Showing papers in "Journal of Nephrology in 2004"

Endothelial dysfunction and oxidative stress in chronic renal failure.

Abstract: Uremic patients have an increased incidence of cardiovascular disease (CVD), endothelial dysfunction and oxidative stress that can contribute to cardiovascular (CV) events. To assess the relationship between endothelial dysfunction, oxidative stress and renal failure severity, we studied 40 patients (age 57 +/- 7 yrs, 24 males) affected by chronic kidney disease (CKD) K/DOQI stage 3-5 (serum creatinine (Cr) 5.6 +/- 2.2 mg/dL) on conservative treatment, 20 uremic patients (age 57 +/- 12 yrs, 13 males) on hemodialysis (HD) and 30 healthy controls (56 +/- 12 yrs, 20 males). Before and 2 hr after oral vitamin C (2 g) administration, we measured brachial artery endothelium-dependent vasodilation (flow mediated dilation (FMD)) to reactive hyperemia following 5 min of forearm ischemia and the response to sublingual glyceril trinitrate (GTN). Measurements were made by high-resolution ultrasound and computerized analysis. FMD was lower in CKD patients than in controls (5.3 +/- 2.2 vs. 6.9 +/- 2.8%; p<0.01) and was further reduced in HD patients (3.6 +/- 2.7; p<0.01 vs. CKD patients). Response to GTN was similar in all groups. FMD was related to Cr clearance (r=0.42; p<0.01) in CKD patients, while it related inversely to Kt/V(urea) (r=-0.52; p<0.05) in HD patients. After vitamin C administration, FMD was significantly enhanced in HD (4.7 +/- 2.4%; p<0.01 vs. baseline), but not in CKD patients. Response to GTN was unaffected. However, vitamin C load reduced oxidative stress markers, and increased plasma antioxidant capability in both groups. In conclusion, the reduced endothelium-dependent dilation in the brachial artery of CKD patients is related to renal failure severity. HD patients showed a more marked alteration, which seems to be related, at least in part, to increased oxidative stress.

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

Abstract: 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.

A twelve week exercise program improves the psychological status, quality of life and work capacity in hemodialysis patients.

Abstract: BACKGROUND Patients with chronic renal failure (CRF) are restricted in physical, emotional and social dimensions of life due to their treatment and their comorbid medical conditions. We aimed to evaluate the effects of a 12-week exercise program on the functional capacity, functional mobility, walking capacity, quality of life and depression in patients with renal failure on hemodialysis (HD). METHODS Twenty patients with renal failure on HD were included and 14 of them completed the study. The patients went through a 12-week exercise program of 90 min/day, 3 days a week. Exercise and walking capacity, functional mobility, psychological status and quality of life were evaluated pre- and post-training. RESULTS Following the exercise, peak oxygen consumption, exercise duration and peak workload improved significantly (respectively, p=0.006, p=0.002 and p=0.002). There were significant improvements in the sit-to-stand-to-sit test and the 6- min walk test (p<0.001 and p=0.002). There was a significant reduction in the depression score (p<0.001). Both physical component scale (PCS) and mental component scale (MCS) of the Kidney Disease Quality of Life Short-Form 36 (SF-36) questionnaire showed significant increases (respectively, p=0.002 and p=0.004). CONCLUSION The application of an appropriate exercise program would improve psychological status and quality of life, as well as work capacity in long-term maintenance HD patients.

Effect of ischemia and reperfusion on enzymes of carbohydrate metabolism in rat kidney.

Abstract: Background: Ischemia results in rapid decline in mitochondrial electron transfer, resulting in decreased ATP levels, and fall in intracellular pH. The purpose of the study was to examine the effects of ischemia and reper- fusion on the activities of enzymes of carbohydrate metabolism in rat kidney. Methods: Ischemia was induced by occlusion of the left renal artery for specified times. The activities of Na-K ATPase, lactate dehydrogenase (LDH), Malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), glucose-6-phosphatase (G6Pase), and fructose-1, 6-bisphosphatase (FBPase) were studied in the homogenates of whole (WC), superficial (SCH), and juxtamedullary (JMCH) cortices and medulla (MH). Results: The activities of LDH, G6Pase, FBPase, and ME rapidly increased whereas those of MDH and G6PDH de- creased by brief ischemia of 5min both in the cortex and medulla. Prolonged ischemia (15-60 min) caused progressive decrease in the enzyme activities. Reperfusion for 60 min caused complete recovery of the enzyme activities studied. Conclusions: The results demonstrate that activities of carbohydrate metabolism enzymes are restored by short-term reperfusion following 30 min ischemia.

Health-related quality of life of family caregivers of dialysis patients.

Abstract: BACKGROUND This study aimed to evaluate the health-related quality of life (HRQOL) and burden on family caregivers of chronic dialysis patients and to analyze which factors were associated with it. METHODS A cross-sectional multicentric study was carried out with 221 patient/caregiver pairs. General population Short Form 36 (SF-36) norms were used to estimate gender and age standardized physical component summary (PCS) and mental component summary (MCS) scores. The Duke-UNC Functional Social Support Questionnaire (FSS), the Zarit Burden Interview (ZBI), and sociodemographic and clinical data were also collected. RESULTS The PCS and MCS of caregivers were slightly worse than that of the Spanish population. Multiple regression analysis showed that: (1) lower PCS was associated with younger age and higher ZBI of the caregiver (R2=0.15); (2) lower MCS was associated with higher ZBI and lower FSS of the caregiver, and lower MCS of the patient (R2=0.29); (3) higher ZBI was associated with lower FSS, PCS and MCS of the caregiver, and to older age and lower PCS and MCS of the patient (R2=0.49). Of caregivers 28.3% had a MCS < or = 42; logistic regression analysis showed that a MCS < or = 42 was associated to higher ZBI and lower FSS scores (p<0.001). CONCLUSIONS The HRQOL of dialysis patient family caregivers is slightly worse than that of the Spanish population of the same age and gender. Younger family members, who are the primary carers of older dialysis patients with poor HRQOL, experienced a higher burden, had a worse HRQOL and had a higher risk of clinical depression; this was worse if low social support was perceived.

Inflammation and oxidative stress in ESRD--the role of myeloperoxidase.

Abstract: It has been increasingly apparent that end-stage renal disease (ESRD) patients carry an inflammatory burden, which may play a pivotal role in the evolution of not only wasting but also of the massive increase in the relative risk of cardiovascular disease (CVD). Also increased oxidative stress (an impairment of the pro- and antioxidant redox balance) is a common feature of ESRD, and it has been speculated that it is interrelated to inflammation. Myeloperoxidase (MPO) is a hemoprotein secreted during activation of neutrophils, which plays an important role in the defense of the organism by catalyzing the production of hypochloric acid (HOCl). MPO has been speculated to be a major oxidative stress pathway in ESRD. Emerging evidence suggests that enhanced MPO-activity, via increased generation of diffusible oxidants and consumption of nitric oxide, may be an important risk factor for vascular disease. Indeed, MPO serum levels are a powerful predictor of cardiovascular events in non-renal patients. As a functional polymorphism (SNP) has been identified at position -463 (where the A allele is associated with lower MPO expression) this sequence of event may be affected by genetic factors. Nutritional and pharmacological antioxidant strategies that interfere with chlorinated MPO-associated oxidative stress pathways need to be investigated in the ESRD patient population.

Serum paraoxonase activity in uremic predialysis and hemodialysis patients.

Abstract: Background Paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme and has been shown to reduce the susceptibility of low-density lipoprotein (LDL) to lipid peroxidation. This study aimed to investigate the activity and phenotype distribution of serum paraoxonase in uremic patients, and to evaluate the correlations of uremia-associated substances (urea, creatinine (Cr) and uric acid) with paraoxonase activity. Methods Twenty-eight patients with chronic renal failure (CRF), 44 patients with CRF undergoing hemodialysis (HD) and 26 healthy controls were included in this study. Paraoxon or phenylacetate was used as a substrate for measuring paraoxonase and arylesterase activity, respectively. The double substrate method was used to assign phenotypes. Serum lipid parameters were determined by routine laboratory methods. Results Paraoxonase activity, HDL-cholesterol and apolipoprotein (apo) AI levels were found to be significantly lower in HD patients than in controls. However, HDL-standardized paraoxonase activity (PON activity/HDL) was not different in the HD patients compared to controls. Arylesterase activity was significantly lower in both CRF and HD patients than in controls. Paraoxonase phenotype distribution was not different among the groups according to the double substrate method. Serum paraoxonase and arylesterase activities correlated inversely with serum urea and Cr levels. Conclusion Patients on long-term HD have reduced paraoxonase/arylesterase activities and this could be related to reduced HDL-cholesterol and apo AI levels, as well as increased urea and Cr levels in uremia.

The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron

Abstract: Anemia is found in about one-third of all cases of congestive heart failure (CHF) The most likely common cause is chronic kidney insufficiency (CKI), which is present in about half of all CHF cases The CKI is likely to be due to the renal vasoconstriction that often accompanies CHF and can cause long-standing renal ischemia This reduces the amount of erythropoietin (EPO) produced in the kidney and leads to anemia However, anemia can occur in CHF without CKI and is likely to be due to excessive cytokine production (for example, tumor necrosis factor-alfa (TNF-alfa) and interleukin-6 (IL-6)), which is common in CHF and can cause reduced EPO secretion, interference with EPO activity in the bone marrow and reduced iron supply to the bone marrow The anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart Long-standing anemia of any cause can cause left ventricular hypertrophy (LVH), which can lead to cardiac cell death through apoptosis and worsen the CHF Therefore, a vicious circle is set up wherein CHF causes anemia, and the anemia causes more CHF and both damage the kidneys worsening the anemia and the CHF further We have termed this vicious circle the cardio renal anemia (CRA) syndrome Patients with CHF who are anemic are often resistant to all CHF medications resulting in being hospitalized repeatedly Many studies also demonstrate that these patients die more rapidly than their non-anemic counterparts do In addition, they have a more rapid deterioration in their renal function and can end up on dialysis There is now evidence from both uncontrolled and controlled studies that early correction of the CHF anemia with subcutaneous EPO and intravenous (iv) iron improves shortness of breath and fatigue, cardiac function, renal function and exercise capability, dramatically reducing the need for hospitalization For these reasons, it is not surprising that quality of life has also been shown to improve As both CHF and end-stage renal disease (ESRD) are rapidly increasing, the possibility that these twin conditions can be improved by the adequate treatment of anemia offers new hope for slowing the progression of both conditions

Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach.

Abstract: Background Acute spontaneous tumor lysis syndrome (STLS) presenting with hyperuricemic acute renal failure (ARF) is a rare disease which can be overlooked in patients with neoplasic disorders, requiring prompt recognition and aggressive management. This study examined the incidence, clinical characteristics and prognosis of this condition. Methods A retrospective study was performed, reviewing the records of all patients who developed ARF at Chang Gung Memorial Hospital between 1st July 1999 and 30th October 2002. Acute STLS was diagnosed based on pretreatment hyperuricemic ARF, ratio of urinary uric acid to creatinine (Cr) >1.0, and significantly elevated lactate dehydrogenase (LDH) (>500 units/L), together with a pathologically proven malignancy. Clinical course, metabolic parameters, response to therapeutics and outcome were assessed in all patients. Results STLS-induced acute uric acid nephropathy was identified in 10 out of 926 ARF patients (1.08%) studied. Most presentations were non-specific or related to malignancy symptoms. All patients had advanced tumors with large tumor burden, and abdominal organ involvement in 80% of patients. The 10 hyperuricemic patients became oliguric despite conservative therapy, and remained hyperuricemic (mean +/- SD: 20.7 +/- 5.0 mg/dL) until dialysis initiation. Seven patients (70%) developed diuresis, with an associated resolution of hyperuricemia, azotemia and metabolic derangements following dialysis initiation. The patients who developed diuresis had mean serum uric acid levels 9.3 +/- 3.1 mg/dL and median levels 9.8 mg/dL. Three patients (30%) survived, with two patients suffering residual renal function impairment. Conclusions Acute STLS presenting with hyperuricemic ARF is a rare cause of acute uric acid nephropathy in patients with bulky or occult neoplastic disorders. The tumors that developed STLS had advanced stage or large tumor burden. Frequent abdominal organ involvement and non-specific initial presentations can obscure the nature of the disease and delay diagnosis. Unlike hyperuricemia and oliguria, which are constant findings, azotemia or impaired renal function is not always manifest on initial presentation. Poor outcomes in patients with STLS developing acute uric acid nephropathy make early recognition, aggressive management and prompt dialysis mandatory.

Ultrapure dialysate improves iron utilization and erythropoietin response in chronic hemodialysis patients - a prospective cross-over study.

Abstract: BACKGROUND The impact of ultrapure dialysis on dialysate-related chronic inflammatory status and anemia in uremic patients on maintenance hemodialysis (HD) remains uncertain. We evaluated ultrapure dialysate effects on erythropoietin (EPO) response and inflammatory status in a prospective, randomized, cross-over study. METHODS Thirty-four HD patients were divided into two groups. One group was treated with conventional dialysate and the other group with ultrapure dialysate for 6 months and crossed over for another 6 months. Bacteria growth and dialysate endotoxin were examined. Parameters including C-reactive protein (CRP), recombinant human erythropoietin (rHuEPO) dose, ferritin, iron saturation and serum albumin were measured at the start, and at 6 and 12 months. RESULTS The endotoxin levels reduced significantly in the ultrapure dialysate by adding a dialysate ultrafilter. After a 6-month treatment with ultrapure dialysate, there were statistically significant differences in the systemic inflammation markers between both groups. Changing from conventional to ultrapure dialysis fluid significantly reduced CRP (7.01 +/- 5.059 to 4.461 +/- 3.754 mg/L, p 0.05). The ferritin level reduced significantly (422 +/- 183 to 272 +/- 162 mcg/L, p<0.05) in the ultrapure dialysate group. After another 6-month cross-over, the study parameters were reversed among the two groups indicating the beneficial effect of ultrapure dialysis. CONCLUSIONS Through endotoxin reduction in conventional dialysate, ultrapure dialysis in dialysis patients manifested a reduced inflammatory parameter, reduced rHuEPO dose and improved iron utilization; and therefore, could be beneficial in anemia treatment.

Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents.

Abstract: Renal fibrogenesis can be induced by several injury mechanisms in different renal diseases, but ultimately produces identical fibrotic changes in the kidney. Recently, a number of agents that can inhibit extracellular matrix (ECM) accumulation have been studied, suggesting a therapeutic utility in the treatment of fibrotic renal disease. Pirfenidone (PFD) is a small molecule that has shown efficacy in various models of renal damage with progressive disease. The apparent absence of toxicity in PFD suggests that it does not affect the normal ECM turnover. Relaxin, a hormone belonging to the insulin-like growth factor (IGF) family, has antifibrotic properties and has been used for a long time to induce transient remissions in patients with scleroderma. Only recently it has been shown to drastically reduce corticomedular scarring in animal models. Bone morphogenetic protein 7 (BMP-7), a member of the transforming growth factor beta (TGF-beta) superfamily, has been shown to reduce glomerular and interstitial area, and prevent glomerular sclerosis even more effectively than enalapril. Finally, hepatocyte growth factor (HGF), with its multiple biological activities on a wide variety of cells, has an organotrophic role in the regeneration and protection of various organs including the kidney. Both endogenous and exogenous HGF have shown suppressive effects on renal fibrosis and chronic renal damage in various animal models. The inhibition of pathological ECM accumulation and the modulation of fibrotic mechanisms with these new antifibrotic agents is an achievable goal and could confer further benefits beyond the current therapies used in the treatment of chronic renal diseases.

Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease.

Abstract: Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis in patients with normal renal function. Plasma homocysteine (Hcy) is increased in patients with chronic renal failure (CRF) and could be linked to their high cardiovascular (CV) morbidity and mortality. We prospectively studied 77 patients (47 males and 30 females aged 62.85 +/- 1.53 yrs) who had been on maintenance hemodialysis (HD) (4 hr/x3/week) for 65.5 +/- 7.23 months. Patients were followed-up for 44 months. At baseline, blood samples were taken for hemoglobin (Hb), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, serum calcium, serum phosphates, parathyroid hormone (PTH), Hcy, vitamin B12, serum and erythrocyte folate and methylentetrahydrofolate-reductase (t-MTH-FR) genotype determination. Plasma Hcy levels of patients were divided into four quartiles. The univariate analysis demonstrated a significant relationship between Hcy and diastolic blood pressure (BP) (r=0.45; p=0.003), and both plasma (r=-0.30; p=0.03) and erythrocyte (r=-0.48; p=0.01) folate levels and CV score (r=0.39; p=0.007). Kaplan-Meier analysis showed that the mortality rate due to CV events was statistically significantly higher in the 4th Hcy quartile (68%; 12 patients) vs. the 3rd quartile (12%; two patients), the 2nd quartile (28%; four patients) and the 1st quartile (14%; two patients) (log-rank test p=0.02). Cox's regression analysis for CV survival showed that Hcy was a positive CV mortality predictor (beta=0.02; hazard ratio=1.031; 95% confidence interval (95% CI): 1.013-1.050; p=0.001), while LDL cholesterol and albumin related negatively to CV mortality (LDL cholesterol: beta=-0.02; hazard ratio=0.095; 95% CI: 0.0957-0.0997; p=0.035; albumin: beta=-2.35; hazard ratio=0.097; 95% CI: 0.011-0.847; p=0.026). Our results show that Hcy is a strong independent mortality predictor in HD patients with a 3% increase in mortality for each 1 micromol/L increase in plasma Hcy concentration. This agrees with previous findings confirming the role of Hcy in predicting CV risk factors in uremic patients.

The fate of bone after renal transplantation.

Abstract: Post-transplantation bone disease is a multifactorial, complex condition. It derives in a significant part from pre-existing renal osteodystrophy, but it is aggravated by factors emerging after renal transplantation. Among the latter factors, the key pathophysiological contributor to bone disease is immunosuppressive agent application (especially glucocorticoids (GC)). Post-transplantation bone disease is detectable even years after renal transplantation in the vast majority of patients, and potentially it never resolves completely. Due to post-transplantation bone disease, a rapid reduction of bone mineral density (BMD) develops that can exceed 10% in the first 12 months. Subsequently, the bone loss slows down or even a secondary increase occurs. Post-transplantation bone disease results in a significantly elevated fracture risk, which largely contributes to the increased morbidity in transplant patients. Currently, vitamin D metabolites and bisphosphonates are the most extensively tested therapeutic agents against this accelerated bone loss. Both substances have proven effective. However, it is yet unproven that they reduce the fracture risk. In patients with adynamic bone disease, bisphosphonate usage cannot be recommended, since this group of drugs could oversuppress bone metabolism.

Vascular access for hemodialysis: the impact on morbidity and mortality.

Abstract: Background In chronic hemodialysis (HD), central venous catheter (CVC) use seems associated with an increased risk of death. This study, using registry data, evaluated the morbidity and mortality risk associated with the use of different permanent vascular access (VA) in a HD patient cohort. Method We evaluated hospitalization and death rate in prevalent and incident HD patients recorded in the uremic registry of Campania (southern Italy) for 2001. Patients were divided into three groups: CVC, artero-venous graft (AVG) and artero-venous fistula (AVF). Results One hundred and eleven dialysis units in the Campania region (69%) provided data. A total of 2201 out of 3387 prevalent HD patients were included: 92 patients (4.2%) were on CVC, 24 patients (1.1%) were on AVG and 2085 patients (94.7%) were on AVF. In comparison with AVF, the CVC group had a greater prevalence of female gender, old age, diabetes, comorbidities, hypoalbuminemia, anemia, erythropoietin (EPO) resistance, and less frequent synthetic membrane use, but had a similar dialysis duration (hr/week). Similar data were collected in the 635 incident patients registered in 2001. During the study, in both prevalent and incident CVC patients, either hospitalization or death rates were enhanced; however, the difference in the relative risk (RR) of death disappeared after correction for age, gender, malnutrition, diabetes, hemoglobin, albumin and comorbidity. Among incident patients, survival analysis was performed in patients remaining on the same VA type throughout the follow-up period; while a similar survival between groups was demonstrated in the 1st year of follow-up, survival was worse in the CVC group during the 2nd year of follow-up; however, this difference also disappeared in the adjusted analysis. Conclusion This cohort study demonstrates that in chronic dialysis patients CVC choice, with respect to AVF, is mainly associated with female gender, advanced age and worse clinical conditions at baseline, and a worst outcome in both prevalent and incident CVC patients compared to AVF patients. Hospitalization, mortality rate and RR of death increased significantly; however, differences disappeared after correction for comorbidity. Therefore, these data suggest that CVC use per se is not associated with increased mortality risks with respect to AVF.

The favorable effect of regional citrate anticoagulation on interleukin-1beta release is dissociated from both coagulation and complement activation.

Abstract: BACKGROUND: It has been claimed that regional citrate anticoagulation (RCA) improves unfavorable calcium and magnesium dependent cellular and humoral events due to blood/dialyzer membrane interactions during hemodialysis (HD). This study aimed to verify whether the favorable effect of RCA on biocompatibility is independent from coagulation pathway modulation. METHODS: A randomized controlled cross-over single blind trial comparing the activity of the coagulation pathway (thrombinantithrombin complexes (TAT), fibrinopeptide A (FPA), prothrombin fragments 1+2 (F 1+2) and D-dimer (DD)), complement activation (C3a) and interleukin-1 beta secretion (IL-1beta) in nine chronic HD patients treated with RCA or heparin. Blood samples were obtained from the arterial (C3a, IL-1beta, TAT, F 1+2, FPA and DD) and venous (TAT, F 1+2, FPA) lines 2 min after starting treatment and repeatedly during the procedure after 15 min (C3a and IL-1beta), 30 min (C3a), 45 (C3a) and 180 min (TAT, F 1+2, FPA and DD). RESULTS: In both treatment protocols significant enhancement was observed in the coagulation activity during the dialysis session, documented by an increase in TAT (p<0.001), F 1+2 (p<0.001) and FPA (p=0.001). Comparing the two anticoagulation modalities, no differences were noticed in the activity of the coagulation pathway, but a significantly higher complement activity (C3a=886 (832-908) vs. 770 (645-857) ng/mL, p<0.05) and lower IL-1beta secretion (235 (206-285) vs. 538 (346-974) pg/mL, p<0.05) was observed in RCA. CONCLUSIONS: Due to an RCA protocol guaranteeing the same extent of anticoagulation activation as standard heparin, we demonstrated that the significantly lower IL-1beta secretion obtained with RCA is independent from the anticoagulation modulation and dissociated from the complement activity.

Is morning urinary protein/creatinine ratio a reliable estimator of 24-hour proteinuria in patients with glomerulonephritis and different levels of renal function?

Abstract: Background: This cross-sectional study was conducted to determine whether a spot urine protein/creatinine ratio (UPr/UCr) provides accurate quantitation of 24-hr urinary protein excretion (24-hr Prot) in out-patients with pri- mary glomerulonephritis (GN) and different renal function levels Methods: Patients were classified into three groups according to creatinine (Cr) clearance (ml/min) and into five categories according to morning UPr/UCr Correlation between 24-hr Prot and UPr/UCr was calculated according to the three renal function levels The Bland and Altman method was used to assess agreement between 24-hr Prot and UPr/UCr Agreement limits were obtained calculating the mean difference between 24-hr Prot and morning UPr/UCr ± 2SD Sensi- tivity and specificity were determined for different renal function levels and UPr/UCr cut-off values Results: High correlation coefficients (r=091, 095 and 098) were observed in patients with normal, reduced and severe- ly reduced renal function Differences and variability between 24-hr Prot and UPr/UCr tended to increase with higher pro- teinuria levels, and this trend was observed for the three renal function levels The best UPr/UCrcut-off values to detect abnormal or nephrotic proteinuria were, respectively, 03 and 26 Conclusions: Correlation and agreement between UPr/UCr and 24-hr Prot was good for all renal function levels, but demon- strated more marked differences as urinary protein excretion increased Morning UPr/UCr had good sensitivity and speci- ficity for the diagnosis of 24-hr Prot, even in patients with reduced renal function

Staphylococcus aureus antigens induce IgA-type glomerulonephritis in Balb/c mice.

Abstract: Background: Staphylococcus aureus (S. aureus) is a common, normal pathogenic flora that colonizes mucosal tissues. We previously reported that glomerulonephritis occurs during methicillin-resistant S. aureus infec- tion, and demonstrated polyclonal elevation of serum immunoglobulin A (IgA) and IgG levels and various histologi- cal findings, such as mesangial extracapillary and endocapillary proliferation. To investigate the pathogenic roles of S. aureus antigens, we induced IgA-type glomerulonephritis in mice by immunization with antigens derived from S. aureus, as a model of human IgA nephropathy (IgAN). Methods: Balb/c mice (Th2 dominant type) and C57BL/6 mice (Th1 dominant type) were immunized biweekly for 4 months with antigens derived from S. aureus mixed with Freund's incomplete adjuvant. Results: Mesangial proliferative glomerulonephritis with IgA, IgG and complement 3 (C3) depositions were observed in all Balb/c mice. Although C3 depositions and cell proliferation in the mesangial area were also seen in C57BL/6 mice, they were not correlated with urinary findings. In Balb/c mice, S. aureus antigens were detected in glomeruli us- ing affinity-purified human anti-S. aureus antibodies, but there was no staining in C57BL/6 mice. The antibodies re- acted with several S. aureus antigens, based on Western blot analysis, and the main 30-35 kDa band differed in inten- sity in Balb/c and C57BL/6 mice. In addition, increased transforming growth factor-β (TGF-β) messenger RNA (mRNA) expression was seen in Balb/c mice compared to C57BL/6 mice. Conclusions: S. aureus antigens including, in particular, a 30-35 kDa protein and the host genetic background could play important roles in IgA-like glomerulonephritis pathogenesis.

Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy.

Abstract: BACKGROUND Polymorphisms in NAD[P]H:quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs) have been reported to be associated with an increased risk for environmentally and/or occupationally induced renal and bladder cancers. Genetic factors related to chronic nephropathy and to urinary bladder or renal cancer development in Balkan endemic nephropathy (BEN) is unknown. In order to evaluate their possible role in BEN susceptibility, we determined the frequencies of NQO1 alleles *1, *2 and *3, as well as the GSTT1 and GSTM1 null genotypes in BEN patients and healthy subjects from a non-endemic region of Bulgaria. METHODS The respective genotypes of 95 unrelated Bulgarian BEN patients and of 112 healthy individuals (control group) were determined by rapid cycle polymerase chain reaction (PCR) and detected with either SYBR green I fluorescent dye or melting curve analysis using allele specific probes. RESULTS NQO1 genotyping showed a higher NQO1*2 allele frequency (23.68%) in BEN patients compared to controls (18.75%; p=0.219), while NQO1*3 allele frequencies were similar in both groups (2.63% in BEN patients vs. 2.23% in controls; p=0.791). The GSTT1 deficiencywas observed in 20% of BEN patients vs. 16.1% of controls (p=0.613). The GSTM1 null genotype was found in 45.3% of BEN patients vs. 51.8% of controls (p=0.674). There was no influence of NQO1 and GSTs genotypes found on BEN risk. CONCLUSIONS Our results established that alleles NQO1*2 and NQO1*3, as well as lack of GSTT1 and GSTM1 did not influence the BEN risk. These findings provide novel information on the genetic heterogeneity in the healthy Bulgarian population.

Long-term outcome in hemodialysis: morbidity and mortality.

Abstract: Despite technical and pharmacological improvements achieved over the past years, long-term prognosis of patients undergoing chronic hemodialysis is still rather poor. Cardiovascular disease is the leading cause of both morbidity and mortality in these patients, mostly because of their severely compromised cardiovascular conditions already at the time of starting hemodialysis. A proper management of factors involved in the development of cardiovascular abnormalities is therefore a basic pre-requisite for improving their clinical outcome. Hypertension and anemia should be adequately evaluated and corrected, in light of their primary involvement in the pathogenesis of left ventricular hypertrophy, whereas treatment of calcium and phosphate metabolism disorders, particularly of high serum phosphorus levels, is needed to prevent the development of severe secondary hyperparathyroidism and mainly vascular calcifications, whose detrimental pathophysiologic consequences on cardiovascular structures are huge. At the same time, the prescription of the hemodialytic treatment should be optimised, with a satisfactory removal of uremic toxins through the delivery of an adequate dialysis dose and with the use of biocompatible membranes, where possible, thus minimizing the inflammatory response secondary to the interaction between blood and the artificial material of the hemodialysis system. The clinical superiority of high-flux membranes, although suggested by all studies performed so far, has still to be demonstrated by well-conducted clinical studies; on-line convective treatments and daily hemodialysis, although promising, also need to be confirmed in randomized trials. In conclusion, long-term outcome of hemodialysis patients may only be improved by a complex, multi-factorial therapeutical approach.

Perceived health-related quality of life and comorbidity in diabetic patients starting dialysis (CALVIDIA study).

Abstract: Background Diabetes mellitus (DM) is a widespread prevalent illness, currently the main cause of end-stage renal disease (ESRD). Material and methods In a longitudinal, prospective study we compared two cohorts of patients starting dialysis therapy, diabetic and non-diabetic ESRD patients. Perceived health was measured by the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire, functional status by the Karnofsky scale and comorbidity by the Charlson age-comorbidity index. A broad spectrum of variables in relation to diabetes, ESRD, comorbidity and renal replacement therapy (RRT) were studied, as well as the distribution of comorbidity frequencies at dialysis start. Results Thirty-four Spanish centers included 232 diabetic patients, 43 type 1 and 189 type 2, mean diabetes duration 18 +/- 9 yrs, and five centers included 121 non-diabetic patients. Out of the 232 diabetic patients, 187 patients (81%) started hemodialysis (HD) and 45 patients (19%) started peritoneal dialysis (PD) (vs. 82% and 18%, respectively in non-diabetic patients). Transient vascular access (VA) for starting RRT was required in 54% of the diabetic patients vs. 53% in the nondiabetic patients. When both study groups were compared, diabetic patients required antihypertensive drugs more frequently than non-diabetic patients and showed higher systolic blood pressure (BP), as well as higher cardiovascular (CV) complication incidences, poorer SF-36 physical component summary scores and mental component summary scores and worse Karnofsky scale scores, with the Charlson age-comorbidity score being higher. Conclusion Diabetic patients starting dialysis in Spain are more often type 2 diabetics, have worse perceived health-related quality of life (HRQoL) in relation to non-diabetic patients, worse functional status and higher incidences of prognostic mortality markers.

Sirolimus-based immunosuppression: present state of the art.

Abstract: Sirolimus, a macrocyclic lactone with a novel mechanism of action, augments acute rejection prophylaxis when administered in combination with cyclosporine (CsA) and steroids and seems to reduce the occurrence and progression of chronic vascular obliterative processes. Although clinical studies in psoriasis patients suggest that sirolimus is not nephrotoxic, the drug does show a range of toxic side effects, including altered lipid metabolism, myelosuppression, arthropathy, and impaired wound healing. Our experience with 1008 renal transplant patients who were administered sirolimus demonstrates that through careful therapeutic drug monitoring, it is possible to maximize the benefits and minimize the hazards of chronic immunosuppression with a sirolimus-based regimen. While sirolimus was initially introduced as an adjunctive agent to calcineurin inhibitors, it now serves as the base for therapies that spare the exposure to these nephrotoxic drugs. However, to optimize the use of sirolimus as base therapy, further work is necessary to determine appropriate target concentrations over time, the requirement for concomitant steroids and/or nucleoside synthesis blockers, and the best countermeasure strategies to overcome the drug's adverse effects.

The pleiotropic effects of mTor inhibitors.

Abstract: mTOR is a downstream effector of phosphatidylinositol-3-kinase pathway, which is involved in the regulation of protein synthesis and interacts with cell cycle progression. Sirolimus and everolimus may interfere with mTOR activity after their binding with FK binding protein. These drugs may prevent rejection of organ transplants by inhibiting the proliferation signals provided by interleukins 2 and 15, so causing lymphocyte cycle arrest in the G1 phase. Experimental studies have also shown that some oncoproteins may derive either from an overactivity of phosphatidylinositol-3-kinase or from a loss of the tumor suppressor PTEN. As mTOR is an important mediator of the kinase cascade and may also be antiangiogenic, it has become an attractive target in some malignancies. In organ transplant recipients some retrospective studies have shown that patients treated with mTOR inhibitors for immunosuppression had a reduced incidence of neoplasia in comparison with patients treated with calcineurin inhibitors. mTOR is also involved in the replication of cytomegalovirus in the host cells, as it favors transcription and translation signals necessary for virus replication. Recent studies reported a very low incidence of cytomegalovirus infection in organ transplant patients treated wih either sirolimus or everolimus. Finally, mTOR inhibitors may offer vascular protection, as they mediate vascular endothelial growth factor. In cardiac transplants treated with everolimus, cyclosporine, and steroids the average increase in maximal intimal thickness and the incidence of vasculopathy were significantly lower than in patients treated with azathioprine, cyclosporine, and steroids.

The quest for a model of type II diabetes with nephropathy: the Goto Kakizaki rat.

Abstract: The Goto Kakakizaki (GK) rat is a moderately diabetic rat strain that was developed by repeated inbreeding of glucose-intolerant Wistar rats over several generations. In contrast to many other rodent models of non-insulin-dependent diabetes, GK rats do not exhibit hyperlipidemia or obesity. Hyperglycemia in the GK rat is associated with the development of age-dependent renal structural changes that are similar to those described in patients with prolonged non-insulin-dependent diabetes mellitus who have not developed overt renal disease. Hyperglycemia in the GK rat is, however, not associated with overt proteinuria or progressive nephropathy. In the present review the metabolic characteristics as well as renal and nonrenal changes observed in GK rats are described. Moreover the effects on renal function and morphology of secondary injurious stimuli, such as mesangioproliferative glomerulonephritis and hypertension, superimposed on type II diabetes in GK rats are discussed.

Tacrolimus based immunosuppression.

Abstract: The safety and efficacy of tacrolimus (Prograf) in renal transplantation is well established. Achieving longterm patient and graft survival are the ultimate goals following transplantation. Many factors negatively impact long-term transplant outcomes, including graft rejection, renal dysfunction and cardiovascular risk factors (hypertension, hyperlipidaemia, and post-transplant diabetes mellitus (PTDM)). Accordingly, careful consideration of the immunosuppressive strategy and its impact on these factors is critical to optimising outcomes. Clinical trials and registry studies conducted over the past decade have demonstrated tacrolimus to be a cornerstone immunosuppressant in renal transplantation. Compared with cyclosporine treatment, tacrolimus has been shown to be associated with decreased acute and chronic rejection, improved renal function over the long-term post-transplant, and a lower incidence of hyperlipidaemia and hypertension. In early studies, the incidence of PTDM was significantly higher in patients receiving tacrolimus; however, recent large clinical trials have revealed no significant between-group differences in the incidence of PTDM with tacrolimus treatment and cyclosporine microemulsion treatment. Together, these findings may translate into improved long-term transplant outcomes with tacrolimus-based immunosuppression. Although approved only for kidney and liver transplantation in the US, Prograf was the calcineurin inhibitor used in the majority of patients transplanted in 2003: kidney (67%), liver (89%), kidney/pancreas (81%), pancreas (77%), lung (65%), heart/lung (48%), and heart (42%).

The effect of high-flux hemodialysis on renal anemia.

Abstract: BACKGROUND Anemia is an important predictor of mortality and morbidity in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Erythropoietin (EPO) is an expensive drug, which increases the cost of therapy. In addition, anemia persists in 20-30% of cases despite EPO treatment. In this study, which depended on the idea that the clearance of moderate and high molecular weight erythropoiesis inhibitors leads to an improvement in terms of anemia, we aimed to investigate the effect of high-flux dialysis on anemia and EPO requirement in patients undergoing HD. METHODS The study included 48 patients with ESRD on chronic HD treatment who could not reach the target hemoglobin (Hb) level, despite treatment with at least 200 IU/kg/week subcutaneous EPO. Patients were randomized into two groups and HD was performed with polysulphone low-flux dialyzer (Fresenius F6 HPS) or polysulphone high-flux dialyzer (Fresenius F60) for 6 months. RESULTS Although the EPO doses were significantly lower (p<0.001) in the high-flux dialysis group, Hb levels showed a significant increase (p<0.001). In the low-flux dialysis group, Hb levels showed no significant increase, despite the steady increase in EPO doses. In the high-flux group, the reduction of beta2-microglobulin (b2-MG) and phosphorus levels during dialysis was significantly higher when compared to the low-flux group (p<0.001). During the follow-up period, while b2-MG levels decreased significantly in the high-flux group (p<0.05), there was an increase in the low-flux group (p<0.05). Kt/V(urea) values showed no significant difference throughout the study. CONCLUSIONS Our results suggest that high-flux dialysis use is effective and this can be an alternative method in terms of controlling renal anemia and reducing the cost of therapy. These beneficial effects of high-flux dialysis are probably mediated by the improved clearance of moderate and high molecular weight toxins.

Crystals, Randall's plaques and renal stones: do bone and atherosclerosis teach us something?

Abstract: The pathogenesis of calcium-oxalate (CaOx) renal stones is still debated and a number of issues needs to be clarified. In particular, it is difficult to combine the intraluminal physical-chemical imbalance and fixed particle theory with the evidence that CaOx stones actually form and grow on Randall's plaque in the renal pelvis. On the basis of recent findings in renal stone research, and data from the biology of ectopic calcification, the hypothesis is advanced that abnormal pre-urine CaOx supersaturation triggers inflammation in the long Henle's loop cells at tip forceps level. This in turn induces differentiation of these cells toward the osteogenic lineage, determining the synthesis of typical bone osteoid proteins (osteopontin, osteocalcin, BMP-2, etc) and hydroxyapatite mineralization of the Henle's basement membrane (beneath the differentiating cells) which precedes Randal's plaque formation. This may constitute a further, still unexplored example of epithelial-mesenchymal-differentiation in the kidney.

Management of calcium refilling post-parathyroidectomy in end-stage renal disease.

Abstract: Background: Management of post-parathyroidectomy hypocalcemia in dialysis patients is not well defined. We reviewed published approaches to treatment in an effort to define a clinical algorithm for controlling serum calcium levels post-operatively. Methods: We conducted a PubMed search for the years 1980-2003 with the keywords “hypocalcemia” and “parathyroidectomy”. Only English language and human subject abstracts were analyzed, and only those ar ticles dealing with secondary or tertiary hyperparathyroidism (HPTH) were reviewed further. Other articles were extracted from cross-referencing. Results: We initially examined 146 articles. This review summarizes the findings of the relevant articles along with our own practice regarding post-parathyroidectomy hypocalcemia management in dialysis patients. The vast majority of patients require intravenous (i.v.) calcium supplements after surgery. There are no available controlled studies on calcium supplementation for post-parathyroidectomy hypocalcemia in this patient population. Calcitriol supplementation proved valuable in two studies. Conclusions: Post-parathyroidectomy hypocalcemia is a common complication, which can be prevented and treated with oral and i.v. calcium supplementation and/or active vitamin D metabolites. Daily follow-up of both serum calcium and phosphorus are mandatory to prevent this major post-operative complication. Based on the available evidence, we propose a protocol for the prevention and treatment of post-parathyroidectomy hypocalcemia, for use in clinical practice. This approach requires validation by a controlled clinical trial. Key words: Hypocalcemia, Hyperparathyroidism, Dialysis, Calcitriol Introduction

Triage: Napoleon to the present day.

Abstract: Triage, the sorting of patients according to the severity of their injuries and the need for urgent surgery was a concept developed by Dr. Larrey, a military surgeon in Napoleon's army. The evolution of the concept in military medicine from that time to the present is described. Triage in civilian practice first became a serious issue with the development of dialysis for chronic renal failure in the 1960s and the problem of the allocation of this scarce and very expensive treatment. With new developments in organ transplantation and technology it continues to be an issue today.

Rapidly progressive glomerulonephritis: current and evolving treatment strategies.

Abstract: Rapidly progressive glomerulonephritis (RPGN) must be diagnosed and treated quickly to prevent irreversible organ injury. The commonest cause of RPGN is anti-neutrophil cytoplasm antibody (ANCA) associated small vessel vasculitis, and the most severe is anti-glomerular basement membrane (GBM) antibody disease. In this review we address pathogenesis, diagnosis, treatment and outcome in these two entities, with emphasis on novel therapies.

Infective endocarditis in maintenance hemodialysis patients: fifteen years' experience in one medical center.

Abstract: BACKGROUND Infective endocarditis (IE) is a serious infectious condition, with high morbidity and mortality in hemodialysis (HD) patients. This study was undertaken to determine the IE risk factors in maintenance HD patients, and the mortality risk factors. METHODS We retrospectively reviewed all IE cases of maintenance HD patients at our center over the past 15 yrs (the study group). Regular HD patients without IE in the same period were used as the control group. The basic data of the two groups were analyzed to determine IE risk factors in HD patients. The in-hospital parameters of survival and mortality in the study group patients were used for mortality risk factors analysis. RESULTS There were 18 definite, and two possible, IE diagnoses in the study group and no cases in the 268 controls. There was no significant difference in age, sex, diabetes, hypertension, underlying malignancy, previous cerebral vascular accident (CVA) history, and calcium multiplied by phosphate product. There was a significant difference between the two groups (study group vs. controls) in pacemaker implant history (15 vs. 1.1%, p<0.01), previous heart surgery history (15 vs. 0.4%, p<0.01), congestive heart failure (CHF) (50 vs. 10.4%, p<0.05), duration on maintenance HD (12.9+/-19.1 vs. 57.9+/-42.3 months, p<0.001), serum albumin at the time of admission (2.91+/-0.40 vs. 3.96+/-0.52 g/dL, p<0.001). There were more patients dialyzed via non-cuffed dual-lumen catheters in the study group (55 vs. 0%, p<0.001), and fewer patients dialyzed via arteriovenous fistula (AVF) (25 vs. 87.7%, p<0.001). The mortality in HD patients with IE was high (60%), especially in patients with methicillin-resistant Staphylococcus aureus (MRSA) endocarditis (100%). The most common pathogen was S. aureus (n=12). MRSA was more common than methicillin-susceptible S. aureus (MSSA) (67 vs. 33%). Univariant analysis of in-hospital clinical parameters for mortality revealed no significant difference in age, diabetes, dual-lumen catheter implantation, serum albumin, time to diagnosis, and time to antibiotic use. Borderline statistical significance was noted in serum C-reactive protein (CRP) (p=0.051), and blood glucose level (p=0.056). There were more IE cases due to MRSA in the mortality group than in the survival group (8 vs. 0 cases, p=0.013), but fewer cases due to MSSA (0 vs. 4 cases, p=0.050). CONCLUSIONS IE should be considered in HD patients with the following risk factors, which include previous heart surgery or pacemaker implantation, shorter HD duration, and especially for patients dialyzed via dual-lumen catheters. The in-hospital clinical parameters including CRP and blood sugar level can offer information concerning prognosis. Since MRSA has increased in recent years and is associated with high mortality, strategies for prevention and treatment require development.