Normal Serum Creatinine Concentrations Research Articles

The relationship of preoperative estimated glomerular filtration rate and outcomes after cardiovascular surgery in patients with normal serum creatinine: a retrospective cohort study

BackgroundAlthough serum creatinine concentration has been traditionally used as an index of renal function in clinical practice, it is considered relatively inaccurate, especially in patients with mild renal dysfunction. This study investigated the usefulness of preoperative estimated glomerular filtration rate (eGFR) in predicting complications after cardiovascular surgery in patients with normal serum creatinine concentrations.MethodsThis study included 2208 adults undergoing elective cardiovascular surgery. Preoperative eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equations. The relationships between preoperative eGFR and 90 day postoperative composite major complications were analyzed, including 90 day all-cause mortality, major adverse cardiac and cerebrovascular events, severe acute kidney injury, respiratory and gastrointestinal complications, wound infection, sepsis, and multi-organ failure.ResultsOf the 2208 included patients, 185 (8.4%) had preoperative eGFR < 60 mL/min/1.73 m2 and 328 (14.9%) experienced postoperative major complications. Multivariable logistic regression analyses showed that preoperatively decreased eGFR was independently associated with an increased risk of composite 90 day major postoperative complications (adjusted odds ratio: 1.232; 95% confidence interval [CI]: 1.148–1.322; P < 0.001). eGFR was a better discriminator of composite 90 day major postoperative complications than serum creatinine, with estimated c-statistics of 0.724 (95% CI: 0.694–0.754) for eGFR and 0.712 (95% CI: 0.680–0.744) for serum creatinine (P = 0.008).ConclusionsDecreased eGFR was significantly associated with an increased risk of major complications after cardiovascular surgery in patients with preoperatively normal serum creatinine concentrations.

When kidneys and lungs suffer together.

A significant interaction between kidneys and lungs has been shown in physiological and pathological conditions. The two organs can both be targets of the same systemic disease (eg., some vasculitides). Moreover, loss of normal function of either of them can induce direct and indirect dysregulation of the other one. Subjects suffering from COPD may have systemic inflammation, hypoxemia, endothelial dysfunction, increased sympathetic activation and increased aortic stiffness. As well as the exposure to nicotine, all the foresaid factors can induce a microvascular damage, albuminuria, and a worsening of renal function. Renal failure in COPD can be unrecognized since elderly and frail patients may have normal serum creatinine concentration. Lungs and kidneys participate in maintaining the acid-base balance. Compensatory role of the lungs rapidly expresses through an increase or reduction of ventilation. Renal compensation usually requires a few days as it is achieved through changes in bicarbonate reabsorption. Chronic kidney disease and end-stage renal diseases increase the risk of pneumonia. Vaccination against Streptococcus pneumonia and seasonal influenza is recommended for these patients. Vaccines against the last very virulent H1N1 influenza A strain are also available and effective. Acute lung injury and acute kidney injury are frequent complications in critical illnesses, associated with high morbidity and mortality. The concomitant failure of kidneys and lungs implies a multidisciplinary approach, both in terms of diagnostic processes and therapeutic management.

Upper Normal Serum Creatinine Concentrations as a Predictor for Chronic Kidney Disease: Analysis of 14 Years' Korean Genome and Epidemiology Study (KoGES).

Both serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) have been used to assess kidney function in public health check-ups. However, when the sCr is within the normal levels but the eGFR is <60 mL/min/1.73 m2, a dilemma arises, as the patients might progress to chronic kidney disease (CKD) after several years. We aimed to evaluate the association between normal sCr and the risk of incident CKD in the general population. For this, 9445 subjects from the Korean Genome and Epidemiology Study, with normal sCr and eGFR of >60 mL/min/1.73 m2 were analyzed. The subjects were classified into quartiles based on sCr levels. The primary outcome was the development of eGFR <60 mL/min/1.73 m2 on two consecutive measures. During a mean follow-up of 8.4 ± 4.3 years, 779 (8.2%) subjects developed eGFR <60 mL/min/1.73 m2. The incidence of the development of eGFR <60 mL/min/1.73 m2 was higher in the higher quartiles than in the lowest quartile. In multivariable Cox analysis, the highest quartile was associated with an increased risk for the development of eGFR <60 mL/min/1.73 m2 (hazard ratio (HR), 4.71; 95% confidence interval (CI), 3.29–6.74 in females; HR, 12.77; 95% CI, 7.69–21.23 in males). In the receiver operating characteristic curve analysis, adding sCr to the traditional risk factors for CKD improved the accuracy of predicting the development of eGFR <60 mL/min/1.73 m2 (area under the curve, 0.83 vs. 0.80 in females and 0.85 vs. 0.78 in males), and the cutoff value of sCr was 0.75 mg/dL and 0.78 mg/dL in females and males. Cautious interpretation is necessary when sCr is within the normal range, considering that the upper normal range of sCr has a higher risk of CKD development.

The role of microalbuminuria as a predictor of subclinical cardiovascular events in rheumatoid arthritis patients and its relation to disease activity.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects many body tissues and leads to major morbidity and mortality. Renal disease in RA is clinically important because it restricts the management of primary disease and increases mortality. The objectives of this study are to (1) investigate the difference between RA patients with and without microalbuminuria (MAU) and (2) find out the relation between MAU and disease activity as well as subclinical cardiovascular effects. Ninety RA patients were divided into two groups according to the presence of MAU, in addition to 30 healthy volunteers. ESR, hs-CRP, RF, lipid profile, urinary microalbumin, GFR, renal function tests, carotid intima media thickness (cIMT), flow-mediated dilatation of the brachial artery (FMD), ECG, and echocardiographic examination were performed for patients and controls. MAU positive RA patients revealed significantly higher lipid profile, ESR, hs-CRP, DAS 28, cIMT, and lower FMD as well as ECG and echocardiographic abnormalities compared to MAU negative RA patients. Moreover, there was significant positive correlation between MAU and DAS28, hs-CRP, LDL, cIMT as well as negative correlation with FMD%. In our study, all RA patients with MAU had a normal serum creatinine concentration and gave a negative result with Albustix. MAU is significantly correlated with ESR, hs-CRP, lipid profile, cIMT, and FMD% in RA patients; therefore, it can be used as an index to measure disease activity as well as subclinical cardiovascular affection in RA patients.

Augmented Renal Clearance in Patients With Febrile Neutropenia is Associated With Increased Risk for Subtherapeutic Concentrations of Vancomycin.

Augmented renal clearance (ARC) has frequently been observed in critically ill patients. The risk factors for ARC in patients, including those in the general ward, and their influences on vancomycin (VCM) treatment remain unclear. The aims of this study were to investigate the risk factors for ARC and to evaluate the influence of ARC on the pharmacokinetic parameters of VCM. This study included a total of 292 patients with VCM treatment who had normal serum creatinine concentrations. ARC was defined by an estimated creatinine clearance ≥130 mL·min·1.73 m. The risk factors for ARC were determined with stepwise logistic regression analysis. The pharmacokinetic parameters of VCM were estimated through the Bayesian method using a 2-compartment model. ARC was observed in 48 patients (16.4%). Age ≤65 years [odds ratio (OR): 5.77; 95% CI: 2.89-11.97; P < 0.0001], brain injury (OR: 5.11; 95% CI: 1.49-17.57; P = 0.0086), febrile neutropenia (OR: 2.76; 95% CI: 1.11-6.67; P = 0.0254), and a mean volume of infusion fluid ≥1500 mL/d (OR: 2.53; 95% CI: 1.27-5.16; P = 0.0091) were independent risk factors for the occurrence of ARC. The patients with ARC exhibited higher VCM clearance values than the non-ARC patients. The median trough serum concentrations of VCM were 7.4 (interquartile range: 5.2-11.6) mcg/mL in the ARC patients and 12.2 (8.9-16.3) mcg/mL in the non-ARC patients (P < 0.0001). Subtherapeutic trough concentrations of VCM (<10.0 mcg/mL) were found in 68.8% of the ARC patients and in 32.8% of the non-ARC patients (P < 0.0001). This observational study investigated the influence of febrile neutropenia on the emergency of ARC for the first time. ARC was strongly associated with VCM pharmacokinetics, and two-thirds of the ARC patients had subtherapeutic VCM concentrations. In patients with ARC, individualized dosing regimens are required to achieve the target trough concentration.

Predicting decline of kidney function in lupus nephritis using urine biomarkers.

To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

Levels of albuminuria and risk of developing macroalbuminuria in type 2 diabetes: historical cohort study.

Although increased urinary albumin excretion may increase the risk of adverse renal outcomes in patients with diabetes, it remains unclear whether microalbuminuria is associated with a higher incidence of macroalbuminuria in the absence of non-diabetic kidney events that frequently develop during the long-term course of type 2 diabetes. This historical cohort study included patients with type 2 diabetes, spot urine albumin:creatinine ratio (ACR) <300 mg/gCr and normal serum creatinine concentrations treated between August 1988 and April 2015. Patients with any evidence suggesting non-diabetic kidney diseases at baseline were excluded. Over a median follow-up of 50 months, 70 of the 1760 included patients developed macroalbuminuria. Twenty-one of these patients were diagnosed with non-diabetic renal events. The five-year cumulative incidence of macroalbuminuria in patients with ACRs of 0–7.5 mg/gCr, 7.5–30 mg/gCr, 30–150 mg/gCr, and 150–300 mg/gCr were 0%, 0.53%, 3.5%, and 36.0%, respectively, with significant differences between each pair of ACR categories. In type 2 diabetes, higher urinary ACR, even within a level of normoalbuminuria, was associated with a greater incidence of macroalbuminuria when non-diabetic renal events were excluded. These results conflict with findings suggesting that microalbuminuria is a poor indicator for the progression of diabetic nephropathy.

Impact of a young parabiotic circulation on renal injury and fibrosis in aged mice

BackgroundAgeing increases susceptibility to acute kidney injury and fibrotic chronic kidney disease, with mechanisms remaining incompletely understood. Results of parabiotic studies show that a young circulation can reverse ageing phenotypes in the brain and heart. We tested the hypothesis that young circulating factors would protect aged mice from experimental acute kidney injury and chronic kidney disease. MethodsParabiotic pairs were established between young (8 weeks old) and old (14 months old) C57BL6/CD45.1 mice to generate young–young, old–old, old–young, and young–old pairings for 28 days. Acute kidney injury was induced via bilateral renal ischaemia reperfusion injury, and fibrosis via unilateral ureteric obstruction for 5–14 days. Creatinine was measured at baseline and after injury. Transcriptome data were assessed at baseline. Fibrosis and macrophage infiltration were measured to assess renal injury in young and old animals in matched and mismatched parabiotic pairs. Data are given as mean [SD]. FindingsDespite normal serum creatinine concentrations, old animals in both old–old and old–young pairings had higher levels of baseline fibrosis than did young–old and young–young pairs (% collagen in young 2·6 [0·3] vs old 8·4 [0·7], p<0·0001). Transcriptomic analysis demonstrated that more than 1000 ageing-associated genes were altered in the baseline kidneys of old animals in old–old pairs compared with young–young pairs (p<0·001). Over 20% of these reverted to a young phenotype in old–young pairings (p<0·001). After acute kidney injury, old–young animals had lower day one serum creatinine than old–old animals (21·1 μmol/L [5·9] vs 61·6 [21·6], p=0·032). In the unilateral ureteric obstruction model, old animals in old–young pairs had reduced scarring, macrophage infiltration, and inflammatory gene transcription compared with old–old pairs (all p<0·05). InterpretationOur data show that the aged kidney has a distinct transcriptomic appearance and worsened injury outcomes. A shared young circulation modifies acute kidney injury and chronic kidney disease, indicating the presence of a factor that modifies renal ageing. FundingWellcome Trust.

Evaluation of renal and hepatic functions in cattle with subclinical and clinical ketosis

The purpose of this study was to research the changes in renal and hepatic functions of high productive dairy cows diagnosed with subclinical and clinical ketosis. The material of the study consisted of 30 dairy cows of high milk production. Diagnosis of ketosis was made according to anamnesis, physical examination, urine ketone bodies, and serum β-hydroxybutyric acid levels. The animals were divided according to their serum β-hydroxybutyric acid levels into control, subclinical, and clinical ketosis groups, each of which included 10 cows. Serum glucose, urea, creatinine, total protein, aspartate amino transaminase (AST), and total bilirubin levels were determined with an automatic biochemistry analyzer using commercial test kits OptiumXceed; a handheld meter was used for the detection of serum β-hydroxybutyric acid levels. The serum β-hydroxybutyric acid levels were 450 ± 0.05, 1310 ± 0.03, and 3920 ± 0.37 mmol/L in the control, subclinical, and clinical ketosis groups respectively, and there were significant differences among the 3 groups (P < 0.001). The intergroup significant differences of some biochemical parameters (glucose, total protein, urea, creatinine, AST, and total bilirubin) were determined. New studies must be conducted to determine the glomerulus filtration rate in animals (particularly those with subclinical ketosis) with normal serum creatinine concentrations and suspected kidney disease.

Fabry Disease Diagnosed Based on the Detection of Urinary Mulberry Bodies.

A 42-year-old Japanese man visited our nephrology department after proteinuria without hematuria was detected in a medical checkup. A physical examination showed no abnormalities. His renal function was normal (serum creatinine concentration: 0.65 mg/dL). The urinary analysis at the first visit revealed fat bodies with a whorl-like appearance; so-called mulberry bodies (Picture 1). These bodies showed a characteristic Maltese Cross configuration under polarized light microscopy (Picture 2), which was highly suggestive of Fabry disease (1). Indeed, the alpha-galactosidase (GLA) activity in the patient's white blood cells was as low as 0.1 nmol/h/mg and his serum globotriaosylceramide level was elevated to 69 nmol/L. A genetic analysis revealed a thymine insertion in exon 5 of the GLA-gene, which confirmed the diagnosis of the classic Fabry disease phenotype (2). In a further examination, left ventricular hypertrophy and whorl-like corneal opacity were observed.

Implications of Augmented Renal Clearance on Drug Dosing in Critically Ill Patients: A Focus on Antibiotics.

Augmented renal clearance (ARC) has been reported in approximately 30-65% of patients in the intensive care unit (ICU) despite the presence of a normal serum creatinine concentration. In certain ICU patient populations (e.g., patients with sepsis or trauma), the incidence increases to roughly 50-85%. Risk factors for ARC include the following: age younger than 50-55 years, male sex, higher diastolic blood pressure, fewer comorbidities, and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) or modified Sequential Organ Failure Assessment (SOFA) score at ICU admission. In addition, patient populations with the highest reported incidence of ARC include those with major trauma, sepsis, traumatic brain injury, subarachnoid hemorrhage, and central nervous system infection. Due to the high incidence of ARC in patients with a normal serum creatinine concentration, clinicians should consider screening ICU patients deemed high risk by using the ARC scoring system or the identification and assessment algorithm provided in this review. In addition, an 8-hour continuous urine collection should be considered to assess a measured creatinine clearance for evaluating the necessity of medication dosage adjustments. There is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes; thus, the risk of underdosing antibiotics in a patient with ARC could increase the risk of treatment failure. This review examines strategies to overcome ARC and summarizes current pharmacokinetic and pharmacodynamic literature in patients with ARC in an effort to provide dosing guidance for this patient population.

Evaluation of some factors affecting the risk of kidney damage in patients with hypertension

Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality worldwide. Prospective data on risk factors for CKD are few. Hypertension is one of the risk factors for CKD. In the past serum creatinine concentration was used as marker of kidney function but it proffers a late reflection of reduced glomerular filtration rate(GFR), which limits its ability to detect impaired kidney function. Cystatin C and NGAL have recently been proven useful to quantitate CKD. Therefore in this study, we assessed the effect of some risk factors on reduction of estimated glomerular filtration rate (eGFR) in patients with high blood pressure. This study was performed on 42 hypertensive patients and 30 healthy volunteers, both with normal serum creatinine and urea concentration. In this study, we measured serum cystatin C and Plasma NGAL. Serum creatinine and urea levels of the patients were measured after an overnight fasting. . Estimated glomerular filtration rate (eGFR) was considered as the gold standard method .Serum cystatin C and plasma NGAL were measured using commercially available human ELISA kits. Logistic regression and T-test were used for statistical analysis. The results of logistic regression showed that among the variables studied, plasma levels of NGAL, age and duration of hypertension were significantly associated with the eGFR<78(P<0.05). Our findings suggest that, increased levels of NGAL, age and duration of hypertension predicts a higher odds of impaired renal function

Intravenous colistin in a patient with serious burns and borderline syndrome: The benefits of therapeutic drug monitoring

Colistin is a decades-old drug that fell out of favour due to its nephrotoxicity. Today, colistin is experiencing a renaissance as a treatment against multiresistant Gram-negative bacteria such as Pseudomonas and Acinetobacter in critically ill patients. The optimal dosing of colistin for most infections is unknown. Here we present the intravenous dosing, optimised by therapeutic drug monitoring (TDM), of a borderline patient with severe burns and a consecutive transfemoral amputation. A 32-year-old woman with severe burns (35% total body surface area) and sepsis exhibited normal serum creatinine (SCr) concentrations at the beginning of her intensive care unit (ICU) stay, but over the course of her ICU stay her SCr increased to 100μmol/L. With the colistin standard dose of 3×3 million units (MU) colistin/day after a loading dose of 9 MU, she failed to achieve effective plasma concentrations. The estimated glomerular filtration rate (eGFR) via CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) revealed GFRs between 180mL/min and 63mL/min after correcting for body surface. The patient required a high daily dosage of colistin (3×6 MU) that exceeded the approved maximum dose. Most clinicians rely heavily on SCr concentrations as the primary biochemical marker of GFR. At most, the CKD-EPI formula is helpful in determining creatinine clearance. The pharmacokinetics of colistin are currently poorly understood. TDM of colistin methanesulfonate and colistin may represent an invaluable approach to optimise colistin drug exposure in ICU patients with fluctuating renal clearance.

Glomerular Filtration Rate in Evaluation of the Effect of Iodinated Contrast Media on Renal Function

The purpose of this study was to use measured glomerular filtration rate (GFR), the reference standard of renal function, to assess the deleterious effect of iodinated contrast media on renal function. Such an effect has been traditionally defined as a greater than 0.5-mg/dL increase in serum creatinine concentration or a 25% or greater increase 24-72 hours after the injection of iodinated contrast medium. This pilot investigation was focused on the consequences of clinically indicated IV injection of iodinated contrast media; intraarterial injection was excluded. One hundred thirteen patients with normal serum creatinine concentrations were enrolled in an approved protocol. At random, as chosen by one of the investigators, patients underwent imaging with one of three monomeric agents (iopamidol 300, iopromide 300, iohexol 300) and one dimeric agent (iodixanol 320). Measured GFR was determined immediately before CT and approximately 3 and 72 hours after the contrast injection for the CT examination. Iodinated contrast medium, a glomerular filtrate with no tubular excretion or reabsorption, was the GFR marker. Measured GFR was determined by x-ray fluorescence analysis with nonisotopic iodinated contrast media. Monomeric and dimeric contrast agents in diagnostic CT volumes (based on bodyweight and imaging protocol) did not induce a significant change in measured GFR (95% confidence by Wilcoxon test), suggesting that use of the evaluated contrast media will not lead to more than a 12% variation. The three monomeric agents studied and the one dimeric agent were equivalent in terms of lack of a significant effect on measured GFR when administered to patients with a normal GFR.

Relationship Between Normal Serum Creatinine Concentration and Periodontal Disease in Japanese Middle‐Aged Males

Periodontitis has been shown to be closely related to diabetes, which was recently found to be associated with lower serum creatinine. Conversely, several studies have suggested a positive relationship between periodontitis and abnormally high concentrations of serum creatinine associated with renal dysfunction, seemingly contradicting the above. This study evaluates periodontal status and serum levels of creatinine within the normal range to resolve this apparent contradiction. A comprehensive health examination of 907 Japanese males, 49 to 59 years old, was performed from 2000 to 2002. A blood sample was collected from the antecubital vein after an overnight fast. The periodontal parameters were periodontal probing depth (PD) and clinical attachment loss (AL). We examined the association between serum creatinine concentration within the normal range and periodontal parameters. Serum creatinine concentration within the normal range was inversely correlated with mean PD and mean AL. In multivariate linear regression analyses, every 0.1-mg/dL increment in serum creatinine concentration was associated with a 0.064-mm decrease in both mean PD and mean AL (P <0.05) after adjusting for confounding variables. This study finds a significant inverse association between normal serum creatinine concentration and periodontal disease.

Serum Cystatin C Is a Major Predictor of Vancomycin Clearance in a Population Pharmacokinetic Analysis of Patients with Normal Serum Creatinine Concentrations

We developed a population pharmacokinetic model of vancomycin by integrating the effects of cystatin C and other demographic factors in a large population of Korean patients with normal serum creatinine concentrations to elucidate the precise role of serum cystatin C concentrations in the prediction of vancomycin clearance. A population pharmacokinetic model of vancomycin was developed using NONMEM software from a total of 1,373 vancomycin concentration measurements in 678 patients whose serum creatinine concentrations were lower than 1.2 mg/dL. Covariate selection revealed that cystatin C was the most influential factor and had negative influence (-0.78) in the relationship. Total body weight, sex, age, and serum creatinine were also significantly correlated with the clearance. The estimated intersubject variabilities of clearance and volume of distribution were 24.7% and 25.1%, respectively. A 14-fold difference in predicted trough concentrations was observed according to only cystatin C concentrations in a population of simulated individuals with median demographic characteristics. The use of serum cystatin C as marker of vancomycin clearance for more accurate predictions of serum vancomycin concentrations could be useful, particularly among patients with normal serum creatinine concentrations.

Immunomodulatory Properties of Mesenchymal Stem Cells Combined with Mycophenolate Mofetil Induce T Cell Regulation and Prolong Renal Allografts Survival in Cynomolgus Monkeys

The induction of tolerance to allografts is one of the major goals in transplantation. Mesenchymal stem cells (MSCs) have been shown to be potent immunomodulatory and immunosuppressive properties in vitro and in vivo. However, to the clinical perspective of MSC-based cell therapy, it has not been clearly defined whether immunosuppressants currently utilized in the clinic may affect immunomodulatory capacities of MSCs. The aim of this study was to investigate the effect of combination therapies of MSCs and mycophenolate mofetil (MMF) on delaying acute rejection of renal allografts in Cynomolgus monkey model. MSCs were isolated from born marrow of Cynomolgus monkey. They were expanded and characterized by morphology, phenotypes and immunosuppressive functions. They were positive for CD90, CD73, CD29, CD105, and negative for CD45, CD34 and MHC-II. Monkeys received adoptive multiple infusions of autogeneic MSCs with a short-term and low-dose of MMF achieved long-term renal graft survival (>90 days post-transplantation) with normal serum creatinine (sCr) concentration and ultrasound imaging of transplanted kidney grafts. Confocal fluorescence microscopy analyses revealed that the transplanted PKH-26 labeled MSCs were found in renal allograft, spleen and lymph nodes of the recipients after the transplantation. The monkeys received MSCs showed high frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs). An increased population of interleukin (IL) 10-secreting type 1 T regulatory (Tr1) cells and T helper (Th) 2-dominant cytokine shift were detected in survival recipients. Immunosuppressive effect of MSCs was not only showed in CD4+ and CD8+ cells, but also in their subsets of CD4+CD28+CD95- and CD8+CD28+CD95-naïve T cells. A depression in the percentages of CD4+CD28-CD95+ and CD8+CD28-CD95+ effecter memory T cells was observed in MSC treated recipients at the early stage of the treatment. In conclusion, this study shows synergistic effects of MSCs with short-term and low-dose MMF regimen in promoting renal allograft survival in Cynomolgus monkeys, also provides information to motivate the development of MSC therapy strategies in clinical transplantation.

Decreased meropenem levels in Intensive Care Unit patients with augmented renal clearance: benefit of therapeutic drug monitoring

One of the first-line drugs for empirical antibiotic therapy in patients with hospital-acquired infections is meropenem. An often neglected problem in sepsis is that patients with a normal serum creatinine concentration (SCr) might display augmented renal clearance (ARC). Here we describe two cases of sepsis with subtherapeutic exposures with standard meropenem dosing in whom therapy could be optimised by therapeutic drug monitoring (TDM). A 37-year-old man with acute lymphatic leukaemia and sepsis had a normal SCr at the beginning of his Intensive Care Unit (ICU) stay but showed decreased SCr of between 30μmol/L and 40μmol/L during his stay. He failed to achieve effective plasma concentrations with the meropenem standard dose of 3g/day. Estimated glomerular filtration rate revealed values between 120mL/min and 160mL/min. He required a high meropenem daily dosage of 12g that was far above the approved maximum dose. A 66-year-old patient undergoing surgery of a pulmonary aspergilloma presented SCr persistently <50μmol/L, indicating ARC between 120mL/min and 150mL/min. This patient required 8g of meropenem to achieve effective plasma concentrations. TDM may represent an invaluable approach to optimising drug exposure of β-lactam antibiotics in patients with ARC in the ICU. Further trials are clearly needed to become better informed about empirical dosing regimens usable in the ICU setting with regard to the relevance of ARC. In the meantime, daily measurement of creatinine clearance as well as TDM can be used to identify patients who manifest ARC, thereby allowing drug therapy to achieve the therapeutic range.

Nephrotic syndrome presenting in a patient with primary Sjögren’s syndrome: questions

Case summary A 17 year-old African American woman with a history of Sjogren’s syndrome presented with several days of periorbital and pedal edema. She also had fatigue, headache, abdominal pain, and diffuse arthralgias. She had no gross hematuria or oliguria. There were no recent sore throats or upper respiratory tract infections. She had no weight loss, night sweats, joint swelling, oral ulcerations, or rash. She had taken several doses of ibuprofen for arthralgias but was not taking any other medications. She was diagnosed with primary Sjogren’s syndrome at 11 years of age after presenting with bilateral parotitis. The diagnosis of Sjogren’s syndrome was based on the parotitis and a history of xerostomia and xerophthalmia. Schirmer’s test was abnormal (prolonged wetting time of filter paper placed in the lower eyelid), indicating abnormal tear production. Sialometry showed inadequate saliva production. Serologic markers at the time of diagnosis of Sjogren’s syndrome included normal serum C3 and C4, elevated antinuclear antibodies (ANA) of 1:2560, elevated anti-Ro/SSA antibody, negative anti-double-stranded DNA antibody, and elevated rheumatoid factor. She had a normal serum creatinine concentration of 0.7 mg/dl and a normal urinalysis with no blood or protein. She was treated with prednisone for 1 year and remained symptom free aside from intermittent mild xerostomia and xerophthalmia. Her father has systemic lupus erythematosus (SLE) and lupus nephritis.

Renal Microvascular Disease Predicts Renal Function in Diabetes

Renal microvascular disease reflected directly by peritubular capillary flow reduction and indirectly by renal function impairment has been documented in early diabetic nephropathy (DN) associated with normoalbuminuria and normal serum creatinine concentration. The renal microvascular disease observed in early DN [chronic kidney disease (CKD) stages 1–2] could progress under current practice to late DN (CKD stages 3–5) with a further reduction in peritubular capillary flow. This advanced renal microvascular disease in late DN is characterized by therapeutic resistance to vasodilators and altered vascular homeostasis associated with impaired nitric oxide production. The renal microvascular disease is progressive as the disease severity progresses and eventually induces chronic renal ischemia and a progressive tubulointerstitial fibrosis. Further study has revealed that early DN is associated with an adequately functional vascular homeostasis. Therefore, recognition and treatment of early renal microvascular disease at early DN (stages 1–2) could enhance renal perfusion and restore renal function.