Determinants of the serum phosphate concentration in chronic kidney disease.

If Ccr is creatinine clearance and EP and TRP are rates of phosphate excretion and reabsorption, the serum phosphate concentration (Ps) is the sum of EP/Ccr and TRP/Ccr, i.e., the amounts of phosphate excreted and reabsorbed per volume of filtrate. At equilibrium, influx of phosphate into plasma determines EP, and EP/Ccr quantifies the contribution of phosphate influx to Ps. We used data obtained at 688 clinic visits of 387 patients to analyze the evolution of Ps in chronic kidney disease (CKD) stages G1 - 5 (dialysis excluded). EP/Ccr was calculated as (Pu×crs)/cru and TRP/Ccr as Ps-EP/Ccr (where u is urine, s is serum, and cr is creatinine). Means of these parameters were plotted against CKD stages, and correlations among variables were determined with regression analyses. In comparison to values in CKD stages G1 - 2, EP/Ccr rose and TRP/Ccr fell by the same amount in CKD G3a and G3b, and Ps did not change. In stages G4 and G5, EP/Ccr increased sharply, TRP/Ccr fell minimally, and Ps rose significantly. At estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2, TRP/Ccr was the principal determinant of Ps at eGFR < 45 mL/min/1.73m2, contributions of EP/Ccr and TRP/Ccr to Ps were comparable. Taken together, our results show that in CKD stages G4 and G5, the effect of phosphate reabsorption on Ps changes negligibly while that of phosphate influx increases dramatically. Because the tubular response to rising EP/Ccr is limited, maintenance of stable Ps in advanced CKD requires extreme reduction of phosphate influx into plasma. TRP/Ccr may define the lowest attainable Ps.

Estimation of health risks associated with dietary cadmium exposure.

In much of the world, currently employed upper limits of tolerable intake and acceptable excretion of cadmium (Cd) (ECd/Ecr) are 0.83 µg/kg body weight/day and 5.24 µg/g creatinine, respectively. These figures were derived from a risk assessment model that interpreted ß2-microglobulin (ß2MG) excretion > 300 µg/g creatinine as a "critical" endpoint. However, current evidence suggests that Cd accumulation reduces glomerular filtration rate at values of ECd/Ecr much lower than 5.24 µg/g creatinine. Low ECd/Ecr has also been associated with increased risks of kidney disease, type 2 diabetes, osteoporosis, cancer, and other disorders. These associations have cast considerable doubt on conventional guidelines. The goals of this paper are to evaluate whether these guidelines are low enough to minimize associated health risks reliably, and indeed whether permissible intake of a cumulative toxin like Cd is a valid concept. We highlight sources and levels of Cd in the human diet and review absorption, distribution, kidney accumulation, and excretion of the metal. We present evidence for the following propositions: excreted Cd emanates from injured tubular epithelial cells of the kidney; Cd excretion is a manifestation of current tissue injury; reduction of present and future exposure to environmental Cd cannot mitigate injury in progress; and Cd excretion is optimally expressed as a function of creatinine clearance rather than creatinine excretion. We comprehensively review the adverse health effects of Cd and urine and blood Cd levels at which adverse effects have been observed. The cumulative nature of Cd toxicity and the susceptibility of multiple organs to toxicity at low body burdens raise serious doubt that guidelines concerning permissible intake of Cd can be meaningful.

The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance.

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-ß-D-glucosaminidase concentrations ([Cd]u and [NAG]u) to the urine creatinine concentration ([cr]u). In theory, the sources of these errors are nullified by normalization of excretion rates (ECd and ENAG) to creatinine clearance (Ccr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, Ex/Ecr and Ex/Ccr were calculated as [x]u/[cr]u and [x]u[cr]p/[cr]u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m2. In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(ECd/Ccr) and log(ENAG/Ccr) than for log(ECd/Ecr) and log(ENAG/Ecr). Doubling of ECd/Ccr and ENAG/Ccr increased POR by 132% and 168%; doubling of ECd/Ecr and ENAG/Ecr increased POR by 64% and 54%. As log(ECd/Ccr) rose, associations of eGFR with log(ECd/Ccr) and log(ENAG/Ccr) became stronger, while associations of eGFR with log(ECd/Ecr) and log(ENAG/Ecr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R2 was consistently higher with normalization to Ccr. Our tabular and graphic analyses uniformly indicate that normalization to Ccr clarified relationships of ECd and ENAG to eGFR.

A generic method for analysis of plasma concentrations
.

The purpose of this NephEd contribution is to introduce a generic method for analyzing plasma concentrations ([x]p). The method is applicable to substances that are filtered by glomeruli, reabsorbed or secreted by tubules, and excreted in urine. The equality from which the method follows states that the filtration rate of substance x is the sum of excretion and net reabsorption rates of x (Fx = Ex + TRx). If x is completely ultrafilterable, Fx = GFR[x]p, and [x]p = Ex/GFR + TRx/GFR. If creatinine clearance (Ccr) is substituted for GFR, Ex/Ccr simplifies to [x]u[cr]p/[cr]u, which can be calculated from measurements in simultaneous aliquots of serum and urine. TRx/Ccr is then deduced as [x]p - Ex/Ccr. The ratios Ex/Ccr and TRx/Ccr - the determinants of [x]p - quantify the amounts of x excreted and reabsorbed per volume of filtrate. If [x]p is abnormal, the generic method identifies which of the determinants is creating the abnormality. If [x]p is normal despite disruptive circumstances, e.g., a reduced GFR, the method elucidates the preservation of normalcy. Herein, we develop these concepts and illustrate their practical utility.

An examination of multiple explanations for secondary hyperparathyroidism
.

AIMS: Seven theories address the evolution of secondary hyperparathyroidism (SHPT) as chronic kidney disease (CKD) progresses. The tradeoff-in-the-nephron hypothesis states that the plasma parathyroid hormone ([PTH]) concentration rises because an increased phosphate concentration in the cortical distal nephron ([P]CDN) reduces the ionized calcium concentration in that segment. In the present study, we compared this hypothesis to its predecessors. MATERIALS AND METHODS: We studied 30 patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 (mean 29.5). To examine historic theories, we performed regressions of [PTH] on plasma concentrations of ionized calcium, phosphorus, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and fibroblast growth factor 23, and on calcium excreted per volume of filtrate (ECa/Ccr). To assess the tradeoff-in-the-nephron hypothesis, we examined regressions of [PTH] on 100/eGFR and phosphorus excreted per volume of filtrate (EP/Ccr). RESULTS: Regressions pertinent to historic theories yielded significant direct relationships between [PTH] and both ECa/Ccr and [FGF23], but neither association supported the theory to which it pertained. [PTH] varied directly with 100/eGFR and with EP/Ccr, a surrogate for [P]CDN. EP/Ccr correlated strongly with 100/eGFR. CONCLUSIONS: The only theory of SHPT that our data support is the tradeoff-in-the-nephron hypothesis. Other theories are not supported.

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption.

BACKGROUND: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]. METHODS: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1-84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations. RESULTS: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption. CONCLUSIONS: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.

Phosphate homeostasis, parathyroid hormone, and fibroblast growth factor 23 in stages 3 and 4 chronic kidney disease.

AIMS: Increased concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) often coincide with normal serum phosphorus ([P]s) in chronic kidney disease (CKD). We hypothesized that the phosphate concentration ([P]f) in the cortical distal nephron (CDN) determines [PTH] and [FGF23] in this circumstance. METHODS: We studied 29 patients with CKD at 4 visits and 28 controls at 1 visit. Assuming GFR = creatinine clearance (Ccr), we examined the following regressions: [P]s on its determinants, EP/Ccr and TRP/Ccr (P excretion and reabsorption per volume of filtrate); [PTH] and [FGF23] on [P]s and EP/Ccr; and TRP/Ccr on [PTH] and [FGF23]. We assumed that EP/Ccr is proportional to [P]f in the CDN. RESULTS: In controls, [P]s correlated with TRP/Ccr but not EP/Ccr. [PTH] and [FGF23] were unrelated to [P]s, EP/Ccr, and TRP/Ccr. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr. [PTH] correlated with [P]s at 2 visits and with EP/Ccr at 4; [FGF23] correlated with [P]s and EP/Ccr at all visits. TRP/Ccr correlated with [FGF23] and [PTH] at one visit each. CONCLUSIONS: [P]f in the CDN, not [P]s, determined [PTH] in CKD. Because [FGF23] was consistently associated with only one determinant of [P]s, EP/Ccr, we infer that [P]f also determined [FGF23]. In patients with CKD, we speculate that [P]f in the CDN regulates FGF23 synthesis at that site.

Parameters of phosphorus homeostasis at normal and reduced GFR: theoretical considerations.

AIMS: Influx and reabsorption of phosphorus (IP and TRP) are assessed with fractional excretion and reabsorption (FEP and FTRP, nl ≤ 20% and ≥ 80%), or with excretion and reabsorption per volume of filtrate (EP/GFR and TRP/GFR, fasting nl ≈ 0.4 and 3.0 mg/dL). We analyzed these parameters at normal and reduced GFR. METHODS: We equated GFR with creatinine clearance (Ccr) to develop necessary equations. We plotted serum phosphorus ([P]s), EP/Ccr, and FEP against their determinants, and TRP/Ccr against EP/Ccr at FEP of 20% or 40%. RESULTS: Linear equations related [P]s to EP/Ccr and TRP/Ccr, and EP/Ccr to [cr]s and [P]u/[cr]u (a surrogate for IP). FEP rose in curvilinear fashion as Esub>P/Ccr rose and TRP/Ccr fell; changes in low values of EP/Ccr and TRP/Ccr induced large changes in FEP. At increased EP/Ccr (as in CKD), maintenance of FEP ≤ 20% required impossibly high TRP/Ccr; at EP/Ccr of 2.0 mg/dL, FEP and FTRP of 40% and 60% required normal TRP/Ccr. CONCLUSIONS: EP/Ccr varies with IP at normal GFR, and with IP and [cr]s at low GFR. FEP, a function of EP/Ccr and TRP/Ccr, varies primarily with the lower ratio, which is always EP/Ccr at normal GFR. At low GFR, high FEP is inevitable if IP is preserved, and TRP/Ccr may be normal despite low FTRP. Contributions of IP and TRP to [P]s should be assessed with EP/Ccr and TRP/Ccr. FEP and FTRP have limitations at any GFR.

Parameters of phosphorus homeostasis at normal and reduced GFR: empiric observations.

AIMS: Influx (IP) determines urinary excretion of phosphorus (EP). Contributions of IP and reabsorption (TRP) to serum phosphorus ([P]s) can be depicted by normalization to creatinine clearance (EP/Ccr and TRP/Ccr) or by calculation of fractional excretion and reabsorption (FEP and FTRP). We analyzed these parameters at normal and reduced GFR. METHODS: We studied 29 patients with chronic kidney disease (CKD) and 28 controls. From [cr] and [P] in serumand urine we calculated [P]u/[cr]u, EP/Ccr, TRP/Ccr, (TRP/Ccr)/(EP/Ccr), FEP, and FTRP. We compared means between groups and examined pertinent linear regressions. RESULTS: [P]s was not different in CKD and controls. [Cr]s, EP/Ccr, and FEP were higher and TRP/Ccr, (TRP/Ccr)/(EP/Ccr), and FTRP were lower in CKD. [P]u/[cr]u, a surrogate for IP, was similar in both groups. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr; EP/Ccr with [P]u/[cr]u and [cr]s; and FEP with EP/Ccr, TRP/Ccr, [P]u/[cr]u, and [cr]s. In controls, [P]s correlated with TRP/Ccr; EP/Ccr with [P]u/[cr]u; and FEP with EP/Ccr and [P]u/[cr]u. In both groups, FEP was a precise inverse function of (TRP/Ccr)/(EP/Ccr). Despite wide variation in TRP/Ccr, FEP was < 20% in 26/28 controls and > 20% in 27/29 patients with CKD. CONCLUSIONS: GFR affected determinants of [P]s, EP/Ccr, and FEP. FTRP was often dissociated from TRP/Ccr at normal or reduced GFR.

Use of sevelamer to examine the role of intraluminal phosphate in the pathogenesis of secondary hyperparathyroidism.

AIMS: Parathyroid hormone (PTH) promotes calcium reabsorption in the cortical distal nephron (CDN). The phosphate concentration ([P]f) rises in that segment in chronic kidney disease (CKD); in theory, high [P]f could reduce availability of calcium for reabsorption and necessitate a compensatory rise in [PTH]. With assumptions, [P]f is proportional to phosphate excreted/volume of filtrate (EP/GFR). We therefore hypothesized that [PTH] would correlate with EP/GFR in CKD, and ΔPTH] would correlate with ΔEP/GFR after sevelamer therapy. METHODS: We conducted a 4-week, placebo-controlled trial of sevelamer carbonate in patients with CKD. [PTH]1-84 and parameters of phosphate homeostasis were measured before and after treatment. GFR was assumed to equal creatinine clearance (Ccr). Pertinent linear regressions were performed. RESULTS: Phosphate excretion fell in the sevelamer group only. Decrements in [PTH] with sevelamer differed from increments with placebo. With either treatment, [PTH] correlated with EP/Ccr and ΔPTH] correlated with ΔEP/Ccr. Changes in [PTH] were minimal in some sevelamer recipients despite reductions in EP/Ccr; calcium excreted/volume of filtrate was low in these subjects. CONCLUSIONS: Phosphate influx affected [PTH] in CKD by determining [P]f in the CDN. In some patients, low calcium influx may have blunted the effect of sevelamer on [PTH].

Tubular calcium reabsorption and other aspects of calcium homeostasis in primary and secondary hyperparathyroidism.

AIMS: Primary hyperparathyroidism (PHPT) causes hypercalcemia by increasing tubular calcium reabsorption. Because chronic kidney disease (CKD) is associated with normocalcemia, we inferred that calcium reabsorption is also normal, and hypothesized that normal reabsorption requires excessive parathyroid hormone (PTH) in CKD. METHODS: The following were obtained in controls and patients with CKD or PHPT: estimated GFR (eGFR); concentrations of PTH 1-84, 1,25-dihydroxyvitamin D, and ultrafilterable and ionized calcium ([PTH], [1,25(OH)2D], [Ca]uf, [Ca]i); and ratios of calcium excreted or reabsorbed per volume of filtrate (ECa/Ccr, TRCa/Ccr). Pertinent linear regressions were examined. RESULTS: In CKD, [PTH] was increased, but ECa/Ccr, TRCa/Ccr, [Ca]uf, and [Ca]i equaled control values. [PTH] was inversely related to eGFR but unrelated to [1,25(OH)2D]. TRCa/Ccr was constant at all [PTH]. In PHPT, [PTH] was no higher than in CKD, but TRCa/Ccr, [Ca]uf, and [Ca]i were increased. [1,25(OH)2D] correlated with [PTH]. In controls, TRCa/Ccr varied directly with [1,25(OH)2D] and inversely with [PTH]. CONCLUSIONS: In controls, calcium reabsorption rose with [1,25(OH)2D], and [PTH] fell in response. In PHPT, [PTH] determined [1,25(OH)2D]; together, the hormones increased calcium reabsorption and caused hypercalcemia. In CKD, normal calcium reabsorption required high [PTH].

Long-term outcomes of community-acquired versus hospital-acquired acute kidney injury: a retrospective analysis.

AIM: To compare long-term outcomes in CA-AKI to HA-AKI. The hypothesis was that renal and patient survival would be better in CA-AKI than in HA-AKI. METHODS: Retrospective cohort analysis of patients hospitalized from 2004 to 2005, in Upstate New York Veterans Affairs hospitals. The groups: CA-AKI (n = 560), HA-AKI (n = 158), or No AKI (NA) (n = 2,320). Risk, injury, failure, loss, and end-stage kidney (RIFLE) criterion was used to define AKI. PRIMARY OUTCOMES: doubling of serum creatinine, endstage renal disease (ESRD), death, and a composite of the three. SECONDARY OUTCOMES: de novo chronic kidney disease (CKD), recovery of renal function, and re-admission rate. The cumulative incidence of outcomes was determined over a period of 3 years after discharge. RESULTS: CA-AKI was 3.5 times as prevalent as HA-AKI. In comparison to patients with HA-AKI, those with CA-AKI had better estimated glomerular filtration rate (71.3 vs. 61.1 mL/min/1.73 m(2), p < 0.001) and lower prevalence of CKD (42.3 vs. 51.9%, p = 0.03) at baseline. More patients with CA-AKI than HA-AKI met RIFLE failure criterion (43.8 vs. 29.1%, p < 0.001). By 3 years, no differences were found for the individual primary and secondary outcomes tested (all p > 0.05). CONCLUSIONS: CA-AKI was found to be considerably more common than HA-AKI and had similar long-term consequences.

The pathogenesis of albuminuria in cadmium nephropathy.

Background: Urinary cadmium excretion (ECd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since ß2-microglobulinuria (Eß2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eß2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. Methods: To depict excretion rates per functional nephron, ECd, Ealb, and Eß2M were normalized to creatinine clearance (Ccr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate Ealb/Ccr, Eß2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eß2M/Ccr on ECd/Ccr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in Ealb/Ccr and Eß2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr. Results: As age or ECd/Ccr rose, Ealb/Ccr and Eß2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eß2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eß2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eß2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eß2M/Ccr did not vary with blood pressure, Ealb/Ccr rose in association with hypertension in two of the four quartiles. Conclusions: Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and ß2M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.

Fractional excretion and reabsorption in chronic kidney disease.

The concepts of fractional excretion and reabsorption are often employed to elucidate the contribution of tubular transport to plasma concentrations. Fractional excretion of substance x, FEx, is the ratio of the urinary excretion rate to the filtration rate of x, or Ex/Fx. Fractional tubular reabsorption of x, FTRx, is the ratio of the reabsorption rate to the filtration rate of x, or TRx/Fx. When plasma is in equilibrium with respect to x, net influx (Ix) from gut and tissue determines Ex, and [x]p = Ex/GFR + TRx/GFR. In chronic kidney disease (CKD), Ex/GFR rises as GFR falls if Ix does not fall commensurately; at the same time, TRx/GFR may fall, remain unchanged, or rise. If TRx/GFR rises, a simultaneous, proportionately greater increment in Ex/GFR causes FEx to rise also and FTRx to fall secondarily. In this circumstance, FTRx is lower than normal even though reabsorption of x is increased per volume of filtrate. This paper reviews pertinent homeostatic principles, illustrates the potential for divergence of TRx/GFR and FTRx as GFR falls, and summarizes the conditions required for the divergence. Clinical examples show reduced FTRx despite increased TRx/GFR for phosphorus and urate, and analyses suggest that such discrepancies are often inevitable. Methods are described and arguments are advanced for using TRx/GFR to quantify tubular function in CKD.

Chemical evidence for the tradeoff-in-the-nephron hypothesis to explain secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) complicates advanced chronic kidney disease (CKD) and causes skeletal and other morbidity. In animal models of CKD, SHPT was prevented and reversed by reduction of dietary phosphate in proportion to GFR, but the phenomena underlying these observations are not understood. The tradeoff-in-the-nephron hypothesis states that as GFR falls, the phosphate concentration in the distal convoluted tubule ([P]DCT]) rises, reduces the ionized calcium concentration in that segment ([Ca++]DCT), and thereby induces increased secretion of parathyroid hormone (PTH) to maintain normal calcium reabsorption. In patients with CKD, we previously documented correlations between [PTH] and phosphate excreted per volume of filtrate (EP/Ccr), a surrogate for [P]DCT. In the present investigation, we estimated [P]DCT from physiologic considerations and measurements of phosphaturia, and sought evidence for a specific chemical phenomenon by which increased [P]DCT could lower [Ca++]DCT and raise [PTH]. METHODS AND FINDINGS: We studied 28 patients ("CKD") with eGFR of 14-49 mL/min/1.73m2 (mean 29.9 ± 9.5) and 27 controls ("CTRL") with eGFR > 60 mL/min/1.73m2 (mean 86.2 ± 10.2). In each subject, total [Ca]DCT and [P]DCT were deduced from relevant laboratory data. The Joint Expert Speciation System (JESS) was used to calculate [Ca++]DCT and concentrations of related chemical species under the assumption that a solid phase of amorphous calcium phosphate (Ca3(PO4)2 (am., s.)) could precipitate. Regressions of [PTH] on eGFR, [P]DCT, and [Ca++]DCT were then examined. At filtrate pH of 6.8 and 7.0, [P]DCT was found to be the sole determinant of [Ca++]DCT, and precipitation of Ca3(PO4)2 (am., s.) appeared to mediate this result. At pH 6.6, total [Ca]DCT was the principal determinant of [Ca++]DCT, [P]DCT was a minor determinant, and precipitation of Ca3(PO4)2 (am., s.) was predicted in no CKD and five CTRL. In CKD, at all three pH values, [PTH] varied directly with [P]DCT and inversely with [Ca++]DCT, and a reduced [Ca++]DCT was identified at which [PTH] rose unequivocally. Relationships of [PTH] to [Ca++]DCT and to eGFR resembled each other closely. CONCLUSIONS: As [P]DCT increases, chemical speciation calculations predict reduction of [Ca++]DCT through precipitation of Ca3(PO4)2 (am., s.). [PTH] appears to rise unequivocally if [Ca++]DCT falls sufficiently. These results support the tradeoff-in-the-nephron hypothesis, and they explain why proportional phosphate restriction prevented and reversed SHPT in experimental CKD. Whether equally stringent treatment can be as efficacious in humans warrants investigation.

Cadmium and Lead Exposure, Nephrotoxicity, and Mortality.

The present review aims to provide an update on health risks associated with the low-to-moderate levels of environmental cadmium (Cd) and lead (Pb) to which most populations are exposed. Epidemiological studies examining the adverse effects of coexposure to Cd and Pb have shown that Pb may enhance the nephrotoxicity of Cd and vice versa. Herein, the existing tolerable intake levels of Cd and Pb are discussed together with the conventional urinary Cd threshold limit of 5.24 µg/g creatinine. Dietary sources of Cd and Pb and the intake levels reported for average consumers in the U.S., Spain, Korea, Germany and China are summarized. The utility of urine, whole blood, plasma/serum, and erythrocytes to quantify exposure levels of Cd and Pb are discussed. Epidemiological studies that linked one of these measurements to risks of chronic kidney disease (CKD) and mortality from common ailments are reviewed. A Cd intake level of 23.2 µg/day, which is less than half the safe intake stated by the guidelines, may increase the risk of CKD by 73%, and urinary Cd levels one-tenth of the threshold limit, defined by excessive ß2-microglobulin excretion, were associated with increased risk of CKD, mortality from heart disease, cancer of any site and Alzheimer's disease. These findings indicate that the current tolerable intake of Cd and the conventional urinary Cd threshold limit do not provide adequate health protection. Any excessive Cd excretion is probably indicative of tubular injury. In light of the evolving realization of the interaction between Cd and Pb, actions to minimize environmental exposure to these toxic metals are imperative.

The Source and Pathophysiologic Significance of Excreted Cadmium.

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-ß-d-glucosaminidase, a marker of cellular damage ([NAG]u); and ß2-microglobulin, an indicator of reabsorptive dysfunction ([ß2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eß2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eß2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

Tradeoff-in-the-Nephron: A Theory to Explain the Primacy of Phosphate in the Pathogenesis of Secondary Hyperparathyroidism.

Chronic kidney disease (CKD) causes secondary hyperparathyroidism (SHPT). The cardinal features of SHPT are persistence of normocalcemia as CKD progresses and dependence of the parathyroid hormone concentration ([PTH]) on phosphate influx (IP). The tradeoff-in-the-nephron hypothesis integrates these features. It states that as the glomerular filtration rate (GFR) falls, the phosphate concentration ([P]CDN) rises in the cortical distal nephron, the calcium concentration ([Ca]CDN) in that segment falls, and [PTH] rises to maintain normal calcium reabsorption per volume of filtrate (TRCa/GFR). In a clinical study, we set GFR equal to creatinine clearance (Ccr) and IP equal to the urinary excretion rate of phosphorus (EP). We employed EP/Ccr as a surrogate for [P]CDN. We showed that TRCa/Ccr was high in patients with primary hyperparathyroidism (PHPT) and normal in those with SHPT despite comparably increased [PTH] in each group. In subjects with SHPT, we examined regressions of [PTH] on EP/Ccr before and after treatment with sevelamer carbonate or a placebo. All regressions were significant, and ∆[PTH] correlated with ∆EP/Ccr in each treatment cohort. We concluded that [P]CDN determines [PTH] in CKD. This inference explains the cardinal features of SHPT, much of the evidence on which other pathogenic theories are based, and many ancillary observations.

Transient Hypocalcemia in a Dialysis Patient With Paget's disease and Presumed Renal Cell Carcinoma.

A 68-year-old man with end-stage renal disease was hospitalized because of radicular pain and weakness in the left arm and hand. Sonography and computed tomography had recently shown a large right renal mass. On admission, magnetic resonance imaging demonstrated vertebral metastases with epidural extension, and radiotherapy was directed to the spine and kidney. Hypocalcemia was first noted on the fourth hospital day. A second computed tomography scan showed bleeding into and around the kidney, and arterial embolization was required to halt the bleeding. Hypocalcemia persisted for at least 27 days at values between 6.0 and 7.7 mg/dL and was consistently associated with ionized calcium concentrations less than or equal to 4.44 mg/dL. After an unrevealing search for a recognized cause, we attributed hypocalcemia to persistent sequestration of calcium in the right retroperitoneum. Exogenous supplementation eventually restored the concentration to normal. In the absence of renal and intestinal loss, hypocalcemia reflects abnormal flux of calcium from the extracellular compartment into tissue. Our patient's repository appears to have been a necrotic and hemorrhagic cancer. Tumor-induced sequestration of calcium should be included in the differential diagnosis of hypocalcemia.

CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals.

BACKGROUND: Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. METHODS AND FINDINGS: In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. CONCLUSIONS: The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.