Tubular biomarkers and histology in lupus nephritis.

INTRODUCTION: The relevance of tubulo-interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. METHODS: A single-center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2-microglobulin, alpha 1-microglobulin, NGAL, uKIM-1, MCP-1, uDKK-3, and uUMOD. The serum markers sKIM-1 and sUMOD were also analyzed. RESULTS: A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p = .001) and tubular atrophy (rho = 0.781, p = .001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = -0.562, p = .037) and tubular atrophy (rho = -0.694, p = .006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM-1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p = .001], MCP-1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p = .001], sKIM-1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p = .001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p = .028]. CONCLUSION: The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients.

Tubular biomarkers in proteinuric kidney disease: histology correlation and kidney prognosis of tubular biomarkers.

Background: Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. Methods: A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (ß2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Results: Multivariate regression analysis identified sUMOD (ß-0.357, P < .001) and uDKK3 (ß 0.483, P < .001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52-69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04-4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Conclusions: Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression.

Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Obesity and chronic kidney disease progression-the role of a new adipocytokine: C1q/tumour necrosis factor-related protein-1.

BACKGROUND: Obesity is a risk factor for incident chronic kidney disease (CKD) in the general population. C1q/tumour necrosis factor-related protein 1 (CTRP1) is a new adipokine with multiple vascular and metabolic effects and may modulate the association between obesity and vascular diseases. The aim of the study is to explore potential links between obesity, CTRP1 levels and CKD progression. METHODS: Patients with Stages 3 and 4 CKD without previous cardiovascular events were enrolled and divided into two groups according to body mass index (BMI). Demographic, clinical and analytical data and CTRP1 levels were collected at baseline. During follow-up, renal events [defined as dialysis initiation, serum creatinine doubling or a 50% decrease in estimated glomerular filtration rate (Modification of Diet in Renal Disease)] were registered. RESULTS: A total of 71 patients with CKD were divided into two groups: 25 obese (BMI >30 kg/m2) and 46 non-obese. CTRP1 in plasma at baseline was higher in obese patients [median (interquartile range) 360 (148) versus 288 (188) ng/mL, P = 0.041]. No significant association was found between CTRP1 levels and CKD stage, presence of diabetes, aldosterone and renin levels, or blood pressure. Obese patients had higher systolic blood pressure (P = 0.018) and higher high-sensitivity C-reactive protein (P = 0.019) and uric acid (P = 0.003) levels, without significant differences in the percentage of diabetic patients or albuminuria. During a mean follow-up of 65 months, 14 patients had a renal event. Patients with CTRP1 in the lowest tertile had more renal events, both in the overall sample (log rank: 5.810, P = 0.016) and among obese patients (log rank: 5.405, P = 0.020). Higher CTRP1 levels were associated with slower renal progression (hazard ratio 0.992, 95% confidence interval 0.986-0.998; P = 0.001) in a model adjusted for obesity, aspirin, albuminuria and renal function. CONCLUSIONS: CTRP1 levels are higher in obese than in non-obese patients with CKD. High CTRP1 levels may have a renal protective role since they were associated with slower kidney disease progression. Interventional studies are needed to explore this hypothesis.

Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study).

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression. STUDY DESIGN: Prospective, multicenter, open-label randomized controlled trial. SETTING AND PARTICIPANTS: One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m2 without previous cardiovascular events. INTERVENTION: Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months. OUTCOMES: The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes. RESULTS: During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered. LIMITATIONS: Small sample size and open-label trial. CONCLUSIONS: Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

The effect of some medications given to CKD patients on vitamin D levels.

BACKGROUND: Vitamin D deficiency and polypharmacy is a common problem over chronic kidney disease (CKD) population. OBJECTIVES: To assess the clinical and analytical characteristics of CKD patients with 25-OH-D3 deficiency (<15 ng/mL), including the possible role of associated drugs. METHODS: A single center observational review of 137 incident patients referred to our outpatient clinic with different stages of CKD and 25-OH-D3<15ng/mL (male gender 53.3%, mean age 70.8 [±16.1] years, mean GFR (MDRD-4) 43.6 [±25.5] ml/min/1.73 m²). 25-OH-D3 levels were collected in spring. Clinical and biochemical data and associated medications were recorded. RESULTS: Mean 25-OH-D3 levels were 8.23 [±4.03] ng/ml. Eighty-eight patients (64.7%) had 3 or more concomitant drugs. Only 7 patients (5.1%) were not receiving any medication. Patients were divided in three groups according the therapies into none (n=26), RAS inhibitors or allopurinol (n=81), and RAS inhibitors plus allopurinol (n=30); with the aim to study the influence of statin therapy. Patients under renin angiotensin (RAS) inhibitors or Allopurinol treatment presented significantly higher 25-OH-D3 levels (p=0.001 and p=0.01 respectively), however patients with Statins treatment had lower 25-OH-D3 level (p=0.039). Personal history of diabetes, cardiovascular events or other therapies did not modify 25-OH-D3 levels, adjusted by age and eGFR. CONCLUSIONS: CKD patients with vitamin D deficiency who received RAS inhibitors or Allopurinol treatment had higher 25-OH-D3 levels, however those with statins treatment had lower vitamin D levels. Randomized controlled trials are required to confirm these findings.

Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial.

BACKGROUND: Asymptomatic hyperuricemia increases renal and cardiovascular (CV) risk. We previously conducted a 2-year, single-blind, randomized, controlled trial of allopurinol treatment that showed improved estimated glomerular filtration rate and reduced CV risk. STUDY DESIGN: Post hoc analysis of a long-term follow-up after completion of the 2-year trial. SETTING & PARTICIPANTS: 113 participants (57 in the allopurinol group and 56 in the control group) initially followed up for 2 years and 107 participants followed up to 5 additional years. INTERVENTION: Continuation of allopurinol treatment, 100mg/d, or standard treatment. OUTCOME: Renal event (defined as starting dialysis therapy and/or doubling serum creatinine and/or ≥50% decrease in estimated estimated glomerular filtration rate) and CV events (defined as myocardial infarction, coronary revascularization or angina pectoris, congestive heart failure, cerebrovascular disease, and peripheral vascular disease). RESULTS: During initial follow-up, there were 2 renal and 7 CV events in the allopurinol group compared with 6 renal and 15 CV events in the control group. In the long-term follow-up period, 12 of 56 participants taking allopurinol stopped treatment and 10 of 51 control participants received allopurinol. During long-term follow-up, an additional 7 and 9 participants in the allopurinol group experienced a renal or CV event, respectively, and an additional 18 and 8 participants in the control group experienced a renal or CV event, respectively. Thus, during the initial and long-term follow-up (median, 84 months), 9 patients in the allopurinol group had a renal event compared with 24 patients in the control group (HR, 0.32; 95% CI, 0.15-0.69; P=0.004; adjusted for age, sex, baseline kidney function, uric acid level, and renin-angiotensin-aldosterone system blockers). Overall, 16 patients treated with allopurinol experienced CV events compared with 23 in the control group (HR, 0.43; 95% CI, 0.21-0.88; P=0.02; adjusted for age, sex, and baseline kidney function). LIMITATIONS: Small sample size, single center, not double blind, post hoc follow-up and analysis. CONCLUSIONS: Long-term treatment with allopurinol may slow the rate of progression of kidney disease and reduce CV risk.

Evaluation of methods based on creatinine and cystatin C to estimate glomerular filtration rate in chronic kidney disease.

PURPOSE: Estimated glomerular filtration rate (GFR) is a useful tool for the detection of chronic kidney disease (CKD). Several methods have been proposed, but findings can vary in specific groups such as patients with diabetes, elderly and high and low body mass index and, also, with the stage of CKD. The objective of this study was comparing the accuracy of the currently used equations for estimating GFR with that of the gold standard technetium-(99m)-diethylene triamine pentaacetic acid (99mTc-DTPA). METHODS: We performed a cross-sectional study of 129 patients with all five CKD stages. GFR was estimated using the following: 24-h urine creatinine clearance, Cockcroft-Gault equation, MDRD equation, CKD-EPI equation, Hoek's cystatin C equation, and isotopic 99mTc-DTPA (as gold standard). We evaluated agreement in the whole study population and according to age, sex, weight, and diabetes. RESULTS: All methods had good agreement. The best agreement was observed with the cystatin C [intraclass coefficient correlation (ICC) 95 % confidence interval (95 % CI), 0.87 (0.82-0.91)], followed by CKD-EPI [ICC 0.83 (0.77-0.88)]. Twenty-four-hour urine creatinine clearance showed the worst agreement in patients older than 65 years [ICC 0.70 (0.56-0.79)]. The Cockcroft-Gault equation showed the worst agreement in younger than 65 years [ICC 0.64 (0.42-0.79)]. The best agreement for classification in the correct CKD stage was with the cystatin C equation [κ = 0.80 (0.74-0.87)]. GFR was overestimated with all methods in CKD stages 4 and 5. CONCLUSIONS: The methods used in clinical practice are adequate for classification of CKD. Cystatin C is the most accurate method, followed by CKD-EPI. The Cockcroft-Gault equation is not accurate in young patients. Twenty-four-hour urine creatinine clearance loses accuracy in patients aged older than 65 years.

Urate reduction and renal preservation: what is the evidence?

Hyperuricemia is common among chronic kidney disease (CKD) patients. Experimental evidence suggests that uric acid itself may harm patients with CKD by contributing to CKD progression. Although controversial, these observations are supported by many large observational studies indicating that increased serum uric acid level predicts the development and progression of CKD in a variety of populations. Interventional studies also suggest that reducing uric acid levels in asymptomatic hyperuricemic patients with CKD is safe and might slow CKD progression. However, these studies are limited in scope and have included a relatively small number of participants. Thus, although these data suggest treating asymptomatic hyperuricemia, further studies are needed before we can advise reducing uric acid levels in patients with CKD.

Intraindividual interleukin-6 variations on the cardiovascular prognosis of patients with chronic renal disease.

In chronic kidney disease (CKD) patients on dialysis, plasma interleukin (IL)-6 levels predict mortality better than other markers. Impact of intraindividual changes of inflammatory markers on cardiovascular (CV) events in CKD patients is unknown. The aim of this study is to demonstrate the relation between CV outcomes and variations of C-reactive protein (CRP), IL-6, IL-1ß, and tumor necrosis factor (TNF)-α in CKD. Ninety patients (mean age: 68.5 ± 12.8 years) at different stages (1-4) of CKD were evaluated. Serum CRP, IL-6, IL-1ß, and TNF-α were measured basally and after taking statins or angiotensin II receptor blockers. Three patterns were defined for each marker (baseline, mean of two measurements, and variation of the marker: increase or decrease after 6 months). During follow-up (mean time: 72.7 ± 19.8 months), 14 patients died, 11 were included on dialysis program, and 29 suffered a CV event. Patients with persistently elevated IL-6 values had higher risk to develop CV events [OR = 1.21 (1.11-1.32), p = 0.001]. Mean of two measurements of IL-6 was a better predictor for events than a single measurement of IL-6, CRP, TNF-α, and IL-1ß. A mean of two determinations of plasma IL-6 greater than 6 pg/mL and previous peripheral vascular disease was related to an increased risk for CV events [2.34 (1.05-5.22), p = 0.037 and 2.95 (1.27-6.93), p = 0.011, respectively] in an adjusted Cox regression model. IL-6 is a better inflammatory marker than CRP, TNF-α, and IL1ß at predicting CV events in CKD nondialysis patients. Mean of two measurements is better than simple determinations at predicting CV outcome.

Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial.

BACKGROUND: Pentoxifylline (PTF) is a potential therapeutic agent in chronic kidney disease due to its antiinflammatory and antiproteinuric effects that may influence the progression of renal disease. SUBJECTS AND METHODS: We conducted a prospective randomized trial of 91 patients with estimated glomerular filtration rate (eGFR) <60 ml/min, calculated with 4-variable Modification of Diet in Renal Disease (MDRD-4) Study equation. Patients were randomly assigned to treatment with PTF 400 mg (twice a day) (n=46) or to continue their usual therapy (n=45). Clinical, biochemical and inflammatory parameters were measured at baseline, and at 6 and 12 months of treatment. The objective of the study was to analyze the effect of PTF treatment on inflammatory markers and secondarily the effect on renal disease progression. RESULTS: Baseline characteristics were similar in the 2 groups. High-sensitivity C-reactive protein (hs-CRP), serum fibrinogen and TNF-alpha decreased significantly in patients treated with PTF in comparison with the control group at 12 months (p=0.002, p=0.001 and p=0.000, respectively). Median urinary albumin excretion did not decrease with PTF treatment. In the PTF group, there was no significant change in eGFR after 12 months (from 42.3 ± 10.2 to 44.7 ± 11.3 ml/min per 1.73 m(2)), whereas in the control group there was a worsening by the end of the study (from 40.1 ± 12.4 to 35.7 ± 13.4 ml/min per 1.73 m(2)) (p=0.000 between groups). CONCLUSIONS: PTF treatment decreases inflammatory markers in chronic kidney disease and stabilizes renal function.

Factors related to the absence of anemia in hemodialysis patients.

BACKGROUND: A small number of hemodialysis (HD) patients have normal hemoglobin (Hb) levels without the need for erythropoiesis-stimulating agents (ESAs). The factors associated with this condition have been little studied. The objective of this prospective study was to determine these factors in a prevalent population of HD patients. MATERIALS AND METHODS: All patients who had normal Hb levels and who had not received ESAs in the last 6 months (non-ESA group) were included. Epidemiological and laboratory data were collected and we performed an abdominal ultrasound to assess hepatic and renal cysts. This group was compared to a control group of 205 prevalent HD patients on ESA therapy (control group). RESULTS: We included 45 patients (16% from the whole group) in the non-ESA group. In this group, there was a higher proportion of men (76.5 vs. 61%), patients were younger (61.1 ± 14.7 vs. 67.5 ± 15.2 years), had a longer duration of renal replacement therapy (RRT) (9.4 ± 8.3 vs. 5.3 ± 5.8 years) and had a higher prevalence of adult polycystic kidney disease (APKD) and hepatitis C virus (HCV) liver disease (42.2 vs. 10.2%), p < 0.01. In the non-ESA group, HCV+ patients had a lower prevalence of APKD (2.2 vs. 38.4%) and hepatic cysts (2.2 vs. 19.2%), but significantly higher endogenous erythropoietin levels (55.8 ± 37.1 vs. 30.9 ± 38.4 mU/ml). No significant differences in anemia, iron metabolism, insulin, IGF-1 and renin were found between non-ESA and control groups. Non-ESA patients had a significantly higher number of renal (90.6 vs. 36.5%) and hepatic cysts (12.5 vs. 3.4%), and these were also larger in size (3.3 ± 2.4 vs. 1.5 ± 0.8 cm). In the multivariate Cox analysis, independent predictor factors for absence of anemia in HD patients were number of renal cysts >10 cysts (95% CI 1.058-1.405; p = 0.00), HCV+ liver disease (95% CI 1.147-1.511; p = 0.05) and time on RRT (95% CI 1.002-1.121; p = 0.05). CONCLUSIONS: The absence of anemia in HD patients is not infrequent. Its frequency is higher in men and younger patients with long-term RRT, in patients with HCV+ liver disease and in APKD. It is associated with increased endogenous erythropoietin production and the presence of renal and hepatic cysts.

Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

BACKGROUND AND OBJECTIVES: Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. RESULTS: Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. CONCLUSIONS: Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.