Glucose Exposure in Peritoneal Dialysis Is a Significant Factor Predicting Peritonitis

INTRODUCTION: Loss of residual renal function (RRF) as well as high peritoneal glucose exposure are associated with increased peritonitis frequency in peritoneal dialysis (PD) patients. Our objective was to investigate the contribution of RRF and peritoneal glucose exposure to peritonitis in PD patients. METHODS: In this prospective longitudinal cohort study, 105 incident end-stage renal disease patients that started PD between January 2006 and 2015 were studied. Follow-up was 5 years with censoring at death or switch to another treatment modality. Cox regression models were used to calculate the association between glucose exposure, RRF, and peritonitis. Kaplan-Meier analysis was used to examine the difference in occurrence of peritonitis between patients with high and low glucose exposure and between those with and without residual diuresis. RESULTS: One hundred and five patients were followed for a mean of 23 months. Fifty-one patients developed a peritonitis. Cox regression models at 6 months showed that glucose exposure and not residual diuresis significantly predicted PD peritonitis. Kaplan-Meier analysis after 6 months of follow-up showed that time to first PD peritonitis was significantly longer in the low glucose exposure group. Similarly, patients with RRF had a significantly longer interval to first peritonitis compared to patients without RRF. CONCLUSION: A higher exposure to glucose rather than loss of RRF is associated with an increased risk of peritonitis. This confirms the detrimental effects of glycemic harm to the peritoneal host defense on invading microorganisms and argues for the use of the lowest PD glucose concentrations possible

Indomethacin Reduces Glomerular and Tubular Damage Markers but Not Renal Inflammation in Chronic Kidney Disease Patients: A Post-Hoc Analysis

Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38–513] vs NSAID 38[17–218] mg/24 h, p<0.01; IgG4: 50[16–68] vs 10[1–38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55–404] vs 50[28–110] ug/24 h, p = 0.03; KIM-1: 9[5]–[14] vs 5[2]–[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term

Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes

OBJECTIVE: We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase-associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid-binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS: Damage markers were measured in triplicate in fresh morning urine samples and in plasma. RESULTS: Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between -0.38 and -0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β -0.26; P = 0.037). CONCLUSIONS: Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease

Albuminuria:: all you need to predict outcomes in chronic kidney disease?

PURPOSE OF REVIEW: Screening for chronic kidney disease frequently starts with assessment of estimated glomerular filtration rate (eGFR). In current approaches, further evaluation will only include measurement of albuminuria in case of eGFR less than 60 ml/min/1.73 m. We will review whether this screening approach is correct. RECENT FINDINGS: Albuminuria is an important predictor of both cardiovascular and kidney outcomes in chronic kidney disease. The predictive value of albuminuria for these endpoints is not only independent of well known risk factors, including diabetes and hypertension, but it is also independent of eGFR. Many individuals with normal eGFR have albuminuria. More research is needed to define why albuminuria adds to eGFR in predicting outcomes. After leakage through the glomerular filter, albumin is not only excreted in urine, but also reabsorbed by tubules. Albuminuria may, therefore, be a marker of both glomerular and tubular damage, whereas eGFR is merely a marker of glomerular damage. SUMMARY: As many individuals with an eGFR more than 60 ml/min/1.73 m have microalbuminuria, and albuminuria is an independent predictor of both renal and cardiovascular outcomes, screening for chronic kidney disease should at least include measurement of albuminuria. Future studies should consider whether the inclusion of (other) markers of tubular damage will further improve our ability to predict outcomes in patients with chronic kidney disease

Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice

Semaphorin 3A (sema3A) was recently identified as an early diagnostic biomarker of acute kidney injury. However, its role as a biomarker and/or mediator of chronic kidney disease (CKD) related to diabetic nephropathy is unknown. We examined the expression of sema3A in diabetic animal models and in humans and tested whether sema3A plays a pathogenic role in the development of diabetic nephropathy. The expression of sema3A was localized to podocytes and epithelial cells in distal tubules and collecting ducts in control animals, and its expression was increased following the induction of diabetes. Quantification of sema3A urinary excretion in three different diabetic mouse models showed that excretion was increased as early as 2 weeks after the induction of diabetes and increased over time, in conjunction with the development of nephropathy. Consistent with the mouse data, increased sema3A urinary excretion was detected in diabetic patients with albuminuria, particularly in those with macroalbuminuria. Genetic ablation of sema3A or pharmacological inhibition with a novel sema3A inhibitory peptide was protected against diabetes-induced albuminuria, kidney fibrosis, inflammation, oxidative stress, and renal dysfunction. We conclude that sema3A is both a biomarker and a mediator of diabetic kidney disease and could be a promising therapeutic target in diabetic nephropathy

Netrin-1, a urinary proximal tubular injury marker, is elevated early in the time course of human diabetes

Netrin-1 was recently identified as an early diagnostic biomarker of chronic kidney disease (CKD) in an experimental animal model. However, its usefulness for early diagnosis of CKD in humans is unknown. The current study evaluated whether netrin-1 is increased in urine from human diabetic patients. Spot urine samples from healthy volunteers, diabetes without microalbuminuria, diabetes with microalbuminuria and diabetes with macroalbuminuria were collected after receiving consent. Netrin-1 in urine was quantified by enzyme-linked immunosorbent assay and the data analyzed to determine whether urinary netrin-1 significantly correlates with disease progression. Urinary netrin-1 levels were significantly increased in normoalbuminuric diabetic patients compared to healthy controls, and still further elevated in patients with microalbuminuria and overt nephropathy. Urinary netrin-1 was significantly associated with albuminuria and estimated glomerular filtration rate, independently of age and sex. Netrin-1 is detectable in urine from diabetic patients and may serve as a useful early diagnostic biomarker predicting the development of CKD in diabetes

Pre-treatment urinary MCP-1 excretion and treatment response.

<p>Scatter plot indicating the relationship between the 24 h -urinary excretion of MCP-1 before start of anti-proteinuric therapy (i.e. NSAID) and the anti-proteinuric response (i.e. delta proteinuria without vs with NSAID). A negative association is present, suggesting that high baseline MCP-1 excretion is associated with poor anti-proteinuric response to therapy.</p