Estimated Glomerular Filtration Rate in Chronic Kidney Disease: A Critical Review of Estimate-Based Predictions of Individual Outcomes in Kidney Disease.

Chronic kidney disease (CKD) is generally regarded as a final common pathway of several renal diseases, often leading to end-stage kidney disease (ESKD) and a need for renal replacement therapy. Estimated GFR (eGFR) has been used to predict this outcome recognizing its robust association with renal disease progression and the eventual need for dialysis in large, mainly cross-sectional epidemiological studies. However, GFR is implicitly limited as follows: (1) GFR reflects only one of the many physiological functions of the kidney; (2) it is dependent on several non-renal factors; (3) it has intrinsic variability that is a function of dietary intake, fluid and cardiovascular status, and blood pressure especially with impaired autoregulation or medication use; (4) it has been shown to change with age with a unique non-linear pattern; and (5) eGFR may not correlate with GFR in certain conditions and disease states. Yet, many clinicians, especially our non-nephrologist colleagues, tend to regard eGFR obtained from a simple laboratory test as both a valid reflection of renal function and a reliable diagnostic tool in establishing the diagnosis of CKD. What is the validity of these beliefs? This review will critically reassess the limitations of such single-focused attention, with a particular focus on inter-individual variability. What does science actually tell us about the usefulness of eGFR in diagnosing CKD?

Ameliorative effects of pre-eclampsia by quercetin supplement to aspirin in a rat model induced by L-NAME.

As an inflammatory disease, pre-eclampsia is correlated with elevation of pro-inflammatory cytokines and maternal endothelial dysfunction. Aspirin plays an important role in the prevention and therapy of pre-eclampsia. Quercetin is a bioflavonoid which has anti-oxidant and reno-protective abilities. We aimed to figure out the effects of quercetin supplement to aspirin on the therapy against pre-eclampsia. Female pregnant Sprague-Dawley rats were divided into five groups according to the drug treatment. Aspirin [1.5 mg/kg body weight (BW)] or quercetin (2 mg/kg BW) treatment was administered from gestational day (GD) 4 to GD19. Rat model of pre-eclampsia was induced by NG-nitro-Larginine-methyl-ester (L-NAME). In pre-eclampsia rats induced by L-NAME, systolic blood pressures (SBP), proteinuria, malonyldialdehyde (MDA), and inflammatory cytokines levels were decreased by the treatment of quercetin supplement to aspirin. In the uterus, quercetin supplement to aspirin prevented the expression of VEGF and sFlt-1 mRNA. The treatment of quercetin supplement to aspirin rescued the declined survival rate and weight of pups caused by L-NAME-induced pre-eclampsia. Based on our study, compared with the treatment of aspirin alone, quercetin supplement to aspirin enhanced the therapeutic effects of aspirin on pre-eclampsia rats induced by L-NAME.

Rapid decline of renal function in patients with type 2 diabetes with heavy proteinuria: a report of three cases.

BACKGROUND: Although there is a large volume of literature regarding the definition and epidemiology of. Type 2 diabetes nephropathy (T2DN). There has been a paucity of data focused on the rate of transition of T2 DN. Based on our personal observation a certain percentage of our incident end stage renal disease (ESRD) patients from T2DN experienced a rapid decline of renal function. Their rapid decline nature of glomerular filtration rate (GFR) of 46 to 60 mL/min per 1.73m2 per year have far exceeded the KDIGO definitions of acute kidney injury (abrupt decrease in kidney function occurring over 7 days or less), acute kidney disease (acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an acute kidney injury initiating event (Chawla et al Nat Rev Nephrol 241-57 2017) or even rapid decliner (eGFR declines > 5 mL/min per 1.73m2 per year) (Chawla et al Nat Rev Nephrol 241-57 2017; Andrassy Kidney Int 622-623 2013). CASE PRESENTATION: We describe here three cases of type 2 diabetic patients that have rapid renal deterioration with rate of decline 46 - 60 mL/min per 1.73m2 per year. All the patients are heavily nephrotic. All of the renal biopsies done showed the classical diabetic changes, hypertensive changes, diffuse tubulointerstitial damage, and interstitial nephritis. All of the patients admitted to taking various form of traditional medications in hope of curing their renal disease. CONCLUSION: We wish to highlight that type 2 diabetics with massive nephrotic range proteinuria have enhanced risk of rapid renal function deterioration. The patients should be educated about the risks of rapid renal function deterioration when there is presence of heavy proteinuria. High grade proteinuria is likely to inflict the diffuse tubulointerstitial inflammation. The interstitial nephritis could be further worsened by traditional supplements consumption. Timely health education and advice must be undertaken to retard this unwanted rapid renal disease progression.

Effect of diet protein restriction on progression of chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Dietary protein restriction has long been thought to play an important role in the progression of chronic kidney disease (CKD); however, the effect of dietary protein on the rate of decline in kidney function remains controversial. OBJECTIVE: We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the influence of protein restriction on chronic kidney disease. METHOD: Ovid MEDLINE (from 1946 to March 5, 2016), EMBASE (from 1966 to March 5, 2016), and the Cochrane Library (Inception to March 5, 2016) were searched to identify RCTs comparing different levels of protein intake for at least 24 weeks in adult patients with CKD. The outcomes included kidney failure events, the rate of change in estimated glomerular filtration rate (eGFR) per year, all cause death events, and changes in proteinuria, serum phosphorus concentration, serum albumin, and body mass index (BMI). RESULTS: Nineteen trials with 2492 subjects were analyzed. A low protein diet reduced the risk of kidney failure (odds ratio (OR) = 0.59, 95% CI: 0.41 to 0.85) and end-stage renal disease (ESRD) (OR = 0.64, 95% CI: 0.43 to 0.96), but did not produce a clear beneficial effect for all cause death events (OR = 1.17, 95% CI: 0.67 to 2.06). The change in the mean difference (MD) for the rate of decline in the eGFR was significant (MD: -1.85, P = 0.001), and for proteinuria (MD: -0.44, P = 0.02). A low protein diet also reduced the serum phosphorus concentration (MD: -0.37, 95% CI: -0.5 to -0.24) and BMI (MD: -0.61, 95% CI: -1.05 to -0.17). However the change in albumin presented no significant difference between two groups (MD: 0.23, 95% CI: -0.51 to 0.97). CONCLUSIONS: Based on the findings of our meta-analysis, protein-restricted diet may reduce the rate of decline in renal function and the risk of kidney failure for CKD populations, but did not produce a clear beneficial effect for all cause death events. Besides However, the optimal level of protein intake in different participants is left unanswered, and the nutritional status should be regarded with caution.

Vitamin D Deficiency in Chronic Kidney Disease: Recent Evidence and Controversies.

Vitamin D (VD) is a pro-hormone essential for life in higher animals. It is present in few types of foods and is produced endogenously in the skin by a photochemical reaction. The final step of VD activation occurs in the kidneys involving a second hydroxylation reaction to generate the biologically active metabolite 1,25(OH)2-VD. Extrarenal 1α-hydroxylation has also been described to have an important role in autocrine and paracrine signaling. Vitamin D deficiency (VDD) has been in the spotlight as a major public healthcare issue with an estimated prevalence of more than a billion people worldwide. Among individuals with chronic kidney disease (CKD), VDD prevalence has been reported to be as high as 80%. Classically, VD plays a pivotal role in calcium and phosphorus homeostasis. Nevertheless, there is a growing body of evidence supporting the importance of VD in many vital non-skeletal biological processes such as endothelial function, renin-angiotensin-aldosterone system modulation, redox balance and innate and adaptive immunity. In individuals with CKD, VDD has been associated with albuminuria, faster progression of kidney disease and increased all-cause mortality. Recent guidelines support VD supplementation in CKD based on extrapolation from cohorts conducted in the general population. In this review, we discuss new insights on the multifactorial pathophysiology of VDD in CKD as well as how it may negatively modulate different organs and systems. We also critically review the latest evidence and controversies of VD monitoring and supplementation in CKD patients.

Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015.

Bone fracture, cardiovascular events, and mortality are three outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD), and the umbrella concept originally described for dialysis patients. The reported association of serum phosphorus or fibroblast growth factor 23 (FGF23) levels with renal outcome suggests that the fourth relevant outcome of CKD-MBD in predialysis patients is renal outcome. We found that proteinuria of 2+ or greater with a dipstick test was associated with low vitamin D status due to urinary loss of 25-hydroxyvitamin D (25D). Moreover, active vitamin D or its analogues decrease proteinuria. Given our finding that maxacalcitol does not repress renin, the reduction of proteinuria by this agent is likely due to direct upregulation of the nephrin and podocin in podocytes. Moreover, this agent downregulates the mesenchymal marker desmin in podocytes and blocks transforming growth factor-beta autoinduction, leading to attenuation of renal fibrosis in a unilateral ureteral obstructive (UUO) model. These facts are reminiscent of the suppression of epithelial-mesenchymal transition (EMT) by vitamin D. EMT blockage may explain our finding that vitamin D prescription in renal transplant recipients is associated with a lower incidence of cancer. We also reported that low vitamin D status and high FGF23 levels predict a worse renal outcome. However, administration of massive doses of 25D exacerbates renal fibrosis in UUO kidneys in 1alpha-hydroxylase knockout mice. Moreover, FGF23 inhibits 1alpha-hydroxylase in proximal tubules and monocytes. Taken together, local 1,25(OH)2D in the kidney tissue but not 25D seems to protect the kidney.

Serum 1,25-dihydroxyvitamin D Better Reflects Renal Parameters Than 25-hydoxyvitamin D in Patients with Glomerular Diseases.

Background: Impaired vitamin D metabolism may contribute to the development and progression of chronic kidney disease. The purpose of this study was to determine associations of circulating vitamin D with the degree of proteinuria and estimated glomerular filtration rate (eGFR) in patients with biopsy-proven glomerular diseases. Methods: Clinical and biochemical data including blood samples for 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were collected from patients at the time of kidney biopsy. Results: Serum 25(OH)D levels were not different according to eGFR. However, renal function was significantly decreased with lower serum 1,25(OH)2D levels (P < 0.001). The proportions of nephrotic-range proteinuria and renal dysfunction (eGFR ≤ 60 mL/min/1.73 m2) progressively increased with declining 1,25(OH)2D but not 25(OH)D. Multivariable linear regression analysis showed that 25(OH)D was significantly correlated with serum albumin and total cholesterol (ß = 0.224, P = 0.006; ß = -0.263, P = 0.001) and 1,25(OH)2D was significantly correlated with eGFR, serum albumin and phosphorus (ß = 0.202, P = 0.005; ß = 0.304, P < 0.001; ß = -0.161, P = 0.024). In adjusted multivariable linear regression, eGFR and 24hr proteinuria were independently correlated only with 1,25(OH)2D (ß = 0.154, P = 0.018; ß = -0.171, P = 0.012), but not 25(OH)D. The lower level of 1,25(OH)2D was associated with the frequent use of immunosuppressive agents (P < 0.001). Conclusion: It is noteworthy in these results that circulating 1,25(OH)2D may be superior to 25(OH)D as a marker of severity of glomerular diseases.

Vitamin D Supplementation Prevents Placental Ischemia Induced Endothelial Dysfunction by Downregulating Placental Soluble FMS-Like Tyrosine Kinase-1.

Maternal vitamin D deficiency in pregnancy has been associated with an increased risk of preeclampsia. Vascular endothelial dysfunction is a major phenotype of pregnancies with preeclampsia, contributing to increased maternal hypertension and proteinuria. We sought to determine whether vitamin D supplementation would alleviate preeclampsia associated endothelial dysfunction and explore the underlying mechanism using the reduced uterine perfusion pressure (RUPP) rat model. RUPP operated rats were supplemented with 1,25(OH)2D (RUPP+VD) on day 1, 7, and 14 of pregnancy by subcutaneous injection. On day 19 of pregnancy, after the measurement of blood pressure and urine collection, maternal blood serum and placenta samples were collected. 1,25(OH)2D treatment significantly improved endothelial dysfunction by reducing apoptosis and increasing nitric oxide (NO) production in blood vessels of RUPP operated rats compared to untreated RUPP rats. 1,25(OH)2D significantly down-regulated the expression of placental soluble FMS-like tyrosine kinase-1 (sFlt-1) in RUPP rats. Furthermore, the circulating sFlt-1 levels in maternal serum were positively correlated with the expression of placental sFlt-1 and were restored to a normal pregnant level by 1,25(OH)2D treatment in RUPP rats. Incubation of endothelial cell line with rat serum from RUPP+VD group significantly increased NO production and decreased caspase-3 activity compared with serum from untreated RUPP rats. Moreover, neutralization of sFlt-1 using the specific antibody mimicked the effect of 1,25(OH)2D, which abolished the deleterious effect of RUPP rat's serum on NO production and apoptosis. These results suggest that vitamin D supplementation is protective against RUPP induced endothelial dysfunction by downregulating placental sFlt-1, which can possibly alleviate preeclampsia associated symptoms.

Proteinuria Detected by Urine Dipstick Test as a Risk Factor for Atrial Fibrillation: A Nationwide Population-Based Study.

Proteinuria is one of the well-known risk factors for cardiovascular disease. However the impact of proteinuria on the incidence of atrial fibrillation (AF) is unclear. In this study, we investigated the association between proteinuria detected using urine dipstick test and the risk of AF. A total of 18,201,275 individuals were analyzed, who had no prior AF and had received biennial health checkups provided by the National Health Insurance Service between 2005 and 2008 in Korea. Incidences of AF were ascertained through the end of 2015. During a mean follow-up of 9.6 years, a total of 324,764 (1.8%) developed AF (1.86 per 1,000 person-years). In Cox regression models, proteinuria was associated with an increased risk of AF: adjusted HR and 95% CI of AF occurrence were 1.13 (1.10-1.16), 1.34 (1.31-1.38), 1.53 (1.48-1.58), 1.82 (1.71-1.94), and 1.86 (1.61-2.16) in individuals with trace, 1+, 2+, 3+, and 4+ proteinuria, respectively, compared with those without proteinuria. The result was consistent even after additional adjustment for estimated glomerular filtration rate. In addition, the risk of AF further increased or decreased according to the follow-up dipstick test results. Thus, proteinuria measured with a dipstick test might be considered a potent risk factor for AF development.

Importancia relativa de los factores determinantes de los niveles séricos de 25-hidroxi-colecalciferol en la enfermedad renal crónica / Relative importance of the determinants of serum levels of 25-hydroxy vitamin D in patients with chronic kidney disease

Introducción: El origen de la carencia de vitamina D en la enfermedad renal crónica (ERC) parece multifactorial, pero es incierta la importancia relativa de cada uno de sus potenciales determinantes. Objetivos: Determinar los factores asociados a los niveles de 25-hidroxi-colecalciferol (25OHD) y su importancia relativa en una cohorte de pacientes con ERC prediálisis. Material y métodos: Se incluyeron pacientes incidentes en una consulta de ERC, excluyendo a aquellos que recibían suplementos de vitamina D o anticonvulsivantes. Además de los datos demográficos y clínicos, se analizó la influencia de la actividad física, estación del año de la extracción, y tratamiento con estatinas, antiangiotensina e inhibidores de la xantino-oxidasa. Para la estimación de la importancia relativa se utilizó el método de ponderación relativa de Johnson, expresando los resultados como porcentajes de contribución al R múltiple. Resultados: Se estudiaron 397 pacientes, de los cuales 30 fueron excluidos. La concentración media de 25OHD fue de 13,7±7,4ng/ml, presentando unos niveles inferiores a 20ng/ml el 81% de los pacientes. Por regresión lineal múltiple y ponderación relativa, los principales determinantes de unos niveles más bajos de 25OHD fueron por orden de importancia: una mayor proteinuria (28,5%), mayor edad (21,4%), disminución de la actividad física (19,4%), sexo femenino (19,3%), y menor bicarbonato sérico (11,4%). Conclusión: La magnitud de la proteinuria y la edad son los factores con mayor importancia relativa como determinantes de los niveles de 25OHD en la ERC (AU)

Introduction: The cause of vitamin D deficiency in chronic kidney disease (CKD) is probably multi-factorial; however, the relative importance of each potential determinant is uncertain. Aims: To determine factors associated with serum levels of 25-hydroxy vitamin D (25OHD) and their relative importance in a cohort of pre-dialysis CKD patients. Material and methods: Incident patients admitted to a CKD outpatient clinic were included. Those who were receiving vitamin D supplements or anticonvulsants were excluded. In addition to demographic and clinical data, information about outdoor physical activity, season of blood collection, prescription of statins, anti-angiotensin drugs and xanthine-oxidase inhibitors were included as potential determinants. Johnson's relative weights analysis was used to estimate the relative importance of each potential determinant and the results were expressed as percentage contribution to multiple R. Results: The study group consisted of 397 patients, 30 of whom were excluded. The mean serum level of 25OHD was 13.7±7.4ng/ml, and 81% of patients had serum levels lower than 20ng/ml. By multiple linear regression and relative weights analyses, the best determinants of low serum 25OHD levels and their relative importance were: higher proteinuria (28.5%), old age (21.4%), low physical activity (19.4%), female gender (19.3%) and low serum bicarbonate levels (11.4%). Conclusions: Proteinuria and age are the determinants with the highest relative importance for predicting 25OHD levels in CKD patients (AU)

[Effect of Astragali and Angelica particle on proteinuria in Chinese patients with primary glomerulonephritis].

OBJECTIVE: To investigate the effect of the traditional Chinese herbs Astragali and Angelicae Sinensis (A & As) particle [contains Huangqi (Radix Astragali Mongolica), Danggui (Radix Angelicae Sinensis), Huzhanggeng (Rhizoma Polygoni Cuspidati) and Danshen (Radix Salviae Miltiorrhizae)] on proteinuria in glomerulonephritis patients with stage 2 chronic kidney disease. METHODS: A prospective, multi-center, and randomized controlled clinical trial was performed for 24 weeks. From March 2011 to April 2012, 158 patients from nine hospitals in China participated. They were randomized into the A & As group (79 cases, A & As particle 15.2 g/day) and losartan group (79 cases, losartan 50 mg/day). At each follow-up visit, clinical data including blood pressure, urinalysis, 24-h-urinary protein excretion, serum albumin and serum creatinine were collected. RESULTS: All 158 patients completed the follow-up. Proteinuria in the losartan group exhibited a biphasic time-dependent decline with a significant steady reduction from baseline to week 12 (P = 0.0014), and a platform level during the remaining 12-week follow-up (P > 0.05). In contrast, there was a continual significant decrease of proteinuria in the A & As group (P < 0.001). When compared with the losartan results, proteinuria in the A & As group from week 16 to week 24 was significantly reduced (P < 0.001). Stable eGFRs and blood pressure were also observed in both groups. Medication side effects were minimal and non-fatal. CONCLUSION: For Chinese glomerulonephritis patients with stage 2 chronic kidney disease, therapy with A & As particles may provide effective anti-proteinuria treatment.

Treatment of IgA nephropathy.

The therapy of IgA nephropathy (IgAN) is cause for debate among nephrologists. Since the early 1980s, many therapeutic attempts have been proposed, but most of them did not prove efficacy. The recent KDIGO Clinical Practice Guideline for Glomerulonephritis recommend long-term ACE-I or ARB treatment when proteinuria is more than 1 g/day, with up-titration of the drug. For patients with GFR >50 ml/min and proteinuria persistently higher than 1 g/day, they suggest a 6-month course of corticosteroid therapy. Based on our experience and the results of the literature, we propose a progressive treatment, which takes into account the time the IgAN is recognized and the clinical conditions present at that time. The treatment can be summarize as follows: (1) in patients with macro-microscopic haematuria, in case with proteinuria less than 0.3 g/day, only annual controls; (2) in patients with proteinuria between 0.3 and 0.9 g/day, ACE-I and/or ARB, with titration of the drugs; (3) in patients with proteinuria higher than 1 g/day, in case with the presence of arterial hypertension and GFR up to 30 ml/min, 6 months course of corticosteroids, in addition to ACE-I and/or ARB; (4) in patients with GFR less than 30 ml/min, ACE-I/ARB, dialysis and kidney transplantation; corticosteroids should be in case considered for patients with persistently high or increasing proteinuria; (5) the immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive renal insufficiency or with vasculitic lesions on renal biopsy.

Impact of BMI on cardiovascular events, renal function, and coronary artery calcification.

BACKGROUND/AIMS: High BMI increases the risk of cardiovascular events (CVEs) in the general population. Conflicting results have been reported on the role of BMI on CVEs and on decline of renal function in patients with chronic kidney disease not on dialysis (CKD). This study evaluates the impact of BMI on CVEs, dialysis initiation, and coronary artery calcification (CAC) in CKD patients. METHODS: CKD patients were divided in normal-BMI and high-BMI patients. CVEs, initiation of dialysis, and extent and progression of CAC were assessed. Univariate and multivariable analysis were performed (adjustment variables: age, diabetes, hypertension, gender, CKD stage, serum concentration of hemoglobin, parathyroid hormone, calcium, phosphorus, albumin, C-reactive protein, LDL-cholesterol, total calcium score, 24-hour proteinuria). Patients were followed to the first event (CVE, dialysis) or for 2 years. RESULTS: 471 patients were evaluated. A CVE occurred in 13.5 and 21.3% (p < 0.05) of normal-BMI and high-BMI patients, respectively. High BMI did not increase the risk for CVEs in univariate (HR: 1.86; 95% CI: 0.97-3.54; p = 0.06) or multivariable analysis (HR: 1.36; 95% CI: 0.57-3.14; p = 0.50). High BMI did not increase the risk for initiation of dialysis in univariate (HR: 0.96; 95% CI: 0.58-1.60; p = 0.9) or multivariable analysis (HR: 1.77; 95% CI: 0.82-3.81; p = 0.14). Adding the interaction term (between BMI and glomerular filtration rate) to other variables, the risk of dialysis initiation significantly increased (HR: 3.06; 95% CI: 1.31-7.18; p = 0.01) in high-BMI patients. High BMI was not a predictor of CAC extent or progression. CONCLUSIONS: High BMI was not a predictor of CVEs. High BMI increased the risk for dialysis initiation, but high BMI was not associated to CAC extent and progression. The presence of confounders may underestimate the impact of high BMI on dialysis initiation.

Effects of Tulbaghia violacea Harv. (Alliaceae) rhizome methanolic extract on kidney function and morphology in Dahl salt-sensitive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tulbaghia violacea has been used traditionally for the treatment of several ailments, including hypertension. The herb has been shown to have antihypertensive properties which have been attributed to its angiotensin-converting enzymeinhibitory (ACEI) activity. It could, therefore, prove beneficial in ameliorating renal pathology associated with hypertension. To evaluate the effects of long-term administration of Tulbaghia violacea on renal function and morphology in the Dahl salt-sensitive (DSS) rat model. MATERIALS AND METHODS: Male DSS rats were treated intra-peritoneally (i.p.) as follows: methanolic extract of Tulbaghia violacea: (TVL) (50 mg/kg/b.w.), captopril: (CAP) (25 mg/kg/b.w.), or distilled water, control: (CON) (3 ml/kg/b.w.). Blood pressure (BP) was measured bi-weekly, whilst 24-h urine volumes and electrolyte concentrations were assessed weekly. Animals were sacrificed on day 49 by halothane overdose. Blood was removed for determination of plasma and serum electrolytes. Left kidney tissues were harvested for the determination of nuclear factor-kappaß (NF-kß) and transforming growth factor-ß (TGF-ß) gene expressions. RESULTS: TVL significantly reduced mean arterial pressure (MAP) and diastolic blood pressure (DBP). TVL showed reduced blood urea nitrogen, serum creatinine, total protein in urine as well as increased serum total protein. TVL decreased thiobarbituric acid reactive substances (TBARS) and increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity and nitric oxide significantly. NF-kß and TGF-ß) gene expressions were significantly reduced in TVL and CAP treated rats. Moreover, renal morphology improved significantly in TVL and CAP treated animals. CONCLUSION: TVL and CAP demonstrated marked improvement in renal function and morphology.

'Huang Qi Elixir' for proteinuria in patients with diabetic nephropathy: a study protocol for a randomized controlled pilot trial.

BACKGROUND: Diabetic nephropathy (DN) is the major complication of diabetes; proteinuria is the hall mark of DN. Currently, the treatment for proteinuria is mainly limited to angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). According to Traditional Chinese Medicine (TCM) theory, Chinese medicinals 'securing essence and tonifying the kidney' may be appropriate for proteinuria. The most promising Chinese medicinals and formulae are introduced in the present study to form a potent formula for DN proteinuria. To make oral administration convenient, the formula will be processed in the form of granules. METHODS/DESIGN: A randomized, multi-center pilot trial will be conducted. Forty eight participants with DN will be randomly assigned to one of four treatment groups: 1. A granule group, at 10 grams, three times daily (G10 group, n = 12); 2. A granule group, at 20 grams, three times daily (G20 group, n = 12); 3. A decoction group (D group, n = 12); and 4. An irbesartan group (Aprovel group, n = 12).The following outcome measures will be used: the percentage change of the albumin-to-creatinine ratio; and the changes in serum creatinine, glomerular filtration rate, fasting plasma glucose and hemoglobulin from baseline to the end of the trial. DISCUSSION: It is notable that most published clinical trials which assessed the efficacy of TCM on DN were of poor methodology and, therefore, their results have been invalidated. It is necessary to carry out well-designed clinical trials to provide sound evidence. The present trial is a study with potentially great value, for it will provide the parameters for future randomized, placebo-controlled, clinical trials with large sample sizes. TRIAL REGISTRATION: The trial is registered on the Chinese Clinical Trial Registry: ChiCTR-TRC-12002718 (http://www.chictr.org/cn/proj/show.aspx?proj=3820).

Blood pressure, proteinuria, and phosphate as risk factors for progressive kidney disease: a hypothesis.

Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD.

Impact of vitamin D on chronic kidney diseases in non-dialysis patients: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: Recent studies have supported a role for both newer and more established vitamin D compounds in improving proteinuria, although systematic evaluation is lacking. Furthermore, concerns remain regarding the influence of vitamin D on the progression of renal function. We analyzed the efficacy and safety of vitamin D in non-dialysis patients and compared the use of newer versus established vitamin D compounds by performing a meta-analysis of randomized controlled trials. DESIGN: A literature search of PubMed (1975 to September, 2012), EMBASE.com (1966 to September, 2012) and Ovid EBM Reviews (through September, 2012) was conducted. RESULTS: Eighteen studies were eligible for final inclusion; of these, six explored the effects of vitamin D on proteinuria, twelve studied the effects of supplementation on renal function, and fifteen discussed the incidence of hypercalcemia. Compared to the placebo or no interference, both the newer and established vitamin D sterols reduced proteinuria to a similar extent (RR, 2.00; 95% CI, 1.42 to 2.81). No decrease in the glomerular filter rate was observed (SMD, -0.10; 95%CI, -0.24 to 0.03), and the risk for dialysis initiation was 1.48 (95% CI, 0.54 to 4.03) with vitamin D treatment. Additionally, there was an increased risk of hypercalcemia for patients treated with either newer or established vitamin D compounds as compared with the controls (RR, 4.78; 95% CI, 2.20 to 10.37). The head-to-head studies showed no differences in the effects of either newer or established compounds on proteinuria or the risk of hypercalcemia. No serious adverse events were associated with the administration of vitamin D. CONCLUSIONS: Vitamin D therapy appears to decrease proteinuria and have no negative influence on renal function in non-dialysis patients. But the occurrence of hypercalcemia should be evaluated when vitamin D is provided. No superiority for newer versus established vitamin D analogue is found.

Renal function and arterial blood pressure alterations after exposure to acetaminophen with a potential role of Nigella sativa oil in adult male rats.

Hepatic injury by acetaminophen (APAP) has been extensively studied, although the alterations of renal functions and arterial blood pressure (ABP) after APAP exposure are still uncertain, and the impact of Nigella sativa oil (NSO) in this case is poorly defined. Sixty adult male albino rats were involved in two sets of experiments. The first was exposed to a single high dose of APAP (2.5 g/kg) orally preceded by 4 ml NSO/kg orally, while the second received 750 mg APAP/kg/day orally for seven consecutive days and was pretreated with 2 ml NSO/kg/day. Proximal tubular injury was assessed by laboratory and histological studies, and arterial blood pressure was recorded in all animals. In both experiments, urinary α-glutathione S-transferase and neutral endopeptidase, and microproteinuria were dramatically increased early indicating glomerulus and proximal tubule dysfunction that was mediated by raising 8-isoprostanes. Concomitantly, urinary albumin, total protein, creatinine, urea, glomerular filtration rate, Na and K levels, plasma creatinine, and urea were all changed significantly after APAP administration. Currently, ABP increased significantly after APAP which was mostly mediated by renal impairment and increased both renin activity and aldosterone secretion. Pretreatment with NSO produced significant normalization of physiological parameters as well as suppression of structural changes. In conclusion, measurement of urinary biomarkers can be considered a powerful tool for early screening of renal injury and alteration of ABP after APAP treatment. Concomitant administration of NSO can counterbalance these detrimental effects.

Renal protection of losartan 50 mg in normotensive Chinese patients with nondiabetic chronic kidney disease.

AIMS: Nondiabetic chronic kidney disease (CKD) is the leading major cause of end-stage renal disease in developing countries including China. Among the 5 stages of CKD, it is critical to retard the progression of stage 3 because renal disorder could accelerate aggravation behind that stage. Data suggest that high dosages of angiotensin receptor blockers (ARBs) could retard the progression of renal disease in hypertensive and/or diabetic patients. Nevertheless, in daily practice of nephrology, quite a number of nondiabetic patients with CKD who are normotensive do not tolerate even moderate dosages of ARBs because of adverse effects such as systemic hypotension, epically for Chinese patients. The aim of this study was to investigate the renoprotective effects of relatively low dosages of ARBs in normotensive Chinese patients with nondiabetic stage 3 CKD. METHODS: A prospective, randomized, parallel-group, open-label study was performed over a period of 12 months. A total of 238 enrolled patients were randomly allocated to treatment with losartan 50 mg (n = 119) or placebo (n = 119). All patients were followed up at 2-month intervals. At each visit, blood pressure was measured, and urinalysis and serum biochemistry tests were performed. RESULTS: Finally, 112 patients given losartan and 114 patients given placebo completed the study. In the losartan group, there was a significant and biphasic time-dependent decline in proteinuria during therapy (1.72 ± 0.47 to 0.99 ± 0.48 g/d; P < 0.001). Conversely, placebo did not simultaneously change the amount of proteinuria (1.73 ± 0.49 to 1.64 ± 0.50 g/d; P = 0.337). Estimated glomerular filtration rate remained stable during the entire study period in the patients given losartan (44.8 ± 8.1 to 44.1 ± 7.7 mL/min per 1.73 m; P = 0.120) but were significantly reduced in the placebo group (44.5 ± 8.5 to 39.1 ± 7.4 mL/min per 1.73 m, P < 0.001). The changes in blood pressure were kept constant in the 2 groups. All adverse events were minimal and nonfatal. CONCLUSIONS: For normotensive patients with nondiabetic stage 3 CKD, therapy with a daily dose of losartan, 50 mg, may perform effective renoprotection without changing blood pressure and be generally safe and well tolerated.

Electroacupuncture and moxibustion decrease renal sympathetic nerve activity and retard progression of renal disease in rats.

BACKGROUND/AIM: Chronic kidney disease (CKD) is an increasing major public health problem worldwide. The sympathetic nervous system and nitric oxide play an important role in the pathogenesis of CKD. Traditional Chinese medicine has accumulated thousands of years of therapeutic experiences. Electroacupuncture (EA) and moxibustion (MO) are two such therapeutic strategies. The aim of this study was to investigate the renal and hemodynamic effects of EA-MO in an experimental model of a CKD. METHODS: Male Wistar rats submitted to 5/6th nephrectomy (5/6 NX) were studied for 8 weeks. There were four groups: (1) control, normal rats; (2) NX, 5/6 NX only; (3) NX-AS, 5/6 NX and EA-MO session using sham points, and (4) NX-AM, 5/6 NX and EA-MO session using real acupoints. Biochemical and blood pressure studies, renal sympathetic nerve activity measurements, nitric oxide levels and the histopathological indices were assessed. RESULTS: The EA- and MO-treated group presented significant improvement in all measured functional and histopathological parameters. CONCLUSION: These findings suggest that EA-MO had beneficial effects on CKD. This effect was probably achieved by the modulation of the renal sympathetic nerve activity and nitric oxide levels, leading to decreased blood pressure, which is associated with less proteinuria.