Clinical Features, Outcomes, and Response to Corticosteroid Treatment of Acute Tubulointerstitial Nephritis: A Single-Centre Retrospective Cohort Study in the Czech Republic.

INTRODUCTION: Acute tubulointerstitial nephritis (ATIN) is a well-recognized cause of acute kidney injury (AKI) due to the tubulointerstitial inflammation. The aim of this study was to explore the clinical features, outcomes, and responses to corticosteroid treatment in patients with ATIN. METHODS: Patients with biopsy-proven ATIN, who were diagnosed between 1994 and 2016 at the Department of Nephrology, Charles University, First Faculty of Medicine, and General University Hospital in Prague, were included in the study. Patient demographics, the aetiological and clinical features, the treatment given, and the outcome at 1 year of follow-up were extracted from patient records. RESULTS: A total of 103 ATIN patients were analysed, of which 68 had been treated with corticosteroids. There was no significant difference in the median serum creatinine 280 (169-569) µmol/L in the conservatively managed group versus 374 (249-558) µmol/L in the corticosteroid-treated group, p = 0.18, and dependence on dialysis treatment at baseline at the time of biopsy (10.3 vs. 8.6%). During the 1 year of follow-up, those ATIN patients who had been treated with corticosteroids did better and showed greater improvement in kidney function, determined as serum creatinine difference from baseline and from 1 month over 1-year period (p = 0.001). CONCLUSIONS: This single-centre retrospective cohort study supports the beneficial role of the administration of corticosteroid therapy in the management of ATIN.

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes.

Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. The aim of this review is to summarize the known experimental and clinical evidence of SGLT2 inhibitors' effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes.

Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in kidney disease.

Matrix metalloproteinases (MMPs) are a group of zinc and calcium endopeptidases which cleave extracellular matrix (ECM) proteins. They are also involved in the degradation of cell surface components and regulate multiple cellular processes, cell to cell interactions, cell proliferation, and cell signaling pathways. MMPs function in close interaction with the endogenous tissue inhibitors of matrix metalloproteinases (TIMPs), both of which regulate cell turnover, modulate various growth factors, and participate in the progression of tissue fibrosis and apoptosis. The multiple roles of MMPs and TIMPs are continuously elucidated in kidney development and repair, as well as in a number of kidney diseases. This chapter focuses on the current findings of the significance of MMPs and TIMPs in a wide range of kidney diseases, whether they result from kidney tissue changes, hemodynamic alterations, tubular epithelial cell apoptosis, inflammation, or fibrosis. In addition, the potential use of these endopeptidases as biomarkers of renal dysfunction and as targets for therapeutic interventions to attenuate kidney disease are also explored in this review.

Renal parenchymal hypertension: relevant new aspects.

Renal parenchymal disease is the most common cause of secondary hypertension, accounting for up to 5% cases of all cases of systemic hypertension. Renal parenchymal hypertension occurs as a complication of a wide variety of glomerular and tubulointerstitial diseases and may aggravate the decline of kidney function. The pathophysiology of renal parenchymal hypertension represents a combined interaction of the impaired sodium handling leading to volume expansion, alteration of the renin-angiotensin system, abnormalities in endogenous vasodepressor compounds and possibly enhanced activity of vasoactive substances. Renal parenchymal hypertension can occur in acute and chronic kidney disease, manifesting early in the renal function impairment. It often requires complex pharmacological treatment of blood pressure and is prognostically unfavorable in terms of cardiovascular and renal complications. This form of secondary hypertension can often be successfully treated by therapy of the underlying renal disease. In case of insufficient blood pressure compensation, renal impairment progresses. The aim of this paper is to give a brief overview of renoparenchymatous hypertension, current diagnostic possibilities and principles of therapy.

Proteinuria from an internists point of view.

A basal level of proteinuria is about 30-100 mg/day, the upper limit of basal proteinuria does not exceed 150 mg/day which is considered non-pathology. Albumin accounts approximately 15 % of basal protein in the urine, other plasma proteins (immunoglobulins, β-2 microglobulin, Tamm-Horsfall mucoprotein) comprise the remaining 85 % of total quantity non-pathology proteinuria. Persistent proteinuria present for more than three months already meets the definition of chronic kidney disease independently of the stage of the estimated glomerular filtration rate. Patients are classified as A1-A3 based on the level of albuminuria. Examination of the albumin in the urine is one of the single sensitive indicators of chronic kidney disease. Proteinuria is an independent risk factor for cardiovascular disease, overall mortality and end stage renal failure both in general population and in population with chronic kidney disease. Presence of the urinary protein is associated with a higher mortality rate in critically ill patients. The degree of proteinuria after kidney transplantation predicts graft and patient survival in this population. Pharmacological and non-pharmacological treatments that attenuate proteinuria have been associated with better prognosis of kidney disease.

Proteinuria from an internists point of view.

A basal level of proteinuria is about 30-100 mg/day, the upper limit of basal proteinuria does not exceed 150 mg/day which is considered non-pathology. Albumin accounts approximately 15 % of basal protein in the urine, other plasma proteins (immunoglobulins, β-2 microglobulin, Tamm-Horsfall mucoprotein) comprise the remaining 85 % of total quantity non-pathology proteinuria. Persistent proteinuria present for more than three months already meets the definition of chronic kidney disease independently of the stage of the estimated glomerular filtration rate. Patients are classified as A1-A3 based on the level of albuminuria. Examination of the albumin in the urine is one of the single sensitive indicators of chronic kidney disease. Proteinuria is an independent risk factor for cardiovascular disease, overall mortality and end stage renal failure both in general population and in population with chronic kidney disease. Presence of the urinary protein is associated with a higher mortality rate in critically ill patients. The degree of proteinuria after kidney transplantation predicts graft and patient survival in this population. Pharmacological and non-pharmacological treatments that attenuate proteinuria have been associated with better prognosis of kidney disease.

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal.

Matrix metalloproteinases (MMPs) are endopeptidases within the metzincin protein family that not only cleave extracellular matrix (ECM) components, but also process the non-ECM molecules, including various growth factors and their binding proteins. MMPs participate in cell to ECM interactions, and MMPs are known to be involved in cell proliferation mechanisms and most probably apoptosis. These proteinases are grouped into six classes: collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs. Various mechanisms regulate the activity of MMPs, inhibition by tissue inhibitors of metalloproteinases being the most important. In the kidney, intrinsic glomerular cells and tubular epithelial cells synthesize several MMPs. The measurement of circulating MMPs can provide valuable information in patients with kidney diseases. They play an important role in many renal diseases, both acute and chronic. This review attempts to summarize the current knowledge of MMPs in the kidney and discusses recent data from patient and animal studies with reference to specific diseases. A better understanding of the MMPs' role in renal remodeling may open the way to new interventions favoring deleterious renal changes in a number of kidney diseases.

Pregnancy-Associated Plasma Protein A2 in Hemodialysis Patients: Significance for Prognosis.

BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) is associated with adverse outcome of long-term hemodialysis patients (HD). The aim of the study was to test whether its homolog pregnancy-associated plasma protein A2 (PAPP-A2) can be detected in serum of HD patients and to define its significance. METHODS: The studied group consisted of 102 long-term HD patients and 25 healthy controls. HD patients were prospectively followed up for five years (2009-2014). PAPP-A2 was measured by surface plasmon resonance biosensor, PAPP-A by time resolved amplified cryptate emission. RESULTS: PAPP-A2, similarly as PAPP-A, was significantly increased in HD patients (median (interquartile range)) PAPP-A2: 6.2 (2.6-10.8) ng/mL, vs. 3.0 (0.7-5.9) ng/mL, p=0.006; PAPP-A: 18.9 (14.3-23.4) mIU/L, vs. 9.5 (8.4-10.5) mIU/L, p<0.001). In HD patients, PAPP-A2 correlated weakly but significantly with PAPP-A (τ=0.193, p=0.004). Unlike PAPP-A, PAPP-A2 was not significant for prognosis of HD patients when tested alone. There was a significant interaction between PAPP-A and PAPP-A2 on the mortality due to infection of HD patients (p=0.008). If PAPP-A was below median, mortality due to infection was significantly higher for patients with PAPP-A2 values above median than for patients with low PAPP-A2 levels (p=0.011). CONCLUSION: PAPP-A2 is increased in HD patients and interacts with PAPP-A on patients´ prognosis.

Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease.

OBJECTIVE: This study was designed to evaluate vitamin D status with separate determination of 25-OH D2 and 25-OH D3 and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD). METHODS: 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay. RESULTS: Plasma vitamin D levels were lower in CKD (30.16 ± 16.74 ng/mL) and HD (18.85 ± 15.85 ng/mL) versus C (48.72 ± 18.35 ng/mL), P < 0.0001. 25-OH D3 was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2 ± 93.8 ug/mL) versus C (222 ± 87.6 ug/mL) and HD (213.8 ± 70.9 ug/mL), P = 0.0003. Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25 ± 0.13 ug/mL) correlated with proteinuria (r = 0.43, P = 0.003). CONCLUSIONS: Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3 was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency.

Placental growth factor, pregnancy-associated plasma protein-A, soluble receptor for advanced glycation end products, extracellular newly identified receptor for receptor for advanced glycation end products binding protein and high mobility group box 1 levels in patients with acute kidney injury: a cross sectional study.

BACKGROUND: Placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A), soluble receptor for advanced glycation end products (sRAGE), extracellular newly identified receptor for RAGE binding protein (EN-RAGE) and high mobility group box 1 (HMGB-1) are novel biomarkers in chronic kidney disease (CKD). However, their clinical significance in acute kidney injury (AKI) is unknown. The aim of this cross-sectional study was to determine whether selected biomarkers are changed in AKI patients. METHODS: Serum PlGF, PAPP-A, sRAGE, EN-RAGE and HMGB-1 levels were assessed in 40 patients with AKI, 42 CKD 5 patients, 31 haemodialysis patients (HD) and 39 age-matched healthy controls. RESULTS: PAPP-A was elevated in AKI (20.6 ± 16.9 mIU/L) compared with controls (9.1 ± 2.3 mIU/L, p < 0.001). PlGF was not increased in AKI (11.7 ± 7.4 pg/mL) versus controls (8.5 ± 2.4 pg/mL, n.s.), as well as sRAGE was not elevated in AKI (2400 ± 1400 pg/mL) compared with controls (1760 ± 730 pg/mL, n.s), but was lower compared with CKD 5 (3200 ± 1500 pg/mL, p < 0.05); EN-RAGE was elevated in AKI 480 ± 450 ng/mL in comparison with controls (60 ± 62 ng/mL), CKD 5 (190 ± 120 ng/mL), and HD (120 ± 100 ng/mL), all p < 0.001. Similarly, HMGB-1 was increased in AKI (5.8 ± 7.5 ng/mL) versus controls (1.7 ± 1.4 ng/mL), CKD 5 (3.2 ± 3.1 ng/mL) and HD (2.5 ± 2.1 ng/mL), all p < 0.001.In AKI group, in multivariate regression analysis: PAPP-A levels were associated with transferrin (p <0.001), negatively with albumin (p < 0.01) and prealbumin (p < 0.05); PlGF levels were associated with C--reactive protein (p < 0.001). EN-RAGE levels were associated with ferritin (p < 0.01) and orosomucoid (p = 0.02), and HMGB-1 levels with leukocyte count (p < 0.01) and negatively with proteinuria (p = 0.02). CONCLUSIONS: In AKI patients, PAPP-A, EN-RAGE and HMGB1 are elevated, but sRAGE and PlGF are not increased. Whereas PAPP-A correlates with markers of nutrition; PlGF, EN-RAGE and HMGB-1 are related to inflammatory parameters.

Changes in levels of matrix metalloproteinase-2 and -9, pregnancy-associated plasma protein-A in patients with various nephropathies.

BACKGROUND: Specific changes and imbalanced concentrations of matrix metalloproteinases (MMPs) and pregnancy-associated plasma protein-A (PAPP-A) may reflect the pathophysiology of various nephropathies (GN). We compared MMP-2, MMP-9 and PAPP-A levels in patients with GN, with those found in healthy controls. METHODS: We studied 45 controls and 128 patients with GN, defined by kidney biopsy: IgA nephropathy (IgAN, n=33), membranous glomerulonephritis (MN, n=23), minimal change nephrotic syndrome (MCNS, n=7), focal segmental glomerular sclerosis (FSGS, n=11), lupus nephritis (LN, n=22) and ANCA-associated glomerulonephritis (AAV, n=32). MMP-2 and MMP-9 levels were assessed using enzyme-linked immunosorbent assay; PAPP-A levels were determined with time-resolved amplified cryptate emission, and routine biochemical parameters were measured. RESULTS: Compared with controls, IgAN patients exhibited a significant decrease in levels of MMP-2 contrasted with increased MMP-9 and unchanged PAPP-A levels. LN patients exhibited a parallel decrease in MMP-2, MMP-9 and PAPP-A levels. In the MCNS/FSGS and AAV patients, MMP-2, MMP-9 and PAPP-A levels were unchanged. In MN patients, increased MMP-9 levels contrasted with unchanged MMP-2 and PAPP-A levels (all p<0.05). Both MMP-2 (r=-0.34, p<0.0001) and PAPP-A levels (r=-0.31, p<0.0001) were inversely correlated with estimated glomerular filtration rate in all GN groups. CONCLUSIONS: Serum levels of MMP-2, MMP-9 and PAPP-A significantly differed between various nephropathies. These findings suggest that MMPs and PAPP-A are involved in different underlying mechanisms in the regulation of glomerular and tubulointerstitial fibrosis and scarring in these renal diseases.

Determinants of circulating matrix metalloproteinase-2 and pregnancy-associated plasma protein-A in patients with chronic kidney disease.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2) and pregnancy-associated plasma protein-A (PAPP-A) have been implicated in chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the serum determinants of MMP-2 and PAPP-A in CKD are unknown. The aim of the present study is to evaluate the clinical significance of MMP-2 and PAPP-A and their determinants in patients with CKD. METHODS: The studied group consisted of 203 subjects: 159 patients with chronic kidney disease stages 1 - 5 (CKD 1 - 5), and 44 healthy control subjects. MMP-2 levels were assessed immunochemically using ELISA (enzyme linked immunosorbent assay), PAPP-A levels were determined immunochemically with TRACE (time-resolved amplified cryptate emission), and routine biochemical parameters were measured using standard methods. RESULTS: Compared with healthy controls, CKD patients (3 - 5) had no significant changes in MMP-2 levels. MMP-2 levels (195 +/- 76 vs. 255 +/- 77 ng/mL, p < 0.0001) were significantly lower in CKD patients (1 - 2) and PAPP-A levels (12.1 +/- 8.5 vs. 9.3 +/- 2.2 mIU/L, p = 0.001) were significantly higher in CKD 4 compared to control subjects. Multivariate analysis revealed that PAPP-A (p < 0.0001), proteinuria (p = 0.002), alpha-2-macroglobulin (p = 0.01), and negatively albumin (p = 0.02) and haemoglobin (p = 0.0002), were independent correlates of MMP-2 after adjustment for age and glomerular filtration rate. Proteinuria (p = 0.02), creatinine (p < 0.0001), and negatively albumin (p = 0.01), were independent correlates of PAPP-A adjusted for age and glomerular filtration rate. CONCLUSIONS: The present study demonstrated that serum MMP-2 and PAPP-A were independent correlates of proteinuria, albumin, and other examined parameters. Our results suggest the possibility that circulating MMP-2 and PAPP-A be used as indicators for renal damage in CKD patients on conservative treatment.

Serum S100A12 (EN-RAGE) levels in patients with decreased renal function and subclinical chronic inflammatory disease.

BACKGROUND: The calcium-binding protein S100A12 (EN-RAGE) causes inflammation through interaction with the multiligand receptor for advanced glycation end products (RAGE). The aim of the study was to determine S100A12 levels and describe their relationship to inflammatory markers in patients with decreased renal function. METHODS: The studied group consisted of 46 patients with various degrees of chronic renal insufficiency (CHRI), 31 long-term hemodialysis (HD) patients and 24 healthy controls. S100A12 and soluble RAGE were assessed immunochemically (ELISA), and routine biochemical parameters were measured. RESULTS: S100A12 levels were not different in CHRI (166 ± 140 ng/ml) and HD patients (127 ± 101 ng/ml) compared to controls (126 ± 106 ng/ml; p = 0.20, n.s.). In CHRI patients, S100A12 correlated with C-reactive protein (CRP) levels, orosomucoid, and inversely with α(2)-macroglobulin. In HD patients, S100A12 correlated with age, CRP, orosomucoid, fibrinogen and leukocyte levels. In multivariate regression analysis after adjustment for age, S100A12 levels remained correlated with: orosomucoid in CHRI patients; CRP, leukocytes, fibrinogen and negatively with sRAGE in HD patients; and leukocytes in controls. CONCLUSIONS: Although S100A12 levels were not elevated in patients with decreased kidney function, a relation to markers of inflammation was found. Further studies are required to demonstrate the significance of S100A12 in patients with decreased renal function.

Placental growth factor in patients with decreased renal function.

BACKGROUND: Patients with decreased renal function are characterized by high cardiovascular morbidity and mortality due to complications of premature atherosclerosis. Placental growth factor (PlGF) is a proatherogenic cytokine and new biomarker of cardiovascular events. The aim of this study was to determine PlGF levels and describe their relationship to renal function and risk factors of atherogenesis in patients with decreased renal function. METHODS: The study group consisted of 114 subjects: 45 patients with various degrees of decreased renal function (CHRI), 31 long-term hemodialysis (HD) patients, and 38 age-matched healthy control subjects. PlGF was assessed immunochemically (enzyme-linked immunosorbent assay) and routine biochemical parameters were measured using standard laboratory methods. RESULTS: PlGF levels were significantly increased in CHRI and HD patients compared to controls (10.5 ± 3.3 pg/mL in CHRI patients and 11.5 ± 3.4 pg/mL HD patients vs. 8.1 ± 1.8 pg/mL in controls, both p < 0.0001). In CHRI patients, PlGF was detectable in the urine, and its urine concentration correlated with its serum levels. In HD patients, PlGF correlated with low-density lipoproteins (r = 0.36, p < 0.05), but was not related to C-reactive protein levels. Higher levels of PlGF were found in CHRI patients with cardiovascular disease, compared with those free of such complication. CONCLUSIONS: PlGF levels are increased in patients with decreased kidney function. PlGF is detectable in the urine, and serum and urine levels of PlGF are significantly interrelated. It is higher in CHRI patients with cardiovascular disease. Further studies are required to demonstrate the usefulness and significance of PlGF in patients with chronic kidney disease.

Associations of serum levels of advanced glycation end products with nutrition markers and anemia in patients with chronic kidney disease.

BACKGROUND: Advanced glycation end product (AGE) levels are elevated in patients with decreased renal function and may contribute to the excessive cardiovascular disease in this population. However, their relation to nutrition, anemia, and micro inflammation is not well characterized. The aim of this study is to determine their relationship in patients with chronic kidney disease (CKD). METHODS: The studied group consisted of 203 subjects: 159 patients with CKD 1-5 and 44 healthy control subjects. AGE levels were assessed by spectrofluorimetry, and routine biochemical parameters were measured using standard methods. RESULTS: AGE levels were significantly increased in CKD patients compared with controls (3.9 ± 1.7 × 105 AU in CKD 1-5 patients vs. 3.2 ± 0.48 × 105 AU in controls, p < 0.0001). AGE levels increased from CKD 3. AGE levels were positively associated with age, albumin, prealbumin, and orosomucoid, and were negatively associated with hemoglobin and estimated glomerular filtration rate. In multiple regression analysis, after adjustment to age and glomerular filtration rate, AGE levels remained independently correlated with albumin and prealbumin and negatively correlated with hemoglobin. CONCLUSIONS: This study is the demonstration that nutrition markers, albumin and prealbumin, are the positive determinants and hemoglobin is the negative determinant of serum AGE levels in patients with CKD.