The Swiss Kidney Stone Cohort: A Longitudinal, Multicentric, Observational Cohort to Study Course and Causes of Kidney Stone Disease in Switzerland.

BACKGROUND: Kidney stone disease has a high prevalence worldwide of approximately 10% of the population and is characterized by a high recurrence rate. Kidney stone disease results from a combination of genetic, environmental, and lifestyle risk factors, and the dissection of these factors is complex. METHODS: The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multicentric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data. SKSC comprises 782 adult patients (age >18 years) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24-h urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits was collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. CONCLUSION: SKSC provides a unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogeneous collective of patients throughout the whole Swiss population.

Phosphate intake, hyperphosphatemia, and kidney function.

Phosphate is essential in living organisms and its blood levels are regulated by a complex network involving the kidneys, intestine, parathyroid glands, and the skeleton. The crosstalk between these organs is executed primarily by three hormones, calcitriol, parathyroid hormone, and fibroblast growth factor 23. Largely due to a higher intake of ultraprocessed foods, dietary phosphate intake has increased in the last decades. The average intake is now about twice the recommended dietary allowance. Studies investigating the side effect of chronic high dietary phosphate intake suffer from incomplete dietary phosphate assessment and, therefore, often make data interpretation difficult. Renal excretion is quickly adapted to acute and chronic phosphate intake. However, at the high ends of dietary intake, renal adaptation, even in pre-existing normal kidney function, apparently is not perfect. Experimental intervention studies suggest that chronic excess of dietary phosphate can result in sustained higher blood phosphate leading to hyperphosphatemia. Evidence exists that the price of the homeostatic response (phosphaturia in response to phosphate loading/hyperphosphatemia) is an increased risk for declining kidney function, partly due by intraluminal/tubular calcium phosphate particles that provoke renal inflammation. High dietary phosphate intake and hyperphosphatemia are progression factors for declining kidney function and are associated with higher cardiovascular disease and mortality risk. This is best established for pre-existing chronic kidney disease, but epidemiological and experimental data strongly suggest that this holds true for subjects with normal renal function as well. Here, we review the latest advances in phosphate intake and kidney function decline.

Dietary vitamin D interacts with high phosphate-induced cardiac remodeling in rats with normal renal function.

BACKGROUND: Vitamin D (VD) and phosphate (Pi) load are considered as contributors to cardiovascular disease in chronic kidney disease and the general population, but interactive effects of VD and Pi intake on the heart are not clearly illustrated. METHODS: We fed normal male rats with three levels of dietary VD (100, 1100 or 5000 IU/kg chow) and Pi (0.2, 0.6 or 1.6%) (3X3 design) for 8 weeks and examined renal and cardiac function and histology. RESULTS: High dietary Pi decreased plasma and renal Klotho and plasma 25-hydroxyvitamin D, and increased plasma Pi, fibroblast growth factor 23 and parathyroid hormone without affecting renal function, while low Pi increased plasma and renal Klotho. Both low and high VD diets enhanced high Pi-reduced Klotho expression. Low dietary VD reduced-plasma Klotho was rescued by a low Pi diet. High dietary Pi reduced-cardiac ejection fraction was not modified by a low or high VD diet, but the dietary VD effects on cardiac pathologic changes were more complex. High dietary Pi-induced cardiac hypertrophy was attenuated by a low VD and exacerbated by a high VD diet. In contrast, high dietary Pi -induced cardiac fibrosis was magnified by a low VD and attenuated by a high VD diet. CONCLUSIONS: High Pi diet induces hypertrophy and fibrosis in left ventricles, a low VD diet accelerates high Pi-induced fibrosis, and a high VD diet exacerbated high Pi -induced hypertrophy. Therefore, cardiac phosphotoxicity is exacerbated by either high or low dietary VD in rats with normal kidney function.

A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects.

Background Despite epidemiologic evidence for increased cardiovascular morbidity and mortality associated with both high dietary and serum phosphate in humans with normal renal function, no controlled phosphate intervention studies of systemic hemodynamics have been reported. Higher serum 25(OH) vitamin D levels are associated with better cardiovascular outcomes, but vitamin D increases intestinal phosphate absorption.Methods We conducted a prospective outpatient study with blinded assessment in 20 young adults with normal renal function randomized to high phosphate (regular diet plus 1 mmol/kg body wt per day of Na as neutral sodium phosphate) or low phosphate (regular diet plus lanthanum, 750 mg thrice/day, plus 0.7 mmol/kg body wt per day of Na as NaCl) for 11 weeks. After 6 weeks, all subjects received vitamin D3 (600,000 U) by intramuscular injection. Outcome parameters were 24-hour ambulatory systolic and diastolic BP (SBP and DBP), pulse rate (PR), biomarkers, and measures of endothelial and arterial function.Results Compared with the low-phosphate diet group, the high-phosphate diet group had a significant increase in mean±SEM fasting plasma phosphate concentration (0.23±0.11 mmol/L); 24-hour SBP and DBP (+4.1; 95% confidence interval [95% CI], 2.1 to 6.1; and +3.2; 95% CI, 1.2 to 5.2 mm Hg, respectively); mean 24-hour PR (+4.0; 95% CI, 2.0 to 6.0 beats/min); and urinary metanephrine and normetanephrine excretion (54; 95% CI, 50 to 70; and 122; 95% CI, 85 to 159 µg/24 hr, respectively). Vitamin D had no effect on any of these parameters. Neither high- nor low-phosphate diet nor vitamin D affected endothelial function or arterial elasticity.Conclusions Increased phosphate intake (controlled for sodium) significantly increases SBP, DBP, and PR in humans with normal renal function, in part, by increasing sympathoadrenergic activity.

The human response to acute enteral and parenteral phosphate loads.

The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; α-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads.

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats.

Chronic metabolic acidosis (CMA) might result in a decrease in vivo in bone mass based on its reported in vitro inhibition of bone mineralization, bone formation, or stimulation of bone resorption, but such data, in the absence of other disorders, have not been reported. CMA also results in negative nitrogen balance, which might decrease skeletal muscle mass. This study analyzed the net in vivo effects of CMA's cellular and physicochemical processes on bone turnover, trabecular and cortical bone density, and bone microarchitecture using both peripheral quantitative computed tomography and µCT. CMA induced by NH4Cl administration (15 mEq/kg body wt/day) in intact and ovariectomized (OVX) rats resulted in stable CMA (mean Δ[HCO3(-)]p = 10 mmol/l). CMA decreased plasma osteocalcin and increased TRAP5b in intact and OVX animals. CMA decreased total volumetric bone mineral density (vBMD) after 6 and 10 wk (week 10: intact normal +2.1 ± 0.9% vs. intact acidosis -3.6 ± 1.2%, P < 0.001), an effect attributable to a decrease in cortical thickness and, thus, cortical bone mass (no significant effect on cancellous vBMD, week 10) attributed to an increase in endosteal bone resorption (nominally increased endosteal circumference). Trabecular bone volume (BV/TV) decreased significantly in both CMA groups at 6 and 10 wk, associated with a decrease in trabecular number. CMA significantly decreased muscle cross-sectional area in the proximal hindlimb at 6 and 10 wk. In conclusion, chronic metabolic acidosis induces a large decrease in cortical bone mass (a prime determinant of bone fragility) in intact and OVX rats and impairs bone microarchitecture characterized by a decrease in trabecular number.

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans.

Endothelin-1 inhibits collecting duct sodium reabsorption and stimulates proximal and distal tubule acidification in experimental animals both directly and indirectly via increased mineralocorticoid activity. Diet-induced acid loads have been shown to increase renal endothelin-1 activity, and it is hypothesized that increased dietary acid-induced endothelin-1 activity may be a causative progression factor in human renal insufficiency and that this might be reversed by provision of dietary alkali. We sought to clarify, in normal human volunteers, the role of endothelin-1 in renal acidification and to determine whether the effect is dependent on dietary sodium chloride. Acid-base equilibrium was studied in seven normal human volunteers with experimentally induced metabolic acidosis [NH(4)Cl 2.1 mmol·kg body weight (BW)(-1)·day(-1)] with and without inhibition of endogenous endothelin-1 activity by the endothelin A/B-receptor antagonist bosentan (125 BID p.o./day) both during dietary NaCl restriction (20 mmol/day) and NaCl repletion (2 mmol NaCl·kg BW(-1)·day(-1)). During NaCl restriction, but not in the NaCl replete state, bosentan significantly increased renal net acid excretion in association with stimulation of ammoniagenesis resulting in a significantly increased plasma bicarbonate concentration (19.0 ± 0.8 to 20.1 ± 0.9 mmol/l) despite a decrease in mineralocorticoid activity and an increase in endogenous acid production. In pre-existing human metabolic acidosis, endothelin-1 activity worsens acidosis by decreasing the set-point for renal regulation of plasma bicarbonate concentration, but only when dietary NaCl provision is restricted.

Effects of acidogenic diet forms on musculoskeletal function.

Chronic metabolic acidosis exerts well-characterized consequences on musculoskeletal function, including physicochemical dissolution of bone with calcium loss from bone, cellular effects on osteoblasts and osteoclasts and disturbed bone matrix mineralization. These mechanisms are responsible for the acidotic bone phenotype with features of both osteoporosis and osteomalacia. In addition, loss of muscle mass, sarcopenia and negative nitrogen balance are consequences of metabolic acidosis. It is becoming increasingly clear that these effects also occur as a consequence of the diet-induced acid loads characteristic of modern diets. Interventional, short- and long-term studies suggest that the result of neutralizing the diet-induced acid loads is skeletal calcium retention, decreased bone resorption and increases in bone mineral density, suggesting that such an intervention may have an important potential to prevent osteoporosis.

[It is more difficult to smash a prejudice than an atom]. / Es ist schwieriger, eine vorgefasste Meinung zu zertrümmern als ein Atom.

The death of a 17-year-old patient caused by hypokalemia-induced arrhythmia illustrates the tragic dangers of the current paranoid preoccupation, particularly of young women, with physical beauty and low body weight. This case also reminds the reader that modern textbooks are not always sufficiently reliable. An intellectual approach how to circumvent diagnostic misinterpretation even in the context of misleading textbook information is proposed.

Quality and cost considerations in hyponatraemic patients needing hospitalisation.

BACKGROUND: Hyponatraemia is the most common electrolyte disorder encountered in hospitalised patients and has an impact on outcome and survival. However, the risk factors are not yet sufficiently known. AIMS OF THE STUDY: This retrospective analysis was conducted with the primary objective to identify the incidence of hyponatraemia in patients, who need hospitalisation from any medical reason, focusing on the quality of treatment and the risk factors for recurrent or prolonged stay due to hyponatraemia. The secondary objectives were the calculation of costs of hyponatraemia caused by hospital stays in the canton of Basel-Landschaft and the additional extrapolation of these costs for the whole country of Switzerland. METHODS: 368 patients with a diagnosis of hyponatraemia admitted to three tertiary care centers in 2011 were included. We analysed the risk factors, causes and manifestations of hyponatraemia and their effects on length of stay and outcome. RESULTS: Female gender (62%), advanced age (average 75 ± 12 years) and the use of thiazides (r = 0.69, p = 0.03) represented the main risk factors with negative prognostic value concerning hyponatraemia. Hyponatraemia was never asymptomatic. Seventy-three patients (20%) were diagnosed with hyponatraemia due to SIADH (syndrome of inappropriate antidiuretic hormone secretion). The in-hospital mortality rate was 9%, irrespective of the severity of hyponatraemia, and every fifth patient had persistent neurological deficits on discharge from the hospital. Age (r = 0.65, p = 0.03), female sex (r = 0.49, p =0.12; in combination with age >75years r = 0.58, p = 0.049), resumption of risk medication (r = 0.563, p = 0.02) and persistent hyponatraemia on discharge (r = -0.51, p = 0.04) were associated with higher probability of relapse. Our data, extrapolated for Switzerland, yield uncovered annual costs of 93 million CHF, mostly due to in-hospital treatment longer than that reimbursed by SwissDRG (observed median of 9 days, cost coverage by SwissDRG 5 days for non-SIADH hyponatraemia and 6.5 days for SIADH). CONCLUSIONS: As even mild hyponatraemia is associated with an increased risk of morbidity and mortality, it is highly important to recognise it. Initial diagnostic evaluation, treatment based on volume status and thorough follow-up are crucial to avoid relapse. Hyponatraemia, based on the results of this retrospective study, constitutes a considerable medical and economic burden in Switzerland and has a serious impact on the hospital balance sheets.

Interrelationships among hypoxia-inducible factor biology and acid-base equilibrium.

In this article, we try to summarize the most important novel biological information on the complex interrelationships between acid-base alterations and hypoxia-inducible factor (HIF) signaling. Extracellular and intracellular acid-base alterations affect HIF signaling in part independently of hypoxia, and involve, among others, effects on cytoprotection and apoptosis. Conversely, HIF signaling may affect systemic and local acid production rates and has been implicated in the mechanism of the acute hyperventilatory response (ie, respiratory alkalosis) in response to hypoxia as well as for hypoxia-induced pulmonary artery hypertension (PAH), although the latter data are quite preliminary and can be explained by alternative mechanisms. Thus, this review calls attention to these relationships for renal physiologists and nephrologists to stimulate focused clinical observations and specific investigative efforts as proposed in this overview.

Effects of potassium citrate or potassium chloride in patients with combined glucose intolerance: A placebo-controlled pilot study.

BACKGROUND: Experimental K(+) depletion reversibly inhibits insulin secretion, while chronic metabolic acidosis decreases insulin sensitivity. We aimed to investigate the effects of potassium supplementation and alkali supplementation in non-acidotic, normokalemic humans with combined glucose intolerance. STUDY DESIGN AND RESULTS: In this double-blind, placebo-controlled study in 11 subjects (7 male, 4 female, ages 47-63 years), 90meqs of oral KCl or Kcitrate per day for 2weeks each increased insulin production as measured by homeostasis model assessment Beta [KCl=86 (CI 81-91), Kcitrate=88 (82-94), placebo=78 (73-83)%, p<0.04], but only Kcitrate attenuated insulin resistance as assessed by HOMA-IR (insulin resistance, Kcitrate=2.8 (2.5-3.1), placebo=3.2 (2.9-3.5), p<0.03) and only Kcitrate increased quantitative insulin sensitivity check index (Quicki, Kcitrate=0.355 (0.305-0.405), placebo=0.320 (0.265-0.375) p<0.04). These results were confirmed by independent measurements, i.e. HOMA C-peptide and whole body insulin sensitivity index measured during oral glucose tolerance testing. Kcitrate significantly decreased systolic and diastolic 24-hour ambulatory blood pressures (-4.0 (-3 to -5) and -2.7 (-1.9 to -3.5), respectively as compared to placebo, p<0.02) while KCl was without a significant effect. CONCLUSIONS: K(+) supplementation in the absence of overt K(+) depletion improves beta-cell function in subjects with combined glucose intolerance. The insulin-sensitizing and hypotensive effect, however, depend on citrate as the accompanying anion.

Arterial neovascularization and inflammation in vulnerable patients: early and late signs of symptomatic atherosclerosis.

BACKGROUND: Atherosclerosis is complicated by cardiovascular events such as myocardial infarction, stroke, or peripheral arterial occlusive disease. Inflammation and pathological neovascularization are thought to precipitate plaque rupture or erosion, both causes of arterial thrombosis and cardiovascular events. We tested the hypothesis that arterial inflammation and angiogenic events are increased throughout the arterial tree in vulnerable patients, ie, in patients who suffered from cardiovascular events, compared with patients who never suffered from complications of atherosclerosis. METHODS AND RESULTS: In a postmortem study, we quantified the inflammatory infiltrate and microvascular network in the arterial wall of iliac, carotid, and renal arteries. Tissue microarray technology was adapted to investigate full-thickness arterial sectors. We compared 22 patients with symptomatic atherosclerosis with 27 patients who never had suffered from any cardiovascular event. The absolute intimal macrophage content was 2- to 4-fold higher in vulnerable patients at all 3 arterial sites analyzed (P<0.05). Patients with symptomatic atherosclerosis had a denser network of vasa vasorum than patients with asymptomatic disease (33+/-2 versus 25+/-2 adventitial microvessels per 1 mm2; P=0.008). Hyperplasia of vasa vasorum was an early and macrophage infiltration was a late sign of symptomatic atherosclerosis. CONCLUSIONS: High intimal macrophage content and a hyperplastic network of vasa vasorum characterize vulnerable patients suffering from symptomatic atherosclerosis. These changes are uniformly present in different arterial beds and support the concept of symptomatic atherosclerosis as a panarterial disease.

Cytologically malignant lymphoid pericardial effusion with benign clinical outcome.

BACKGROUND: Isolated malignant pericardial effusion is a manifestation of primary cardiac lymphoma (PCL) and primary effusion lymphoma (PEL), rare types of non-Hodgkin's lymphoma (NHL). The diagnosis is based on different cytological methods and analyses including DNA-image cytometry (ICM-DNA). DNA-aneuploidy has been reported to be highly specific for malignancy. CASE DESCRIPTIONS AND RESULTS: A 75-year-old man and a 66-year-old woman underwent urgent pericardiocentesis for cardiac tamponade due to large pericardial effusion. In both patients pericardial fluid analysis showed highly atypical blastic lymphoid cells expressing CD45 (both patients) and CD20 (assessed only in one patient), and ICM-DNA revealed significant DNA-aneuploidy (2c deviation index 9.22 and 10.73 respectively, 75% and 60% respectively of the target nuclei in aneuploid areas). Extensive staging examinations did not identify any other tumour manifestation. Although in neither of the two patients systemic chemotherapy was administered, both were free of cancer after a follow-up of ten and nine years respectively. CONCLUSIONS: Despite the highly atypical cytomorphology including unequivocal DNA aneuploidy, long-term survival in both patients strongly suggests that pronounced reactive lymphocytic changes are probably due to viral pericarditis rather than PCL or PEL as underlying conditions. It seems that DNA-aneuploidy may be not absolutely specific for the detection of malignant lymphoid cells in pericardial fluid.

Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study.

OBJECTIVE: Vitamin D (D3) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA(1c)) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM. MATERIALS AND METHODS: We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D3 or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA(1c) levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values. RESULTS: After 6 months of D3 supply, there was a significant intergroup difference in the change in HbA(1c) levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D3 group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D3 group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D3 group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints. CONCLUSIONS: D3 improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA(1c) positively compared with placebo in patients with T2DM.

Effect of potassium citrate on bone density, microarchitecture, and fracture risk in healthy older adults without osteoporosis: a randomized controlled trial.

CONTEXT: The acid load imposed by a modern diet may play an important role in the pathophysiology of osteoporosis. OBJECTIVE: Our objective was to evaluate the skeletal efficacy and safety and the effect on fracture prediction of K-citrate to neutralize diet-induced acid loads. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled trial at a teaching hospital. SUBJECTS: Subjects included 201 elderly (>65 yr old) healthy men and women (t-score of -0.6 at lumbar spine). INTERVENTION: Intervention was 60 mEq of K-citrate daily or placebo by mouth. All subjects received calcium and vitamin D. OUTCOME MEASURES: The primary outcome was change in areal bone mineral density (aBMD) at the lumbar spine by dual-energy x-ray absorptiometry after 24 months. Secondary endpoints included changes in volumetric density and microarchitectural parameters by high-resolution peripheral quantitative computed tomography in both radii and both tibiae and fracture risk assessment by FRAX (Switzerland). RESULTS: K-citrate increased aBMD at lumbar spine from baseline by 1.7 ± 1.5% [95% confidence interval (CI) = 1.0-2.3, P < 0.001] net of placebo after 24 months. High-resolution peripheral quantitative computed tomography-measured trabecular densities increased at nondominant tibia (1.3 ± 1.3%, CI = 0.7-1.9, P < 0.001) and nondominant radius (2.0 ± 2.0%, CI = 1.4-2.7, P < 0.001). At nondominant radius, trabecular bone volume/tissue volume increased by 0.9 ± 0.8%, (CI = 0.1-1.7), trabecular thickness by 1.5 ± 1.6% (CI = 0.7-2.3), and trabecular number by 1.9 ± 1.8% (CI = 0.7-3.1, for all, P < 0.05). K-citrate diminished fracture prediction score by FRAX significantly in both sexes. CONCLUSIONS: Among a group of healthy elderly persons without osteoporosis, treatment with K-citrate for 24 months resulted in a significant increase in aBMD and volumetric BMD at several sites tested, while also improving bone microarchitecture. Based on the effect on fracture prediction, an effect on future fractures by K-citrate is possible.

Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA).

This review summarizes the evidence for a hypertensinogenic effect of Erythropoietin (Epo) in normal human subjects and predialysis, hemodialysis, and continuous ambulatory peritoneal dialysis (CAPD) patients. The possible mechanisms of Epo-induced hypertension are examined with in vivo animal and in vitro data, as well as pathophysiological human studies in both normal subjects and CKD patients. The evidence for a hypertensinogenic effect of erythropoiesis-stimulating agents (ESAs) in normal subjects, predialysis CKD, hemodialysis, and CAPD patients is compelling. Epo increases BP directly and notably independently of its erythropoietic effect and its effect on blood rheology. The potential for the development of future agents that might act as specific stimulators of erythropoiesis, devoid of direct hemodynamic side effects is underscored.

Partial neutralization of the acidogenic Western diet with potassium citrate increases bone mass in postmenopausal women with osteopenia.

Chronic acid loads are an obligate consequence of the high animal/grain protein content of the Western diet. The effect of this diet-induced metabolic acidosis on bone mass is controversial. In a randomized, prospective, controlled, double-blind trial, 161 postmenopausal women (age 58.6 +/- 4.8 yr) with low bone mass (T score -1 to -4) were randomly assigned to 30 mEq of oral potassium (K) citrate (Kcitrate) or 30 mEq of K chloride (KCl) daily. The primary end point was the intergroup difference in mean percentage change in bone mineral density (BMD) at lumbar spine (L2 through L4) after 12 mo. Compared with the women who received KCl, women who received Kcitrate exhibited an intergroup increase in BMD (+/-SE) of 1.87 +/- 0.50% at L2 through L4 (P < 0.001), of 1.39 +/- 0.48% (P < 0.001) at femoral neck, and of 1.98 +/- 0.51% (P < 0.001) at total hip. Significant secondary end point intragroup changes also were found: Kcitrate increased L2 through L4 BMD significantly from baseline at months 3, 9, and 12 and reached a month 12 increase of 0.89 +/- 0.30% (P < 0.05), whereas the KCl arm showed a decreased L2 through L4 BMD by -0.98 +/- 0.38% (P < 0.05), significant only at month 12. Intergroup differences for distal radius and total body were NS. The Kcitrate-treated group demonstrated a sustained and significant reduction in urinary calcium excretion and a significant increase in urinary citrate excretion, with increased citrate excretion indicative of sustained systemic alkalization. Urinary bone resorption marker excretion rates were significantly reduced by Kcitrate, and for deoxypyridinoline, the intergroup difference was significant. Urinary net acid excretion correlated inversely and significantly with the change in BMD in a subset of patients. Large and significant reductions in BP were observed for both K supplements during the entire 12 mo. Bone mass can be increased significantly in postmenopausal women with osteopenia by increasing their daily alkali intake as citrate, and the effect is independent of reported skeletal effects of K.