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The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m 2 . The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Although high serum levels of galactose-deficient IgA1 (an important biomarker of IgA nephropathy (IgAN)) are found in most patients with IgAN, their relationship to disease severity and progression remains unclear. To help clarify this we prospectively enrolled 275 patients with IgAN and followed them for a median of 47 months (range 12-96 months). Serum galactose-deficient IgA1 was measured at the time of diagnosis using a lectin-based ELISA, and renal survival was modeled using the Cox proportional hazards method. The serum levels of galactose-deficient IgA1 were higher in patients with IgAN compared to those in healthy controls. Importantly, in adjusted analysis, higher levels of galactose-deficient IgA1 were independently associated with a greater risk of deterioration in renal function with a hazard ratio of 1.44 per standard deviation of the natural log-transformed galactose-deficient IgA1 concentration. In reference to the first quartile, the risk of kidney failure increased such that the hazard ratio for the second quartile was 2.47, 3.86 for the third, and 4.76 for the fourth quartile of the galactose-deficient IgA1 concentration. Hence, elevated serum levels of galactose-deficient IgA1 are associated with a poor prognosis in IgAN.

Abnormalities of bone mineral metabolism and vascular calcification are prevalent in patients with kidney failure. Clinical management is based on biochemical targets, in particular parathyroid hormone (PTH) concentrations, but this has many limitations including high biological variation. A possible alternative is bone-specific alkaline phosphatase (ALP); therefore, we evaluated the biological variation of this marker in patients undergoing hemodialysis. Bone ALP was measured in non-fasting serum samples taken twice a week over a 6-week period in 22 stable hemodialysis patients and 12 healthy volunteers. The within-individual coefficients of variance were calculated and used to derive the critical difference required to be certain that an observed change was significant. The coefficient of variance for bone ALP was significantly higher in hemodialysis patients compared to healthy individuals. Seven samples were required to estimate the homeostatic set point of bone ALP, within 10%, in a hemodialysis patient. The concentration of serial bone ALP measurements would need to change by 36% between any two measurements before it can be considered a significant change. Since the biological variation of bone ALP is less than half that reported for PTH, our study provides further support for the use of bone ALP as an alternative marker of bone mineral metabolism in the setting of chronic kidney disease-mineral and bone disorder.

A reduction of either blood pressure or glycemia decreases some microvascular complications of type 2 diabetes, and we studied here their combined effects. In total, 4733 older adults with established type 2 diabetes and hypertension were randomly assigned to intensive (systolic blood pressure less than 120 mm Hg) or standard (systolic blood pressure less than 140 mm Hg) blood pressure control, and separately to intensive (HbA1c less than 0.060) or standard (HbA1c 0.070-0.079) glycemic control. Prespecified microvascular outcomes were a composite of renal failure and retinopathy and nine single outcomes. Proportional hazard regression models were used without correction for type I error due to multiple tests. During a mean follow-up of 4.7 years, the primary outcome occurred in 11.4% of intensive and 10.9% of standard blood pressure patients (hazard ratio 1.08), and in 11.1% of intensive and 11.2% of standard glycemia control patients. Intensive blood pressure control only reduced the incidence of microalbuminuria (hazard ratio 0.84), and intensive glycemic control reduced the incidence of macroalbuminuria and a few other microvascular outcomes. There was no interaction between blood pressure and glycemic control, and neither treatment prevented renal failure. Thus, in older patients with established type 2 diabetes and hypertension, intensive blood pressure control improved only 1 of 10 prespecified microvascular outcomes. None of the outcomes were significantly reduced by simultaneous intensive treatment of glycemia and blood pressure, signifying the lack of an additional beneficial effect from combined treatment.

The serum glycoprotein fetuin-A is an important inhibitor of extra-osseous calcification, but correlations between serum fetuin-A levels and the extent of vascular calcification are controversial. In this study, we used a rat model of adenine-induced renal failure with secondary hyperparathyroidism that exhibits all characteristic features of patients with chronic kidney disease. These rats had medial vascular calcification along with reduced levels of both serum and hepatic fetuin-A. Treatment with an inhibitor of ectopic calcification, alendronate, decreased bone turnover and eliminated completely the vascular calcification in this rat model, but there was no change in the levels of hepatic and serum fetuin-A. Centrifugation of the serum of untreated rats with renal failure gave a small precipitate composed of fetuin-A, calcium, magnesium, and phosphate; this complex, absent from normal rat serum, was not found in the serum of alendronate-treated rats with renal failure. Rat serum contained three types of phosphorylated fetuin-A, as well as unphosphorylated forms, but only the fully phosphorylated fetuin-A was present in the mineral complex. The amount of this complex reflected the risk of mineral precipitation. Our results suggest that the measurement of serum fetuin-mineral complex rather than fetuin-A alone might provide a better indication of extra-osseous calcification propensity.

We compared the Swedish Coronary Angiography and Angioplasty Registry with the Swedish 'Hospital Discharge Register' to assess contrast media (CM)-induced renal failure. Hospitals used only one type CM. From 2000 to 2003, iodixanol (iso-osmolar) was used in 45 485 patients, ioxaglate (low osmolar) in 12 440 subjects. To include the earlier used CM iohexol (low osmolar), analysis extended back to 1990 (86 334 patients). Incidence of clinically significant renal failure was greatest for patients receiving the iso-osmolar CM iodixanol (1.7%). Ioxaglate-treated patients had a significantly lower renal failure incidence (0.8%, P<0.001). The odds ratio for iodixanol-treated patients was significantly higher than for ioxaglate (1 vs 0.48, P<0.001). In subsets of either diabetic patients or patients with previous renal failure, odds ratios for renal failure remained greater in the iodixanol groups (P<0.01). Hospitals switching CM to iodixanol experienced a doubling in clinically significant renal failure after cardiac procedures. Dialysis was required in 0.2% of patients receiving iodixanol, which was significantly higher (P<0.01) than for ioxaglate-treated patients (0.1%). Iohexol-treated patients had a similar low risk for developing clinically significant renal failure (0.9%) as ioxaglate. In conclusion, risk of developing renal failure and required dialysis after coronary procedures is higher when patients received iodixanol than ioxaglate or iohexol.

Based on in vitro data, protein-bound uremic retention solutes have increasingly been recognized to play a pathophysiological role in the uremic syndrome. p-Cresol, a representative of this group of molecules, has been shown to be implicated in uremic immunodeficiency and endothelial dysfunction, potentially linking its serum levels to mortality. Thus far, however, no clinical information on this issue is available. To determine the relationship between p-cresol and all-cause mortality, 175 prevalent hemodialysis (HD) patients were enrolled in a prospective study. At baseline, serum levels of the water-soluble solutes urea, creatinine, and phosphate, the middle molecule beta2-microglobulin, total and free concentrations of the protein-bound solute p-cresol, and several risk factors for mortality were evaluated. During a median follow-up of 34 months, 60 patients died. Baseline comorbidity (Davies score) (hazard ratio (HR), 1.49; 95% confidence interval (95% CI), 1.19-1.86), impaired nutritional status (HR, 4.22; 95% CI, 2.15-8.29), time since initiation of dialysis (HR, 0.98; 95% CI, 0.97-1.00), and higher free concentrations of the protein-bound solute p-cresol (HR, 2.28; 95% CI, 1.12-4.64) were independently associated with mortality (multivariate Cox proportional hazards analysis). Our data suggest that free serum levels of p-cresol, a representative of the protein-bound uremic retention solutes, are associated with mortality in HD patients. These findings may encourage nephrologists to widen their field of interest beyond the scope of small water-soluble uremic solutes and middle molecules.

Previously, uremic toxins were sometimes regarded as a large, mysterious, but also anonymous group of factors potentially contributing to morbidity and mortality in end-stage renal disease. By identifying the protein-bound solute p-cresol as a risk factor for mortality in dialysis patients, Bammens and colleagues for the first time present evidence of a clinically relevant uremic toxin in relation to clinical outcome.

Background: Diagnosis of pheochromocytoma in renal failure poses a diagnostic dilemma due to lack of reliability of conventional urinary measurements of catecholamine excess. Measurements of the plasma metanephrines, normetanephrine and metanephrine (the O-methylated metabolites of norepinephrine and epinephrine), provide an alternative diagnostic test. The metanephrines may be measured as free metabolites or after a deconjugation step where measurements reflect mainly sulfate-conjugated metabolites. The influence of renal insufficiency states on these various measurements is unclear., Methods: Plasma free and deconjugated metanephrines and catecholamines in 17 patients on dialysis with end-stage renal disease and 19 patients with renal insufficiency (creatinine clearance, 5-78 mL/min) were compared with levels in 89 hypertensives, 68 healthy normotensives, and 51 patients with von Hippel-Lindau syndrome., Results: Patients with renal failure had up to two-fold higher plasma concentrations of catecholamines and free metanephrines, and more than 12-fold higher plasma concentrations of deconjugated metanephrines than comparison groups. Plasma free metanephrines and catecholamines were, respectively, within the 95% confidence intervals of reference groups in 75% and 42% of the dialysis patients, and in 74% and 68% of patients with renal insufficiency. In contrast, no dialysis patient and only half the renal insufficiency patients had plasma levels of deconjugated metanephrines within the reference intervals. Plasma levels of deconjugated metanephrines, but not free metanephrines, showed strong inverse relationships with creatinine clearance., Conclusion: Plasma concentrations of free metanephrines are relatively independent of renal function and are, therefore, more suitable for diagnosis of pheochromocytoma among patients with renal failure than measurements of deconjugated metanephrines.

Background: Cardiovascular disease is known to be the most important complication among patients with renal failure, and oxidative stress has been proposed to play a major role as the source of such complications. Human serum albumin (HSA) is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing powers, of reversibly oxidized human non-mercaptoalbumin-1 (HNA-1), and strongly oxidized human non-mercaptoalbumin-2 (HNA-2)., Methods: We used the "redox state of HSA" as a marker to investigate the current status of oxidative stress in predialysis patients with renal failure. The subjects were 55 nondialysis patients (31 males and 24 females) with chronic renal diseases, and having various degrees of renal function. The subjects' redox state of HSA was determined by a high-performance liquid chromatographic (HPLC) procedure, and the results presented in terms of the ratios between HNA-total(HNA-1 + HNA-2) and HNA-2., Results: The values for each fraction of HNA-total (f(HNA-total)) and f(HNA-2) were increased with a decrease of renal functions, and a significant positive correlation with serum creatinine (R= 0.529, P < 0.0001 and R= 0.618, P < 0.0001) was detected. Multiple (forward stepwise) regression analysis using f(HNA-total) and f(HNA-2) as the criterion variables was performed, and creatinine was adopted as significant explanatory variable in both equations., Conclusion: We found that even before dialysis, oxidative stress was enhanced in correlation with the level of renal dysfunction among patients with chronic renal failure. In the future, antioxidant strategies should become part of treatment for predialysis renal failure.

Background: Circulating homocysteine, a risk factor for cardiovascular disease (CVD), is often elevated in chronic kidney disease and end-stage renal disease (ESRD) patients. Little is known about the risk of elevated homocysteine associated with less advanced renal insufficiency in the community., Methods: Serum homocysteine concentration measures (umol/L) from the National Health and Nutrition Examination Survey (NHANES) 1991-1994 participants who were aged >/=40 years and fasted >/=6 hours (1558 men and 1829 women) were categorized as <9, 9 to 11.9, 12 to 14.9, and >/=15. Renal function levels were determined by Modified Diet in Renal Disease (MDRD) estimated glomerular filtration rate (GFRest) (mL/min/1.73 m(2)) and the urinary albumin-to-creatinine ratio (ACR) (mg/g). Cumulative odds ratios (OR) of exceeding any given homocysteine cut point were computed by gender, using ordinal logistic regression. Each model included GFRest (<60, 60 to 90, >/=90), ACR (<15, 15 to <30, >/=30), age, race/ethnicity, red blood cell folate, serum vitamin B(12), and dietary vitamin B(6) intake as independent variables., Results: The adjusted ORs for elevated homocysteine risk were 9 to 11 times greater in adults with the lowest GFRest levels (<60 mL/min/1.73 m(2)) compared to those with normal GFRest levels. Association measures for marginal GFRest levels (60 to 90 mL/min/1.73 m(2)) were weaker but significant. Albuminuria (ACR >/=30 mg/g) was a significant, independent renal risk factor for elevated homocysteine in men and women (adjusted OR = 1.78, 95% CI 1.08-2.93, and adjusted OR = 1.83, 95% CI 1.21-2.76, respectively) relative to those with low normal albumin excretion, but high normal albuminuria (ACR = 15-30 mg/g) was not., Conclusion: In the general population, renal insufficiency is strongly associated with an increased risk of elevated circulating homocysteine, independent of B vitamin status. These results raise the possibility that elevated homocysteine may be an important risk factor to explain the heavy burden of CVD associated with kidney disease.

Background: Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake., Methods: Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points., Results: FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet., Conclusion: Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.

Background: Chronic kidney disease (CKD) increases risk of death among patients with coronary artery disease. Mortality risks associated with CKD among patients with cardiovascular disease (CVD) are not well defined. Anemia is associated with increased mortality in end-stage renal disease (ESRD) patients and may also increase risk among patients with CVD., Methods: A random sample of patients admitted to the hospital in a single southern state with a principal diagnosis of acute myocardial infarction (ICD-9 codes 410.xx) were followed up after hospital discharge., Results: CKD was found in 60% of the cohort. Hematocrit of >or=40 was found in 46% of the patients; 26.0% had a hematocrit between 36% and 39%, 21.8% between 30% and 35%, and 5.9% had a hematocrit of less than 30%. The 1-year death rates among individuals with and without CKD were 31.7% and 10.4% respectively [odds ratio (OR) = 4.00 (2.34, 6.91)]. The mortality at one year was 18.6% for individuals with a hematocrit greater than or equal to 40%; 23.5% (OR = 1.35; 95% CI = 0.78, 2.32) for hematocrit 36% to 39%; 30.7% (OR = 1.94; 95% CI = 1.12, 3.34) for hematocrit between 30% and 35%; and 35.8% (OR = 3.16; 95% CI = 1.35, 7.40) for those with a hematocrit less than 30% (chi2 for trend was 12.2, P = 0.007). Both hematocrit and serum creatinine were independently associated with increased risk of death during follow-up after controlling for other patient risk factors., Conclusion: CKD and decreasing hematocrit were frequent among older patients hospitalized for acute myocardial infarction and are independent predictors of subsequent risk of death.

Background: The remnant kidney model of renal failure is associated with normal or suppressed plasma renin and angiotensin (Ang) II levels when hypertension is established. However, the hypertension responds to angiotensin-converting enzyme (ACE) inhibition and Ang II receptor antagonism, suggesting a role for Ang II in the hypertensive process. Bradykinin (BK) is a potent vasoactive peptide that may also participate in this model., Methods: Ang II and BK peptides were measured in the ischemic peri-infarct portion and the intact portion of the remnant kidney at two, five, and seven weeks after surgery. Plasma Ang II, renin, angiotensinogen, and aldosterone levels were also measured., Results: Ang II levels in the peri-infarct portion were higher than in the intact portion at all time points and were higher than in sham-operated kidney at two weeks. Ang II levels in the intact portion were similar to the levels in kidneys of sham-operated rats at two and five weeks and were suppressed at seven weeks. BK levels were increased in the peri-infarct portion at all time points and in the intact portion at two and five weeks. Plasma Ang II and aldosterone levels were also elevated at two weeks., Conclusions: Peri-infarct renal tissue Ang II levels and plasma Ang II and aldosterone levels increase transiently during the evolution of hypertension in the remnant kidney model. Sustained hypertension is associated with an increase in intrarenal BK levels but not with persistent increases in intrarenal or circulating Ang II levels.

Background: Inhibition of the renin-angiotensin system is known to raise serum potassium [K(+)] levels in patients with renal insufficiency or diabetes. No study has evaluated the comparative effects of an angiotensin-converting enzyme (ACE) inhibitor versus an angiotensin receptor blocker (ARB) on the changes in serum [K(+)] in people with renal insufficiency., Methods: The study was a multicenter, randomized, double crossover design, with each period lasting one month. A total of 35 people (21 males and 14 females, 19 African Americans and 16 Caucasian) participated, with the mean age being 56 +/- 2 years. Mean baseline serum [K(+)] was 4.4 +/- 0.1 mEq/L. The glomerular filtration rate (GFR) was 65 +/- 5 mL/min/1.73 m(2), and blood pressure was 150 +/- 2/88 +/- 1 mm Hg. The main outcome measure was the difference from baseline in the level of serum [K+], plasma aldosterone, and GFR following the initial and crossover periods., Results: For the total group, serum [K(+)] changes were not significantly different between the lisinopril or valsartan treatments. The subgroup with GFR values of < or = 60 mL/min/1.73 m(2) who received lisinopril demonstrated significant increases in serum [K(+)] of 0.28 mEq/L above the mean baseline of 4.6 mEq/L (P = 0.04). This increase in serum [K(+)] was also accompanied by a decrease in plasma aldosterone (P = 0.003). Relative to the total group, the change in serum [K(+)] from baseline to post-treatment in the lisinopril group was higher among those with GFR values of < or = 60 mL/min/1.73 m(2). The lower GFR group taking valsartan, however, demonstrated a smaller rise in serum [K(+)], 0.12 mEq/L above baseline (P = 0.1), a 43% lower value when compared with the change in those who received lisinopril. This blunted rise in [K(+)] in people taking valsartan was not associated with a significant decrease in plasma aldosterone (P = 0.14)., Conclusions: In the presence of renal insufficiency, the ARB valsartan did not raise serum [K(+)] to the same degree as the ACE inhibitor lisinopril. This differential effect on serum [K(+)] is related to a relatively smaller reduction in plasma aldosterone by the ARB and is not related to changes in GFR. This study provides evidence that increases in serum [K(+)] are less likely with ARB therapy compared with ACE inhibitor therapy in people with renal insufficiency.

Background: Animal and in vitro data suggest that dyslipidemia plays an important role in the initiation and progression of chronic renal disease, but few prospective studies have been conducted in humans., Methods: We studied the relationship of plasma lipids to a rise in serum creatinine of 0.4 mg/dL or greater in 12,728 Atherosclerosis Risk in Communities (ARIC) participants with baseline serum creatinine that was less than 2.0 mg/dL in men and less than 1.8 mg/dL in women., Results: During a mean follow-up of 2.9 years, 191 persons had a rise in creatinine of 0.4 mg/dL or greater, yielding an incidence rate of 5.1 per 1000 person years. Individuals with higher triglycerides and lower high-density lipoprotein (HDL) and HDL-2 cholesterol at baseline were at increased risk for a rise in creatinine after adjustment for race, gender, baseline age, diabetes, serum creatinine, systolic blood pressure, and antihypertensive medication use (all P trends

Background: The aim of this study was to define cut-off values for serum creatinine as an indicator of several levels of renal impairment., Methods: To identify the suitable values, receiver operating characteristic curves were constructed based on the data of 984 laboratory assessments of renal function. The glomerular filtration rate was measured with inulin clearance. Three levels of renal impairment were analyzed. An index that gave the same weight to false positive and false negative results was used to determine the thresholds. Robustness of the results was tested using a "bootstrap" technique., Results: Considering an inulin clearance of less than 80 ml/min/1.73 m2, the cut-off value for serum creatinine was 11.5 mumol/liter for men and 90 mumol/liter for women. The cut-off value for a clearance of less than 60 ml/min/1.73 m2 was 137 mumol/liter for men and 104 mumol/liter for women. For a clearance of less than 30 ml/min/1.73 m2, the cut-off value was 177 mumol/liter for men and 146 mumol/liter for women., Conclusion: This method is useful to determine a cut-off value for serum creatinine in epidemiological studies concerning early chronic renal failure screening. The value of the glomerular filtration rate of reference and the weight of false positive and false negative results have to be adapted to the aim of the individual study design.

Background: The aim of this study was to establish whether there is a differential effect of mode of dialysis, hemodialysis (HD), or continuous ambulatory peritoneal dialysis (CAPD) on the dyslipidemia of renal failure., Methods: The lipoprotein profile was determined in 61 non-diabetic patients on chronic HD (N = 30) and CAPD treatment (N = 31), and in a control group of 27 healthy subjects. The analysis included the measurement of individual apolipoprotein (apo) A- and apo B-containing lipoproteins (LPs) separated by sequential immunoaffinity chromatography. Apo A-containing lipoproteins include lipoprotein A-I with apo A-I and lipoprotein A-I:A-II with apo A-I and apo A-II as the main protein constituents, whereas apo B-containing lipoproteins comprise simple cholesterol-rich lipoprotein B (LP-B), with apo B as the only protein moiety and complex triglyceride (TG)-rich lipoprotein B complex (LP-Bc) particles with apo B, apo A-II, apo C, and/or apo E as the protein constituents., Results: CAPD patients had significantly higher concentrations of total cholesterol (6.8 vs. 5.1 mmol/liter), low-density lipoprotein (LDL) cholesterol (4.6 vs. 3.2 mmol/liter), TG (2.3 vs. 1.5 mmol/liter), apo B (155.3 vs. 105.7 mg/dl), LP-B (136.0 vs. 91.9 mg/dl), and LP-Bc (19.3 vs. 13.8 mg/dl) than HD patients. Both HD and CAPD patients had significantly higher TG, VLDL cholesterol, apo C-III, and apo E and significantly lower high-density lipoprotein cholesterol, apo A-II, and lipoprotein A-I:A-II levels than control subjects. The distribution of apo C-III in high-density lipoprotein and VLDL-LDL was altered in CAPD patients in comparison with control subjects. This suggests that the removal of TG-rich lipoproteins is less efficient in patients on CAPD. Normotriglyceridemic (NTG; TG < or = 1.7 mmol/liter, 150 mg/dl) CAPD patients had significantly higher levels of TC, LDL cholesterol, apo B, and LP-B than NTG-HD patients. There was little difference in the LP-Bc levels between NTG-CAPD, NTG-HD, and controls. Similarly, hypertriglyceridemic (HTG) CAPD patients had significantly higher TC, LDL cholesterol, apo B, and LP-B levels than HTG-HD patients. The LP-Bc levels were significantly increased in HTG-HD and HTG-CAPD patients compared with controls, but the slightly higher levels in the CAPD patients did not differ significantly from the HD group., Conclusion: CAPD and HD patients have a lipoprotein profile characteristic of renal failure. Patients on long-term CAPD have higher levels of cholesterol-rich apo B-containing lipoproteins unrelated to TG levels. Many patients on CAPD also have a substantial elevation of the plasma concentrations of TG-rich LPs. The clinical significance of increased levels of potentially atherogenic LP-B during CAPD remains to be investigated.

Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can results from defective remethylation of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic aberration in the MTHFR gene (677 C to T substitution) has been shown to result in reduced MTHFR activity. We tested the hypothesis that elevation of tHcy plasma levels in hemodialysis patients is influenced by the 677 C to T mutation of the MTHFR gene and examined the relation of the genotype with tHcy, folate and vitamin B12 plasma levels in these patients. The allelic frequency of the MTHFR mutation was evaluated in 203 patients maintained on chronic hemodialysis treatment. Total Hcy, folate, vitamin B12 levels and the MTHFR mutation were analyzed in 69 of the 203 patients and in 69 age- and sex-matched healthy control subjects. The allelic frequency of the 677 C to T transition in the MTHFR gene in hemodialysis patients was 34.7% versus 35.5% in healthy controls. Of 203 patients 26 (12.8%) were homozygous for the mutation (+/+) versus 10.2% in healthy subjects. The heterozygous (+/-) genotype was identified in 43.8% of patients versus 50.7% in controls. The mean tHcy level in hemodialysis patients was 28.7 +/- 11.0 mumol/liter versus 10.0 +/- 3.0 mumol/liter in control subjects. The mean tHcy levels were 36.4 +/- 13.4 mumol/liter in (+/+) patients and 12.2 +/- 4.5 mumol/liter in (+/+) controls, 28.7 +/- 10.8 mumol/liter in (+/-) patients and 9.9 +/- 2.7 mumol/liter in (+/-) controls and 25.4 +/- 8.5 mumol/liter in (-/-) hemodialysis patients versus 9.7 +/- 2.8 mumol/liter in (-/-) controls: There was no significant difference of folate and vitamin B12 concentrations in patients and controls with different MTHFR genotypes. Analysis of covariance including age, gender, folate concentrations, vitamin B12 levels, albumin and creatinine as covariables revealed a significant influence of the (+/+) genotype, albumin and folate status on tHcy levels in hemodialysis patients. Together, our data demonstrate that the extent of hyperhomocysteinemia in hemodialysis patients is not only the result of uremia or folate status, but is also genetically determined by the (+/+) MTHFR genotype. The presence of the 677 C to T mutation in the MTHFR gene does not appear to represent a risk factor for development of end-stage renal disease.

We have recently demonstrated elevations of separate amino- and carboxy-terminal parathyroid hormone-related protein (PTHrP) fragments in patients with humoral hypercalcemia of malignancy (HHM) using both a two-site immunoradiometric assay (IRMA) with amino-terminal specificity for PTHrP, and with a carboxy-terminal radioimmunoassay (RIA) for PTHrP(109-138). PTHrP(109-138) immunoactivity from plasma of patients with HHM could not be extracted using an amino-terminal PTHrP immunoaffinity column, indicating that the carboxy-terminal region circulates as a discrete peptide. Carboxy-terminal immunoreactive (i) PTHrP levels were also elevated in normocalcemic patients with chronic renal failure (without cancer), whereas amino-terminal iPTHrP levels were normal in patients with renal failure. In order to further define the renal handling of carboxy-terminal PTHrP peptides, we have evaluated circulating iPTHrP(109-138) concentrations in patients with a wide range of renal function. We studied 25 patients with abnormal renal function of diverse etiologies whose creatinine clearances ranged from 66 ml/min to less than 5 ml/min. All patients had undetectable or low (< or = 2 pmol/liter) concentrations of iPTHrP(1-74). iPTHrP(109-138) concentrations were undetectable in patients with creatinine clearances > or = 20 ml/min, but became elevated in patients with creatinine clearances < 20 ml/min. The log of iPTHrP(109-138) correlated negatively with the log of creatinine clearance (r = 0.88, P = 0.0001). Mean iPTHrP(109-138) levels were slightly higher for patients on hemodialysis (32.7 +/- 3.1 pM) than for those on chronic ambulatory peritoneal dialysis (22.1 +/- 3.4 pM; P < 0.05), suggesting that some carboxy-terminal PTHrP fragments may be cleared to a greater extent by the peritoneal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)