Contribution of polyclonal free light chain deposition to tubular injury.

INTRODUCTION: Excretion of monoclonal free light chains (MFLC) beyond the renal threshold can cause kidney injury, but evidence for polyclonal free light chains (PFLC)-mediated injury is limited. We aimed to study the degree of PFLC deposition in the proximal tubules of chronic kidney disease (CKD) and hypothesized that excess deposition may contribute to tubular injury. METHODS: In this retrospective study, immunohistochemical staining to assess the degree of FLC deposition, periodic acid-Schiff staining for the degree of tubular brush border injury and trichrome staining for interstitial fibrosis were evaluated. Normal renal parenchyma from tumor nephrectomy specimens (control group I, n = 39), minimal change disease controls (group II, n = 13), renal biopsies from CKD and proteinuria (polyclonal study group III, n = 33) and monoclonal light chain nephropathy (group IV, n = 37) were studied. The results of the study including serum creatinine were compared between groups. RESULTS: Both polyclonal and monoclonal groups (groups III and IV) had significantly higher light chain deposition and brush border injury by periodic acid-Schiff scores compared to control groups (groups I and II). When the first three polyclonal groups (groups I-III) were analyzed together, polyclonal light chain deposition was significantly correlated with serum creatinine levels, brush border injury and interstitial fibrosis. CONCLUSION: The results of our study suggest that in CKD patients with proteinuria, excess PFLC deposition in the proximal tubules may cause acute tubular injury akin to monoclonal gammopathy and lead to renal chronicity.

Primary cilia metaplasia in renal transplant biopsies with acute tubular injury.

Primary cilia are hair-like organelles singly distributed along the apical surface of proximal and distal nephron tubules as mechanosensors. The goal of this study was to use electron microscopy to systemically evaluate cilia changes in acute tubular injury (ATI) from both transplant and native renal biopsies. Three groups of cases were included: control group 1-native biopsies without major changes in renal tubules; study group 2-native biopsies with prominent ATI; and study group 3-renal transplant biopsies with prominent ATI (delayed renal function group). Extensive search for ciliary structures along renal tubules was conducted in each case, focused on proximal tubular areas with injured (diminished) apical microvilli. Singly located cilia were found in 3/19 specimens in control group 1, 4/18 in group 2 (native ATI), and 6/24 in group 3 (transplant ATI). Importantly, there were clusters of cilia in proximal tubules with markedly diminished apical microvilli in 3/24 biopsies from 2 patients in group 3, but none from groups 1 and 2. The clusters of cilia ranged from 6 to 15 individual cilia along the apical surface with diminished apical microvilli. Under high magnifications, the cilia demonstrated 9 pairs of peripheral microtubules without a central pair of microtubules, consistent with primary cilia (9 + 0) rather than motile cilia (9 + 2). In summary, the authors found clusters of cilia in proximal tubules with remarkable apical microvillar injury in 3 renal transplant biopsies with ATI, implying a reactive, or repairing, process following tubular injury, thus they name this finding "cilia metaplasia".

Body composition modifications in patients under low protein diets.

OBJECTIVE: To review the effect of low protein diets on body composition in patients with chronic kidney disease. METHODS: A selected literature review of body composition methods applicable to clinical practice, and a chronological appraisal of relevant studies using low and very low protein diets chosen for their major emphasis on nutritional status and body composition were used for the present study. RESULTS: Body composition methods were categorized by compartments, techniques, ease of use, clinical applicability, advantages, and disadvantages. One publication of body composition in chronic undernutrition was evaluated because of the absence of kidney disease as a confounder. The remaining studies covered chronic kidney disease stages III-V treated with low and very low protein diets. CONCLUSIONS: Very low protein diets are capable of sustaining mean lean and body cell mass for an extended period in patients with chronic kidney disease stages late III-V. However, intercurrent illness and periods of spontaneous reduction in caloric and protein intake markedly increase the risk for malnutrition. Use of these diets requires regular clinical monitoring by nephrologists and renal dietitians, with particular attention to nutritional surveillance, dietary protein and energy intake, and body composition changes.

Primary nonfunction of renal allograft secondary to acute oxalate nephropathy.

Primary nonfunction (PNF) accounts for 0.6 to 8% of renal allograft failure, and the focus on causes of PNF has changed from rejection to other causes. Calcium oxalate (CaOx) deposition is common in early allograft biopsies, and it contributes in moderate intensity to higher incidence of acute tubular necrosis and poor graft survival. A-49-year old male with ESRD secondary to polycystic kidney disease underwent extended criteria donor kidney transplantation. Posttransplant, patient developed delayed graft function (DGF), and the biopsy showed moderately intense CaOx deposition that persisted on subsequent biopsies for 16 weeks, eventually resulting in PNF. The serum oxalate level was 3 times more than normal at 85 µmol/L (normal <27 µmol/L). Allograft nephrectomy showed massive aggregates of CaOx crystal deposition in renal collecting system. In conclusion, acute oxalate nephropathy should be considered in the differential diagnosis of DGF since optimal management could change the outcome of the allograft.

Adjuvant role of p53 immunostaining in detecting BK viral infection in renal allograft biopsies.

BK virus infection is a significant threat to renal transplant outcome. Detecting viral infection in renal transplant biopsies using SV40 staining is less than ideal. SV40 antibody reacts with the large T-antigen of BK virus only at the early phases of infection and can miss cells in later stages of infection. As p53 is upregulated during both early and late phases of infection, this study set out to determine whether p53 staining could improve detection of BK virus infection in renal transplant patients. The control group consisted of 16 renal allograft biopsies without histologic evidence of BK virus infection, while the BK group consisted of 15 renal allograft biopsies with histologic evidence of BK virus infection. The biopsies from both groups were immunohistochemically stained with both SV40 and p53 antibodies. Dual staining with both markers was also performed to identify their nuclear co-localization. In the BK group, the percent of p53 staining (16.6 ± 4.8 %) was significantly higher than the percent of SV40 staining (5.4 ± 2.7%). BK virus infected cells revealed a unique p53 immunostaining pattern (strong nuclear staining with a central halo). Co-localization of SV40 and p53 was identified in cells that had characteristic nuclear features of BK virus infection by histology. The sensitivity and specificity for using p53 staining to identify BK infected cells was 92% and 86 %, respectively. In conclusion, p53 staining detects a higher percentage of BK virus infected cells than SV40 staining alone. Thus, for diagnosis of BK virus infection in renal allograft biopsies, p53 staining is a sensitive and specific method when used along with SV40 staining.

Anemia management with darbepoetin-alfa in outpatient hemodialysis patients switched from epoetin-alfa: a community hospital experience.

Epoetin-alfa (EA) and darbepoetin-alfa (DA) are agents for treating anemia in dialysis patients. In September 2005, our free-standing outpatient hemodialysis center (community-hospital based) implemented an interchange from EA to DA. Since then, all hemodialysis patients receive DA as the preferred agent. We performed this observational study to compare effectiveness of DA with EA in anemia management in a cohort of hemodialysis outpatients. We studied 98 hemodialysis outpatients who received twice to thrice weekly EA from January to August 2005. These patients were switched to DA in September 2005, and baseline DA dose was calculated from the conversion table in the package insert. After a 4 month titration phase, the same cohort of patients, now on once weekly DA, was followed from January to September 2006. Dose of EA or DA was adjusted to maintain hemoglobin at 11 to 13 g/dL. Hematologic and dialysis parameters were collected on a monthly basis, and inpatient data were excluded. Mean ± standard deviation age was 65.8 ± 14.2 years, with 42 (42.9%) women. Mean ± standard deviation hemoglobin level was 12.5 ± 1.6 g/dL during EA and 12.5 ± 1.6 g/dL during DA therapy (P = 0.23). Proportion of patients achieving hemoglobin (11-13 g/dL) was 44.5% ± 28.9% with EA and 49.8% ± 25.8% with DA (P = 0.09). Average intrapatient absolute hemoglobin variability was 1.0 ± 0.5 g/dL on EA and 1.1 ± 0.5 g/dL on DA (P = 0.29). Median (and interquartile range) EA dose used was 11,400 (7,050-22,800) IU/week, and median DA dose was 59.8 (40-91.6) mcg/week with an EA:DA dose conversion ratio of 191:1. Patients on EA or DA had similar dialysis adequacy, albumin, and iron parameters. DA is as effective as EA in treating anemia in hemodialysis outpatients. Dose requirement of DA is greater than 200:1 of the amount of EA and may not translate into cost savings.

Dietary sodium intake and arterial blood pressure.

We sought to summarize major recent studies in the field of dietary sodium intake and arterial blood pressure, and discuss the following trials. INTERSALT: Sodium intake correlates with the rise in blood pressure with age, but not with the prevalence of hypertension. The population study identified a minimal impact of sodium intake on blood pressure (0.9 mm Hg/10 mmol difference in salt intake). DASH: This diet induced significant reductions in blood pressure compared with the control diet. Further decreases were observed with DASH and a 50 mmol/day sodium intake. VANGUARD: Blood pressure was inversely related to urinary potassium, calcium and magnesium but not to sodium excretion. TONE: Cardiovascular events were highest in the usual care group (83%) and lowest in the sodium reduction-plus-weight loss group (56%). META-ANALYSIS: A systematic review of 11 long-term controlled randomized trials reported a small decrease (1.1 mm Hg) in median systolic but not diastolic blood pressure with a reduced dietary sodium intake. In conclusion, (1) sodium restriction in hypertensive patients reduces blood pressure, and (2) the long-term impact of reduced salt intake on blood pressure, mortality, and morbidity remains to be defined.

Hypoalbuminaemia--a marker of cardiovascular disease in patients with chronic kidney disease stages II-IV.

UNLABELLED: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD) patients. Serum albumin, a negative acute-phase reactant and marker for underlying inflammation and/or malnutrition, is an independent predictor of CVD and mortality in CKD VI patients. Such an association in patients with less severe CKD is not well established. We conducted a cross sectional study of all CKD II-IV patients attending the nephrology clinic (N=376; mean age: 57+/-17 years; GFR: 47+/-20 mL/min/1.73 m(2); females 48%; blacks 15%; diabetics 27%; hypertensive 79%). Laboratory and clinical data including risk factors and evidence of CVD were obtained at the point of the most recent visit. The association between risk factors and CVD was evaluated by logistic regression. In the simple logistic regression model, age (p<0.0001), sex (P= 0.02), hypertension (P<0.0001), diabetes (P<.0001), dyslipidemia (p=.01), and serum albumin (p<.0001) were found to be statistically significant. Serum albumin was found to be an independent predictor (p=0.04) of CVD by multiple logistic regression analysis using the above risk factor variables. IN CONCLUSION: a) hypoalbuminaemia is an independent predictor of CVD in early CKD stages; b) hypoalbuminaemia may be used to identify the population at higher risk for CVD.

Metabolic and nutritional complications of renal transplantation.

Renal transplantation is the gold standard therapy for patients with end-stage renal disease. However, renal transplantation is associated with various metabolic and nutritional complications. This review focuses primarily on factors that have a significant impact on cardiovascular disease, namely, hyperlipidemia, posttransplant diabetes mellitus, and hyperhomocysteinemia. The prevalence of hyperlipidemia in renal transplant patients is estimated at 80% to 90%. Corticosteroids, cyclosporine, and sirolimus are commonly associated with hyperlipidemia. The incidence of posttransplant diabetes mellitus is estimated to be 24% at 36 months post transplant. Glucocorticoids induce metabolic changes that result in hyperglycemia. Calcineurin inhibitors have direct islet cell toxicity and induced alterations in the transcriptional regulation of insulin. Hyperhomocysteinemia is common in renal transplant recipients and is an independent risk factor for cardiovascular disease.

Prospective nutritional surveillance using bioelectrical impedance in chronic kidney disease patients.

Malnutrition is a well-known risk factor influencing survival in chronic maintenance dialysis patients. Chronic kidney disease (CKD) patients are also predisposed to malnutrition because of dietary restrictions and the catabolic effects of uremia. Therefore, a significant degree of malnutrition may be present before the initiation of renal replacement therapy. We consequently initiated a prospective evaluation of subjects attending the CKD clinic, where all patients are seen by a renal dietitian and nutritional, biochemical, and bioimpedance parameters are measured every 3 months. A total of 40 patients have completed 9 months of follow-up and are the subject of this report. Their mean age is 65 +/- 12 years, 48% female, 68% black, and 58% diabetic patients. The glomerular filtration rate did not change during follow-up (36 +/- 12 versus 34 +/- 14 mL/min/1.72 m 2 , at baseline and 9 months, respectively). Similarly, no differences between baseline and 9 months were noted in weight (88.0 +/- 20.3 versus 86.8 +/- 18.7 kg, respectively) or body mass index (30.6 +/- 5.8 versus 30.2 +/- 5.4 kg/m 2 , respectively). In addition, no differences between baseline and 9 months were noted in total body water (44.4 +/- 11.4 versus 44.6 +/- 10.8 L, respectively), body cell mass (25.3 +/- 7.4 versus 25.2 +/- 7.0 kg, respectively), and fat-free mass (59.2 +/- 16.6 versus 59.4 +/- 15.7 kg, respectively). The bioimpedance vector decreased with time in 25 subjects (62%), indicating a state of overhydration. Subjects were further analyzed by vector category. Body cell mass did not change in either group. As expected, total body water increased in the group with a decreasing bioimpedance vector. Because body cell mass did not increase, the greater total body water reflected an increase in extracellular volume (edema). In the group with stable vectors, no changes were noted with time in weight or total body water. These results indicate that CKD patients with stable renal function following a judicious dietary protein intake (0.6 to 0.8 g/kg normalized body weight/day) have no loss of body cell mass or fat-free mass over a 9-month period. Of note, a high proportion of patients (62%) developed clinically unrecognized fluid retention, which is promptly identified by a decreasing bioimpedance vector.

Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review.

BACKGROUND: Vascular calcification (VC) is a recognized process involved in senescence and atherosclerosis. Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are conditions associated with metabolic disorders related to soft tissue calcification. METHODS: We performed a systematic review of the literature confined to patients with CKD or ESRD with clinical observations of VC. Case reports of calciphylaxis were excluded. We identified 30 studies over 20 years: 11 prospective cohort, 7 cross-sectional, 11 case-control, and 1 retrospective cohort; n = 2918 subjects, mean age 51 years, 59% men and 41% women. Imaging methods used included: x-ray 43%, computed tomography 30%, ultrasound 17%, and other methods 10%. RESULTS: The most consistent determinants of VC were older age and dialysis vintage. Eight analyses determined a relationship between VC and measures of calcium-phosphate balance while 20 analyses specifically did not find such a relationship. Three studies suggested the degree of calcium loading, treatment with phosphate binders, or treatment with vitamin D analogues were related to VC. When taken into consideration, the lipid profile (primarily low high-density lipoprotein cholesterol, elevated triglycerides, elevated low-density lipoprotein, and elevated total cholesterol) were predictive factors in four analyses. CONCLUSIONS: VC is a common observation in CKD and ESRD and is mainly related to age, length of time on dialysis therapy, and possibly dyslipidemia. The calcium-phosphorus balance and its related treatments are likely not related to this unique form of vascular calcification. Further research into the determinants and potential treatments for vascular calcification is warranted.

Optimal dialysis for the end-stage renal disease patient with cardiovascular disease.

The increasing incidence and prevalence of end-stage renal disease (ESRD) that requires renal replacement therapy has placed a focus on the dialysis procedure itself with respect to its hemodynamic and cardiovascular complications. More than 50% of patients with ESRD will die of cardiovascular disease (CVD). A considerable contribution to cardiovascular events occurs with the dialysis procedure itself. This paper explores the intradialytic complications of hemodialysis as they relate to the cardiovascular system and highlights opportunities for research and improved quality of care.

Best method for estimating urea volume of distribution: comparison of single pool variable volume kinetic modeling measurements with bioimpedance and anthropometric methods.

The urea volume of distribution (Vurea) is a key component of the Kt/V parameter calculated during urea kinetic modeling. The Vurea parameter has been approximated empirically using total body water (TBW) estimates derived from anthropometric formulas or measured by bioelectric impedance analysis (BIA). The author compared TBW values derived using various anthropometric formulas (Watson, Hume, Randall, Tzamaloukas, Chertow) and BIA to the Vurea parameter calculated using three point variable volume single pool urea kinetic modeling. A total of 127 chronic hemodialysis patients were studied (mean age 66 +/- 13 years; 42% female; 37% black; 47% diabetic). Agreement between anthropometric formulas, BIA, and Vurea values was assessed by linear regression and Bland Altman analyses. The closest correlations were obtained with the BIA (r = 0.972), Chertow (r = 0.917), and Tzamaloukas (r = 0.905) methods. When compared with Vurea, 95% confidence intervals by Bland Altman analysis were lowest with BIA (4L) and highest with the Watson method (8L). These results indicate that BIA best approximates Vurea in dialysis patients.

Hypoalbuminemia is a marker of overhydration in chronic maintenance patients on dialysis.

Hypoalbuminemia is an important risk factor for increased morbidity and mortality in patients on dialysis. Hypoalbuminemia is usually attributed to malnutrition or a state of chronic inflammation. However, hypoalbuminemia could result from hemodilution caused by chronic volume expansion. We prospectively evaluated 142 patients on chronic dialysis for 12 consecutive months (mean age: 62 +/- 14 years; 41% women, 37% African American, 43% diabetic, 27% peritoneal dialysis). Intracellular (ICW) and extracellular (ECW) water content was estimated using single frequency bioelectrical impedance. Values in each albumin grouping (group 1, < 3.5 g/dl; group 2, 3.5-4.0 g/dl; group 3, > 4.1 g/dl) are expressed as annual mean +/- SEM. Group 1 patients had lower body weight, body mass index, blood urea nitrogen, serum creatinine, dietary protein intake, and ICW content than those in groups 2 and 3. ECW was significantly increased in group 1 when compared with groups 2 and 3 (p < 0.001). A significant correlation was found between ECW and serum albumin concentration (R = 0.2230; p < 0.0001). Resistance and reactance were decreased in group 1 when compared with groups 2 and 3 (p < 0.05 and 0.001, respectively), causing the resultant bioimpedance vector to move away from the normal population range into the overhydration boundaries. We conclude that, in addition to malnutrition and chronic inflammation, overhydration is a contributor to hypoalbuminemia in patients on chronic dialysis.

Body composition analysis by bioelectrical impedance in chronic maintenance dialysis patients: comparisons to the National Health and Nutrition Examination Survey III.

OBJECTIVE: To compare bioelectrical impedance analysis derived parameters in chronic maintenance dialysis patients to those obtained in National Health and Nutrition Examination Survey (NHANES) III. DESIGN: Cross-sectional nutritional surveillance study. SETTING: Hospital-based, not-for-profit chronic maintenance dialysis center. PATIENTS: A total of 913 chronic maintenance dialysis patients and a subset of 10,263 subjects from NHANES III who underwent bioelectrical impedance analysis. Independent (Predictor) Variables: Bioelectrical impedance parameters including resistance, reactance, phase angle, and total body capacitance. MAIN OUTCOME MEASURES: Total body water, intracellular and extracellular water, body cell mass, fat free mass, fat mass. RESULTS: Relative to NHANES III, end-stage renal disease patients have lower resistance (3%), reactance (26%), phase angle (28%); and intracellular water (9%) values, whereas extracellular water content is 17% higher (P < .001). In addition, body cell mass, fat free mass, and fat mass were lower in end-stage renal disease patients when compared with NHANES III subjects (9%, 3%, and 12%, respectively; P < .001). CONCLUSIONS: End-stage renal disease patients have a lower tissue mass than the general population and remain in a state of overhydration while on chronic maintenance dialysis therapy.

Impedance vector distribution by sex, race, body mass index, and age in the United States: standard reference intervals as bivariate Z scores.

Bioelectrical impedance measurements were collected in the Third National Health and Nutrition Examination Survey (NHANES III), but their results have not been published. In the NHANES III population, resistance (R) and reactance (Xc) values at 50-kHz frequency were obtained with a Valhalla Scientific meter (model 1990B; San Diego, CA, USA). The RXc graph method was used to identify bivariate pattern distributions of mean vectors (95% confidence ellipses by sex, race, age, and body mass index [BMI]), and individual impedance vectors (50%, 75%, and 95% tolerance ellipses). Data from 10 222 adults (5261 men and 4961 women) formed 90 four-way classification groups, with two sexes, three races or ethnicities (non-Hispanic white, non-Hispanic black, Mexican American), five age classes (20-29, 30-39, 40-49, 50-59, and 60-69 y), and three BMI classes (19-24.9, 25-29.9, and 30-34.9 kg/m(2)). Sex, race or ethnicity, BMI and age, in decreasing order, influenced the vector distribution pattern. Mean vectors in women were significantly longer than those in men. Within each sex, the mean vector of non-Hispanic white subjects was shorter and with a smaller phase angle than that of corresponding BMIs from the two other race/ethnic populations. Tolerance ellipses were calculated from sex- and race-specific reference populations 20 to 69 y old and 19 < or = BMI < 30 kg/m(2) (8022 subjects, 4226 men and 3796 women). After transformation of impedance vector components into bivariate Z scores (standardized deviates, as differences from the mean divided by the standard deviation of the reference population), we constructed one standard, reference, RXc-score graph (50%, 75%, and 95% tolerance ellipses) that can be used with any analyzer in any population. The pattern of impedance vector distribution and reference bivariate intervals for the individual impedance vector are presented for comparative studies (free software at E-mail: apiccoli@unipd.it).