0.64 (95% CI 0.45–0.82) and 0.78 (95% CI 0.62–0.95), respectively. The leave-one-out sensitivity analyses found no outliers and Galbraith plots indicated no substantial heterogeneity. Evidence from this meta-analysis suggested that high circulating 25(OH)D levels may be associated with decreased mortality but not incidence of pancreatic cancer. Our findings may provide some clues for the treatment of pancreatic cancer and remind us to be cautious about widespread vitamin D supplementation for the prevention of pancreatic cancer.

Hadi H.H., Al-Mayali H.H., Abdalsada H.K., Moustafa S.R., Almulla A.F., Al-Hakeim H.K.

Background. Numerous hemodialysis patients (HD) suffer from severe, life-threatening inflammation that must be treated to prevent further complications. Early diagnosis of inflammation in HD is highly needed. The present study used matrix metalloproteinase-1 (MMP3) and tissue inhibitor of metalloproteinases-1 (TIMP1) to differentiate between patients with/without inflammation using the neural network analysis (NN). Methods. The positive results of C-reactive protein were used as a criterion for the presence of inflammation in the patients (HD+CRP) versus the negative group (HD-CRP). The NN analysis was used to discriminate between groups using the measured biomarkers. Results. HD+CRP patients have a higher duration of disease, MMP3 and lower calcium than the HD-CRP level is significantly higher, while vitamin D is significantly lower in the HD+CRP group compared with both other groups (all p0.05). TIMP1 is significantly correlated with inorganic phosphate and CRP. In NN#1, the model for the prediction of HD+CRP from HD-CRP has an area under the curve (AUC) of the receiver operating characteristic (ROC) of 0.907 with a sensitivity and specificity 89.2% and a specificity of 100.0%. The top predicting variable for the prediction of HD+CRP is MMP3 (100%), followed by creatinine (87.1%). MMP3 is linked to the pathophysiology of HD, at least through their correlation with the inflammation in HD. In NN#2, the AUC of the ROC for predicting the kidney disease and subsequent HD was 98.9%, with a sensitivity of 100.0% and a specificity of 97.1%. The top four predicting variables for the prediction of high risk of inflammation in HD patients are urea (100%), creatinine (100%), MMP3 (59.7%), and vitamin D (57.1%). Conclusion. The NN analysis may differentiate between HD patients with inflammation from the HD without inflammation. Also, the measured parameters, especially MMP3, TIMP1, and vitamin D are useful as a diagnostic tools for the kidney diseases and inflammation linked with the disease.

Nakayama M., Kobayashi S., Kusakabe M., Ohara M., Nakanishi K., Akizawa T., Fukagawa M.

Abstract Background Tenapanor is a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporter. This is the first trial to assess the efficacy and safety of tenapanor in Japanese patients with hyperphosphatemia who are undergoing peritoneal dialysis. Methods This phase 3, open-label, multicenter, single-arm clinical trial targeted patients whose serum phosphorus was within 3.5–7.0 mg/dL with phosphate binders at screening. After phosphate binder washout, tenapanor was orally administered twice-daily, stepwise from 5 to 30 mg/dose for 16 weeks. The primary endpoint, mean change in serum phosphorus level, was evaluated at week 8. The 16-week treatment period was completed with tenapanor alone, and only one phosphate binder type was allowed for combined use after the primary endpoint. Results Of the 54 patients enrolled, 34 completed the study. At week 8, the primary endpoint, mean change in serum phosphorus level (last observation carried forward), was − 1.18 mg/dL (95% confidence interval: − 1.54, − 0.81 mg/dL) with tenapanor. From a baseline value of 7.65 mg/dL, serum phosphorus decreased to 6.14 and 5.44 mg/dL at weeks 8 and 16, respectively, and 46.3% and 76.5% of patients achieved serum phosphorus within 3.5–6.0 mg/dL at week 8 and week 16, respectively. The most common adverse event, diarrhea, occurred in 74.1% of patients; the severity of diarrhea was mild or moderate. Thus, the discontinuation percentage due to diarrhea was low at 5.6%. Conclusions Administration of tenapanor resulted in a sufficient reduction in serum phosphorus level at week 8 and was considered safe and tolerable. Trial registration NCT04766385.

Egan C.E., Qazi M., Lee J., Lee-Saxton Y.J., Greenberg J.A., Beninato T., Zarnegar R., Fahey T.J., Finnerty B.M.

Introduction Secondary hyperparathyroidism (sHPT) is prevalent in dialysis patients and can lead to tertiary hyperparathyroidism (tHPT) after kidney transplantation. We aimed to assess the association of pretransplant sHPT treatment on posttransplant outcomes. Methods We reviewed kidney transplant patients treated with parathyroidectomy or cinacalcet for sHPT. We compared patients biochemical and clinical parameters, and outcomes based on sHPT treatment. Results A total of 41 patients were included: 18 patients underwent parathyroidectomy and 23 patients received cinacalcet prior to transplantation. There were no significant differences between demographics, comorbidities, allograft characteristics or pre-sHPT intervention parathyroid hormone (PTH) and calcium levels. Patients that underwent parathyroidectomy were on dialysis for longer, although not significantly (71.9 versus 42.3 mo, P = 0.051). At time of transplantation, patients treated by parathyroidectomy had increased rates of controlled sHPT (88.9%; 16/18 versus 47.8%; 11/23, P = 0.008). Patients treated by parathyroidectomy had decreased development of tHPT (5.9%; 1/17; versus 42.1%; 8/19, P = 0.020) as well as decreased rates of posttransplant treatment with cinacalcet (11.1%; 2/18 versus 52.2%; 12/23, P = 0.008). Three patients treated with cinacalcet underwent parathyroidectomy after transplantation. Median PTH after transplant remained lower in patients treated by parathyroidectomy prior to transplant compared to those treated with cinacalcet (60.7 [interquartile range 39.7-133.4] versus 170.0 [interquartile range 128.4-292.7], P = 0.001). Allograft function and survival were similar for parathyroidectomy and cinacalcet, with median follow-up after transplantation of 56.7 and 34.2 mo, respectively. Conclusions sHPT treated by parathyroidectomy is associated with controlled PTH levels at transplantation and decreased rates of tHPT. Long-term outcomes should be studied on a larger scale.

Vega-Vega O., Caballero-Islas A.E., Del Toro-Cisneros N., Hernandez-Ordoñez S.Ó., Arvizu-Hernández M., Martínez-Rueda A., Camacho-Colin D., Gómez-Correa L.L., Correa-Rotter R.

<b><i>Introduction:</i></b> Expanded hemodialysis (HDx) is expected to provide enhanced permeability of medium-sized molecules, selective solute retention, and better internal retrofiltration. The primary objective of this study was to compare the efficiency for removal of β2-microglobulin with 3 different extracorporeal therapies (ETs): high-flux hemodialysis (HF), online hemodiafiltration (OL-HDF), and HDx. The secondary objective was to evaluate the efficiency of removal of other uremic toxins, including urea, phosphate, CRP, IL-6, IL-10, TNF-⍺, indoxyl sulfate, and p-cresol. <b><i>Methods:</i></b> This single-center, randomized, and cross-over study was performed. Patients were randomized to determine the initial modality of treatment, each period lasted 4 weeks and between one modality and another, there was a washout period of 1 week. Reduction ratios (RRs) of different-size molecules and albumin were calculated for the different ET. <b><i>Results:</i></b> Twenty-two patients were included, β2-microglobulin RR was greater during both OL-HDF and HDx as compared to HF (RR 62% vs. 73% vs. 27%, respectively, <i>p</i> = &lt;0.0001), and there was no significant difference between HDx and OL-HDF (<i>p</i> = 0.09). A decrease in serum phosphate levels was observed in the HDx and OL-HDF periods, contrary to an increase in HF (−0.79 mg/dL vs. −1.02 mg/dL vs. + 0.11 mg/dL, respectively, <i>p</i> = &lt;0.0001). There was no difference in RRs of other molecules (BUN, CRP, IL-6, IL-10, TNF-⍺, indoxyl sulfate, and p-Cresol). There was no decrease in serum albumin in any ET. <b><i>Conclusion:</i></b> HDx provides enhanced removal of β2-microglobulin and phosphate as compared to HF, and similar efficacy as with OL-HDF. HDx should be considered an alternative to chronic convective therapies.

Li H., Shi X., Tan R., Shi W., Liu J., Ge S., Hu W., Han L., Liu Y., Li Z., Zhang J., Cao Y., Chen W.

AbstractBackgroundProtein and phosphorus intake, which affect chronic kidney disease (CKD), is assessed using cumbersome food diaries. Therefore, more straightforward and accurate methods of assessing protein and phosphorus intake are needed. We decided to investigate the nutrition status and dietary protein and phosphorus intake of patients with stages 3, 4, 5, or 5D CKD.MethodsThis cross‐sectional survey included outpatients with CKD at seven class A tertiary hospitals in Beijing, Shanghai, Sichuan, Shandong, Liaoning, and Guangdong in China. Protein and phosphorus intake levels were calculated using 3‐day food records. Protein levels and calcium and phosphorus serum concentrations were measured; urinary urea nitrogen was determined using a 24‐h urine test. Protein and phosphorus intakes were calculated using the Maroni and Boaz formulas, respectively. The calculated values were compared with the recorded dietary intakes. An equation that regressed phosphorus intake on protein intake was constructed.ResultsThe average recorded energy and protein intake was 1637.5 ± 595.74 kcal/day and 56.97 ± 25.25 g/day, respectively. Overall, 68.8% of patients had a good nutrition status (grade A on the Subjective Global Assessment). The correlation coefficient between protein intake and calculated intake was 0.145 (P = 0.376) and that between phosphorus intake and calculated intake was 0.713 (P < 0.001).ConclusionProtein and phosphorus intakes correlated linearly. Chinese patients with stage 3–5 CKD had low daily energy intake but high protein intake. Malnutrition was present in 31.2% of patients with CKD. The phosphorus intake could be estimated from the protein intake.

Murashima M., Hamano T.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex combination of biochemical abnormalities of bone markers such as calcium, phosphate, and parathyroid hormone (PTH), abnormalities in bone turnover or mineralization, and vascular calcification. The goal of treatment for CKD-MBD is to prevent the adverse consequences associated with these abnormalities. The mainstay of treatment at present is phosphate restriction, phosphate binders, native and active vitamin D, calcimimetics, and combination of these agents depending on the available biochemical markers.

Asmar J., Chelala D., El Hajj Chehade R., Azar H., Finianos S., Aoun M.

Background Many studies have assessed the association between anemia and mortality in hemodialysis but few compared patients with and without diabetes. Our study aims to investigate the impact of hemoglobin and iron parameters on mortality in hemodialysis patients with or without diabetes. Methods This is a two-center retrospective study that included all adult patients who started hemodialysis between February 2012 and February 2020, followed until January 2021. Averages of hemoglobin, ferritin and transferrin saturation of entire follow-up were recorded. Kaplan Meier survival, log rank test and cox regression analyses were performed to assess the association between anemia biomarkers and mortality. Results A total of 214 patients were included. Mean age was 67.98 ±12.41 years, mean hemoglobin was 10.92 ±0.75 g/dL, mean ferritin was 504.43 ± 221.42 ng/mL and mean transferrin saturation was 26.23 ±7.77%. Log rank test showed an association between hemoglobin ≥11 g/dL and better survival in patients without diabetes (P = 0.028). Based on cox regression analysis, hemoglobin was associated with all-cause mortality in all patients (HR = 0.66; CI:0.49,0.89; P = 0.007). When comparing patients with and without diabetes, this association remained significant only in patients without diabetes (HR = 0.53; CI:0.37,0.77; P<0.001). Based on different multivariate models, hemoglobin, ferritin and age were independent factors associated with mortality in patients without diabetes. Conclusions This study showed that hemoglobin ≥11 g/dL is associated with better survival in hemodialysis patients without diabetes but not in those with diabetes. These differences need to be further explored in other countries and settings. An individualization of the hemoglobin target level might be necessary to improve patients’ outcomes.

Nitta K., Hanafusa N., Akiyama K., Kawaguchi Y., Tsuchiya K.

Chronic kidney disease—mineral and bone disorder (CKD-MBD) is a systemic disorder that increases the risk of morbidity and mortality in dialysis patients. CKD-MBD is highly prevalent in dialysis patients, and appropriate treatment is important for improving their outcomes. Inorganic phosphate, fibroblast growth factor 23, parathyroid hormone, and calciprotein particles are markers for critical components and effectors of CKD-MBD, and higher circulating levels of these markers are linked to cardiovascular diseases. In this short review, we focus on the pathogenesis and management of CKD-MBD in CKD patients, especially those on dialysis therapy, and discuss the prospects for improving the management in CKD patients, including those on dialysis.

Yao M., Liu Y., Sun M., Qin S., Xin W., Guan X., Zhang B., He T., Huang Y.

Cardiorenal syndrome (CRS) is defined as a disorder of the heart and kidney, in which acute or chronic injury of one organ may lead to acute or chronic dysfunction of the other. It is characterized by high morbidity and mortality, resulting in high economic costs and social burdens. However, there is currently no effective drug-based treatment. Emerging evidence implicates the involvement of mitophagy in the progression of CRS, including cardiovascular disease (CVD) and chronic kidney disease (CKD). In this review, we summarized the crucial roles and molecular mechanisms of mitophagy in the pathophysiology of CRS. It has been reported that mitophagy impairment contributes to a vicious loop between CKD and CVD, which ultimately accelerates the progression of CRS. Further, recent studies revealed that targeting mitophagy may serve as a promising therapeutic approach for CRS, including clinical drugs, stem cells and small molecule agents. Therefore, studies focusing on mitophagy may benefit for expanding innovative basic research, clinical trials, and therapeutic strategies for CRS.