The metabolic syndrome and chronic kidney disease

PURPOSE OF REVIEW: The metabolic syndrome is a constellation of physical and laboratory abnormalities including hypertension, hyperglycemia, hyperlipidemia and abdominal obesity. Over the past decade, the metabolic syndrome has emerged as a critically important risk factor for cardiovascular disease. RECENT FINDINGS: A large population-based cross-sectional analysis (the National Health and Nutrition Evaluation Survey III) found that the presence of the metabolic syndrome was associated with chronic kidney disease, defined as an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m and was also associated with proteinuria. More recently, a prospective cohort study found that the presence of the metabolic syndrome was associated with incident chronic kidney disease by the same definition, even when excluding individuals with diabetes mellitus and hypertension. More studies are required to determine whether the relationship between the metabolic syndrome and chronic kidney disease is mainly mediated by hyperglycemia (with insulin resistance) and hypertension, or other metabolic or hemodynamic factors. SUMMARY: The metabolic syndrome is associated with chronic kidney disease. Efforts aimed at determining the mechanisms underlying this association and strategies for the prevention of chronic kidney disease (or slowing the progression of chronic kidney disease) in affected patients should be research priorities in the future.     

Correlation of Tc-99m-red blood cell phleboscintigraphy with clinical severity of chronic venous disease

Equilibrium red blood cell phleboscintigraphy of the lower limbs for the diagnostic management of chronic venous disease has been proposed. The aim of this study was to verify the correlation of the phleboscintigraphic assessment of chronic venous disease with the clinical grading of the severity of the disease, since other diagnostic modalities have been recently demonstrated a poor and only partial correlation. Equilibrium Tc-99m-red blood cell phleboscintigraphy was performed in 27 patients with chronic venous disease. Scintigraphic images of 52 limbs were classified according to a four-class qualitative grading of the severity of the venous disease, and a quantitative scintigraphic index (saphena /femoral ratio) was assigned to each limb. The scintigraphic qualitative grading showed a highly significant correlation with the clinical grading (Rs=0.82, p<0.01), a good interobserver and intraobserver agreement (86.5% and 92.3%, respectively) and more than 90% sensitivity and specificity to identify the categories "minimal or no chronic venous disease" or "more significant disease" (assessed according to the Bayes theorem). Sensitivity and specificity results for the quantitative assessment were not as good. Phleboscintigraphy correlates well with the clinical grading of the severity of chronic venous disease of the lower limbs and may have potential as a valuable diagnostic tool for the noninvasive assessment of chronic venous disease.     

Prevalence of chronic kidney disease and survival among aboriginal people

Globally, it is known that the incidence of end-stage renal disease is higher among Aboriginals, but it is unknown whether this is due to an increased prevalence of chronic kidney disease or other unidentified factors. We studied 658,664 people of non-First Nations and 14,989 people of First Nations and found that the age- and sex-adjusted prevalence of chronic kidney disease was significantly higher among those of non-First Nations compared to those of First Nations (67.5 versus 59.5 per 1000 population; P < 0.0001). However, severe chronic kidney disease (estimated glomerular filtration rate <30 ml/min per 1.73 m2) was almost two-fold higher among people of First Nations (P < 0.0001). Cox proportional hazards models suggested that compared to people of non-First Nations, those of First Nations with chronic kidney disease had a 77% increased risk of death after adjusting for age, gender, diabetes and baseline eGFR. In conclusion, whether the higher incidence of end-stage renal disease among people of First Nations is due to suboptimal management of chronic kidney disease and its associated comorbidities, more rapid loss of kidney function, or other unidentified factors remains to be determined.     

Incomplete membranous obstruction of the inferior vena cava. Hemodynamic measurements and correction by balloon membranotomy and surgical resection.

This report discusses a patient with chronic liver disease and portal hypertension, initially thought to be caused by chronic bile duct obstruction or chronic hepatitis B. For evaluation of portal hypertension, hepatic vein catheterization was performed, disclosing incomplete membranous obstruction of the inferior vena cava at the level of the diaphragm--the probable cause of the liver disease. The obstruction was corrected by balloon membranotomy and surgical resection of the membrane. Hepatic vein catheterization in patients with chronic liver disease and portal hypertension allows detection of this lesion as well as evaluation of hepatic and portal hemodynamics.     

合并不同疾病的男性骨量异常患者骨代谢、骨密度及骨折情况研究

目的了解合并不同疾病的男性骨量异常患者骨代谢指标、骨密度(bone mineral density,BMD)及骨折的情况。方法对2006年1月至2017年12月在上海市第一人民医院内分泌科骨质疏松亚专科就诊的928例男性骨量异常患者进行回顾性研究。根据研究目的不同,将患者分为有或无糖尿病组、有或无慢性肝病组、有或无慢性肾病组、有或无慢性胃病组、有或无心血管疾病组及骨量减低组和骨质疏松组。分别观察各组各项指标的差异。结果单因素回归分析提示受试者年龄、体重、L1~4BMD、股骨颈BMD、全髋BMD、β-CTX、慢性胃病、骨质疏松症是骨折史的影响因素,差异具有统计学意义(P<0.05);骨折史与受试者年龄、β-CTX、慢性胃病、骨质疏松症因素成正相关,与体重、L1~4BMD、股骨颈BMD、全髋BMD成负相关;多因素回归分析提示年龄、BALP、2型糖尿病、骨质疏松是骨折的危险因素,而25OHD水平是骨折的保护性因素。结论对于男性骨量异常患者,需要重点关注年龄较大、β-CTX和BALP水平较高、合并慢性胃病以及2型糖尿病的患者,对这类患者应积极进行抗骨质疏松干预及治疗,以减少此类患者骨折的发生率。     

Treatment of experimental renal osteodystrophy with pamidronate

We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increased compared to rats with a uninephroctomy and none of these parameters was affected by pamidronate treatment. In the femoral midshaft, chronic renal disease reduced cortical bone mineral density and content. No difference was observed in the breaking load of the femoral midshaft. In the distal femur, a high-turnover renal osteodystrophy was found but pamidronate suppressed this bone turnover and increased bone mineral content. Treatment had no effect on chronic disease-induced augmentation of osteoid volume or fibroblast surface. These studies show that in this model of stage 3 renal disease, pamidronate increased mineral content in the femoral midshaft and distal metaphysis primarily by adding bone to endocortical and trabecular surfaces but did not reduce osteitis fibrosa.     

Comparison of human bronchiolar smooth muscle responsiveness in vitro with histological signs of inflammation.

A study was carried out to test the hypothesis that chronic inflammation is associated with increased sensitivity or contractility of human airway smooth muscle. Bronchiolar strips from 30 patients, 12 of whom had chronic bronchitis, were examined in the organ bath for their responses to histamine, methacholine, and leukotriene (LT) C4. The same airways were also studied histologically and small airway disease was quantified by subjective grading of the degree of inflammatory cell infiltration, smooth muscle hypertrophy, fibrosis, and goblet cell hyperplasia. The degree of small airway disease varied widely among patients both with and without chronic bronchitis. Multiple regression analysis failed to show increased sensitivity (-log EC50) to histamine, methacholine, or LTC4 in relation to small airway disease. In contrast, the only significant correlations found were between a decreased -log EC50 to histamine and methacholine and an increased small airway disease score. Contractile responses (Tmax) to histamine and methacholine in peripheral airways tended to be higher in patients with chronic bronchitis than in those without. Tmax was not related to small airway disease scores. These results suggest that chronic airway inflammation does not cause in vitro hyperresponsiveness of human small airway smooth muscle.     

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease.     

Low birth weight is associated with chronic kidney disease only in men

The association of low birth weight and chronic kidney disease was examined in a screened volunteer population by the National Kidney Foundation's Kidney Early Evaluation Program. This is a free, community-based health program enrolling individuals aged 18 years or older with diabetes, hypertension, or a family history of kidney disease, diabetes, or hypertension. Self-reported birth weight was categorized and chronic kidney disease defined as an estimated glomerular filtration rate less than 60 ml per min per 1.73 m(2) or a urine albumin/creatinine ratio >or=30 mg/g. Among 12 364 participants, 15% reported a birth weight less than 2500 g. In men, significant corresponding odds ratios were found after adjustment for demographic characteristics and health conditions to this low birth weight and chronic kidney disease, but there was no association among women. There was no significant interaction between birth weight and race for either gender. Efforts to clinically understand the etiology of this association and potential means of prevention are essential to improving public health.     

Primary hypertension and nephropathy

PURPOSE OF REVIEW: The relationship between primary hypertension (formerly called essential hypertension) and hypertension-associated chronic kidney disease is complex and poorly understood. The strong association between hypertension-associated chronic kidney disease and cardiovascular disease supports the existence of common mediators. We will review data indicating common mediating mechanisms for cardiovascular disease and chronic kidney disease in primary hypertension. RECENT FINDINGS: Chronic kidney disease develops in primary hypertension due to local and systemic inflammatory mediators that cause endothelial injury. This injury is an important early step in the development of hypertension-associated vasculopathy that causes nephron ischemia with nephrosclerosis. Similar mechanisms mediate endothelial injury in cardiovascular disease and its progression. Subjects with primary hypertension at increased risk for chronic kidney disease are at higher risk for cardiovascular disease, the major cause of mortality in primary hypertension. SUMMARY: Primary hypertension is a modifiable risk factor for both cardiovascular disease and chronic kidney disease. Better understanding of how primary hypertension leads to these outcomes might help in the development of pharmacologic strategies that retard and/or prevent chronic kidney disease in primary hypertension. Because of the strong association between cardiovascular disease and chronic kidney disease in primary hypertension, this improved understanding will likely lead to better therapies to hinder the development and/or progression of cardiovascular disease, in addition to its benefits in preventing hypertension-associated chronic kidney disease.     

Association of metabolic syndrome and chronic kidney disease among Uygur adults in Moyu country in Xinjiang Uygur Autonomous Region

Objective To examine the effects of different compositions of metabolic syndrome[Overweight and (or) obesity, hyperglycemia, hypertension, dyslipidemia] on chronic kidney disease. Methods A total of 1552 health data were collected from the survey of chronic kidney diseases among Uygur adults in Moyu country in Xinjiang Uygur Autonomous Region and the relationship between metabolic syndrome and chronic kidney disease was analyzed by using SPSS 15.0 software package. Results Before and after adjusting of age and gender, the prevalence of metabolic syndrome was 14.18% and 14.45% (95% CI 14.30%-14.60%). The prevalence of albuminuria (7.27% vs 3.83%,χ2=5.42, P=0.02), reduced estimated glomerular filtration rate (9.55% vs 3.45%,χ2=16.96, P=0.00) and chronic kidney disease(13.64% vs 6.76%,χ2=12.52, P =0.00) increased in residents diagnosed as metabolic syndrome than those without metabolic syndrome. The prevalence of chronic kidney disease increased with the increasing number of metabolic syndrome elements. Conclusions The prevalence of chronic kidney disease is associated with the accumulation of metabolic syndrome compositions. Early intervention on metabolic risk factors may reduce the risk of chronic kidney disease.     

Excess weight as a risk factor for kidney failure

PURPOSE OF REVIEW: The increasing incidence of end-stage renal disease and the epidemic of obesity are major public health problems. We review recent epidemiological evidence that excess weight is an important risk factor for chronic kidney disease and end-stage renal disease. RECENT FINDINGS: A cohort study of over 300 000 adults and 8 million years of follow-up determined that elevated BMI was a significant risk factor for end-stage renal disease. This relationship was evident starting at a BMI of 25 kg/m and persisted after adjustment for hypertension and diabetes. A population-based case-control study showed that a BMI of at least 25 kg/m at age 20 was significantly associated with development of advanced chronic kidney disease. This was true even among those without diabetes or hypertension. SUMMARY: Excess weight is a common, strong and modifiable risk factor for chronic kidney disease and end-stage renal disease. Even individuals who are not overtly obese are at risk. Excess weight contributes to chronic kidney disease and end-stage renal disease over and above its role in hypertension and diabetes. Weight loss may represent a novel intervention to reduce risk of chronic kidney disease development and progression.     

The interrelation between sclerosing cholangitis and ulcerative colitis in patients undergoing liver transplantation.

Thirty-six patients underwent orthotopic liver transplantation (OLT) for primary sclerosing cholangitis under cyclosporine, azathioprine, and steroid immunosuppression. Of these patients, 29 suffered from chronic ulcerative colitis. The purpose of this study is to determine (1) whether replacement of the diseased liver and the altered immunocompetence suppresses the manifestation of chronic ulcerative colitis, and (2) if active colonic disease alters allograft function. Thirty of 36 patients survived OLT. After OLT, seven of 14 patients with symptomatic colon disease at the time of transplantation continue to suffer from active chronic ulcerative colitis, and three of 13 who were asymptomatic developed clinically active disease. Intractable colonic disease was the indication for post-OLT proctocolectomy in three patients, and one refused an indicated colectomy. Despite the long duration of the disease, none developed colonic malignancy. Long-term graft assessment showed good hepatocyte synthetic function in patients suffering from either active or inactive disease. Liver alkaline phosphatase, however, was significantly higher in patients suffering from active colonic disease. Furthermore, the alkaline phosphatase in symptomatic patients was higher than that seen in a matched cohort undergoing OLT for chronic active hepatitis or primary biliary cirrhosis. These results suggest that (1) liver replacement and immunosuppression in patients suffering from sclerosing cholangitis and ulcerative colitis do not alter the course of the colon disease, and (2) active chronic ulcerative colitis does not adversely affect allograft function, although elevation of alkaline phosphatase may be the harbinger of recurrence over the long term.     

Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.

The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to be an underlying or a contributory cause of death (obstructive lung disease related death); in 73 subjects it was considered to be the underlying cause of death (obstructive lung disease death). Forced expiratory volume in one second, expressed as a percentage of the predicted value (FEV1% pred), and the presence of chronic phlegm were used to characterise ventilatory function and chronic mucus hypersecretion respectively. For mortality analysis the proportional hazards regression model of Cox was used; it included age, sex, pack years, inhalation habit, body mass index, alcohol consumption, and the presence or absence of asthma, heart disease, and diabetes mellitus as confounding factors. By comparison with subjects with an FEV1 of 80% pred or more, subjects with an FEV1 below 40% pred had increased risk of dying from all causes (relative risk (RR) = 5.0 for women, 2.7 for men), a higher risk of obstructive lung disease related death (RR = 57 for women, 34 for men), and a higher risk of obstructive lung disease death (RR = 101 for women, 77 for men). Chronic mucus hypersecretion was associated with only a slightly higher risk of death from all causes (RR = 1.1 for women, 1.3 for men). The association between chronic mucus hypersecretion and obstructive lung disease death varied with the level of ventilatory function, being weak in subjects with normal ventilatory function (for an FEV1 of 80% pred the RR was 1.2), but more pronounced in subjects with reduced ventilatory function (for an FEV1 of 40% pred the RR was 4.2). A similar though statistically non-significant trend was observed with regard to obstructive lung disease related death. This study shows that impaired lung function is very strongly related to total mortality, obstructive lung disease related mortality, and obstructive lung disease mortality and suggests that chronic mucus hypersecretion, in those with impaired ventilatory function, is also a significant risk factor for death from obstructive lung disease.     

Perceived knowledge among patients cared for by nephrologists about chronic kidney disease and end-stage renal disease therapies

The need to educate patients in order to enable them to participate in making appropriate choices for all therapeutic options in end stage renal disease would seem obvious yet there are many barriers to providing such information. We measured 'perceived knowledge' of the therapeutic options for end stage renal disease in a cohort of patients with chronic kidney disease in established treatment programs. A self administered questionnaire was given to 676 patients with stage 3-5 chronic kidney disease as part of the CRIOS study designed to identify trends in practice patterns and outcomes over a 4 year period. The median patient age was 66, about three-fourths were Caucasian and almost half were diabetic. When patients were asked to rate their level of knowledge, about one-third reported limited or no understanding of their chronic kidney disease and no awareness regarding their treatment options. A significant and substantial number of patients indicated they had no familiarity with transplant, hemodialysis, and continuous ambulatory or automated peritoneal dialysis. Perceived knowledge improved with the progression of kidney disease and frequency of nephrology visits; however, only about half of patients with 4 or more nephrology appointments in the prior year reported knowing of hemodialysis, continuous ambulatory peritoneal dialysis or transplant. Age, gender and disease had no impact on levels of patient knowledge, but African-Americans reported having significantly less understanding than Asians or Caucasians. These findings suggest that the lack of perception concerning the treatment options chronic kidney and end stage renal disease reflects, in part, problems with the education of patients by nephrologists and not a lack of referral of these patients to nephrologists for care. The discrepancy of perceived knowledge between African-Americans and other races needs special attention.     

Fat-soluble vitamins in advanced CKD/ESKD: a review

Patients requiring dialysis often experience a significant decline in their nutritional status through a combination of chronic disease, reduced appetite, and dietary restrictions, which places them at risk for vitamin deficiencies. The concept of vitamin deficiency has evolved from obvious deficiency states to the subtle effects that suboptimal intake may have on chronic disease prevalence or progression. The purpose of this study was to summarize the current state of knowledge regarding the status of the fat-soluble vitamins (A, D, E, and K) in patients with chronic kidney disease receiving hemodialysis.     

Transvascular lipoprotein transport in patients with chronic renal disease

BACKGROUND: While increased plasma cholesterol is a well-established cardiovascular risk factor in the general population, this is not so among patients with chronic renal disease. We hypothesized that the transvascular lipoprotein transport, in addition to the lipoprotein concentration in plasma, determines the degree of atherosclerosis among patients with chronic renal disease. METHODS: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL) in 21 patients with chronic renal disease and in 42 healthy control patients. Autologous 131-iodinated LDL was reinjected intravenously, and the 1-hour fractional escape rate was taken as index of transvascular transport. RESULTS: Transvascular LDL transport tended to be lower in patients with chronic renal disease than in healthy control patients [3.3 (95% CI 2.4-4.2) vs. 4.2 (3.7-4.2)%/hour; NS]. However, this tendency disappeared when transvascular LDL transport was corrected for distribution volume of LDL [1.7 (1.2-2.2) vs. 1.8 (1.6-2.0) %/(hour x (L/m(2))); NS]. There was significant variation in transvascular LDL transport between diabetic patients with chronic renal disease, nondiabetic patients with chronic renal disease, and healthy control patients [5.0 (3.2-7.8) vs. 3.0 (2.2-3.8) vs. 4.2 (3.6-4.8) %/hour; P < 0.01 after adjustment for distribution volume of LDL]. This variation was unlikely caused by altered hepatic LDL receptor expression or glycosylation of LDL in diabetes patients. CONCLUSION: Transvascular LDL transport may be increased in diabetic patients with chronic renal disease, suggesting that lipoprotein flux into the arterial wall is increased. A similar mechanism does not operate in nondiabetic patients with chronic renal disease.     

Liver disease in recipients of long-functioning renal allografts

After noting that hepatic failure was the leading cause of death in our transplant recipients whose renal allografts had functioned for more than five years, we reviewed retrospectively the post-transplant course of these patients to assess the long-term effect of liver disease in this population. Sufficient data was available to evaluate 184 of 217 long-term survivors (85%). Twenty-six patients (14%) experienced a doubling of SGOT and/or SGPT of greater than six months' duration and were defined as having chronic liver disease. The etiology of chronic liver disease was identified in 14 patients (54%), of whom 11 were HBsAg positive. Evidence of chronic hepatitis developed in only six of 26 patients (22%) during the first four years post transplant. Once enzyme abnormalities occurred, they were unremitting until death or end of the study in 73% of patients. Actuarial survival of patients with chronic liver disease was markedly decreased compared to long-surviving transplanted controls. Ten of the 12 deaths in patients with hepatocellular abnormalities were due to hepatic failure, of which eight occurred in the setting of extrahepatic sepsis. Chronic liver disease is a late complication of transplantation and is associated with significant mortality due to an increased susceptibility to overwhelming sepsis.     

Acute decompensation and absence of brain and kidney dysfunction predict long-term efficacy of plasma exchange in hyper-bilirubinemic cirrhotic patients awaiting liver transplantation

Various artificial liver support systems are currently used in patients with decompensated chronic liver disease or acute liver failure as a bridge to recovery or to orthotopic liver transplantation (OLT). Between June 2004 and September 2006, 9 subjects were treated with plasma exchange (PE) for acute decompensation on chronic liver disease or chronic decompensation in end-stage liver disease. All of them were awaiting OLT or were listed at the moment of decompensation. Grade II to III hepatic encephalopathy (HE) was present in 4 patients, significant renal dysfunction in 3 patients, and ascites in 6 patients. Baseline serum total bilirubin was 35.1+/-11.2 mg/dL (mean value+/-SD). The patients underwent a mean of 12.1 2-hour exchanges over 1 to 8 weeks. The 3 who recovered were alive after a mean follow-up of 22.7+/-10.3 months. There were 3 patients who underwent transplantation and 3 who died due to liver failure during treatment. Only subjects with acute decompensation and without HE or significant renal dysfunction survived without OLT. PE did not significantly modify the grade of HE or the renal function. PE seemed to be a safe, long-term, effective therapeutic option for acute decompensation among subjects with chronic liver disease without brain or renal dysfunction.     

Body fat measurement in chronic kidney disease: implications in research and clinical practice

PURPOSE OF REVIEW: The paradoxical and inverse association between body mass index and mortality risk in patients with end-stage renal disease has raised a question of whether an increased fat mass is good or bad for patients with chronic kidney disease. The purpose of this review is to update the concept on body fat in patients with chronic kidney disease. RECENT FINDINGS: A greater fat mass is an independent predictor of better survival in patients on maintenance hemodialysis. Following the initiation of dialysis, chronic kidney disease patients gain body weight due mainly to increased fat mass. Fat mass gain over time predicts better survival in hemodialysis patients. In predialysis chronic kidney disease, there is also an inverse association between body mass index and mortality risk. The metabolic syndrome and a high body mass index are independent predictors for development of chronic kidney disease and end-stage renal disease, respectively. In diabetic patients with chronic kidney disease, however, a high initial body mass index is associated with a slower decline in glomerular filtration rate. SUMMARY: The impacts of fat mass on survival and renal function appear to vary depending upon the absence or presence, and stages of chronic kidney disease. Further research is required for optimal nutritional management and improved outcomes of patients with chronic kidney disease.