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A 41 year old woman (gravida 1 para 0) presented to the antenatal day unit at 32 weeks’ gestation with a blood pressure of 157/93 mm Hg. Her first recorded BMI in pregnancy was 32. She was a non-smoker and had no known drug allergies. Her history included a thoracic spine fracture and two lumbar disc protrusions that had been asymptomatic since 2002. Earlier in the day, she had a headache that was relieved by paracetamol. Urinalysis showed 1+protein and a urinary protein creatinine ratio of 19 mg/mmol. Further measurements found a blood pressure of 163/96 mm Hg. The patient was admitted to the antenatal ward and started on an antihypertensive. Once her blood pressure was stable she was discharged with regular follow-up. At 34 weeks’ gestation she presented to labour ward triage with a blood pressure of 158/98 m Hg despite antihypertensive treatment. She was admitted to the antenatal ward, her antihypertensive therapy was increased, and a second line agent was started. Urinary protein creatinine ratio was 39 mg/mmol; 24 hour urine collection showed 540 mg/24 hour of protein. An ultrasound scan for growth, liquor volume, and umbilical cord dopplers was normal. Induction of labour was arranged at 37 weeks’ gestation. ### 1. What is the most likely diagnosis and what are the risk factors in this case? #### Short answer Gestational hypertension developing into pre-eclampsia. Risk factors include nulliparity, maternal age >40 years, and body mass index >25. #### Discussion Hypertension can be graded according to severity (box 1).1 The National Institute for Health and Care Excellence (NICE) classifies hypertensive disorder of pregnancy as chronic hypertension, gestational hypertension, or pre-eclampsia.1 Chronic hypertension is defined as pre-existing hypertension or hypertension diagnosed before 20 weeks’ gestation. Gestational hypertension is new …

Objective: To evaluate diagnostic accuracy of spot urine protein-creatinine ratio for the diagnosis of proteinuria among patients with preeclampsia taking 24 hours urinary protein concentration > 300 mg/24hrs as gold standard. Study Design: This was a cross sectional study. Introduction: Preeclampsia can lead to significant morbidity and mortality. One of the important characteristic of diagnosis of preeclampsia is proteinuria. Gold standard for detection of significant proteinuria among these patients is 24 hours urinary proteins level (>300 milli grams). However, spot urinary protein-creatinine ratio can also detect proteinuria and save patients from botheration for collection of 24 hours urine. Previously, variable sensitivities, specificities and diagnostic accuracy of spot urinary protein-creatinine ratio had been calculated. So, this study was designed to determine diagnostic accuracy of spot urinary protein-creatinine ratio. Methods: 551 patients with preeclampsia were included. All patients had spot urinary protein-creatinine ratio (>0.3 was cutoff for proteinuria). All patients had 24 hours urinary protein test (>300 grams cutoff for proteinuria) as gold standard. Diagnostic accuracy of urinary protein-creatinine ratio was detected by determining sensitivity, specificity and accuracy. Results: Sensitivity, specificity, and accuracy of spot urinary protein-creatinine ratio were 95.8%, 94.2% and 91.6%, respectively. Conclusions: Due to its high sensitivity, specificity and diagnostic accuracy, urinary protein-creatinine ratio is a reliable test for diagnosing proteinuria among patients with preeclampsia.

To compare the efficacy of spot urinary protein/creatinine ratio with 24h urinary protein excretion in women with pre-eclampsia.A total of 85 women with hypertensive disorders during pregnancy were prospectively studied. Urine protein/creatinine ratio in spot urine sample was compared with 24h urinary protein. Sensitivity and specificity for urinary spot P/C (protein/creatinine) ratio was assessed, and receiver operating curve was used to determine the value against the gold standard of300mg proteinuria in 24h urinary sample.Of 85 women, complete data were available for 81 women. There was a strong correlation between spot urinary P/C ratio and 24h urine protein excretion (r=0.81, P value0.000). The optimal spot P/C ratio cut-off point was 0.14 for 300mg/24h of protein excretion (preeclampsia) with a sensitivity of 82% and specificity of 79%.We found a strong correlation between spot urinary P/C and 24h urinary protein. Spot urinary protein/creatinine ratio is a good predictor of proteinuria for pre-eclampsia.

Introduction Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease. Methods Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti−transforming growth factor−β antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria. Results Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was –18.5% (P = 0.008), +10.5% (P = 0.52), and +9.0% (P = 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252. Discussion The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.

Background: The nephrotic syndrome is associated with an increased risk of venous and arterial thrombosis. There are little published data on the distribution, interpretation or determinants of serum D-dimer levels in patients with the nephrotic syndrome. We aimed to describe this relationship. Methods: This was a cross-sectional study of 100 patients with the nephrotic syndrome. Multivariate linear regression was used to evaluate for independent predictors of elevated D-dimer levels. Patients were observed for a period of 2 years after the baseline measurement of D-dimer level to assess for subsequent clinically evident thrombosis. Results: On univariate linear regression, D-dimer elevation was associated with age in years β (95% CI) 0.02 (0.016, 0.03), log-transformed urinary protein:creatinine ratio in g/g 0.439 (0.32, 0.558) and inversely with serum albumin in g/l –0.05 (–0.073, –0.035) and estimated glomerular filtration rate (eGFR) in ml/min/1.73 m2 –0.01 (–0.016, –0.003). On multivariate linear regression, age in years β (95% CI) 0.019 (0.012, 0.026), serum albumin in g/l –0.023 (–0.043, –0.003), and log-transformed urinary protein:creatinine ratio in g/g 0.266 (0.124, 0.408) were independently associated with elevated D-dimer levels. Conclusion: D-dimer levels are commonly raised in the nephrotic syndrome in the absence of clinically evident thrombosis, and are independently associated with age, degree of proteinuria and serum albumin, but not with eGFR. Baseline levels of D-dimer did not predict subsequent episodes of clinically evident thrombosis after 2 years of follow-up.

Catheter-based renal nerve ablation (CBRNA) is a promising new approach to reducing blood pressure in human patients with drug-resistant hypertension.1 The concept behind the method was derived from many decades of work in laboratory animals that showed the significant effect of renal nerves on blood pressure regulation in experimental hypertension and the physiological mechanisms underlying that effect.2 Early indications of efficacy of CBRNA in human trials, however, led to an explosion of interest in the procedure and its rapid application to thousands of patients worldwide.3 Most studies have appropriately focused on the clinical efficacy and safety of the procedure. On the other hand, comparatively little attention has been paid to identifying the specific physiological mechanisms responsible for the persistent fall in blood pressure seen in some (but not all) patients. A highly publicized recent report4 on the first prospective, double-blind, randomized, sham-controlled trial in patients with severe resistant hypertension (Symplicity HTN-3) showed that CBRNA failed to lower blood pressure significantly more than a sham procedure. The report has re-energized consideration of the physiological conditions under which the renal nerves are most likely to affect blood pressure in hypertension and the mechanisms responsible. It also has brought to the foreground questions about precisely how much renal nerve damage is necessary to meaningfully affect blood pressure in hypertensive subjects. Two articles appearing in this issue of the Journal, one by Henegar et al. 5 and one by Linz et al.,6 report data from experimental animal studies that shed significant new light on these issues. The most directly germane is the study by Henegar et al.5 These investigators used a well-characterized dog model of hypertension and a catheter device designed for human applications (St. Jude Medical EnligHTN system) to investigate the acute and chronic effects of renal denervation on blood pressure and other relevant physiological variables. Several valuable features of the study design deserve mention. First, renal denervation was performed in dogs with established hypertension. In most previous work on renal denervation in laboratory animals, denervation was done before the onset of hypertension. The approach used by Henegar et al. is more clinically relevant and recognizes the well-known fact that many interventions that mitigate hypertension development have little or no effect on blood pressure once hypertension is established. Second, the dogs were made hypertensive by high-fat feeding; this has clinical relevance because many patients with drug-resistant hypertension are overweight.7 Third, the investigators did a thorough job of quantifying the damage to the renal nerves caused by the ablation procedure using both histology and measurement of renal content of norepinephrine. This is important because at present it is not clear how much damage to the renal nerves is necessary to affect blood pressure, and similar quantification is not possible on a routine basis in the clinical setting. Last, but not least, blood pressure measurements were performed using repeated sampling for 18 hours a day for the duration of the study. This kind of recording (roughly equivalent to ambulatory measurements in humans) is critical to detect the small changes in blood pressure typically seen after renal denervation. The main findings of the Henegar et al. study were that CBRNA lowered BP significantly and persistently in obese hypertensive dogs without a major change in renal function and that this was associated with relatively modest damage to the renal nerves (approximately 42% loss as assessed by histology or norepinephrine content). Although the experiments were not designed specifically to explore the mechanisms responsible for the fall in blood pressure, some of the data collected are informative. No significant changes in heart rate, glomerular filtration rate, plasma renin activity, extracellular fluid volume, plasma volume (estimated from plasma protein concentration), plasma aldosterone, or plasma cortisol were found after CBRNA. Interestingly, the fall in blood pressure did not reach a peak steady-state value until several days after the procedure, suggesting the involvement of more slowly acting blood pressure control mechanisms. Similarly detailed time-course data are virtually absent from clinical studies. It is of substantial importance that only partial loss of renal nerve integrity was required to significantly reduce blood pressure in this study. Moreover, there was a trend (although not statistically significant) for the antihypertensive effect of CBRNA to correlate with the degree of denervation. A noteworthy limitation of all human trials of CBRNA to date (including Symplicity HTN-3) is a lack of data on the completeness of denervation. The little evidence we have in human patients indicates that denervation is far from complete, even when the procedure is performed by experts.8 This could be a major factor in explaining why blood pressure responses vary widely between patients. A logical (although not necessarily correct) assumption is that the magnitude of fall in blood pressure after CBRNA in any given subject will depend on the degree to which their blood pressure is being controlled by physiological mechanisms responsive to renal sympathetic nerve activity (RSNA) (e.g., renin release, sodium reabsorption, and renal vascular resistance). Elegant investigations in human subjects by Esler and colleagues reveal that RSNA is increased in some, but not all, patients with essential hypertension.9 To our knowledge there is no direct evidence for renal sympathetic overactivity in drug-resistant hypertension, but such patients often are obese, and many obese individuals have elevated RSNA.10 One clear link between obesity, sympathetic overactivity, and hypertension is obstructive sleep apnea (OSA),11 a prevalent condition in patients with drug-resistant hypertension.12 Therefore it is important to determine the impact of the renal sympathetic nerves on physiological responses to OSA, including systemic blood pressure. This was the goal of a paper by Linz et al. 6 They used an acute model of OSA in anesthetized pigs that involved repetitive obstruction of the trachea with negative pressure (NTP) every 15 minutes for 4 hours. They continuously recorded blood pressure and renal and femoral blood flow and determined plasma renin activity, plasma aldosterone, urinary protein/creatinine ratio, and glomerular filtration rate several times during the 4-hour protocol. In a subgroup of pigs, the effects of NTP were investigated after renal denervation was performed using the standard surgical approach of stripping away visible nerves and applying a phenol solution to the perivascular region. Another group of pigs was pretreated with the angiotensin receptor blocker irbesartan before being subjected to NTP. The results were striking: although the interapneic values of the measured variables were not affected by renal denervation, the marked postapneic increases in blood pressure and renal vascular resistance seen in untreated pigs were significantly attenuated by renal denervation (but not by irbesartan). Likewise, the gradual increments in plasma renin activity, plasma aldosterone, and urinary protein/creatinine ratio seen in control pigs during repetitive NTP were nearly eliminated in pigs with renal denervation. Although this was an acute protocol and renal denervation was surgical rather than by catheter, the results highlight some important issues discussed earlier. First, the findings support the common-sense view that the magnitude of any physiological response to renal denervation will depend on the level of renal sympathetic activity at the time of denervation. Accordingly, identification of patients likely to respond to CBRNA should include consideration of other pathologies (such as obesity and OSA) that are associated with increased RSNA. Second, it is notable that a large component of the systemic blood pressure response to NTP appears to depend on neurogenic changes in renal vascular resistance (femoral resistance changed very little). This suggests that under some conditions the mechanism of the antihypertensive response to CBRNA may simply be a reduced contribution of the renal vasculature to total peripheral resistance. Of course the impact of renal denervation on hormones and renal injury in this study also identify other potential mechanisms by which renal nerves could influence long-term blood pressure regulation. Collectively these articles show that well-designed, animal-based experimental physiology can importantly complement the results of clinical trials and clinical research in our efforts to establish the clinical utility (if any) of CBRNA in treating hypertension.

Background Measurement of protein excretion is not only used for diagnostic purpose but also to monitor disease severity and prognosis in children with nephrotic syndrome (NS). The common method to measure proteinuria is 24-hour urine collection. However, 24-hour urine collection is cumbersome, time consuming, and tedious. An alternative simplified method is the measurement of protein/creatinine ratio in single-voided urine specimens. Objective The aim of this study was to determine whether urine protein/creatinine ratio is accurate to predict pathologic (> 100 mg/m2/day) and massive proteinuria (> 1 g/m2/day). Methods Seventy single voided and 24-hour urine specimens were collected from children aged 3-18 years. The relationship between urinary protein/creatinine ratio and total daily protein excretion was calculated using correlation and linear regression analysis. Diagnostic test was conducted to estimate the accuracy of protein/creatinine ratio for the diagnosis of pathologic and massive proteinuria in NS. Results Correlation coefficient between quantity of protein in 24-hour urine specimens and protein/creatinine ratio in singlevoided urine specimens was 0.96 (R2=0.93). Both sensitivity and specificity of urinary protein/creatinine ratio were 87% in diagnosing pathologic proteinuria, whereas the sensitivity and specificity of the ratio to predict massive proteinuria were 88% and 91%, respectively. Conclusion The urinary protein/creatinine ratio in single voided urine specimen has a good accuracy to predict pathologic and massive proteinuria in children with NS aged 3-18 years.

Study Objective. To compare the renoprotective and blood pressure-lowering effects of combination losartan-low-dose hydrochlorothiazide with losartan alone in hypertensive patients with stage 3 chronic kidney disease (CKD). Design. Prospective, open-label, randomized, controlled study. Setting. Outpatient clinic at a university-affiliated hospital in Japan. Patients. Sixty adults (mean age 67 yrs) with stage 3 CKD who had been receiving losartan 50 mg/day and had not achieved their target blood pressure of 130/80 mm Hg. Intervention. Patients were randomly assigned to receive combination losartan 50 mg-hydrochlorothiazide 12.5 mg/day in addition to losartan 50 mg/day (combination therapy group, 30 patients) or to receive losartan 100 mg/day (control group, 30 patients) over a 24-week period. Measurements and Main Results. Efficacy was determined by monitoring clinical and laboratory parameters. Mean baseline systolic and diastolic blood pressures were 158/90 mm Hg in both groups; at 24 weeks of treatment, these blood pressures significantly decreased to 133/79 mm Hg in the combination therapy group compared with both baseline and the values in the control group (145/83 mm Hg). Although serum creatinine concentration increased and the estimated glomerular filtration rate decreased significantly in both groups, the urinary protein:creatinine ratio was significantly lower in the combination therapy group. With stratification of patients on the basis of whether they had diabetes mellitus, we found that the reduction in the urinary protein:creatinine ratio was more evident in the combination therapy group. No significant increase in the occurrence of adverse metabolic effects was noted in either group. Conclusion. In these hypertensive patients with stage 3 CKD, combination therapy with the maximum recommended daily dose of losartan of 100 mg and a low dose of hydrochlorothiazide of 12.5 mg ameliorated proteinuria and reduced blood pressure more effectively than treatment with losartan 100 mg alone, irrespective of whether the patients had diabetes.

Hypertension causes proteinuria and is an important factor in the progress of renal dysfunction. Increases in various proteins in urine are caused by malfunction of the glomerulus and the renal tubules. In the present study, the effects of hypertension on urinary excretion levels of various proteins were investigated to show the tubular cell malfunction in hypertensive patients.The subjects included 55 non-diabetic hypertensive patients without previous treatment and 42 normotensive individuals without microalbuminuria. Total urinary protein/creatinine ratio was measured, and urinary proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).Total urinary protein/creatinine ratio was higher in hypertensive patients than in normotensive individuals (122.0+/-11.0 vs. 60.6+/-3.1 mg/gCr; p0.001). SDS-PAGE resolved 15 protein fractions from the urine of both groups. Thirteen fractions were more intensely stained in samples from the hypertensive than from the normotensive. Two fractions did not differ between the groups. Hypertension increased the urinary excretion of various proteins including proteins of less than 40 kDa, called tubular proteins, in addition to albumin.Hypertension differently influenced the excretion of each urinary protein fraction. Tubular malfunction should be considered in hypertensive patients in addition to glomerular malfunction.

Summary Aims Advanced glycation end products (AGE), which form from the non-enzymatic reaction of proteins and sugars, have been implicated in the pathogenesis of diabetic nephropathy. Recently, a compound [N-phenacylthiazolium bromide (PTB)] has been described which cleaves α,β-dicarbonyl compounds. In the present study we used diabetic C57BL/6 mice to determine if PTB altered renal AGE levels and reduced diabetic glomerulosclerosis. Methods Mice with stable hyperglycaemia induced by streptozotocin were given daily subcutaneous injections of either PTB (10 μg/g) or saline for 12 weeks. Renal-collagen bound AGE and urinary AGE-peptides were measured by ELISA using an anti-AGE-RNase antibody. Renal collagen-released Ne(carboxymethyl)lysine (CML) and pentosidine were determined by high pressure liquid chromatography (HPLC). Glomerular lesions (volume and mesangial/total surface area) were evaluated by computer-assisted image analysis. We determined urinary protein/creatinine ratio as a functional parameter. AGE localization was examined by immunohistochemistry using the anti-AGE-RNase antibody. Results Renal collagen-bound AGE were decreased and urinary AGE excretion was increased in PTB-treated diabetic mice. However, collagen-released CML and pentosidine were similar in both groups. Glomerular histology and morphometric analysis revealed also no differences between PTB-and saline-treated diabetic mice. The urinary protein/creatinine ratio was unaffected by PTB-treatment. AGE staining by anti-AGE-RNase antibody was present in Bowman's capsules, glomerular basement membranes and cortical tubules. It was decreased in all structures in PTB-treated diabetic mice. Conclusion In summary, PTB decreased renal AGE accumulation but did not ameliorate glomerular lesions or proteinuria. Thus, cleavage of AGE by PTB is not sufficient to prevent development of diabetic nephropathy in C57BL/6 mice.

Increased severity of glomerulonephritis in C-C chemokine receptor 2 knockout mice. Background The C-C chemokine receptor 2 (CCR2) is expressed on monocytes and facilitates monocyte migration. CCR2 is a prominent receptor for monocyte chemoattractant protein-1 (MCP-1). This chemokine recruits monocytes to sites of inflammation. It has been suggested that CCR2 and its ligand, MCP-1, play a role in the pathogenesis of glomerulonephritis. The goal of this study was to determine the contribution of CCR2 in a murine model of accelerated nephrotoxic nephritis. We measured the extent of development of renal disease in CCR2 wild-type and knockout mice after the administration of antiglomerular basement membrane antibody. Methods Eight groups of animals were treated ( N = 10 per group). Four days after IgG immunization, CCR2 wild-type and knockout mice received control serum or nephrotoxic serum. The urinary protein/creatinine ratio was measured on days 1 and 3; plasma and kidneys were collected on days 4 and 7. Kidneys were evaluated by light microscopy, immunohistochemistry, and immunofluorescence. The genotype of mice was confirmed by tissue analysis. Results Protective effects of CCR2 knockout on the urinary protein/creatinine ratio were observed on day 1, as values for this parameter were significantly lower (35 ± 3.6) than in nephritic wild-type mice (50 ± 6.8). There was a marked increase in proteinuria in nephritic wild-type mice on day 1 compared with vehicle-treated, wild-type animals (5 ± 1.0). On day 3, the ameliorative effects of CCR2 knockout were not observed; the increase in the urinary protein/creatinine ratio was similar in nephritic CCR2 wild-type (92 ± 11.2) and knockout mice (102 ± 9.2). Plasma markers of disease were evaluated on days 4 and 7. At these time points, there were no beneficial effects of CCR2 receptor knockout on plasma levels of urea nitrogen, creatinine, albumin, or cholesterol. On day 7, blood urea nitrogen (248 ± 19.9 mg/dL) and plasma cholesterol were higher in nephritic CCR2 knockout mice than in wild-type mice (142 ± 41.7 mg/dL) that received nephrotoxic serum. Histopathologic injury was more severe in nephritic CCR2 knockout mice than nephritic wild-type mice on day 4 (3.1 ± 0.3 vs. 2.0 ± 0.3) and day 7 (3.6 ± 0.2 vs. 2.9 ± 0.3). By immunohistochemical analysis at day 4, there were significantly fewer mac-2–positive cells, representative of macrophages in the glomeruli of nephritic CCR2 knockout (2.1 ± 0.6) mice than nephritic wild-type (3.9 ± 0.5) animals. By indirect immunofluorescence, there was a moderate, diffuse linear IgG deposition of equivalent severity present in glomeruli of both wild-type and CCR2 knockout nephritic mice. Conclusion These results suggest that our strategy was successful in reducing macrophage infiltration, but this model of glomerulonephritis is not solely dependent on the presence of CCR2 for progression of disease. After a transient ameliorative effect on proteinuria, CCR2 knockout led to more severe injury in nephritic mice. This raises the intriguing possibility that a CCR2 gene product ameliorates glomerulonephritis in this murine model. Although effects that occur in chemokine knockout mice are not equivalent to those expected with prolonged use of a chemokine antagonist, this study may nevertheless have implications for consideration of long-term use of chemokine antagonists in renal disease.

BACKGROUND: Podocyte depletion causes glomerulosclerosis, and persistent podocyte loss drives progression to ESKD. Urinary sediment podocin (u-sed Pod) mRNA excretion and urinary supernatant podocalyxin (u-sup PCX) protein have been used to monitor disease activity in glomerular diseases. However, the differences in these markers among pathologies have not been investigated. We examined the roles of these markers in kidney diseases. METHODS: From January 2013 to March 2016, early morning urine samples were collected from 12 healthy controls and 172 patients with kidney disease (n=15 patients with minor glomerular abnormality with mild proteinuria and/or microscopic hematuria, n=15 with minimal change nephrotic syndrome [MCNS], n=15 with membranous nephropathy [MN], n=60 with IgA nephropathy [IgAN], n=19 with crescentic GN [Cres GN], n=10 with lupus nephritis [LN], and n=38 with other kidney diseases). We examined u-sed Pod mRNA excretion, u-sup PCX protein, and the urinary protein-creatinine ratio (u-PCR). RESULTS: u-sed Pod mRNA excretion was significantly correlated with u-sup PCX protein (r=0.37, P

We present a case of pseudo–acute kidney injury (AKI) following capmatinib therapy in an 84-year-old man with combined non–small cell (adenocarcinoma) and small cell lung cancer with MET exon 14–skipping mutation. His past medical history was significant for chronic kidney disease stage 3 with a baseline serum creatinine (Scr) of 1.6 mg/dL rising to 2.44 mg/dL (estimated glomerular filtration rate [GFR] 24 mL/min/1.73 m2) while on capmatinib. Scr improved to 1.84 mg/dL with the cessation of capmatinib but rose again to 2.22 mg/dL upon resumption of therapy. Further investigation with cystatin C and renal iothalamate clearance showed that despite fluctuation in Scr levels, there was not much variation in GFR calculated using these methods. Urinalysis and urinary protein-creatinine ratio were unremarkable. Treatment with capmatinib was continued at reduced dose and a third instance of rise in Scr was observed, followed by a spontaneous return to baseline. Thus, MET inhibitor therapy can result in an asymptomatic rise in Scr, and it must be distinguished from AKI with more accurate non–creatinine-based methods to evaluate GFR. This could spare such patients from invasive diagnostic tests, such as a kidney biopsy, and premature cessation of prognostically important cancer therapies.

Nephrotic syndrome (NS) is a glomerular disease that is most often found in children with proteinuric as clinical manifestation. Gambier extract is a traditional medicine that has antioxidant effect. Its use to treat proteinuric has never been done. Therefore, we conducted an analytical study on the effect of gambier on proteinuric and superoxide dismutase (SOD) activity in proteinuric Wistar rat’s model. This research is an experimental study with a posttest control group design. The aim is analyzing the effect of giving gambier extract in decreasing urinary protein creatinine ratio and increasing SOD activity. Male Wistar rats were given an injection of puromycin aminonucleoside 1.5mg/100g body weight (BW), subcutaneously for 5 consecutive days for being nephrosis. The experimental animals in this study were divided into four groups: K1, the control group, consist of group of rats that were injected with 0.15ml/100 g BW of aquabidest and not given gambier extract. While K2 group consist of rats induced by Puromycin and given 1 ml of aquabidest. K3 consist of groups of rats induced by Puromycin and then given gambier extract 26mg/200g BW. Group K4 consist of rats induced by Puromycin and then given 80mg/200g BW of gambier extract. The four groups were given treatment for 14 days, after which the rats were placed in a metabolic cage for 24 hours to collect urine samples and then knocked down with ketamine for intra-cardiac blood collection. The results of this study showed differences between the four groups of rats in terms of the mean urine protein/creatinine ratio (p=0.015) and SOD activity (p=0.036). Groups of rats that were given gambier extracts 80mg/200g BW had lower urine protein / creatinine ratio and higher SOD activity. Therapy of gambier 80 mg/200g BW is better in managing proteinuric compared to 26mg/200g.

Introduction. Percentage of galactose-deficient IgA1 (Gd-IgA1) relative to total IgA in serum was recently reported to correlate with proteinuria at time of sampling and during follow-up for pediatric and adult patients with IgA nephropathy. We sought to determine whether this association exists in another cohort of pediatric patients with IgA nephropathy.Methods. Subjects were younger than 18 years at entry. Blood samples were collected on one or more occasions for determination of serum total IgA and Gd-IgA1. Gd-IgA1 was expressed as serum level and percent of total IgA. Urinary protein/creatinine ratio was calculated for random specimens. Spearman’s correlation coefficients assessed the relationship between study variables.Results. The cohort had 29 Caucasians and 11 African-Americans with a male : female ratio of 1.9 : 1. Mean age at diagnosis was 11.7 ± 3.7 years. No statistically significant correlation was identified between serum total IgA, Gd-IgA1, or percent Gd-IgA1 versus urinary protein/creatinine ratio determined contemporaneously with biopsy or between average serum Gd-IgA1 or average percent Gd-IgA1 and time-average urinary protein/creatinine ratio.Conclusion. The magnitude of proteinuria in this cohort of pediatric patients with IgA nephropathy was influenced by factors other than Gd-IgA1 level, consistent with the proposed multi-hit pathogenetic pathways for this renal disease.

The study was carried out to evaluate the possible effects of hormone replacement therapy (HRT) on renal functions in postmenopausal women.A total of 85 postmenopausal women without a history of medical illness were enrolled in the study. They were divided into HRT users and control groups. After 30 weeks of HRT use, the changes in serum urea, creatinine, uric acid, urinary protein, urinary creatinine, urinary protein/creatinine ratio and glomerular filtration rate (GFR) (mL/min/1.73 m(2)) were evaluated.HRT was associated with statistically significant increases in glomerular filtration rate (p0.01), while serum urea, creatinine, uric acid, urinary protein, urinary creatinine and urinary protein/creatinine ratio did not change significantly in both groups.In our study, we suggested that usage of hormone replacement therapy appeared to affect renal functions in postmenopausal women. There were beneficial effects of HRT on GFR in our postmenopausal patients. HRT may have possible protective mechanisms for kidney against adverse effects of aging.

Proteinuria evaluation is important for the differential diagnosis of renal disease and the assessment of prognosis and response to therapy. Qualitative proteinuria correlates poorly with quantitative 24-hour protein levels because of hydration and methodologic problems associated with observer error. The authors automated quantitative urinary protein and osmolality measurements and evaluated whether a urinary protein-osmolality ratio (mg/L/mOsm/kg) in the random urinalysis predicts the 24-hour urine protein level. They compared this ratio with the (1) 24-hour protein levels in 78 normal women and 53 normal men; (2) 24-hour protein levels in 129 proteinuric patients; and (3) urinary protein-creatinine ratio in 131 normal patients and 105 proteinuric patients. The normal urinary protein-osmolality ratio was less than 0.12 (sensitivity, 96%; specificity, 93%). This compared to a urinary protein-creatinine ratio of less than 0.05 (sensitivity, 96%; specificity, 90%). A urinary protein-osmolality ratio of greater than 2.5 indicates a level of more than 3.0 g/24 hour (sensitivity, 91%; specificity, 98%). The urinary protein-osmolality ratio = 1.12x + 0.05 (r = 0.88), where x = 24-hour protein. The authors conclude that the quantitative urinary protein-osmolality ratio is better than a qualitative urinalysis and urinary protein-urinary creatinine ratio for detecting or assessing abnormal proteinuria and allows for a reasonable prediction of 24-hour protein levels.

Data reproducibility and single-center bias are concerns in preclinical research and compromise translation from animal to human. Multicenter preclinical randomized controlled trials (pRCT) may reduce the gap between experimental studies and RCT and improve the predictability of results, for example Jak1/2 inhibition in lupus nephritis. To evaluate this, we conducted the first pRCT in the kidney domain at two Spanish and two German academic sites. Eligible MRL/MpJ-Faslpr mice (female, age13-14 weeks, stress scores of less than two and no visible tumor or signs of infection) were equally randomized to either oral treatment with the Jak1/2 inhibitor baricitinib or vehicle for four weeks. Central blinded histology analysis was performed at an independent fifth site. The primary endpoint was the urinary protein/creatinine ratio. Baricitinib treatment did not significantly affect proteinuria, histological markers of activity and chronicity, or the glomerular filtration rate but significantly improved plasma autoantibody levels and lymphadenopathy. Data heterogeneity was noted across the different centers referring in part to phenotype differences between MRL/MpJ-Faslpr mice bred at different sites, mimicking well patient phenotype diversity in lupus trials. Multicenter pRCT can overcome single-center bias at the cost of increasing variability and reducing effect size. Thus, our pRCT predicts a low effect size of baricitinib treatment on human lupus nephritis in heterogeneous study populations.

We examined the relative feasibility of using random urinary dipstick testing and urinary protein/creatinine ratios in the quantitation of proteinuria. Sixty-four children with relapsing nephrotic syndrome, ranging in age from 1 1/2 to 16 years, contributed 145 timed urine collections and 150 random specimens, which were analyzed by urinary protein dipstick, quantitation of protein and creatinine, or both. Total protein excretion was expressed as grams per surface area per day and the urinary protein/creatinine ratio as milligrams of protein per milligram of creatinine. Degrees of proteinuria were designated as physiologic (less than 0.1 gm/m2/day), intermediate (greater than 0.1 and less than 1.0 gm/m2/day), or nephrotic (greater than 1.0 gm/m2/day). The log regression analysis of the 24-hour urinary protein/creatinine ratio (y) and total protein excretion (x) was highly significant (r = 0.97; p less than 0.001). The upper and lower confidence limits of the urinary protein/creatinine ratio (1.0 and 0.1, respectively) closely approximated the designations for nephrotic and physiologic proteinuria, respectively. These values were therefore used to classify degrees of proteinuria by the urine protein/creatinine ratio. The validity of these tests was assessed by sensitivity, specificity, and predictive value, and compared with that of random testing by urinary dipstick. The urinary protein/creatinine ratio offered good reliability as a test for classifying degrees of proteinuria and accurately predicting nephrotic and physiologic proteinuria. The random dipstick testing was reliable only when results were distinctly positive and when sensitivity and specificity were low. The error in the total protein excretion value that was imposed by collection errors with high and low variations in the creatinine value (57% of samples) was largely corrected by normalization of the data by log transformation. When controlled for creatinine excretion, linear regression analysis allowed calculation of total protein excretion (TP) from the urinary protein/creatinine ratio (U P/Cr) by the following equation: TP (gm/m2/day) = 0.63 (U P/Cr) at all levels of proteinuria. The random urinary protein/creatinine ratio appeared to offer the most sensitive test for classification of proteinuria in children with nephrosis, with the advantages of ease and expediency not afforded by the 24-hour urine quantitation.

In patients with a single functioning kidney, renal function was assessed at regular intervals over a period of 10 years. Serum creatinine, glomerular filtration rate (GFR), blood pressure, and urinary protein–creatinine ratio were assessed at the age of 2, 5 and 10 years. Between January 1980 and December 2005, 99 such patients were diagnosed in the first year of life. They were divided into three groups: A, patients with multicystic kidney disease and a normal contralateral kidney (n = 36); B, patients with a normal solitary kidney without uropathy (n = 20); and C, patients with obstructive uropathy and one nonfunctioning kidney (n = 43). Serum creatinine levels increased significantly with increasing age in every group. In group C, serum creatinine was significantly elevated compared with group A in all age categories (p = 0.043, p = 0.019, p = 0.001 respectively). Median figures of GFR remained within normal limits over the 10-year period. GFR was significantly lower in group C compared with group A (p = 0.001, p = 0.009, p = 0.019 respectively) and B in all age categories (p = 0.013, p = 0.002, p = 0.016 respectively). There were no changes in blood pressure over time and no differences among the three groups were observed. At the age of 10 years, the patients in group C had a significantly higher median urinary protein–creatinine ratio (p = 0.022) than those in groups A and B. There was also an increasing level of proteinuria with increasing age in group C (p = 0.002). In conclusion, renal function was stable over time in all patients, but children with obstructive uropathy have a lower median GFR and higher serum creatinine level for the whole study period. Hypertension was exceptionally observed in group C, with obstructive uropathy, as was an elevated urinary protein–creatinine ratio.

Diabetic nephropathy (DN) is one of the major complications of diabetes and contributes significantly towards end-stage renal disease. Previous studies have identified the gene encoding carnosinase (CN-1) as a predisposing factor for DN. Despite this fact, the relationship of the level of serum CN-1 and the progression of DN remains uninvestigated. Thus, the proposed study focused on clarifying the relationship among serum CN-1, indicators of renal function and tissue injury, and the progression of DN. A total of 14 patients with minimal changes disease (MCD) and 37 patients with DN were enrolled in the study. Additionally, 20 healthy volunteers were recruited as control. Further, DN patients were classified according to urinary albumin excretion rate into two groups: DN with microalbuminuria (n = 11) and DN with macroalbuminuria (n = 26). Clinical indicators including urinary protein components, serum carnosine concentration, serum CN-1 concentration and activity, and renal biopsy tissue injury indexes were included for analyzation. The serum CN-1 concentration and activity were observed to be the highest, but the serum carnosine concentration was the lowest in DN macroalbuminuria group. Moreover, within DN group, the concentration of serum CN-1 was positively correlated with uric acid (UA, r = 0.376, p = 0.026) and serum creatinine (SCr, r = 0.399, p = 0.018) and negatively correlated with serum albumin (Alb, r = − 0.348, p = 0.041) and estimated glomerular filtration rate (eGRF, r = − 0.432, p = 0.010). Furthermore, the concentration of serum CN-1 was discovered to be positively correlated with indicators including 24-h urinary protein–creatinine ratio (24 h-U-PRO/CRE, r = 0.528, p = 0.001), urinary albumin-to-creatinine ratio (Alb/CRE, r = 0.671, p = 0.000), urinary transferrin (TRF, r = 0.658, p = 0.000), retinol-binding protein (RBP, r = 0.523, p = 0.001), N-acetyl-glycosaminidase (NAG, r = 0.381, p = 0.024), immunoglobulin G (IgG, r = 0.522, p = 0.001), cystatin C (Cys-C, r = 0.539, p = 0.001), beta-2-microglobulin (β2-MG, r = 0.437, p = 0.009), and alpha-1-macroglobulin (α1-MG, r = 0.480, p = 0.004). Besides, in DN with macroalbuminuria group, serum CN-1 also showed a positive correlation with indicators of fibrosis, oxidative stress, and renal tubular injury. Taken together, our data suggested that the level of CN-1 was increased as clinical DN progressed. Thus, the level of serum CN-1 might be an important character during the occurrence and progression of DN. Our study will contribute significantly to future studies focused on dissecting the underlying mechanism of DN.

Background: Lupus nephritis (LN) is a common and serious manifestation of SLE, occurring in more than half of patients with SLE during their course of illness, in 10–25% of such patients, kidney disorder progresses to end-stage renal disease (ESRD). Objective: To determine the predictors of remission in patients with biopsy-proven lupus nephritis, and to assess the long-term renal remission rate in our lupus nephritis patients. Patients and Methods: This is a retrospective observational study carried out at the Rheumatology and Nephrology Units, Internal Medicine Department, Menoufia and Mansoura Universities Hospitals, Egypt for a 1-year duration between 1 June 2019 and 1 June 2020. A total of 60 patients with biopsy-proven LN were studied. Results: In the current study, after six months of follow-up, about two-thirds of patients achieved remission. The urinary protein creatinine ratio (UPCR) of 4.9 g/g, systemic lupus erythematosus disease activity index (SLEDAI) of 20 and Hb of 8.8 g/dl at the third month are valuable for predicting remission at the sixth month in active lupus nephritis. On multivariate analysis, serum creatinine (SCr) at the time of diagnosis is the only independent predictor of remission (complete or partial) at 6 months. According to the receiver operating characteristic curve, the cut-off value of SCr ≤ 2.9 mg/dL with 100% specificity and 98 % sensitivity was a predictor for renal remission. Conclusion:The UPCR of 4.9 g/g, SLEDAI of 20 and Hb of 8.8 g/dl at the third month are valuable for predicting remission at the sixth month in active lupus nephritis. Serum creatinine level ≤2.9 mg/dL at the time of diagnosis was the only independent predictor of complete remission at 6 months.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics may exert synergistic antiproteinuric effects. Eighteen patients with a proteinuria >1 g/24 h after 6 mo of treatment with ramipril at 5 mg/d were assigned to receive in random order ramipril at 10 mg/d, valsartan at 160 mg/d, or combined ramipril at 5 mg/d and valsartan at 80 mg/d in addition to their antihypertensive treatment. The treatment periods lasted 4 wk and were separated by a 4-wk washout with ramipril at 5 mg/d. At the end of this crossover sequence, patients received combined ramipril at 5 mg/d, valsartan at 80 mg/d, and an increased furosemide dosage for an additional 4-wk period. The primary end point was the urinary protein/creatinine ratio for two 24-h urine collections at the end of each treatment period. No significant differences were noted between the study end points of the ramipril 10, valsartan 160, and combined ramipril 5 and valsartan 80 treatment groups. However, the urinary protein/creatinine ratio was lower with combined ramipril 5 and valsartan 80-increased furosemide dosage than with valsartan 160 and combined ramipril 5 and valsartan 80, with a similar tendency compared with ramipril 10. Combined ramipril 5 and valsartan 80-increased furosemide dosage decreased systolic home BP and increased serum creatinine but did not significantly increase the number of symptomatic hypotension cases compared with the other three treatments. Thus, in patients with severe proteinuria and hypertension, a cautious increase in diuretic dosage in addition to combined angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decreases proteinuria and BP but may expose the patient to prerenal failure.

Background Measurement of proteinuria in women with hypertensive disorders of pregnancy is of major importance in the diagnosis and management of preeclampsia. Urinary protein/creatinine ratio, which is commonly used to detect kidney damage in preeclampsia, suffers from important analytical limitations, including poor harmonization of results between laboratories. Adoption of albuminuria could help reduce interlaboratory bias, since methods used to quantify it are better harmonized. Methods A total of 27 urinary samples collected from hypertensive women evaluated for preeclampsia were sent to four different clinical laboratories in Canada. Urinary proteins and albumin as well as urinary creatinine were measured in duplicates in one batch to calculate protein/creatinine (PCR) and albumin/creatinine (ACR) ratio. Statistical analyses were done to evaluate interlaboratory variability of urinary proteins and urinary albumin. Results Interlaboratory bias for urinary proteins ranged from 64.7% at low concentration to 3.9% at higher concentrations. In contrast, urinary albumin interlaboratory bias ranged from 29.2% to 4% from low to high concentrations. Coefficient of variation for urinary proteins reached a maximum of 91.5% in lower concentration while urinary albumin highest value was 42.7%. When looking at PCR and ACR ratio, eight samples had PCR measurement range that contained the diagnostic threshold used to detect kidney damage in HDP (30 mg/mmol), while only four samples had ACR ratio measurement range that contained the diagnostic threshold used outside of pregnancy in Canada (2 mg/mmol). Conclusion Interlaboratory bias was lower for urinary albumin measurement compared to urinary proteins in hypertensive women evaluated for preeclampsia. Better harmonization with the use of albumin instead of protein measurement would reduce instances where results of different laboratories lead to opposite diagnosis of kidney damage in pregnancy.

Background: Angiotensin II-Receptor Blockers (ARBs) has a questionable nephroprotective effect especially in diabetic nephropathy. Nephrin protein molecules exist in the slit diaphragm of the glomerular filtration membrane and control the passage of plasma protein. Aim of Study: To examine the possible role of Nephrin in the pathogenesis of diabetic nephropathy and the protective effect of ATII-RB (candesartan) on diabetic nephropathy. Material and Methods: Thirty-two male rats were used in this experiment. Half of the rats were fed a high-fat diet (HFD) and the other half were fed a standard diet for 4 weeks. A model of diabetic nephropathy (DN) was created by a 35mg/kg intraperitoneal dose of Streptozotocin (STZ) in the HFD-fed rats. Then the rats were divided into four groups (8 rats/group). (1) Normal control (NC) group; (2) Diabetic nephropathy (DN) group; (3) ARB-treated NC group: Normal rats were treated with the ARB (Candesartan Cilexetil), in a dose 0.1mg/kg; (4) ARB-treated DN group: The rats with DN and received the above dose of candesartan for 4 weeks. The urine was collected to measure the urine flow rate, urinary concentrations of Nephrin, creatinine, and protein. Blood samples were used to measure urea, creatinine, glucose, insulin, and the homeostatic model assessment (HOMA-IR). Then renal tissue samples were used to measure Superoxide dismutase (SOD) activity and Malondialdehyde (MDA) in addition to histopathological examination. The mean arterial blood pressure (MABP) was also recorded. Results: Candesartan treatment in the DN group showed significant reductions of glucose, HOMA-IR, amelioration of renal antioxidant system, reductions in creatinine, reduction of proteinuria, reduction of urinary Nephrin, and MABP. Histological improvement was also detected in the form of mild glomerulosclerosis and interstitial fibrosis. The urinary Nephrin was 90 times high in the condition of DN. This huge rise of urinary Nephrin was significantly reduced by Cande-sartan treatment. Moreover, in the DN group the urinary Nephrin level showed a significant correlation with glucose level, serum creatinine, urinary protein-creatinine ratio, and MABP.Conclusion: ATII-RB could reduce urinary Nephrin ex-cretion and possibly alters its expression through its inhibitory effect on the reactive oxygen species, the Renin-Angiotensin-Aldosterone system and subsequently maintains the normal physiological activity of podocytes in rats with STZ-induced diabetic nephropathy.

Chronic kidney disease (CKD) is a disease characterized by the gradual and functional loss of renal mass, affecting its physiology leading to clinical manifestations. The CKD reaches dogs of several breeds causing important clinical alterations. Some laboratory tests are determinant for the correct diagnosis and thus for the implementation of the most appropriate treatment. The urinalysis, urinary protein-creatinine ratio (UPC) evaluation, urea, and creatinine dosage together with the symmetric dimethylarginine dosage (SDMA), urinary tract ultrasonography and blood pressure monitoring, are the main methods used for diagnosis. In this way, this work aimed to report a case of CKD in a Teckel dog attended at the Veterinary Hospital of the Federal University of Jataí (UFJ), discussing the main clinical manifestations, laboratory, and image alterations, as well as the correct staging according to IRIS (Interest Renal International Society), from which the best treatment option to be adopted is determined.

Introduction Clinical studies have indicated a relationship between diabetic nephropathy (DN) and the incidence and prevalence of renal cell carcinoma (RCC). However, the mechanism linking diabetic nephropathy and renal cell carcinoma has not yet to be identified. Methods In this study, a total of 42 male Sprague Dawley (SD) rats were randomly assigned to a DN group (n=35) and a control group (n=7). All animals in the DN group were unilaterally nephrectomized and treated with streptozotocin with the development of blood glucose levels >16.7mmol/L and dominant proteinuria and were compared to controls without such changes. Histopathologic alterations in the kidneys were examined by HE staining and Ki-67 immunohistochemistry. Differentially expressed genes were identified and validated by RNA-seq and PCR. Results As the results, except for two rats that failed to develop the DN model and were excluded from the analysis, 33 rats in the DN group with overt signs of DN demonstrated significantly higher food and water intake, urine production, and urine protein and urinary protein/creatinine ratio than controls. Overall, 15.2% (n=5/33) of DN animals developed RCC while none tumors were observed in the control group (n=0/7). RNA-seq analysis in these animals indicated different TRPV5 gene expression and calcium pathway expression in DN animals with developing tumors, when compared with animals with no obvious tumors. In addition, DN animals diagnosed with RCC showed increased expression of GLUT2 and c-met, when compared to controls and DN animals without tumors. Discussion In conclusion, the disordered calcium metabolism, especially disturbed TRPV5 mediated Ca2+ signal, may have been related to the development of RCC in DN rats. Further studies related to the detailed mechanism are still needed.

Objectives To compare membranous lupus nephritis (MLN) and proliferative lupus nephritis (PLN) with respect to survival, demographic, clinical and laboratory characteristics; and to investigate predictors of renal and patient survival. Methods Single-centre retrospective observational study. Patients with biopsy-proven PLN, MLN and mixed lupus nephritis were included. Groups were compared using appropriate statistical tests and survival was analysed through the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of renal and patient survival. Results A total of 187 patients with biopsy-proven lupus nephritis (135 with PLN, 38 with MLN and 14 with mixed LN) were followed for up to 42 years (median 12 years). There was a higher proportion of MLN amongst Afro-Caribbeans than amongst Caucasians (31% vs 15%, P = 0.010). Patients with MLN had significantly lower anti-dsDNA antibodies (P = 0.001) and higher C3 levels (P = 0.018) at diagnosis. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75 and 66% for PLN and 100, 97, 92 and 84% for MLN, respectively (P = 0.028). Cumulative patient survival at 5, 10, 15 and 20 years was 94, 86, 80 and 76%, with no difference between PLN and MLN. Urinary protein-creatinine ratio above 42 mg/mmol and eGFR below 76 ml/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to end-stage renal disease. eGFR below 77 ml/min/1.73 m2, at one year, development of end-stage renal disease and Afro-Caribbean ethnicity were associated with higher mortality. Conclusion Patients with MLN and PLN differ significantly regarding serological profiles and renal survival, suggesting different pathogenesis. Renal function at year one predicts renal and patient survival.

The use of renin-angiotensin system (RAS) inhibitors is standard of care in people with early to moderate chronic kidney disease (CKD). Less is known regarding the efficacy of RAS inhibitors in very advanced CKD. In this study, we describe patterns of use of RAS inhibitors and associations of these patterns of use with risk for CKD progression and mortality in patients with advanced CKD.Propensity-matched cohort study.We identified 678 participants who were enrolled in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rates (eGFRs) 30 mL/min/1.73 mUse of RAS inhibitors within the first year after the baseline visit, characterized by 4 patterns of use: never users, always users, dynamic users, and new users.Progression to end-stage renal disease (ESRD) and all-cause mortality.We generated propensity scores and matched participants in the always users group with a 1:1 ratio with a participant from the other 3 groups, matching by age, sex, race, diabetes, hypertension, systolic blood pressure, eGFR, urinary protein-creatinine ratio, and serum potassium level. Cox models were used to test the association of patterns of RAS inhibitor use with risk for kidney failure and death.Of the 678 participants with eGFRs 30 mL/min/1.73 mObservational study.Use of RAS inhibitors in patients with eGFRs 30 mL/min/1.73 m

It is hypothesized that chronic kidney disease (CKD) induces oxidant stress which contributes to the decline in kidney function. However, few studies have incorporated longitudinal designs and no studies have investigated this association among children. Using data from the Chronic Kidney Disease in Children (CKiD) study, we examined longitudinal associations between urinary biomarkers of oxidant stress, 8-OH deoxyguanosine (8-OHdG) and F2-isoprostane, and measures of renal function and blood pressure among children with CKD. Baseline levels of 8-OHdG were positively associated with estimated glomerular filtration rate (eGFR) over time and a log-unit increase in baseline 8-OHdG predicted a 5.68 ml/min/1.73 m2 increase in eGFR (95% Confidence Interval (CI): 3.75, 7.61). This association was attenuated when longitudinal measures of 8-OHdG were analyzed in relation to longitudinal eGFR (per log-unit increase in 8-OHdG, β = 0.81, 95% CI: 0.22, 1.39). Baseline 8-OHdG concentrations were also associated with decreased proteinuria over time, as measured by urinary protein:creatinine ratio. In addition, F2-isoprostane concentrations were associated with increases in eGFR, but only when baseline levels (vs. longitudinal levels) were considered in relation to longitudinal eGFR. There were no significant associations between either 8-OHdG or F2-isoprostane and blood pressure over time. Urinary measures of oxidant stress are not associated with worsening GFR over time. Our findings suggest that excretion of these biomarkers may be influenced by changes in glomerular and tubular function in varying patterns, which would limit their value in evaluating the impact of oxidant stress on CKD progression in children.

Background Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). Methods We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. Results Crohn’s disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9 years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100 mg/mmol in 70.8% of patients (mean 254 mg/mmol). Estimated glomerular filtration rate (eGFR) was >60 mL/min/1.73 m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1–2 and 38% C1–2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2 years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n = 3) or a >50% decrease in eGFR from initial values (n = 1). A similar evolution was observed in patients with primitive IgAN. Conclusions This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes.

Objectives Following intravascular hemolysis, free hemoglobin A is bound to haptoglobin (Hp), internalized by monocytes bearing the hemoglobin scavenger receptor, CD163, and broken down via the heme-oxygenase (HO)-1 enzyme into the cytoprotective metabolites biliverdin and carbon monoxide. This triggers an IL10 positive feedback loop which augments CD163 expression; thereby increasing hemoglobin scavenging capacity and limiting the vascular insult caused by oxidative free heme. During iatrogenic hemolysis caused by cardiopulmonary bypass, we have demonstrated that serum Hp is temporarily consumed while the surface CD163 and HO-1 expression is up-regulated. In homozygous sickle cell disease (HbSS), chronic hemolysis is linked with exhaustion of serum Hp and suppression of CD163 compared to HbAA controls. Our objective was to determine if the extent of Hp depletion correlates with the CD163 suppression and with select clinical features within the Barbadian HbSS population. Design & Methods Persons with HbSS were referred from private and public hematology clinics and support groups. Exclusion criteria were blood transfusion in the last three months, a sickle crisis in the last month and the use of oral corticosteroids, since these may affect CD163 expression. A history of painful crises, leg ulcers, renal compromise and pulmonary hypertension was ascertained. Urine samples were analyzed for albumin:creatinine ratio and echocardiograms were analyzed for the tricuspid regurgitant jet velocity (TRJV). Whole blood was collected in EDTA and analyzed by two color flow cytometry for the mean fluorescent intensity (MFI) of CD163 expression on gated CD14+ monocytes. Plasma Hp was analyzed by ELISA. The association between Hp concentration and CD163 was analyzed using median regression. The effect of Hp concentration on clinical outcome was explored using logistic regression, adjusting for the effects of age, sex, and total hemoglobin. Results Forty-eight persons with HbSS participated. Forty-seven percent of participants had at least one painful crisis in the past year and 28% of participants had a history of chronic leg ulceration. Forty-one persons had urinalysis, of these 44% of persons were diagnosed with renal compromise as defined by a urinary protein/creatinine ratio of >30mg/g; at least 15% had macro-albuminuria (urinary protein/creatinine ratio of >300mg/g). Thirty-two participants had echocardiograms, 19% indicated pulmonary hypertension (pHTN) as defined by a TRJV ≥ 2.5m/s. The mean (95% CI) Hp concentration was 4 (3.2 to 4.8) [reference range in HbAA 41-165mg/dl]. Linear regression showed that for every 1mg/dl increase in Hp concentration, CD163 MFI increased by 0.17 (95% CI 0.05 – 0.3) p=0.01 (Figure 1). For every 1mg/dl decrease in Hp levels; the odds of reporting a pain crisis in the last year increase by 1.38 (95%CI 0.84 to 2.27) p=0.2; the odds of having renal compromise increase by 3.56 (1.19 to 10.7) p=0.02 and the odds of reporting a history of leg ulcer increase by 1.33 (0.71 to 2.49) p=0.37 (Figure 2). For every 1mg/dl decrease in Hp, the TRJV increases by 0.10 (-0.15 to 0.34) p=0.36. Conclusion Depletion of serum Hp correlates with diminished CD163 expression and with increasing severity of clinical features in HbSS. This suggests that the fault in the hemoglobin scavenging apparatus is probably due to chronic depletion of Hp. Replacement of Hp may therefore be a viable therapeutic prospect aimed at restoring the positive feedback loop and conferring vascular protection. Disclosures: No relevant conflicts of interest to declare.

Although a previous study has reported the relationship between intact parathyroid hormone (iPTH) and whole parathyroid hormone (wPTH) levels in patients undergoing dialysis, the w/i PTH ratio (whole/intact PTH ratio) among predialysis chronic kidney disease (CKD) patients remains unclear. The present study therefore aimed to examine the relationship between w/i PTH ratio and kidney function and determine other factors affecting the w/i PTH ratio. An observational study including 773 predialysis CKD patients was conducted. The correlation between w/i PTH ratio and kidney function, as well as clinical factors at different CKD stages, were assessed using univariate and multivariate analyses. In addition, the relationship between w/i PTH ratio and composite renal outcome [kidney transplantation, dialysis, and 30% decline in estimated glomerular filtration rate (eGFR)] was examined. The w/i PTH ratio decreased as the CKD stage progressed. Patients in each CKD stage (1/2, 3, 4, and 5) had a w/i PTH ratio of 0.85, 0.81, 0.78, and 0.59, respectively. The inflection point in the correlation lines between eGFR and w/i PTH ratio was 24.1 mL/min/1.73 m2. In multivariate analysis, the w/i PTH ratio was significantly correlated with serum calcium levels only in the CKD5 group and with eGFR in the CKD3, CKD4 and CKD5 group. Furthermore, w/i PTH ratio, eGFR, serum phosphate levels, and urinary protein/creatinine ratio were determined to be significant independent predictors for composite renal outcome. Our study demonstrated that changes in the w/i PTH ratio were associated with kidney function, abnormal mineral metabolism, and renal outcome.

Introduction: This study investigated the association of urinary transforming growth factor-β1 (uTGF-β1) with prevalent chronic kidney disease (CKD) in the HIV-infected population. Methods: HIV-positive patients without CKD (HIV+CKD−, n = 194) and 114 with CKD (HIV+CKD+) who did not have hypertension, diabetes mellitus, or hepatitis B or C, had their urinary protein-creatinine ratio (uPCR), serum transforming growth factor (TGF)–β1, and uTGF-β1 measured. uTGF-β1-creatinine ratios (uTGF-β1Cr) were calculated. Spearman correlation was used to determine the association between uTGF-β1Cr and various attributes, and the Cuzick trend test was used to assess the presence of a linear trend in median uTGF-β1Cr levels across the stages of CKD. Multivariable robust linear regression models were used to assess independent association with variability in uTGF-β1Cr and estimated glomerular filtration rate (eGFR) levels. Results: The age of the participants was 38.3 ± 10.3 years with 73.4% women. The median uTGF-β1Cr was higher among HIV+CKD+ (4.85 ng/mmol [25th–75th percentile 1.96–12.35] vs. 2.95 [1.02–5.84]; P = 0.001]). There was significant correlation between uTGF-β1Cr and age (P = 0.02), eGFR (P = 0.001), and uPCR (P < 0.001) in the HIV+CKD+ group. Among the HIV+CKD+ patients, there was gradual reduction in the median level of uTGF-β1Cr with CKD severity (P = 0.04). HIV+CKD+ patients had significantly higher levels of uTGF-β1Cr after controlling for potential confounders. Using eGFR as dependent variable, proteinuria explained the changes associated with uTGF-β1Cr levels. Conclusion: HIV+CKD+ patients express higher levels of uTGF-β1 especially in the early stages of CKD apparently related to proteinuria levels. Keywords: CKD, HIV, Nigeria, urinary TGF-β1

BackgroundInterstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis.MethodsSeventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes.ResultsPatients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P ConclusionsUrinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

Background Childhood nephrotic syndrome is a clinical entity characterized by massive loss of urinary protein (primarily albuminuria) leading to hypoproteinemia (hypoalbuminemia) and edema. The mechanism of development of childhood nephrotic syndrome is not yet clear. Kidney disease involves an interplay between inflammatory and biochemical changes with the development of innate immune response and accumulation and activation of leucocytes, particularly monocytes/macrophages in the kidney. The moncyte chemotactic protein-1 (MCP-1) is one of the CC chemokine family and it plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. Aim of the Work The aim was to measure the urinary levels of MCP-1 in children with nephrotic syndrome and compare these levels in remission and relapse as well as in steroid sensitive and steroid resistant cases. Patients and method The study included 70 patients with nephrotic syndrome following up in Pediatric Nephrology Clinic, Ain Shams University diagnosed for at least one year and 20 age and sex matched healthy children as control group. Patients with renal impairment and secondary nephrotic syndrome were excluded from the study. Patients were divided into Group A: 35 patients in remission and Group B: 35 patients in relapse. Subgrouping according to the clinical type of nephrotic syndrome was done. Patients were subjected to thorough history taking and careful clinical examination. Routine laboratory investigations were done (s. albumin, s. creatinine, s. cholesterol, complete urialysis and urinary protein/creatinine ratio) together with quantitative determination of urinary monocyte chemotactic protein-1 in cases and controls. Results We found a highly significant difference in urinary MCP-1 between group A, group B, and controls, the highest being group B. the levels in patients in remission still exceeded the controls significantly. However, in group B, no significant difference was found between clinical types of the disease in urinary MCP-1. The same was found in group A. no difference was found between males and females in group A as regards urinary MCP-1 levels yet females had significantly higher levels in group B. This difference was not seen in controls. We found no significant difference in MCP-1 levels in patients receiving different treatment modalities. Conclusion Urinary MCP-1 is a highly sensitive and specific biomarker in childhood nephrotic syndrome (98.5% and 100% respectively), being highly elevated in both remission and relapse, but is not a suitable prognostic biomarker being insignificantly different among different clinical types of nephrotic syndrome.

Objectives: Tenofovir disoproxil fumarate (TDF) has been reported to cause nephrotoxicity necessitating cessation in some patients. No information is available on the nephrotoxic effect of TDF in Omani or regional patients with HIV infection. We sought to determine the prevalence of the nephrotoxic effects of TDF in our cohort of Omani patients with HIV and investigate the nephrotoxic effects of other cofactors. Methods: We conducted an observational cohort study on 83 Omani patients currently on TDF-containing antiretroviral therapy. Renal dysfunction was monitored by measuring the serum creatinine estimated glomerular function rate (eGFR), urinary protein creatinine ratio (uPCR), and fractional excretion of phosphate (FEPi). Fisher’s exact test was used to determine any additional nephrotoxic effects of cofactors. Results: The median values for the duration of TDF use, patient age, and body mass index (BMI) at the time of the study were 178 weeks (range = 3–554), 42 years (range = 21–80), and 27 (range = 17.4–42.7), respectively. The median initial CD4 count and viral load were 205 × 106/L (range = 3–1745) and 37 250 copies/mL (range = undetectable–9 523 428), respectively. FEPi was high in two (2.4%) patients, moderate in 26 (31.3%), and low in 55 (66.3%) patients. uPCR was high in 10 (12.0%) patients, moderate in 28 (33.7%), and low in 45 (54.2%) patients. No cofactors added to the nephrotoxicity except hypertension (p = 0.045). Conclusions: Better definitions for TDF-associated toxicity are needed. uPCR is not a very good indicator of TDF-associated tubular dysfunction. Omani patients with HIV on TDF have a 4% prevalence of renal toxicity, but a study with a larger number of patients is required to explore this observation further. Cofactors like duration of TDF use, age, BMI, gender, diabetes mellitus, and use of protease inhibitors did not have an impact on the severity of FEPi and uPCR.

Achievement of complete renal remission (CR) is an important goal in lupus nephritis (LN) treatment. The use of cyclosporine (CsA) for active LN has been challenged because of variations in CsA doses and reports of adverse reactions (AR). A cohort of 62 patients with active LN (induction-resistant LN and flared LN) who were treated with CsA was evaluated. CsA was started at 50 mg/day and titrated up 25 mg/day every 2–4 weeks until CR was achieved or until treatment termination because of AR. The range of CsA dosage was 50–200 mg/day, and mean CsA dose was 102.8 ± 50.43 mg/day (1.73 ± 0.91 mg/kg/day). CsA plus mycophenolate mofetil and prednisolone was administered to 35.5% of patients, while the other 64.5% were treated with CsA and prednisolone. 90.32% had achieved CR and 4.84% had partial remission after 12 months of treatment. UPCR (urinary protein:creatinine ratio) decreased significantly in both groups (2.58 ± 3.37 to 0.36 ± 0.71 and 2.32 ± 1.45 to 0.29 ± 0.24 respectively) (P

Current interventions are not effectives in preventing sepsis-induced acute kidney injury and its long-term outcomes or even after second renal insult. Therapeutic strategies using lipid mediators, as aspirin-triggered resolvin D1 (ATRvD1), can contribute for resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing the proteinuria excretion, UPC ratio, glomerular cell number and extracellular matrix deposition. Pro-fibrotic markers, as transforming growth factor β (TGFb), type 3 collagen and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from renal apoptosis and recruitment of F4/80+ cells. Interleukin-1b (IL-1b) levels were increased in subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-a (TNF-a), IL-10 and IL-4 mRNA expression was increased in the kidney of BSA-challenged post-septic mice and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.

Background This study aimed to establish and validate an easy-to-operate novel scoring system based on simple and readily available clinical indices for predicting the progression of chronic kidney disease (CKD). Methods We retrospectively evaluated 1045 eligible CKD patients from a publicly available database. Factors included in the model were determined by univariate and multiple Cox proportional hazard analyses based on the training set. Results Independent prognostic factors including etiology, hemoglobin level, creatinine level, proteinuria, and urinary protein/creatinine ratio were determined and contained in the model. The model showed good calibration and discrimination. The area under the curve (AUC) values generated to predict 1-, 2-, and 3-year progression-free survival in the training set were 0.947, 0.931, and 0.939, respectively. In the validation set, the model still revealed excellent calibration and discrimination, and the AUC values generated to predict 1-, 2-, and 3-year progression-free survival were 0.948, 0.933, and 0.915, respectively. In addition, decision curve analysis demonstrated that the model was clinically beneficial. Moreover, to visualize the prediction results, we established a web-based calculator (https://ncutool.shinyapps.io/CKDprogression/). Conclusion An easy-to-operate model based on five relevant factors was developed and validated as a conventional tool to assist doctors with clinical decision-making and personalized treatment.

We report a case of minimal change disease (MCD) with severe acute kidney injury (AKI) following the first injection of the ChAdOx1 nCoV-19 (AZD1222) vaccine from Oxford-AstraZeneca against coronavirus disease 2019 (COVID-19). A 71-year-old man with a history of dyslipidemia and a baseline serum creatinine of 0.7mg/dL presented with nephrotic syndrome, AKI, and severe hypertension 13 days after receiving the Oxford-AstraZeneca vaccine. Refractory hyperkalemia and hypervolemia with oligoanuria prompted initiation of hemodialysis. His serum albumin was 2.6g/dL and his urinary protein-creatinine ratio was 2,321mg/mmol. Given a high suspicion for rapidly progressive glomerulonephritis, empirical glucocorticoid treatment was initiated (3 methylprednisolone pulses followed by high-dose prednisone). A kidney biopsy showed MCD and acute tubular injury. Kidney function and proteinuria subsequently improved, and hemodialysis was discontinued 38 days after the start of therapy. This case describes de novo MCD after the Oxford-AstraZeneca vaccine. It adds to the few published case reports of MCD after the Pfizer-BioNTech COVID-19 vaccine. Further reports and studies will be needed to elucidate whether MCD is truly associated with COVID-19 vaccination.

Background and Aims Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator and different studies have suggested its involvement in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes. We also tested whether the use of optimal doses of RAS blockade in monotherapy had an influence on the levels of IL-6 in comparison with dual blockade. Method IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in the PRONEDI trial (EUDRACT 2004-002470-31), a multicenter, randomized controlled clinical trial. The study included type 2 diabetes patients with a clinical diagnosis of DKD, stage 2 or 3 CKD, and a urinary protein/creatinine ratio (UPCR) >300 mg/g (morning urine spot) on 2 separate opportunities. The primary composite endpoint was a >50% increase in baseline serum creatinine, end stage kidney disease (ESKD) or death. Cox regression model was adjusted for potential confounders or modifiers including eGFR calculated using the CKD-EPI equation and UPCR. Mixed models were adjusted to study longitudinal data. Results The recruitment period was 18 months and the median follow-up was 36 (IQR: 20-48) months, after which 27 patients (38.6%) reached the primary endpoint. At baseline mean IL-6 levels in the whole cohort were 4.58 ± 2.90, at 4 months 4.61 ± 3.10 and at 12 months: 6.14 ± 4.97. Patients were further divided into three groups according to the tertiles of baseline IL-6 levels (tertile 1: 0.65–2.65 pg/mL; tertile 2: 2.66–4.83 pg/mL and tertile 3: 4.84–13.30 pg/mL). There were no differences among the groups in demographic characteristics, cardiovascular risk factors, serum creatinine or proteinuria among the groups. Correlation analyses for IL6 and other inflammatory parameters were carried out for all subjects. The results showed that inflammatory parameters had a significant correlation between them. IL-6 levels correlated with TNFα (r: 0.29; 95% CI: 0.05 - 0.49 p= 0.02), C-reactive protein (r= 0.61; 95%CI: 0.44 - 0.74 p Patients with the highest IL-6 levels (>4.84 pg/ml) experienced a significantly faster evolution to endpoint (mean survival: 33.2 months, CI 95%: 25.2-41.3) than the other 2 groups. In the multivariate Cox regression analysis, the highest levels of IL-6 (Tertile 3) were significantly associated with the primary outcome (HR:3.86; 95%CI: 1.08-13.86) after being adjusted for baseline serum creatinine and proteinuria. The time-dependent area under the ROC curve at two years of follow-up was 0.88 (95% CI: 0.79 - 0.97). The best cut-off IL-6 level was found at 4.68 pg/ml (sensitivity: 100%, specificity: 78.7%) Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade. Conclusion In conclusion, our results show that higher levels of IL-6 are independently associated with progression of DKD in patients with type 2 diabetes, and that treatment with RAS blockade does not influence these levels. Serum IL-6 may be used as a noninvasive biomarker of progression to ESKD. Since our results show that higher IL-6 levels are associated with a worse renal prognosis, anti- inflammatory drugs that modulate IL-6 could be promising therapeutic agents to improve outcomes. Further studies focusing on the potential applications of anti-IL6 treatment in DKD are warranted.

Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0·618, P 30 ml/min/1.73 m2 [HR 4·11, (95% CI 1·45-11·65); P = 0·008] and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis [HR 6·72, (95% CI 1·83-24·74); P = 0·004], and also predicted renal progression [HR 1·91, (95% CI 1·18-3·07); P = 0·008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.

Background: Up to 60% of pediatric renal transplant recipients with end-stage renal disease due to primary focal and segmental glomerulosclerosis (FSGS) may develop recurrent disease. Such recurrence is associated with poor prognosis if no remission is achieved. We report a single center experience with a protocol based on plasmaphereis and increased immunosuppression that resulted in a high long-lived remission rates.Methods: This retrospective cohort study included consecutive pediatric renal transplant patients with recurrent FSGS treated with a standardized protocol using plasmapheresis and cyclophosphamide to supplement usual post-transplant immunosuppression with calcineurin inhibitors and steroids. Relapse was defined as urinary protein/creatinine ratio >1.0g/g and remission as Results: 15 patients with FSGS recurrence post-transplant were treated. All had therapy-resistant FSGS in native kidneys and had been on dialysis from 4-10 years. Of the 15, one died perioperatively from a pulmonary thromboembolism. 13 others achieved a complete remission within 3 months of treatment for FSGS recurrence. After a median follow-up period of 4 years, there were no recurrences of significant proteinuria. Conclusion: The addition of plasmapheresis and cyclophosphamide to a calcineurin- and steroid-based immunosuppression regime was highy successful in inducing high remission rates with recurrent FSGS. Prospective trials are needed to evaluate further the efficacy of increased immunosuppression along with plasmapheresis in this setting.

Background : Ehrlichiosis is a tick-borne disease highly prevalent in Brazil, and is relevant in canine clinical practice due to its high morbidity and mortality. Its clinical signs are nonspecific and its phases are acute, lasting 2 to 4 weeks; subclinical, i.e., asymptomatic; and chronic, resembling an autoimmune disease. The purpose of this study was to identify the occurrence of reactivity to Ehrlichia canis of bitches treated at the Veterinary Medical Teaching Hospital of the Universidade Federal Fluminense (UFF) - Niteroi, RJ, Brazil , based on serological examination by iELISA, and to compare the hematological, biochemical, urinary protein-creatinine and urinary density profiles of reactive and non-reactive animals. Materials, Methods & Results : This study involved solely bitches, regardless of breed, starting at 1 year of age. One hundred and thirty bitches, 1 to 16 year-old (mean age 7.02 ± 4.00), weighing 1.5 to 50 kg (mean weight 12.12 ± 10.65) were subjected to clinical examination and abdominal ultrasound. Complete blood count, biochemical measurements, urinalysis and serology for E. canis were also performed. The serum was used in the iELISA to identify immunoglobulin G (IgG), using a canine Ehrlichia Imunotest® diagnostic kit (Imunodot®, Jaboticabal, SP, Brazil) according to the manufacturer’s instructions. Sixty animals (46.20%) were reactive to E. canis . According to their owners, only 5 (8.3%) of the 60 seroreactive animals had a history of tick-borne disease. The most common profile was that of mixed breed animals living with their owners, older than 7 years, who had not been treated preventatively with specific drugs against ectoparasites. Laboratory tests showed significant differences between groups in terms of total protein (TP), and calcium and urinary protein-creatinine ratio (UPC). TP and UPC were elevated in the non-reactive group, while the only significant change in the reactive group was mild hypocalcemia. In this study, 30% (18/60) of the bitches were seroreactive to E. canis and had hypocalcemia. Of these, 50% (9/18) had a UPC above 0.5. Furthermore, 66.7% (12/18) of this group with hypocalcemia also showed urine density (UD) of less than 1024. Among these 18 bitches, 5 had both alterations, i.e., UPC > 0.5 and UD < 1024. Discussion : In this study, a high prevalence of bitches seroreactive to Ehrlichia canis was observed, despite the absence of clinical and/or laboratory signs indicative of the disease. In the investigation of IgG class antibodies, it is not possible to determine the exact time of infection, and titers may remain high for a period of more than 11 months, even after treatment and elimination of the bacterium. The fact that most seroreactive bitches showed no symptoms compatible with the disease either before or during the study suggests that they were in the subclinical phase of ehrlichiosis. The main reason for calcium metabolism disorders is a phosphorus imbalance, a condition that occurs in kidney diseases. Isosthenuria reflects the kidney’s inability to concentrate urine. This finding may be one of the first clinical manifestations of chronic kidney disease (CKD), especially in dogs. On the other hand, the UPC ratio may increase with the progression of CKD. The presence of hypocalcemia, isosthenuria and increased UPC associated with seroreactivity suggests that infection by E. canis may be associated with the onset of CKD. Veterinarians should keep in mind the complexity of the pathophysiology of ehrlichiosis to ensure the disease is not underdiagnosed in any of its phases, thereby ensuring the correct treatment is provided. Such awareness is expected to reduce the chronicity of the disease and underlying sequelae among dogs. Keywords: Ehrlichia canis , serology, tick, clinic, renal. Descritores: Ehrlichia canis , sorologia, carrapato, clinica, renal. Titulo: Perfil clinico e laboratorial de cadelas sororeativas para erliquiose tratadas em um Hospital Veterinario Universitario em Niteroi, Estado do Rio de Janeiro, Brasil

Background : The use of prescription diets for cats with chronic kidney disease (CKD) is one of the main management approach of this disease in cats, and is considered a renoprotective strategy that may promote increased survival and/or improve quality of life, according to the stage of CKD. Besides that, nutritional assessment is important to monitor the maintenance of quality of life of the patients and their response to disease, especially those with chronic conditions. The aim of this study was to follow the clinical and nutritional status of cats with chronic kidney disease (CKD) IRIS stages II, III and IV fed with a renal prescription diet, followed for 12 months. Materials, Methods & Results : Patients were fed exclusively with a dry renal prescription diet and medications for the management of CKD were prescribed when needed. Exclusion criteria were cats that already received a renal prescription diet or medications for the treatment of CKD. Cats were evaluated every 2 months, considering body weight (BW), body condition score (BCS), muscle mass score (MMS), clinical and laboratory parameters. In all assessments, a complete blood count and biochemistry were performed by conventional methods with the patient fasted for 12 h. In addition, urinalysis, urinary protein:creatinine ratio (UPC) and urine culture were performed from a urine sample collected by cystocentesis. The quantitative variables were tested for their stability on consecutive assessments using the non-parametric Friedman test, and did not present significant variation during follow-up, except for systolic blood pressure (SBP). Eight cats with a diagnosis of CKD were included in the study and 6 of them remained in the same CKD stage during follow-up. On cat died due to an unrelated CKD cause. Regarding nutritional assessment, 5 of 7 cats maintained BW during the 12 months. Of these, 4 also maintained MMS and BCS. Three of 7 cats presented a decrease in MMS, 2 of which presented also a decreased BW and one maintained BW. Discussion : IRIS staging results combined with Friedman’s analysis demonstrated that the diet and the clinical management were effective in the non-progression of CKD in this study. As renal injury is not expected to be reversed in CKD, the maintenance of cats in the same IRIS stages and the minimum variation of the parameters is considered a positive result in this study. Hypertensive cats started on antihypertensive therapy during the study, achieving adequate control of SBP in most cases, what can justify the variation of this clinical parameter over the 12 months. Hyperphosphatemia was a frequent alteration, included stage II cats, and presented a positive response to nutritional and medical therapy. Despite CKD staging progression was not observed in most cats using serum creatinine as a single parameter, some cats presented BW and MMS reduction, which may have influenced this result. Weight loss and muscle wasting may have occurred by several reasons, including periods of hyporexia, presence of concomitant diseases, aging process or reduced protein content on renal prescription diets. This study enhances the importance of the association of clinical and nutritional management in the maintenance of cats with CKD. We suggest that other studies are done during longer periods of time and with a larger sample to support the results found. We also suggest new studies to evaluate the protein requirements for cats with CKD.

Case report - Introduction Granulomatosis with Polyangiitis (GPA) is a rare small- to medium-vessel vasculitis associated with anti-neutrophil cytoplasmic autoantibody (ANCA). Its multi-systemic features include pulmonary, ear, nose, and throat (ENT), renal, and neurological manifestations. Its incidence is estimated to be 10.2 cases per million population. It is challenging to diagnose when its symptoms are treated in isolation from one another. This case highlights the difficulty in diagnosing GPA in a patient with respiratory symptoms during the Coronavirus Disease 2019 (COVID-19) pandemic and describes the challenges of managing it in the context of a subsequent COVID-19 infection as the mainstay of treatment remains immunosuppression. Case report - Case description A 78-year-old female non-smoker with a history of leg ulcers developed a 3-month history of cough and haemoptysis and was treated in primary care for suspected sinus and chest infections. She then presented to Accident and Emergency twice for the same symptoms and was discharged after having her antibiotics changed. 2 weeks later, she presented for the third time with cough, ongoing haemoptysis, conjunctivitis in the right eye, pain over the right side of her head, and discharge from her right ear. She was admitted as she was pyrexical, tachycardic and her CRP was 60. COVID-19 swabs were negative. ENT team recommended IV ceftriaxone and metronidazole for suspected orbital cellulitis. Blood cultures remained negative. CT sinuses with contrast showed right sided thrombosis of transverse sinus and bilateral mastoid effusion of the middle ear. Following neurology review, she was anticoagulated with dalteparin. A day later, she was transferred to the Respiratory ward and dropped her Haemoglobin level to 70. Her chest radiograph showed diffuse alveolar haemorrhage and CT images showed widespread bilateral peri-hilar consolidation. A rheumatology opinion was sought and vasculitic screen showed ANCA 268, and PR3 >177. Her urinary protein/creatinine ratio was elevated at 90. Rheumatology team confirmed multi-systemic GPA and recommended starting oral Prednisolone 60 mg daily. After the renal team was consulted, she was moved to a side-room and started on IV Methylprednisolone (pulsed with three doses), along with cyclophosphamide and rituximab. Dalteparin was discontinued. 2 days later, she desaturated, and became pyrexical. Repeat COVID-19 swabs were positive. Three Consultants agreed that Plasma Exchange and Non-Invasive Ventilation (NIV) would be inappropriate. A Do Not Attempt Resuscitation form was signed, and prognosis was discussed with the patient and her 78-year-old husband who requested to visit. Patient deteriorated and unfortunately died 6 days later. Case report - Discussion This case is interesting because it highlights the diagnostic challenge of GPA. Retrospectively, it may be noted that doctors persisted in treating suspected infection although the patient continued to deteriorate. However, a diagnosis should be re-considered if the patient does not respond to treatment and it is important to consider vasculitis as a cause of haemoptysis. Anticoagulation was started since the benefits were considered to outweigh the risks as her haemoptysis was of small volume. The patient soon developed pulmonary haemorrhage, so the risks of anticoagulation should not be underestimated in vasculitis. The Rheumatology team’s cautious approach to immunosuppression was in stark contrast to the renal team’s aggressive approach. The Renal team believed that concerns about protecting the patient from COVID-19 when she was negative from this infection should not take precedence over appropriate immunosuppression from a potentially fatal vasculitis. The patient was admitted at the start of the COVID-19 pandemic and was negative for COVID-19 on admission. She was nursed in a bay on the Respiratory ward where she later became COVID-19 positive. This raises questions about whether the earlier test was a false negative result or whether her infection was hospital-acquired. Infection control guidelines were changing rapidly at the start of the COVID-19 pandemic. The decision to avoid plasma exchange was based on the findings of the PEXIVAS trial. NIV was avoided as it required a full-face mask to minimize particle dispersion but would pose an asphyxiation risk as patient was coughing up blood. Finally, the team learnt to be flexible in these extraordinary circumstances when dealing with the end-of-life decisions of the COVID-19 positive patient. Although her husband was a vulnerable person because of his age, he was given the opportunity to visit while wearing Personal Protective Equipment and agreed to self-isolate for two weeks. Case report - Key learning points This case helped me appreciate the complexity of deciding to immunosuppress an already severely ill patient in the context of the COVID-19 pandemic. I recognised that the patient had a poor prognosis with or without immunosuppression and our role as healthcare professionals was to give her the best chance of recovery. The conference will allow me to interact with other colleagues and discuss what they would do in this situation as our Rheumatology and Renal teams had different approaches. After further reading on false negative results, we found that Johns Hopkins researchers found that testing people for SARS-CoV2 too early in the course of infection is likely to result in a false negative test even though they may eventually test positive for the virus. I have also learnt about the PEXIVAS trial which found that the addition of plasma exchange to standard therapy does not reduce the risk for all-cause mortality among patients with severe ANCA-associated vasculitis. Moreover, a reduced-dose regimen of glucocorticoids is non-inferior to a standard-dose protocol, while reducing the risk for serious infections. Diffuse alveolar haemorrhage (DAH) is not treatable with arterial embolization or bronchoscopic methods due to the diffuse nature of the bleeding. Extracorporeal membrane oxygenation (ECMO) has been used to support patients with DAH but the use of ECMO is controversial due to the need for anticoagulation. The conference will help me deepen my understanding of epidemic rheumatology which will be useful for my clinical practice going forward, especially if there is a second wave of the COVID-19 pandemic. I am keen to use this event to engage with other clinicians on immunosuppression in the context of infection so that I may confidently manage similarly complex cases in the future.

Rationale & Objective Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. Study Design Prospective cohort study. Setting & Participants Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). Exposures Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. Outcomes Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. Analytical Approach A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. Results Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19 mL/min/1.73 m2) and declining slope of eGFR (8 mL/min/1.73 m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136 mg/g) and increasing UPCR (240 mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). Limitations Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. Conclusions Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

Clinicopathological significance of light chain deposition in IgA nephropathy and the relation of monotypic IgA deposition to bone marrow abnormalities are important issues to be clarified. We retrospectively investigated light chain deposition in 526 patients with IgA nephropathy. We divided the patients into 5 groups according to the balance of intensity of both light chain deposition: lambda monotypic, lambda dominant, polytypic, kappa dominant and kappa monotypic. Clinicopathological parameters were compared among the groups. The relation of monotypic IgA deposition to hematological malignancy was also evaluated. The prevalence of monotypic IgA deposition was 6.3%, 33 patients (21 lambda and 12 kappa). Thirty-two (4.0%) and 10 patients (1.9%) were classified into lambda and kappa dominant groups, respectively. Polytypic IgA deposition was observed in 455 patients (85.7%). Age of onset, age at biopsy, urinary protein creatinine ratio, the percentage of global glomerulosclerosis, and the degree of IgA and C3 deposition were different among the groups. However, there was no gradual difference according to the groups. No patient with monotypic IgA deposition showed hematological abnormality at biopsy and during follow-up. The prevalence of IgA monotypic deposition was extremely low. Clinicopathologically, we could not differentiate patients with monotypic IgA deposition from those with polytypic one and no hematological disorder was documented in patients with monotypic IgA deposition. Whether IgA nephropathy with monotypic IgA deposition and that with polytypic one is the same entity or not, and relation between monotypic IgA deposition and hematological malignancy should be clarified by further investigations.

Rationale & Objective Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. Study Design Prospective cohort. Setting & Participants African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. Predictors Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Outcomes Incident KFRT, all-cause mortality. Analytical Approach Cox proportional hazards models. Results Among 500 participants with available samples, mean glomerular filtration rate was 44.7 mL/min/1.73 m2, and median urinary protein-creatinine ratio was 0.09 g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P ≤ 0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P > 0.05 for interaction). Limitations Limited generalizability to other ethnic groups or causes of CKD. Conclusions Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.