In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients.
The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference.
No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa.
The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.
Erythropoietin stimulating agents; Hemoglobin; Reticulocytes; Variability
Angiomyolipomas are benign tumors of the kidney. Typical angiomyolipomas are usually recognized by identifying fat components before any intervention. On the contrary, solid renal masses without evident fatty components but containing calcifications on the computed tomography scan are suspicious for malignancy. However, as in this rare case, rules of diagnostic imaging are of exceptions.
A 40-year-old man presented with left flank pain. The plain X-ray showed multiple coarse calcifications of 4.0 x 3.2 cm in diameter on the left upper quadrant abdomen. Computed tomography scan further revealed a solid renal mass and inside the mass there were calcifications. The size of the tumor was 5.6 × 5.5 × 6.3 cm. We performed a radical nephrectomy, and the histopathology showed a minimally fat-contained angiomyolipoma of multiple calcifications. The patient was free of recurrence or metastases after a follow-up period of 3 years.
An angiomyolipoma containing calcification is rare. An angiomyolipoma with minimal fat concomitant with calcifications is an even rarer presentation. It is very difficult to differentiate a minimal-fat angiomyolipoma with calcifications from a renal cell carcinoma preoperatively. In such a circumstance, a well-planned partial nephrectomy may be optimal for the patient, regardless of the tumor size.
Angiomyolipoma; Calcifications; Radical nephrectomy; Renal cell carcinoma
Thrombotic thrombocytopenic purpura (TTP) is frequently associated with renal abnormalities, but there have been few reports about renal abnormalities in patients with hereditary TTP. In particular, little is known about the long-term prognosis of patients with childhood-onset congenital TTP.
We report a Japanese patient with congenital TTP (Upshaw–Schulman syndrome) who was followed for 19 years after initiation of hemodialysis when he was 22 years old. At the age of 6 years, the first episode of purpura, thrombocytopenia, and proteinuria occurred without any precipitating cause. He underwent living-related donor kidney transplantation from his mother, but the graft failed after 5 months due to recurrence of TTP. Even after resection of the transplanted kidney and resumption of regular hemodialysis, TTP became refractory to infusion of fresh frozen plasma (FFP). Therefore, splenectomy was performed and his disease remained in remission for 10 years. However, TTP recurred at the age of 39 years. Plasma activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) was less than 3%, while ADAMTS13 inhibitor was not detected (< 0.5 Bethesda units/mL). The patient died suddenly after hemodialysis at the age of 41 years. Subsequent genetic analysis of this patient and his parents revealed two different heterozygous mutations of ADAMTS13, including a missense mutation in exon 26 (c.T3650C causing p.I1217T) inherited from his father and a missense mutation in exon 21 (c.G2723A causing p.C908Y) inherited from his mother. The former mutation has not been detected before in Japan, while the latter mutation is common in Japan. A retrospective review showed that serum C3 levels were consistently low while C4 levels were normal during follow-up, and C3 decreased much further during each episode of TTP.
Congenital TTP was diagnosed from the clinical, biochemical, and genetic findings. Infusion of FFP controlled each thrombotic episode, but the effect was limited and of short duration. Review of the complement profile in this patient suggested that a persistently low serum C3 level might be associated with refractory TTP and a worse renal prognosis.
Congenital thrombotic thrombocytopenic purpura; ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13); Chronic hemodialysis; Complement activation; C3; Alternative pathway
Achieving target levels of laboratory parameters of bone and mineral metabolism in chronic kidney disease (CKD) patients is important but also difficult in those living with end-stage kidney disease. This study aimed to determine if there are age-related differences in chronic kidney disease-mineral and bone disorder (CKD-MBD) characteristics, including treatment practice in Hungarian dialysis patients.
Data were collected retrospectively from a large cohort of dialysis patients in Hungary. Patients on hemodialysis and peritoneal dialysis were also included. The enrolled patients were allocated into two groups based on their age (<65 years and ≥65 years). Characteristics of the age groups and differences in disease-related (epidemiology, laboratory, and treatment practice) parameters between the groups were analyzed.
A total of 5008 patients were included in the analysis and the mean age was 63.4±14.2 years. A total of 47.2% of patients were women, 32.8% had diabetes, and 11.4% were on peritoneal dialysis. Diabetes (37.9% vs 27.3%), bone disease (42.9% vs 34.1%), and soft tissue calcification (56.3% vs 44.7%) were more prevalent in the older group than the younger group (p<0.001 for all). We found an inverse relationship between age and parathyroid hormone (PTH) levels (p<0.001). Serum PTH levels were lower in patients with diabetes compared with those without diabetes below 80 years (p<0.001). Diabetes and age were independently associated with serum PTH levels (interaction: diabetes × age groups, p=0.138). Older patients were more likely than younger patients to achieve laboratory target ranges for each parameter (Ca: 66.9% vs 62.1%, p<0.001; PO4: 52.6% vs 49.2%, p<0.05; and PTH: 50.6% vs 46.6%, p<0.01), and for combined parameters (19.8% vs 15.8%, p<0.001). Older patients were less likely to receive related medication than younger patients (66.9% vs 79.7%, p<0.001).
The achievement of laboratory target ranges for bone and mineral metabolism and clinical practice in CKD depends on the age of the patients. A greater proportion of older patients met target criteria and received less medication compared with younger patients.
Calcium (Ca); Chronic kidney disease-mineral and bone disorder (CKD-MBD); Chronic kidney disease (CKD); End-stage renal disease (ESRD); Parathyroid hormone (PTH); Phosphate (PO4)
Chronic kidney disease is associated with disruption of the endocrine system that distorts the balance between calcitriol, calcium, phosphate and parathyroid hormone in the calcium regulation system. This can lead to calcification of the arterial tree and increased risk of cardiovascular disease and death. In this study we develop a health metric, based on biomarkers involved in the calcium regulation system, for use in identifying patients at high risk for future high-cost complications.
This study is a retrospective observational study involving a secondary analysis of data from the kidney disease registry of a regional managed care organization. Chronic kidney disease patients in the registry from November 2007 through November 2011 with a complete set of observations of estimated glomerular filtration rate, calcitriol, albumin, free calcium, phosphate, and parathyroid hormone were included in the study (n = 284). Weibull regression model was used to identify the most significant lab tests in predicting “waiting time to hospitalization”. A multivariate linear path model was then constructed to investigate direct and indirect effects of the biomarkers on this outcome.
The results showed negative significant direct effects of phosphate and parathyroid hormone on “waiting time to hospitalization”. Base on this result, the risk of hospitalization increases 16.8% for each 0.55 mg/dl increase in phosphate level and 13.5% for each 0.467 increase in the natural logarithm of parathyroid hormone. Positive indirect effects of calcitriol surrogate (calcidiol), free calcium, albumin and estimated glomerular filtration rate were observed but were relatively small in magnitude.
Variables involved in the calcium regulation system should be included in future efforts to develop a quality of care index for Chronic Kidney disease patients.
Quality of care metric; Risk assessment; Prediction; Censored Weibull regression; Path modeling; Direct and indirect effects
In recent years, the imbalance in phosphate homeostasis in patients with end-stage renal disease (ESRD) has been the subject of much research. It appears that, while hyperphosphatemia may be a tangible indicator of deteriorating kidney function, lack of phosphate homeostasis may also be associated with the increased risk of cardiovascular events and mortality that has become a hallmark of ESRD. The need to maintain phosphorus concentrations within a recommended range is reflected in evidence-based guidelines. However, these do not reflect serum phosphorus concentrations achieved by most patients in clinical practice. Given this discrepancy, it is important to consider ways in which dietary restriction of phosphorus intake and, in particular, use of phosphate binders in patients with ESRD can be made more effective. Poor adherence is common in patients with ESRD and has been associated with inadequate control of serum phosphorus concentrations. Studies indicate that, among other factors, major reasons for poor adherence to phosphate binder therapy include high pill burden and patients’ lack of understanding of their condition and its treatment. This review examines available evidence, seeking to understand fully the reasons underlying poor adherence in patients with ESRD and consider possible strategies for improving adherence in clinical practice.
Adherence; Chronic kidney disease; Hyperphosphatemia; Phosphate binder; Pill burden
Increasing evidence suggests a mechanistic link between the glycemic environment and renal and cardiovascular events, even below the threshold for diabetes. We aimed to assess the association between HbA1c and chronic kidney disease (CKD) and cardiovascular disease (CVD).
A cross-sectional study involving a random representative sample of 2270 adults from southern Spain (Malaga) was undertaken. We measured HbA1c, serum creatinine and albuminuria in fasting blood and urine samples.
Individuals without diabetes in the upper HbA1c tertile had an unfavorable cardiovascular and renal profile and shared certain clinical characteristics with the patients with diabetes. Overall, a higher HbA1c concentration was strongly associated with CKD or CVD after adjustment for traditional risk factors. The patients with known diabetes had a 2-fold higher odds of CKD or CVD. However, when both parameters were introduced in the same model, the HbA1c concentration was only significantly associated with clinical endpoints (OR: 1.4, 95% CI, 1.1-1.6, P = 0.002). An increase in HbA1c of one percentage point was associated with a 30% to 40% increase in the rate of CKD or CVD. This relationship was apparent in persons with and without known diabetes. ROC curves illustrated that a HbA1c of 37 mmol/mol (5.5%) was the optimal value in terms of sensitivity and specificity for predicting endpoints in this population.
HbA1c levels were associated with a higher prevalence of CKD and CVD cross-sectionally, regardless of diabetes status. These data support the value of HbA1c as a marker of cardiovascular and renal disease in the general population.
Glycated hemoglobin; Chronic kidney disease; Cardiovascular disease
About 39,000 patients were newly prescribed renal replacement therapy in Japan in 2011, resulting in a total of more than 300,000 patients being treated with dialysis. This high prevalence of treated end stage kidney disease (ESKD) patients is an emergent problem that requires immediate attention. We launched a prospective cohort study to evaluate population specific characteristics of the progression of chronic kidney disease (CKD). In this report, we describe the baseline characteristics and risk factors for cardiovascular disease (CVD) prevalence among this cohort.
New patients from 16 nephrology centers who were older than 20 years of age and who visited or were referred for the treatment of CKD stage 2–5, but were not on dialysis therapy, were recruited in this study. At enrollment, medical history, lifestyle behaviors, functional status and current medications were recorded, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by a modified three-variable equation.
We enrolled 1138 patients, 69.6% of whom were male, with a mean age of 68 years. Compared with Western cohorts, patients in this study had a lower body mass index (BMI) and higher proteinuria. The prevalence of CVD was 26.8%, which was lower than that in Western cohorts but higher than that in the general Japanese population. Multivariate analysis demonstrated the following association with CVD prevalence: hypertension (adjusted odds ratio (aOR) 3.57; 95% confidence interval (CI) 1.82-7.02); diabetes (aOR 2.45; 95% CI 1.86-3.23); hemoglobin level less than 11 g/dl (aOR 1.61; 95% CI 1.21-2.15); receiving anti-hypertensive agents (aOR 3.54; 95% CI 2.27-5.53); and statin therapy (aOR 2.73; 95% CI 2.04-3.66). The combination of decreased eGFR and increased proteinuria was also associated with a higher prevalence of CVD.
The participants in this cohort had a lower BMI, higher proteinuria and lower prevalence of CVD compared with Western cohorts. Lower eGFR and high proteinuria were associated with CVD prevalence. Prospective follow up of these study patients will contribute to establishment of individual population-based treatment of CKD.
Chronic kidney disease; Cohort study; Epidemiology; Cardiovascular disease; Nephrologist
Proton pump inhibitors (PPI) are a widely-used class of drugs for the treatment of gastro-esophageal reflux disease and other acid-related disorders of the gastrointestinal tract. As a class, PPIs have demonstrated a favorable safety profile. However, case reports have suggested that this class of drugs may be linked to acute kidney injury, which may in turn lead to chronic injury or failure. The objective of this study was to determine if an association between PPIs and kidney failure exists and to estimate an effect size for the relationship between PPI use and renal disease.
A nested case–control study was conducted in a privately insured population in a single Midwestern state including a total of 184,480 patients aged 18 years or older who were continuously enrolled with the insurer for at least 24 months between September 2002 and November 2005.
Of the patients eligible for the study, 854 cases were identified as having at least two claims for an acute renal disease diagnosis. Cases were randomly matched with up to four controls (n = 3,289) based on age, gender, county of residence, and date of entry into the cohort. Patient demographic data, PPI use, illnesses, and medications associated with renal disease and a proxy for health status using pre-existing patient comorbidities were collected from inpatient, professional, and prescription claims data. Conditional logistic regression models were used to evaluate the association between renal disease and PPI use.
Renal disease was positively associated with PPI use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.27, 2.32, p < 0.001) even after controlling for potential confounding conditions. After removing patients with potential confounding disease states from the study population, the number of cases (195 of the 854) and controls (607) was lower, but the relationship between renal disease and PPI use remained consistent (OR 2.25, CI 1.09-4.62, p < 0.001).
Patients with a renal disease diagnosis were twice as likely to have used a previous prescription for a PPI. Therefore, it is necessary for physicians to increase recognition of patient complaints or clinical manifestations of this potentially harmful event in order to prevent further injury.
Proton pump inhibitors; Kidney failure; Renal disease; Nephritis
The aim of this study was to describe the findings of renal biopsies from a large nephrology center in Iasi, Romania, performed between 2005 and 2010. We compared these findings with our previous ones, from 1995 to 2004, as well as with similar reports.
We studied retrospectively 239 renal biopsies. The indications for renal biopsy were categorized into: nephrotic syndrome, acute nephritic syndrome, asymptomatic urinary abnormalities, acute kidney injury, and chronic kidney disease of unknown etiology.
During the past 16 years, a gradual increase in the annual number of renal biopsies/per million population (p.m.p.)/year was observed, although this incidence remained lower than in other European countries. Nephrotic syndrome was the indication for renal biopsy in over 50% of cases. Glomerulonephritis (GN) was the main histological diagnosis in 91% of cases, of which 56% were primary GN and 35% were secondary GN. The frequency of various types of primary GN was: membranoproliferative GN (MPGN) - 29.3%, membranous nephropathy (MN) -27.5%, focal segmental glomerulosclerosis (FSGS) - 17.2%, mesangial GN (including IgAN) -13.7%, crescentic GN - 9.4%, and minimal change disease (MCD) - 2.5%. Compared to the previously reported period (1994–2004), we observed a significant decrease in the frequency of MPGN and significant increases in the frequency of FSGS and, particularly MN - which more than doubled.
We report significant changes in the histological spectrum of GN in North-Eastern Romania in 2005–2010, compared to the previously reported 10-yrs. These changes seem to be following a trend that has also been observed in Western countries a few decades ago, and which may have a socioeconomic explanation.
Glomerular disease; Glomerulonephritis; Kidney disease; Tubulointerstitial disease
The current literature recognises that left ventricular hypertrophy makes a key contribution to the high rate of premature cardiovascular mortality in dialysis patients. Determining how we might intervene to ameliorate left ventricular hypertrophy in dialysis populations has become a research priority. Reducing sodium exposure through lower dialysate sodium may be a promising intervention in this regard. However there is clinical equipoise around this intervention because the benefit has not yet been demonstrated in a robust prospective clinical trial, and several observational studies have suggested sodium lowering interventions may be deleterious in some dialysis patients.
The Sodium Lowering in Dialysate (SoLID) study is funded by the Health Research Council of New Zealand. It is a multi-centre, prospective, randomised, single-blind (outcomes assessor), controlled parallel assignment 3-year clinical trial. The SoLID study is designed to study what impact low dialysate sodium has upon cardiovascular risk in dialysis patients. The study intends to enrol 118 home hemodialysis patients from 6 sites in New Zealand over 24 months and follow up each participant over 12 months. Key exclusion criteria are: patients who dialyse more frequently than 3.5 times per week, pre-dialysis serum sodium of <135 mM, and maintenance hemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials, which contraindicate the SoLID study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will be dialysed using dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure is left ventricular mass index, as measured by cardiac magnetic resonance imaging, after 12 months of intervention. Eleven or more secondary outcomes will be studied in an attempt to better understand the physiologic and clinical mechanisms by which lower dialysate sodium alters the primary end point.
The SoLID study is designed to clarify the effect of low dialysate sodium upon the cardiovascular outcomes of dialysis patients. The study results will provide much needed information about the efficacy of a cost effective, economically sustainable solution to a condition which is curtailing the lives of so many dialysis patients.
Australian and New Zealand Clinical Trials Registry number: ACTRN12611000975998
Home hemodialysis; Dialysis; Left ventricular mass; Sodium; Blood pressure; Fluid overload; Dialysate
Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs.
Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT.
Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT.
These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction.
Contrast-induced nephropathy (CIN) is the third leading cause of hospital-acquired acute kidney injury, and it is associated with poor long-term clinical outcomes. Although systolic heart failure is a well-known risk factor for CIN, no studies have yet evaluated the association between diastolic dysfunction and CIN.
We conducted a retrospective study of 735 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) and had an echocardiography performed within one month of the procedure at our institute, between January 2009 and December 2010. CIN was defined as an increase of ≥ 0.5 mg/dL or ≥ 25% in serum creatinine level during the 72 hours following PTCA.
CIN occurred in 64 patients (8.7%). Patients with CIN were older, had more comorbidities, and had an intra-aortic balloon pump (IABP) placed more frequently during PTCA than patients without CIN. They showed greater high-sensitivity C-reactive protein (hs-CRP) levels and lower estimated glomerular filtration rates (eGFR). Echocardiographic findings revealed lower ejection fraction and higher left atrial volume index and E/E’ in the CIN group compared with non-CIN group. When patients were classified into 3 groups according to the E/E’ values of 8 and 15, CIN occurred in 42 (21.6%) patients in the highest tertile compared with 20 (4.0%) in the middle and 2 (4.3%) in the lowest tertile (p < 0.001). In multivariate logistic regression analysis, E/E’ > 15 was identified as an independent risk factor for the development of CIN after adjustment for age, diabetes, dose of contrast media, IABP use, eGFR, hs-CRP, and echocardiographic parameters [odds ratio (OR) 2.579, 95% confidence interval (CI) 1.082-5.964, p = 0.035]. In addition, the area under the receiver operating characteristic curve of E/E’ was 0.751 (95% CI 0.684-0.819, p < 0.001), which was comparable to that of ejection fraction and left atrial volume index (0.739 and 0.656, respectively, p < 0.001).
This study demonstrated that, among echocardiographic variables, E/E' was an independent predictor of CIN. This in turn suggests that diastolic dysfunction may be a useful parameter in CIN risk stratification.
Contrast-induced nephropathy; Diastolic dysfunction; E/E’
Cardiovascular risk is increased in the early stages of chronic kidney disease (CKD) and also found to be ongoing in renal transplant (Rtx) patients. As a sign of atherosclerosis, increased carotid intima-media thickness (CIMT) has been widely accepted as a strong predictor of cardiovascular disease (CVD) and mortality in CKD patients. A novel markers, soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and neutrophil-to-lymphocyte ratio (NLR) were introduced as potential markers in inflammatory disorders including CKD. The role of Rtx in terms of atherogenesis is still unclear. We aimed to investigate the relationship between sTWEAK, NLR and CIMT in Rtx patients without overt CVD and to compare these results with those obtained from healthy subjects.
Cross-sectional analysis in which CIMT measurements, NLR and serum TWEAK levels were assessed in 70 Rtx patients (29 females; mean age, 40.6 ± 12.4 years) and 25 healthy subjects (13 females, mean age; 37.4±8.8 years).
sTWEAK levels were significantly decreased (p=0.01) and hs-CRP, NLR and CIMT levels of Rtx patients were significantly increased compared to healthy subjects (p<0.0001, p=0.001, p<0.0001, respectively). sTWEAK was also found to be decreased when eGFR was decreased (p=0.04 between all groups). CIMT was positively correlated with sTWEAK and NLR in Rtx patients (r=0.81, p<0.0001 and r=0.33, p=0.006, respectively). sTWEAK was also positively correlated with NLR (r=0.37, p=0.002). In the multivariate analysis only sTWEAK was found to be an independent variable of increased CIMT.
sTWEAK might have a role in the pathogenesis of ongoing atherosclerosis in Rtx patients.
sTWEAK; Neutrophil-to-lymphocyte ratio; Carotid intima-media thickness; Renal transplantation
Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein which is synthesized in a variety of cell types. AZGP1 has functionally been implicated in lipid metabolism, the regulation of cell cycling and cancer progression. Previous studies have shown increased circulating AZGP1 levels in patients with chronic kidney disease but AZGP1 has not been investigated in acute kidney injury (AKI). In this study, serum AZGP1 levels were measured in acute and chronic kidney disease to test for a correlation to renal function and other clinical parameters.
We performed ELISA based measurements of AZGP1 serum levels in 21 patients suffering from grade 3 AKI and in 20 chronic hemodialysis patients. In AKI patients, AZGP1 was first measured before initiation of acute renal replacement therapy and a second measurement was done during renal functional recovery. Sera of healthy blood donors served as controls. The association of AZGP1 with acute and chronic renal dysfunction was analysed, as well as the correlation with clinical parameters, body composition and biochemical variables.
Levels of circulating AZGP1 were significantly elevated in AKI patients. High initial levels of AZGP1 correlated with extra-renal complications but not with parameters of renal function. At follow-up, AZGP1 levels were still increased but now correlated significantly with creatinine, eGFR and urea. Circulating AZGP1 in chronic hemodialysis patients was higher than in AKI patients. An association to parameters of lipid metabolism was not found.
This study illustrates that circulating AZGP1 is not only elevated in chronic hemodialysis patients but also sharply increases during the early phase of AKI. The unexpected association with extra-renal complications during AKI needs further exploration as it might point to unknown biological effects of AZGP1.
Zinc-alpha2-glycoprotein; Hemodialysis; Acute kidney injury; Adipokine
Cortical perfusion of the renal transplant can be non-invasively assessed by color Doppler ultrasonography. We performed the Dynamic Tissue Perfusion Measurement (DTPM) of the transplant’s renal cortex using color Doppler ultrasonography (PixelFlux technique), and compared the results with the histopathological findings of transplant biopsies.
Ninety-six DTPM studies of the renal transplant’s cortex followed by transplant biopsies were performed in 78 patients. The cortical perfusion data were compared with the parameter of peritubular inflammatory cell accumulation (PTC 0 to 3) based on Banff-classification system.
A significant decrease of cortical perfusion could be demonstrated as the inflammatory cells accumulation in peritubular capillaries increased. Increasing peritubulitis caused a perfusion loss from central to distal layers of 79% in PTC 0, of 85% in PTC 1, of 94% in PTC 2, and of 94% in PTC 3. Furthermore, the perfusion loss due to peritubular inflammation was more prominent in the distal cortical layer. The extent of perfusion decline with increasing peritubulitis (from PTC 0 to PTC 3) was 64% in proximal 20% cortical layer (p20), 63% in proximal 50% cortical layer (p50), increased to 76% in distal 50% cortical layer (d50), and peaked at 90% in the distal 20% cortical layer (d20). For those without peritubulitis (PTC 0), the increase in the the Interstitial Fibrosis/Tubular Atrophy (IF/TA) score was accompanied by a significantly increased cortical perfusion. A Polyomavirus infection was associated with an increased cortical perfusion.
Our study demonstrated that the perfusion of the renal transplant is associated with certain pathological changes within the graft. DTPM showed a significant reduction of cortical perfusion in the transplant renal cortex related to peritubular capillary inflammation.
Placental growth factor [PlGF) is a cardiovascular (CV) risk marker, which is related to left ventricle hypertrophy (LVH) in animal models. Currently there are no data available regarding the possible relationship of PlGF and the development of LVH or diastolic dysfunction in patients with chronic kidney disease (CKD) and the relationship of PlGF to other CV risk factors in CKD patients. The aim of our study was to determine the possible association of PlGF and several other CV risk markers to echocardiographic parameters in CKD population.
We prospectively examined selected laboratory (PlGF, fibroblast growth factor-23 -FGF23, vitamin D, parathyroid hormone, extracellular newly identified RAGE-binding protein - EN-RAGE, B-type natriuretic peptide - BNP) and echocardiographic parameters in 62 patients with CKD 2–4. Mean follow-up was 36 ±10 months. Laboratory and echocardiographic data were collected 2–3 times, at the shortest interval of 12 months apart. Multivariate regression analysis was used to detect independent correlations of variables.
Increased left ventricular mass index (LVMI, g/m2.7) was found in 29% patients with CKD 2–4, left ventricular (LV) diastolic dysfunction was detected in 74.1% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 30.6% patients). After 36 ± 10 months increased LVMI was found in 37.1% patients with CKD 2–4, LV diastolic dysfunction was detected in 75.8% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 32.3% patients). Following independent correlations were found: LVMI was related to PlGF, cholesterol, BNP, systolic blood pressure and serum creatinine. EN-RAGE correlated positively with left atrial diameter and inversely with E/A ratio. During the follow-up we found a significant increase in LVMI and left atrial diameter, whereas a significant decrease in LVEF was noted.
According to our data, PlGF is independently related to increased LV mass in CKD, whereas EN-RAGE is more likely related to diastolic dysfunction in this population.
Cardiovascular disease; Chronic kidney disease; Echocardiography; Extracellular newly identified RAGE-binding protein (EN-RAGE); Left ventricular mass index; Left ventricular hypertrophy; Left ventricular diastolic function; Placental growth factor (PlGF)
It is important to ensure an adequate sodium and volume balance in neurosurgical patients in order to avoid the worsening of brain injury.
Indeed, hyponatremia and polyuria, that are frequent in this patient population, are potentially harmful, especially if not promptly recognized.
Differential diagnosis is often challenging, including disorders, which, in view of similar clinical pictures, present very different pathophysiological bases, such as syndrome of inappropriate antidiuresis, cerebral/renal salt wasting syndrome and diabetes insipidus.
Here we present the clinical report of a 67-year-old man with a recent episode of acute subarachnoid haemorrhage, admitted to our ward because of severe hyponatremia, hypokalemia and huge polyuria.
We performed a complete workup to identify the underlying causes of these alterations and found a complex picture of salt wasting syndrome associated to primary polydipsia. The appropriate diagnosis allowed us to correct the patient hydro-electrolyte balance.
The comprehension of the pathophysiological mechanisms is essential to adequately recognize and treat hydro-electrolyte disorders, also solving the most complex clinical problems.
Hyponatremia; Polyuria; Hypokalemia; Primary polydipsia; Salt wasting syndromes; Subarachnoid haemorrhage
Temsirolimus has important clinical activity in both untreated and previously treated patients with advanced renal cell carcinoma. Targeted therapy–related stomatitis and mucositis have occurred during targeted therapies, but there is no consensus on which strategy is the most effective. We herein report a case in which several sessions of endoscopic hemostasis with argon plasma coagulation (APC) effectively resolved life-threatening gastrointestinal bleeding that had occurred during targeted therapy. This is the first case report of such an adverse drug reaction in the literature.
A 47-year-old female patient with advanced renal cell carcinoma was treated with temsirolimus. Eight weeks after starting targeted therapy, the patient was admitted to our hospital for worsened fatigue, pallor, and hematemesis. A complete blood count showed a marked drop in her hemoglobin level from 10.1 g/dl 4 days earlier to 2.9 g/dl. Esophagogastroduodenoscopy revealed diffuse mucosal bleeding of the antrum. Endoscopy revealed diffuse reddish spots that resembled gastric antral vascular ectasia (GAVE) extending from the pylorus into the antrum. One month after endoscopic hemostasis with APC and stopping temsirolimus, significant improvement was shown in the gastric erythema and GAVE like lesions.
Minor hemorrhagic events are relatively common in patients treated with targeted agents. Life-threatening hemorrhagic events are rarer than minor hemorrhagic complications. In the present case, endoscopic hemostasis with APC effectively prevented severe anemia and blood loss due to gastrointestinal bleeding.
Gastrointestinal bleeding; Temsirolimus; Gastric antral vascular ectasia; Targeted therapy; Argon plasma coagulation
Kidney injury molecule-1 (KIM-1) is a biomarker useful for detecting early tubular damage and has been recently reported as a useful marker for evaluating kidney injury in IgA nephropathy (IgAN). We therefore investigated whether treatment decreases urinary KIM-1 excretion in IgAN.
We prospectively enrolled 37 patients with biopsy-proven IgAN. Urinary KIM-1 was assessed before and after treatment, which included low salt diet, blood pressure control, pharmacotherapy with angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors, and immunosuppressive agents as necessary. The median treatment duration was 24 months.
Urinary KIM-1/creatinine (Cr) was significantly decreased in patients with IgAN after treatment compared to baseline (P < 0.0001, 1.16 [0.51-1.83] vs 0.26 [0.12-0.65] ng/mg). There was a decrease in the amount of proteinuria after treatment, but it was not statistically significant (P = 0.052, 748.1 [405-1569.7] vs 569.2 [252.2-1114] g/d). Estimated glomerular filtration rate (eGFR) did not change with treatment (P = 0.599, 79.28 ± 30.56 vs 80.98 ± 32.37 ml/min/1.73 m2). Urinary KIM-1 was not correlated with proteinuria baseline or follow up (pre-: R = - 0.100, P = 0.577, post-: R = 0.001, P = 0.993). In patients with higher baseline urinary KIM-1, both urinary KIM-1 level and proteinuria were significantly decreased following treatment.
Treatment decreases urinary KIM-1/Cr in patients with IgAN. It also reduces proteinuria in patients with higher baseline urinary KIM-1. These results suggest a potential role for urinary KIM-1 as a biomarker for predicting treatment response in IgAN, however, further study is needed to verify this.
Biomarker; IgA nephropathy; KIM-1; Treatment in IgA nephropathy reduced the urinary KIM-1 excretion
Most kidney disorders involve some degree of inflammation, i.e. induction of pro-inflammatory mediators and leukocyte recruitment. But what are the factors that determine inflammation as a trigger or a consequence of kidney injury? Which types of renal inflammation can be targeted by the novel more selective immunosuppressive and anti-inflammatory agents? How to dissect the mechanisms behind innate and adaptive immune responses that are orchestrated inside or outside the kidney but both cause renal immunopathology i.e. renal inflammation? How to dissect leukocytic cell infiltrates into pro-inflammatory leukocytes from anti-inflammatory and pro-regenerative leukocytes? How to dissect leukocytes that support epithelial repair from those that promote renal fibrosis. The term ‘renal inflammation’ has moved far beyond the descriptive category of ‘mixed leukocytic cell infiltrates’ as commonly described in kidney biopsies. It is time to face the complexity of renal inflammation to finally benefit from the new age of novel immunomodulatory medicines.
Glomerulonephritis; Acute kidney injury; Chronic kidney injury; Chemokines; Macrophages; B cells; T cells
Individuals with end-stage renal disease (ESRD) have excess risk of various cancer types. However, the total burden of human papillomavirus-related cancers remains unknown.
We performed a nationwide observational cohort study during 1994–2010.
For each person with ESRD, we sampled 19 population controls (without ESRD) matched on age, gender and municipality. Participants were followed until first diagnosis of human papillomavirus-related cancer, death, emigration, or 31 December 2010, whichever came first.
Human papillomavirus-related cancers were extracted from Danish medical administrative databases. We considered cancers of the cervix, vulva, vagina, penis, anus, and subsets of head and neck cancers as human papillomavirus-related. We calculated incidence rates of human papillomavirus-related cancer and used Poisson regression to identify risk factors for human papillomavirus-related cancer.
Among 12,293 persons with ESRD and 229,524 population controls we identified 62 and 798 human papillomavirus-related cancers, respectively. Incidence rates of human papillomavirus-related- cancer were 102 per 100,000 person-years (95% confidence interval [CI]; 79.5-131) among persons with ESRD and 40.8 per 100,000 person-years (95% CI; 38.1-43.7) among population controls. ESRD patients had 4.54 (95% CI, 2.48-8.31) fold increased risk of anal cancer and 5.81 fold (95% CI; 3.36-10.1) increased risk of vulvovaginal cancer. Adjusted for age, comorbidity, and sex, ESRD patients had 2.41 (95% CI; 1.83-3.16) fold increased risk of any human papillomavirus-related cancer compared with population controls. Compared with dialysis patients renal transplant recipients had an age-adjusted non-significant 1.53 (95% CI, 0.91-2.58) fold higher risk of human papillomavirus-related cancer.
Persons with ESRD have excess risk of potentially vaccine-preventable human papillomavirus-related cancers.
Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication following coronary bypass graft (CABG) surgery. Multi-factorial causes of CSA-AKI involve oxidative stress and inflammation. Erythropoietin (EPO) has been shown from many studies to have a reno-protective effect. The present study was conducted to examine the role of EPO in preventing CSA-AKI.
This prospective, randomized, double-blind, placebo-controlled trial was conducted in the Cardiovascular and Thoracic Unit. One hundred patients randomly received either 200 U/kg of rHuEPO (n = 50) or saline (n = 50) intravenously three days before operation, and rHuEPO 100 U/kg or saline at operation time. The serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and urine neutrophil gelatinase-associated lipocaline (NGAL) were measured in order to evaluate renal injury following CABG.
The incidence of CSA-AKI was significantly lower in rHuEPO group (14%) when compared with the placebo group (38%; p < 0.01). The mean intensive care unit (ICU) and hospital stays of the rHuEPO group were significantly shorter than the placebo group (p < 0.01). Postoperative increases in SCr and decreases in eGFR were significantly lower in the rHuEPO group than the placebo group (p < 0.05). The mean urine NGAL in rHuEPO group was significantly lower than the placebo group at 3 hr, 6 hr, 12 hr and 18 hr after CABG (p < 0.05), respectively.
Prophylaxis administration with intravenous rHuEPO before cardiac surgery decreased the incidence of CSA-AKI and urine NGAL with reduced days in ICU and hospital in elective CABG patients.
Erythropoietin; Acute kidney injury; Neutrophil Gelatinase-Associated Lipocalin (NGAL); Cardiac surgery
Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with chronic kidney disease (CKD) be assigned according to stage and composite relative risk on the basis of glomerular filtration rate (GFR) and albuminuria criteria. The aim of this post-hoc analysis was to investigate the effects of add-on therapy with calcium channel blockers (CCBs) on changes in the composite ranking of relative risk according to KDIGO guidelines. Benidipine, an L- and T-type CCB, and amlodipine, an L-type CCB to angiotensin II receptor blocker (ARB), were examined.
Patients with blood pressure (BP) > 130/80 mmHg, an estimated GFR (eGFR) of 30–90 mL/min/1.73 m2, and albuminuria > 30 mg/gCr, despite treatment with the maximum recommended dose of ARB, were randomly assigned to two groups. Each group received one of two treatments: 2 mg benidipine daily, increased to 8 mg daily (n = 52), or 2.5 mg amlodipine daily, increased to 10 mg daily (n = 52).
After 6 months of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The eGFR was significantly decreased in the amlodipine group, but there was no significant change in the benidipine group. The decrease in albuminuria in the benidipine group was significantly lower than in the amlodipine group. The composite ranking of relative risk according to the new KDIGO guidelines was significantly improved in the benidipine group; however, no significant change was noted in the amlodipine group. Moreover, significantly fewer cases in the benidipine group than the amlodipine group showed a reduced risk category score.
The present post-hoc analysis showed that compared to amlodipine benidipine results in a greater reduction in albuminuria accompanied by an improved composite ranking of relative risk according to the KDIGO CKD severity classification.
Trial registration Number: UMIN000002644
Benidipine; Calcium channel blocker; Kidney Disease: Improving Global Outcomes (KDIGO); T-type calcium channel
The addition of relevant parameters to acute kidney injury (AKI) criteria might allow better prediction of patient mortality than AKI criteria alone. Here, we evaluated whether inclusion of AKI duration could address this issue.
AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 2,143 critically ill patients, within 15 days of patient admission. AKI cases were categorized according to tertiles of AKI duration: 1st tertile, 1–2 days; 2nd tertile, 3–5 days; and 3rd tertile, ≥6 days. The hazard ratios (HRs) for overall survival rates in three groups were calculated after adjustment for multiple covariates compared with ICU patients without AKI as the reference group. The predictive ability for mortality was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve.
AKI increased the HRs for overall mortality, and the mortality rate increased with AKI duration: the adjusted HRs were 1.99 (1st tertile), 2.67 (2nd tertile), and 2.85 (3rd tertile) compared with the non-AKI group (all Ps < 0.001). The AUC of the ROC curve for overall mortality based on the AKI duration groups (0.716) was higher than the AUC of AKI staging using the KDIGO guidelines (0.696) (P = 0.001). When considering KDIGO stage and AKI duration together, the AUC (0.717) was also significantly higher than that using the KDIGO stage alone (P < 0.001).
AKI duration is an additional parameter for the prediction of mortality in critically ill patients. The inclusion of AKI duration could be considered as a refinement of the AKI criteria.
Acute kidney injury; Acute renal failure; Duration; Mortality; Survival