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Hypertension (HTN) is one of the key global cardiovascular risk factors, which is tightly linked to kidney health and disease development. Podocytes, glomerular epithelial cells that play a pivotal role in maintenance of the renal filtration barrier, are significantly affected by increased glomerular capillary pressure in HTN. Damage or loss of these cells causes proteinuria, which marks the initiation of the HTN-driven renal damage. It goes without saying that effective blood pressure (BP) management should not only mitigate cardiovascular risks but also preserve renal function by protecting podocyte integrity. This review offers a comprehensive examination of current BP management strategies and their implications for podocyte structure and function and emphasizes strategies for the reduction of proteinuria in HTN. We explore primary and secondary antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, as well as newer therapies (sodium-glucose cotransporter-2 blocking and endothelin receptor antagonism), emphasizing their mechanistic roles in safeguarding podocytes and curtailing proteinuria., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To study the functional state of the kidneys in men and women with various types of cerebrovascular diseases (CVD)., Material and Methods: The study included 378 patients with CVD: transient ischemic attack (TIA), stroke (ischemic and hemorrhagic), and chronic brain ischemia. The average age of men and women was 61.4±13.0 and 63.8±11.8 years, respectively. The excretory function of the kidneys was assessed in all participants., Results: TIA was recorded in 20.9% of men and 13.4% of women. Stroke was verified in 35.7% of patients (56.4% men and 34.3% women, p< 0.05). Recurrent ischemic stroke was more common in men (12.9%) than in women (6.9%, p< 0.05). The frequency of proteinuria was 34.1%, with nephrotic proteinuria and hematuria more often noted in men. The functional state of the kidneys (optimal, slightly reduced, moderately reduced, and significantly reduced excretory function) was identified in 37.8%, 34.1%, 17.7%, and 6.3% of patients, respectively. Severely reduced kidney function was recorded in 3.4% of patients. The glomerular filtration rate according to the CKD-EPI (67.9±24.1 ml/min), MDRD (62.9±22.8 ml/min), and Cockcroft-Gault (67.7±24.4 ml/min) formulas was lower in men compared to women (78.3±25.3 ml/min, 76.3±3.2 ml/min, 81.2±36.5 ml/min, p< 0.05). In men and women, a correlation was established between pathomorphological changes on brain MRI and the level of red blood cells, glucose, total cholesterol and creatinine., Conclusion: In patients with CVD, the frequency of proteinuria is 34.1%. Nephrotic proteinuria and hematuria are more common in men. Changes in the functional state of the kidneys are manifested as slight and moderate reductions in excretory function. In women, the excretory function of the kidneys and proteinuria are closely related to pathomorphological changes in the brain.

The integrity of the glomerular filtration barrier maintains protein excretion below 150 mg/day. When urinary proteins increase, this indicates damage to the filtration barrier. However, proteinuria is not only a marker of kidney damage but also exacerbates it through various mechanisms involving the glomerular and tubulointerstitial compartments. Therefore, it is essential to intervene with renoprotective action that reduces the proteinuria. In this context, Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are cornerstone treatments. Recent advancements include sodium-glucose cotransporter 2 inhibitors, initially used for glycemic control, now recognized for their renoprotective properties in both diabetic and non-diabetic populations. Another drug, Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has emerged as a promising agent, offering anti-inflammatory and antifibrotic benefits with fewer side effects than traditional steroidal options. Finally, dual inhibition of angiotensin II and endothelin-1 receptors through agents like Sparsentan presents a novel approach with significant antiproteinuric effects in IgA nephropathy and focal segmental glomerulosclerosis. This brief review summarizes the mechanisms by which proteinuria promotes kidney damage and the renoprotective therapeutic approaches available, which can be combined with lifestyle modifications and specific treatments for underlying diseases to mitigate the progression of chronic kidney disease.

Objective: To examine changes in glomerular hyperfiltration and other measures of kidney function in youth with type 2 diabetes treated with dulaglutide or placebo., Research Design and Methods: Post hoc analysis was performed on kidney laboratory data from 154 youths (age 10-18 years) with type 2 diabetes enrolled in a completed placebo-controlled glycemic control trial of dulaglutide., Results: Mean estimated glomerular filtration rate (eGFR) decreased from baseline to 26 weeks in participants treated with dulaglutide versus placebo (-5.8 vs. -0.1 mL/min/1.73 m2; P = 0.016). Decreases in eGFR were observed primarily in participants with baseline glomerular hyperfiltration. At 26 weeks, the prevalence of both glomerular hyperfiltration and proteinuria increased with placebo but decreased with dulaglutide (P = 0.014 and 0.004 vs. placebo, respectively)., Conclusions: Dulaglutide was associated with attenuated glomerular hyperfiltration and proteinuria in youth with type 2 diabetes. The impact of these changes on the risk of diabetic kidney disease is unclear., (© 2024 by the American Diabetes Association.)

Introduction: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established., Method: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis., Results: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16-1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001)., Conclusion: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Aims: It is unclear whether the effect of proteinuria on rapid kidney function decline is equivalent among diabetic kidney disease (DKD), non-DKD with diabetes (NDKD+DM), and nephrosclerosis without diabetes (NS-DM), particularly in advanced chronic kidney disease patients., Methods: In total, 1038 chronic kidney disease patients who participated in the BRIGHTEN study were included in the present study. A linear mixed effect model was applied to estimate the annual estimated glomerular filtration rate decline in each disease group., Results: The prevalence of rapid decliners (rapid kidney function decline, defined as an eGFR loss of > 5 mL/min/1.73 m 2 /year) in the DKD group (44.6 %) was significantly higher compared with the NDKD+DM (27.9 %) and NS-DM (27.0 %) groups. By contrast, the prevalence of rapid decliners in different urine total protein to creatinine ratio (UPCR) categories (<0.5, 0.5 to < 1.0, 1.0 to < 3.5, and ≥ 3.5 g/g) were equivalent between the DKD and NS-DM groups. Moreover, the prevalence of a UPCR < 1.0 g/g in rapid decliners of the NS-DM group was more than double than in those of the DKD and NDKD+DM groups., Conclusions: The risk of rapid kidney function decline in NS-DM patients with low levels of proteinuria may be greater than initially predicted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The BRIGHTEN study was funded by Kyowa Kirin Co. Ltd. (KKC). KKC proposed the concept of this trial and provided information, but did not take any part in collecting, analysing, or interpreting the results. The Translational Research Centre for Medical Innovation, a third-party organization that is independent of the primary investigator’s institution, was contracted to perform the trial and manage the data. TG and MM received honoraria from KKC. YS, TW, and IN received honoraria and subsidies or donations from KKC., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To suppress the incidence of end-stage kidney disease, we need to identify chronic kidney disease (CKD) patients with a high risk of rapid decline in the estimated glomerular filtration rate (eGFR). However, the current status of eGFR slope and its associated factors in the Japanese population have not been fully elucidated., Methods: Among examinees aged 40-70 years in the 2014 Specific Health Checkup conducted by the National Health Insurance in Kobe, Japan (n = 61,985), we prospectively observed 7291 examinees with CKD stage G3 from 2014 to 2018., Results: Until 2018, 4221 examinees continued to undergo annual SHCs for a total of five checkups per subject and had available records of all necessary data. The median eGFR change was -0.22 ml/min/1.73 m 2 /year. Only 9.2% of those subjects showed rapid eGFR decline (faster than -2.0 ml/min/1.73 m 2 /year). Logistic regression analysis identified diabetes, smoking habits, high urinary protein levels, older age, high systolic blood pressure, and low serum low-density lipoprotein cholesterol levels as independent predictors for rapid eGFR decline. Hemoglobin A1c levels did not contribute to the eGFR slope in CKD stage-G3 subjects with diabetes and proteinuria., Conclusion: Most Japanese CKD stage-G3 subjects had a very slow decline in eGFR. A small proportion of CKD individuals who have a predictive factor of rapid eGFR decline should receive considerable attention from a nephrologist., (© 2024. The Author(s).)

Sarcopenia is one of the most common geriatric syndromes in the elderly. It is defined as a decrease in muscle mass and function, and it can lead to physical disability, falls, poor quality of life, impaired immune system, and death. It is known that, the frequency of sarcopenia increases in the kidney patient population compared to healthy individuals. Although it is known that kidney disease can lead to sarcopenia; our knowledge of whether sarcopenia causes kidney disease is limited. Prior studies have suggested that protein energy wasting may be a risk of de novo CKD. Proteinuria is an important manifestation of kidney disease and there is a relationship between sarcopenia and proteinuria in diabetes, geriatric population, kidney transplant, and nephrotic syndrome. Does proteinuria cause sarcopenia or vice versa ? Are they both the results of common mechanisms? This issue is not clearly known. In this review, we examined the relationship between sarcopenia and proteinuria in the light of other studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Patients hospitalized with AKI have higher subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality than their counterparts without AKI, but these higher risks may be due to differences in prehospitalization patient characteristics, including the baseline level of estimated glomerular filtration rate (eGFR), the rate of prior eGFR decline, and the proteinuria level, rather than AKI itself., Methods: Among 2177 adult participants in the Chronic Renal Insufficiency Cohort study who were hospitalized in 2013-2019, we compared subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality between those with serum creatinine-based AKI (495 patients) and those without AKI (1682 patients). We report both crude associations and associations sequentially adjusted for prehospitalization characteristics including eGFR, eGFR slope, and urine protein-creatinine ratio (UPCR)., Results: Compared with patients hospitalized without AKI, those with hospitalized AKI had lower eGFR prehospitalization (42 versus 49 ml/min per 1.73 m 2 ), faster chronic loss of eGFR prehospitalization (-0.84 versus -0.51 ml/min per 1.73 m 2 per year), and more proteinuria prehospitalization (UPCR 0.28 versus 0.16 g/g); they also had higher prehospitalization systolic BP (130 versus 127 mm Hg; P < 0.01 for all comparisons). Adjustment for prehospitalization patient characteristics attenuated associations between AKI and all three outcomes, but AKI remained an independent risk factor. Attenuation of risk was similar after adjustment for absolute eGFR, eGFR slope, or proteinuria, individually or in combination., Conclusions: Prehospitalization variables including eGFR, eGFR slope, and proteinuria confounded associations between AKI and adverse cardiovascular outcomes, but these associations remained significant after adjusting for prehospitalization variables., (Copyright © 2023 by the American Society of Nephrology.)

Background: Nutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria., Case Presentation: The patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman's space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months., Conclusions: The present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation., (© 2022. The Author(s).)

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

Qualitative and quantitative measurement of urine protein excretion is one of the most common tests performed during pregnancy. For more than 100 years, proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines recommend that proteinuria is sufficient but not necessary for the diagnosis. Still, in clinical practice, most patients with gestational hypertension will be diagnosed as having preeclampsia based on the presence of proteinuria. Although the reference standard for measuring urinary protein excretion is a 24-hour urine collection, spot urine protein-to-creatinine ratio is a reasonable "rule-out" test for proteinuria. Urine dipstick screening for proteinuria does not provide any clinical benefit and should not be used to diagnose proteinuria. The classic cutoff cited to define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3% to 8% of pregnancies. Although this threshold is widely accepted, its origin is not based on evidence on adverse pregnancy outcomes but rather on expert opinion and results of small studies. After reviewing the available data, the most important factor that influences maternal and neonatal outcome is the severity of blood pressures and presence of end organ damage, rather than the excess protein excretion. Because the management of gestational hypertension and preeclampsia without severe features is almost identical in frequency of surveillance and timing of delivery, the separation into 2 disorders is unnecessary. If the management of women with gestational hypertension with a positive assessment of proteinuria will not change, we believe that urine assessment for proteinuria is unnecessary in women who develop new-onset blood pressure at or after 20 weeks' gestation. Furthermore, we do not recommend repeated measurement of proteinuria for women with preeclampsia, the amount of proteinuria does not seem to be related to poor maternal and neonatal outcomes, and monitoring proteinuria may lead to unindicated preterm deliveries and related neonatal complications. Our current diagnosis of preeclampsia in women with chronic kidney disease may be based on a change in protein excretion, a baseline protein excretion evaluation is critical in certain conditions such as chronic hypertension, diabetes, and autoimmune or other renal disorders. The current definition of superimposed preeclampsia possesses a diagnostic dilemma, and it is unclear whether a change in the baseline proteinuria reflects another systemic disease such as preeclampsia or whether women with chronic disease such as chronic hypertension or diabetes will experience a different "normal" pattern of protein excretion during pregnancy. Finally, limited data are available regarding angiogenic and other biomarkers in women with chronic kidney disease as a potential aid in distinguishing the worsening of baseline chronic kidney disease and chronic hypertension from superimposed preeclampsia., (Published by Elsevier Inc.)

The Latin American Society of Nephrology and Hypertension conducted a prospective cohort, multinational registry of Latin American patients with kidney impairment associated to COVID-19 infection with the objective to describe the characteristics of acute kidney disease under these circumstances. The study was carried out through open invitation in order to describe the characteristics of the disease in the region. Eight-hundred and seventy patients from 12 countries were included. Median age was 63 years (54-74), most of patients were male (68.4%) and with diverse comorbidities (87.2%). Acute kidney injury (AKI) was hospital-acquired in 64.7% and non-oliguric in 59.9%. Multiorgan dysfunction syndrome (MODS) due to COVID-19 and volume depletion were the main factors contributing to AKI (59.2% and 35.7% respectively). Kidney replacement therapy was started in 46.2%. Non-recovery of renal function was observed in 65.3%. 71.5% of patients were admitted to ICU and 72.2% underwent mechanical ventilation. Proteinuria at admission was present in 62.4% of patients and proteinuria during hospital-stay occurred in 37.5%. Those patients with proteinuria at admission had higher burden of comorbidities, higher baseline sCr, and MODS was severe. On the other hand, patients with de novo proteinuria had lower incidence of comorbidities and near normal sCr at admission, but showed adverse course of disease. COVID-19 MODS was the main cause of AKI in both groups. All-cause mortality of the general population was 57.4%, and it was associated to age, sepsis as cause of AKI, severity of condition at admission, oliguria, mechanical ventilation, non-recovery of renal function, in-hospital complications and hospital stay. In conclusion, our study contributes to a better knowledge of this condition and highlights the relevance of the detection of proteinuria throughout the clinical course., Competing Interests: The authors have declared that no competing interests exist.

Aims/introduction: To investigate the association between cardiovascular autonomic neuropathy (CAN) assessed by the coefficient of variation of the R-R interval and the reduction in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes., Materials and Methods: This retrospective observational cohort study enrolled type 2 diabetes patients who had their coefficient of variation of the R-R interval measured on an electrocardiogram from January 2005 to December 2018. CAN was defined using the reference coefficient of variation of the R-R interval value based on age and sex. The primary outcome was set as a 40% eGFR decline from baseline. Regression analyses using the Cox proportional hazards model were carried out to evaluate the association., Results: Of the 831 patients, 118 (14.2%) were diagnosed with CAN. In the analysis of the primary outcome, the median follow-up period was 5.3 years, and 25 (21.2%) patients with CAN and 78 (10.9%) patients without CAN developed a 40% eGFR decline. In the univariate regression analysis, CAN was significantly associated with a 40% eGFR decline (hazard ratio 2.42, 95% confidence interval 1.54-3.80). In the multivariate analysis, CAN remained almost significant after adjusting for the prognostic risk factors for CAN and the decline in the renal function, and an interaction with proteinuria was found. In analyses for the interaction effect between CAN and proteinuria, the presence of CAN synergistically increased the risk of an eGFR decline in patients with macroproteinuria., Conclusions: CAN strongly increased the risk of a 40% eGFR decline from baseline, especially in type 2 diabetes patients with macroproteinuria., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Both frailty and chronic kidney disease (CKD) increase with age and share many similarities. Many studies have demonstrated an association between frailty and chronic kidney disease (CKD), but an association with dipstick proteinuria is limited., Methods: This is the cross-sectional analysis of the Nambu Cohort Study at the beginning of observation. Frailty was diagnosed using Kihon Checklist. Logistic analysis was used to evaluate the association between frailty and CKD or dipstick proteinuria., Results: Among a total of 630 outpatients [age, 78 (70-84) years, men, 50%], the prevalence of patients with pre-frailty and frailty was 32% and 40%, respectively. The proportion of patients with pre-frailty and frailty increased with decreasing estimated glomerular filtration rate (eGFR) and increasing dipstick proteinuria levels. The odds ratios (95% confidence intervals) for CKD stage of 60 < eGFR ≤ 45 ml/min/1.73 m 2 , and 45 ml/min/1.73 m 2  < eGFR for frailty was 0.87 (0.56-1.35) and 2.54 (1.46-4.53), respectively, compared with non-CKD as a reference. Furthermore, the odds ratios for the frailty of dipstick proteinuria with ± and + or over were 1.36 (0.88-2.09) and 1.78 (1.00-3.17), respectively, when dipstick proteinuria-was used as a reference. Moreover, the combination of eGFR and dipstick proteinuria levels increased the odds ratio for pre-frailty and frailty., Conclusion: Elderly patients with CKD had a higher prevalence of pre-frailty and frailty. By adding urinary protein information to eGFR, the link between CKD and frailty becomes even more robust., (© 2021. Japanese Society of Nephrology.)

Background and Objective: The link between lung disease and kidney disorders has already been confirmed. Previous studies have documented that obstructive pulmonary disease is an independent predictor of decreased renal function, which reduces glomerular filtration rate. Recently, mesenchymal stem cells are the most important cell used in cell therapy. Accordingly, the present experiment was designed to evaluate the efficacy of adipose-derived mesenchymal stem cells (AMSCs) on improvement of renal function in elastase induced-pulmonary emphysema rats., Materials and Methods: Thirty male Sprague-Dawley rats divided into the 3 groups. Following intra-tracheal administration of elastase, the in vivo emphysema model established and confirmed according to the specific markers. Subsequently, systemic AMSCs injection was developed. the kidney injuries markers such as Blood urea nitrogen (BUN), creatinine, sodium and potassium as well as the kidney histopathologic parameters were assessed in all groups. Moreover, the oxidative stress markers levels including Malondialdehyde (MDA), Total antioxidant capacity (TAC), Catalase (CAT) and Glutathione peroxidase (GPx) were measured in kidney tissue and also inflammatory cytokines including IL-10, IL-6, and IFN-Ƴ were assessed in serum samples., Results: The marked rise in kidney injuries markers were observed which showed by enhancement of BUN and Creatinine levels in emphysema rats compared to the control. Furthermore, the results demonstrated increases in MDA levels and decreases in antioxidant activity which was in line with increases in inflammation cytokines in renal tissue. Conversely, AMSCs treatment improved renal function as shown by the decreases BUN, Creatinine and proteinuria. Furthermore, renal histological assay demonstrate improvement in glomerular and tubular damage and inflammatory cells accumulation., Conclusions: Our results documented the promising kidney-protective properties of Adipose-Derived Mesenchymal Stem Cells in the kidney injuries induced by emphysema., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To investigate the relationship between preoperative proteinuria and postoperative acute kidney injury (AKI)., Methods: We performed a search on databases included PubMed, Embase, the Cochrane Library, and Web of Science, from December 2009 to September 2020. Data extracted from eligible studies were synthesized to calculate the odds ratio (OR) and 95% confidence interval (CI). A fixed or random effects model was applied to calculate the pooled OR based on heterogeneity through the included studies., Results: This meta-analysis of 11 observational studies included 203,987 participants, of whom 21,621 patients suffered from postoperative AKI and 182,366 patients did not suffer from postoperative AKI. The combined results demonstrated that preoperative proteinuria is an independent risk factor for postoperative AKI (adjusted OR = 1.65, 95%CI:1.44-1.89, p <  0.001). Subgroup analysis showed that both preoperative mild proteinuria (adjusted OR = 1.30, 95%CI:1.24-1.36, p  < 0.001) and preoperative heavy proteinuria (adjusted OR = 1.93, 95%CI:1.65-2.27, p  < 0.001) were independent risk factors for postoperative AKI. The heterogeneity was combined because its values were lower. Further subgroup analysis found that preoperative proteinuria measured using dipstick was an independent risk factor for postoperative AKI (adjusted OR = 1.48, 95%CI:1.37-1.60, p <  0.001). Finally, preoperative proteinuria was an independent risk factor for postoperative AKI in the non-cardiac surgery group (adjusted OR = 2.06, 95%CI:1.31-3.24, p  = 0.002) and cardiac surgery group (adjusted OR = 1.69, 95%CI:1.39-2.06, p <  0.001)., Conclusion: Preoperative proteinuria is an independent risk factor for postoperative AKI and in instances when proteinuria is detected using dipsticks.

Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies., (© 2021. Springer Nature Limited.)

Background: Patients with diabetic or hypertensive kidney disease rarely undergo kidney biopsy because nephrologists commonly believe that biopsy-related risk outweighs the potential benefits of obtaining histologic information to guide clinical decisions. Although kidney function is acutely regulated, histologic changes such as interstitial fibrosis, tubular atrophy, and glomerulosclerosis may represent chronic kidney damage, and thus might provide additional information about disease severity. However, whether histologic analysis provides information complementary to clinically used kidney function measurements, such as eGFR and proteinuria, is unclear., Methods: We performed a standardized semiquantitative histologic analysis of 859 nephrectomies obtained from individuals with or without diabetes mellitus or hypertension and varying degrees of kidney dysfunction. Changes in glomeruli, tubules, interstitium, and the vasculature were scored using 17 descriptive parameters in a standardized manner. We used multivariable linear and logistic regression analyses and unbiased, hierarchical clustering to assess associations between histologic alterations and clinical variables., Results: At CKD stages 3-5, eGFR correlates reasonably well with the degree of glomerulosclerosis and interstitial fibrosis and tubular atrophy (IFTA). In patients with CKD stages 1-2, the degree of histologic damage was highly variable and eGFR poorly estimated the degree of damage. Individuals with diabetes mellitus, hypertension, or Black race had significantly more glomerulosclerosis and IFTA, at the same eGFR level. Inclusion of glomerulosclerosis improved the kidney function decline estimation, even at early disease stages., Conclusions: Histologic analysis is an important complementary method for kidney disease evaluation, especially at early disease stages. Some individuals present with relatively severe structural damage despite preserved eGFR., (Copyright © 2021 by the American Society of Nephrology.)

Diabetic kidney disease (DKD) is a highly heterogenous disease, including the proteinuric and the nonproteinuric pattern. Oxidized low-density lipoprotein (ox-LDL) is progressively increased in DKD and causes direct damage to kidney tubular epithelial cells through a mechanism similar to that underlying the deleterious effect of lipid peroxides in the vascular endothelium. We aimed to examine the association between plasma ox-LDL cholesterol and clinical endpoints in DKD patients. Ninety-one patients with established proteinuric DKD and diabetic retinopathy were enrolled and prospectively followed for 10 years or the occurrence of death, or at least 30% decline in eGFR, or progression to end-stage kidney disease (ESKD) requiring renal replacement therapy (primary outcome). At the end of the study, both eGFR and proteinuria were reassessed. Secondary outcomes of the study were the percentage change in eGFR and proteinuria over time for each patient. At baseline, patients were divided into 2 groups according to the median ox-LDL value (i.e., below or equal and above 66.22 U/L). Both Kaplan-Meier curves ( p = 0.001, log-rank test) and univariate Cox regression analysis showed that high ox-LDL was associated with the primary outcome (HR = 3.42, 95%CI = 1.55 - 7.56, p = 0.002). After adjustment for various well-known cofounders, multivariate Cox analysis showed that the association between increased circulating ox-LDL levels and the composite kidney endpoint remained significant (HR = 2.87, 95%CI = 1.14-7.20, p = 0.025). Regarding the secondary outcome of eGFR decline, the assessment of areas under the curves (AUC) showed that ox-LDL outperformed several cofounding factors (AUC 71%, 95%CI = 0.59 - 0.83, p = 0.001) and had better accuracy to predict deterioration of eGFR over time than baseline proteinuria (AUC 67%, 95%CI = 0.54 - 0.79, p = 0.014). Increased ox-LDL might be associated with disease progression in proteinuric DKD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Stefanos Roumeliotis et al.)

Chronic kidney disease in its later stages is associated with increased risk of kidney cancer. We investigated whether chronic kidney disease at milder stages is associated with increased kidney cancer risk, using a retrospectively selected cohort of 9,809,317 adults in the Republic of Korea who participated in a nationwide health screening (2009-2016). We examined the impact of estimated glomerular filtration rate (eGFR), dipstick proteinuria, and interactive associations between the 2 factors on the risk of incident kidney cancer. During a median follow-up period of 7.3 years, 10,634 kidney cancers were identified. After adjustment for multiple confounders, participants with a reduced eGFR had an increased risk of kidney cancer (for eGFR <30 mL/minute/1.73 m2, adjusted hazard ratio = 1.18 (95% confidence interval: 1.01, 1.39); for eGFR 30-59 mL/minute/1.73 m2, adjusted hazard ratio = 1.22 (95% confidence interval: 1.14, 1.31)) compared with those with an eGFR of 60-89 mL/minute/1.73 m2. A dose-response relationship between the severity of proteinuria and incident kidney cancer was observed. Analyses of joint effects of eGFR and dipstick proteinuria showed that with the presence of proteinuria, kidney cancer incidence was markedly increased along with decreasing eGFR. Reduced eGFR and proteinuria are significantly associated with subsequent risk of kidney cancer, possibly in a synergistic manner., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children., Methods: We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR., Results: SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months., Conclusions: Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria., (© 2021. The Author(s).)

Introduction: The association between the degree of isolated gestational proteinuria and preeclampsia with severe features and other placental-mediated complications is controversial. The aim of this study was to evaluate whether a higher isolated proteinuria level is associated with an increased frequency of preeclampsia with severe features., Material and Methods: This retrospective cohort study included pregnant women who were past 24 weeks of gestation and were diagnosed as having new-onset proteinuria ≥300 mg in a 24-h urine collection. Exclusion criteria included diagnosis of preeclampsia within 72 h from admission, chronic renal disease or chronic hypertension. The study population was divided into tertiles by proteinuria level and the association with preeclampsia with severe features was assessed in both bivariable and multivariable analysis. The main outcome measures was the development of preeclampsia with severe features., Results: Overall, 165 women were diagnosed with isolated gestational proteinuria, and 38 (23.0%) of them developed preeclampsia with severe features. Women in the increasing proteinuria tertile were more likely to develop preeclampsia with severe features (5.5%, 21.8%, 41.8%, respectively; p = 0.004). A multivariable logistic regression model controlling for background characteristics as well as gestational age at diagnosis, blood pressure, and kidney and liver function tests showed an increased risk of 14% to develop preeclampsia with severe features for every 500-mg rise in proteinuria level (adjusted odds ratio = 1.14, 95% confidence interval 1.03-1.27)., Conclusions: A higher isolated gestational proteinuria level was associated with an increased risk to develop preeclampsia with severe features among pregnant women past 24 weeks of gestation., (© 2021 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective/background: Individuals with sickle cell anaemia (SCA) may manifest various forms of renal abnormalities. Proteinuria is an early marker of renal dysfunction and a strong risk factor for chronic kidney disease (CKD) progression in both patients with SCA and non-SCA population. Currently, the degree of attention given to proteinuric CKD far exceeds that of nonproteinuric CKD, and risk factors that might trigger a progressive decline of the glomerular filtration rate (GFR) in the absence of proteinuria have not been well evaluated in SCA. The aim of this study was to compare the clinical and laboratory parameters among SCA patients with proteinuric and nonproteinuric CKD., Methods: This was a cross-sectional study conducted at the University of Maiduguri Teaching Hospital in north-eastern Nigeria between January 2013 and April 2018. Clinical variables including age of diagnosis of SCA, frequency of vaso-occlusive crises, number of hospitalizations per annum and transfusion therapy were collected. Laboratory data including haematological profile and renal function test were obtained from routine blood sampling., Results: A total of 257 patients with SCA (HbSS) were enrolled during the study period of which 42 had proteinuric CKD, and 48 had nonproteinuric CKD. The two groups were matched for the number of hospital admission (p = .063) and blood transfusion per year (p = .450), frequency of painful crisis (p = .210), systolic blood pressure (p = .084) and diastolic blood pressure (p = .400). In the proteinuric CKD group, the mean serum creatinine was higher (332.17 µmol/L, p = .001) and the estimated GFR was lower (31.88 mL/min, p = .046). The serum alkaline phosphatase was higher in the nonproteinuric CKD group (81.81 IU/L, p = .012)., Conclusion: Nonproteinuric CKD was more frequent than proteinuric CKD in our study population; however, the proteinuric group presented with more advanced disease., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest, (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Uricase-deficient rats could be one of the optimal model animals to study hyperuricemia. The present study aimed to find the biological differences between uricase-deficient (Kunming-DY rats) and wild-type male rats. Uricase-deficient rats and wild-type rats were commonly bred. Their body weight, water and food consumption, 24-h urine and feces, uric acid in serum and organs, and serum indexes were recorded or assayed. Organs, including the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum, were examined using a routine hematoxylin-eosin staining assay. We found that the growth of male uricase-deficient rats was retarded. These rats excreted more urine than the wild-type rats. Their organ indexes (organ weight body weight ratio), of the heart, liver, kidney, and thymus significantly increased, while those of the stomach and small intestine significantly decreased. The uricase-deficient rats had a significantly higher level of serum uric acid and excreted more uric acid via urine at a higher concentration. Except for the liver, uric acid increased in organs and intestinal juice of uricase-deficient rats. Histological examination of the uricase-deficient rats showed mild injuries to the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum. Our results suggest that uricase-deficient rats have a different biological pattern from the wild-type rats. Uricase deficiency causes growth retardation of young male rats and the subsequent increase in serum uric acid results in mild organs injuries, especially in the kidney and liver., Competing Interests: The authors have declared that no competing interests exist.

Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease and progression to end-stage renal disease in elderly patients. AKI is also a relatively common complication after kidney transplantation (KTx) associated with graft failure. Since the lifespan of a transplanted kidney is limited, the risk of the loss/deterioration of graft function (DoGF) should be estimated to apply the preventive treatment. The collection of saliva and urine is more convenient than collecting blood and can be performed at home. The study aimed to verify whether non-invasive biomarkers, determined in saliva and urine, may be useful in the prediction of DoGF in kidney transplant recipients (KTRs) ( n = 92). Salivary and serum toxins ( p -cresol sulfate, pCS; indoxyl sulfate, IS) concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Urinary proteins, hemoglobin, and glucose were measured using a semi-quantitative strip test. Salivary IS (odds ratio (OR) = 1.19), and proteinuria (OR = 3.69) were demonstrated as independent factors for the prediction of DoGF. Satisfactory discriminatory power (area under the receiver operating characteristic curve (AUC) = 0.71 ± 0.07) and calibration of the model were obtained. The model showed that categories of the increasing probability of the risk of DoGF are associated with the decreased risk of graft survival. The non-invasive diagnostic biomarkers are a useful screening tool to identify high-risk patients for DoGF.

Massive proteinuria in nephrotic syndrome causes depletion of various proteins. Iron deficiency can occur due to urinary loss of iron, transferrin, and soluble transferrin receptors. We conducted this cross-sectional study of 52 children with proteinuric nephrotic syndrome, aged 1-12 years (mean 7.1±2.7 years). Hemoglobin (Hb), RBC indices (MCV, MCH, MCHC), percentage of hypochromic RBCs (Hypo-He), reticulocyte hemoglobin content (Ret-He), and serum ferritin were examined. Seven (13%) patients had iron deficiency anemia and another 10 (19%) exhibited iron deficiency. A higher proportion of children with steroid-resistant disease had anemia than did steroid-sensitive children (P=0.076). Thus, children with nephrotic syndrome may have iron deficiency (32.7%), which needs to be screened., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m 2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

Objective: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis., Methods: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files., Results: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients., Conclusion: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Research regarding renal involvement in SSc has almost exclusively focused on scleroderma renal crisis (SRC). There are relatively limited data regarding renal impairment in SSc beyond SRC. We performed an electronic search using the key words systemic sclerosis or scleroderma combined with each of the following: renal dysfunction, kidney, glomerular filtration rate (GFR), proteinuria and hematuria. We searched for reports relevant to renal dysfunction in SSc beyond SRC. In 796 SSc patients recruited in five studies. 251 (31.5%) had GFR < 90 ml/min whereas 155(19.5%) patients had GFR < 60 ml/min. Most data indicate that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula should be considered as the most suitable tool for assessing renal function in SSc pts, since it provides similar results to measured GFR. These data indicate that renal dysfunction in SSc in not uncommon and therefore patients with SSc should have their renal function assessed by GFR estimation on a regular basis.

Although gestational hypertension (GH) is a well-known disorder, gestational proteinuria (GP) has been far less emphasized. According to international criteria, hypertensive disorders of pregnancy include GH but not GP. Previous studies have not revealed the predictors of progression from GP to preeclampsia or those of progression from GH to preeclampsia. We aimed to determine both sets of predictors. A retrospective cohort study was conducted with singleton pregnant women who delivered at 22 gestational weeks or later. Preeclampsia was divided into three types: new onset of hypertension/proteinuria at 20 gestational weeks or later and additional new onset of other symptoms at < 7 days or at ≥ 7 days later. Of 94 women with preeclampsia, 20 exhibited proteinuria before preeclampsia, 14 experienced hypertension before preeclampsia, and 60 exhibited simultaneous new onset of both hypertension and proteinuria before preeclampsia; the outcomes of all types were similar. Of 34 women with presumptive GP, 58.8% developed preeclampsia; this proportion was significantly higher than that of 89 women with presumptive GH who developed preeclampsia (15.7%). According to multivariate logistic regression models, earlier onset of hypertension/proteinuria (before or at 34.7/33.9 gestational weeks) was a predicator for progression from presumptive GH/GP to preeclampsia (odds ratios: 1.21/1.21, P value: 0.0044/0.0477, respectively).

Ambulatory blood pressure monitoring (ABPM) can produce many variables, of which the lowest nocturnal systolic blood pressure (LNSBP) currently used in calculating morning surge is occasionally overlooked in recent kidney studies compared with other ABPM parameters. We explored the clinical effects of LNSBP in elderly patients with chronic kidney disease (CKD) in a multicenter, observational cohort study. A total of 356 elderly patients with CKD from 19 clinics were included in this analysis. We used multiple logistic regression and survival analyses to assess the associations between the lowest nocturnal systolic blood pressure and heavy proteinuria and kidney disease outcomes, respectively. The median age was 66 years, and 66.6% were men. The median eGFR was 49.2 ml/min/1.73 m 2 . Multivariate logistic regression analysis demonstrated that LNSBP (OR 1.24; 95% CI 1.10-1.39; P < 0.001; per 10 mmHg) was associated with heavy proteinuria. During the median follow-up of 23 months, 70 patients (19.7%) had a composite outcome; of these, 25 initiated dialysis, 25 had 40% eGFR loss, and 20 died. Cox analysis showed that the renal risk of LNSBP for CKD outcomes remained significant even after adjusting for background factors, including age, sex, medical history of hypertension and diabetes, smoking status, eGFR, 24-h proteinuria, and etiology of CKD (HR 1.18; 95% CI 1.06-1.32; P = 0.002; per 10 mmHg). Concentrating on LNSBP could be valuable in guiding antihypertensive treatment to control heavy proteinuria and improve renal prognosis in elderly CKD patients.

Background: Living kidney donors are carefully screened, but despite overall good health, long-term donor outcomes have been shown to vary by predonation demographics. Since 2013, the United Network for Organ Sharing has mandated 2-year postdonation follow-up with measurements of kidney function and proteinuria., Methods: Using data from the Scientific Registry of Transplant Recipients, we sought to analyze donor factors associated with the percent change of kidney function from baseline (predonation) to 2-year postdonation, along with incidence of proteinuria reported within the same follow-up period., Results: Older donor age, male gender, black race, and body mass index >25 kg/m2 were independently associated with a greater percent decline in estimated glomerular filtration rate (eGFR). Male gender, black race, and higher body mass index were also independently associated with incident proteinuria. In contrast, younger donor age was associated with proteinuria, but proteinuria did not correlate with greater decline in eGFR in the overall cohort., Conclusions: Donor factors associated with lower eGFR at 2-year postdonation were similar to those previously found to be associated with long-term risk for end-stage renal disease. Early postdonation assessment of kidney function and proteinuria may help to identify donors who are at greater risk of end-stage renal disease and who may benefit from more intense long-term monitoring., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction., Objective: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes., Results: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations., Conclusion: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Metformin has protective effects on diabetic nephropathy. However, the mechanism underlying the renoprotective action of metformin in spontaneously hypertensive rats (SHR) is not completely understood. We determined the role of metformin in proteinuria and investigated the mechanism. We measured the urinary protein concentration (mg/day) in 48-week-old SHR. Matched control animals were of the same genetic strain, Wistar-Kyoto (WKY). The rats received metformin (100 mg/kg/day) or vehicle for 10 months. Metformin improved renal function and reduced the proteinuria (urine protein: 48.4 ± 3.7 vs. 25.4 ± 1.8 mg, P < 0.01) induced by long-term high blood pressure. Metformin increased the production of vascular endothelial growth factor (VEGF)-A in rat kidneys and cultured rat podocytes. Metformin activated hypoxia-inducible factor-2α (Hif-2α) in response to VEGF but did not affect Hif-1α in rat kidneys and cultured rat podocytes. Metformin reduced the proteinuria induced by long-term high blood pressure in vivo and increased the VEGF-A production in rat kidneys and cultured rat podocytes, probably by activating the Hif-2α-VEGF signaling pathway. These findings provide a new mechanism for the renoprotective effects of metformin., (Copyright © 2020. Published by Elsevier B.V.)

Intrauterine growth restriction (IUGR) is, in general, accompanied by a reduction of the nephron number, which increases the risk of hypertension and renal dysfunction. Studies have revealed that ouabain can partially restore the number of nephrons during IUGR. However, there is limited information regarding the melioration of nephric structure and function. We used maternal malnutrition to induce an IUGR model in rats. Subsequently, we used a mini-pump to administer ouabain to IUGR rats during pregnancy. Male offspring were divided randomly into two groups. One group was fed a normal diet, whereas the other was fed an isocaloric 8% high-salt diet. Maternal malnutrition led to a reduction in the birth weight and number of nephrons in offspring. At the end of a 40-week follow-up period, offspring from the IUGR group had high blood pressure and abnormal excretion of urinary protein; these parameters were exacerbated in offspring fed a high-salt diet. However, ouabain administration during pregnancy could partially restore the number of nephrons in IUGR offspring, normalize blood pressure, and reduce urinary protein excretion, even when challenged with a high-salt diet. Pathology findings revealed that IUGR, particularly following feeding of a high-salt diet, damaged the ultrastructure of glomeruli, but these harmful effects were ameliorated in offspring treated with ouabain. Collectively, our data suggest that ouabain could rescue nephrogenesis in IUGR newborns and protect (at least in part) the structure and function of the kidney during adulthood even when encountering unfavorable environmental challenges in subsequent life.

Background: Effective follow-up after living kidney donation is important for maintaining the renal function of the donor. We investigated whether the estimated glomerular filtration rate (eGFR) and urinary protein and enzyme levels can provide important information regarding the state of the remaining kidney after donor nephrectomy., Methods: Seventy-five living donations were included (prospective/retrospective) in the study. The following parameters were measured up to 1 year after donor nephrectomy: serum creatinine and cystatin C as markers of the GFR; the high-molecular-weight urinary proteins as markers of glomerular injury; and the low-molecular-weight urinary proteins and urinary enzymes as markers of tubular function., Results: One year after kidney donation, the creatinine and cystatin C values were 1.38-fold increased than their initial values, while the eGFR was 32% lower. At that time, 38% of donors had a moderate or high risk of CKD progression. The biochemical urinary glomerular and tubular kidney markers examined showed different behaviors. After a transient increase, the glomerular proteins normalized. Conversely, the detection of low-molecular-weight urinary proteins and enzymes reflected mild tubular damage at the end of the study period., Conclusions: Our findings suggest that for the evaluation of mild tubular damage, low-molecular-weight marker proteins should be included in the urine diagnostic of a personalized living kidney donor follow-up., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects., Summary: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: How to manage patients with severe kidney disease in pregnancy is still a matter of discussion, and deciding if and when to start dialysis is based on the specialist's experience and dialysis availability. The effect of toxic substances usually cleared by the kidney may be more severe and readily evident. The review, and related case, underlines the importance of considering the presence of additives in food in delicate conditions, such as CKD pregnancy. The Case: A 39-year-old indigenous woman from a low-resourced area in Mexico was referred to the obstetric nephrology at 25 gestational weeks because of serum creatinine at 3.6 mg/dL, hypertension on low-dose alpha-methyl-dopa, and nephrotic-range proteinuria. Kidney ultrasounds showed small poorly differentiated kidneys; foetal ultrasounds detected a female foetus, normal for gestational age. The patient's baseline protein intake, which was estimated at 1.2-1.3 g/kg/day, was mostly of animal-origin (>70%) poor-quality food ("junk food"). In the proposed diet, protein intake was only slightly reduced (1.0-1.2 g/kg/day), but the source of proteins was changed (only 30% of animal origin) with attention to food quality. A remarkable decrease in BUN was observed, in concomitance with adequate dietary follow-up, with rapid rise of BUN when the patient switched temporarily back to previous habits. A healthy female baby weighing 2,460 g (11th centile for gestational age) was delivered at 37 gestational weeks. Discussion and Literature Review: While data on patients with chronic kidney disease are scant, the long list of contaminants present in food, especially if of low quality, should lead us to reflect on their potential negative effect on kidney function and make us realize that eating healthy, unprocessed "organic" food should be encouraged, in delicate conditions such as pregnancy and breastfeeding and for young children, in particular when kidney function is failing. The case herein described gave us the opportunity to reflect on the importance of diet quality and on the potential risks linked to food additives, many of which, including phosphates and potassium, are not declared on food labels, while others, including dyes, antioxidants, thickeners, emulsifiers, and preservatives, are qualitatively, but not quantitatively, reported., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Glomerular inflammation is a putative aggravation factor for type 2 diabetic nephropathy and urinary thrombin is a novel marker of glomerular inflammation. To clarify the relationship between glomerular inflammation and progression of the nephropathy, we measured urinary thrombin in 118 patients with type 2 diabetic nephropathy at different stages. To investigate the implications of urinary thrombin in the nephropathy, we compared urinary thrombin with expression of tissue factor, the trigger of blood coagulation activation, in glomeruli and with markers of renal injury (estimated glomerular filtration rate (eGFR) and proteinuria). Urinary thrombin was found in 4.9% (3/61), 0.0% (0/12), 29.6% (8/27) and 50.0% (9/18) of patient groups at stages 1, 2, 3 and 4, respectively. Thus, urinary thrombin was negligible in the patients at early stages (stages 1 and 2), but was present predominantly in the patients at advanced stages (stages 3 and 4). Tissue factor was expressed in accumulated macrophages in glomeruli, which indicates that thrombin may be generated in inflamed glomeruli presumably via inflammation-induced activation of the exudated coagulation factors into glomerular tissues and then be excreted in urine. Urinary thrombin was significantly associated with both decreased eGFR and increased proteinuria in type 2 diabetic nephropathy. Therefore, increased urinary thrombin in patients with advanced stages of type 2 diabetic nephropathy suggests that glomerular inflammation may injure the tissues, thereby impairing renal function. Monitoring an effect of anti-diabetic treatments on glomerular inflammation in the patients with type 2 diabetic nephropathy may be a possible application of urinary thrombin.

We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn-hooded hypertensive (FHH) rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH. Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH. Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 Dicer-substrate short interfering RNA (DsiRNA) and primary podocytes isolated from FHH rats. There were increased F/G-actin ratios and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, glomeruli, and podocytes of FHH rats. The expression of nephrin at the slit diaphragm and the levels of focal adhesion proteins integrin-α 3 and integrin-β 1 were decreased in the glomeruli of FHH rats. Cell migration was enhanced and adhesion was reduced in podocytes of FHH rats as well as in immortalized mouse podocytes transfected with Add3 DsiRNA. Mean arterial pressures were similar in FHH and FHH. Add3 transgenic rats at 16 wk of age; however, FHH rats exhibited enhanced proteinuria associated with podocyte foot process effacement. These results demonstrate that reduced ADD3 function in FHH rats alters baseline podocyte pathophysiology by rearrangement of the actin cytoskeleton at the onset of proteinuria in young animals.

Background: Little is known about the association between pre-operative proteinuria and post-operative acute kidney injury (AKI) in noncardiac surgery., Methods: This is a retrospective cohort study. Adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data for analyses or pre-operative dialysis were excluded. Exposure of interest was pre-operative proteinuria, defined as (+) or more by dipstick test. The outcome variable was post-operative AKI, defined by Kidney Disease: Improving Global Outcomes criteria, within 1 week after surgery. Multivariable logistic regression analyses were performed., Results: Among 5168 subjects, 309 (6.0%) developed AKI. Pre-operative proteinuria was independently associated with post-operative AKI, with an odds ratio (OR) [95% confidence interval (CI)] of 1.80 (1.30-2.51). A sensitivity analysis restricted to elective surgery yielded a similar result. As proteinuria increased, the association with AKI became stronger [OR (95% CI) 1.14 (0.75-1.73), 1.24 (0.79-1.95), 2.75 (1.74-4.35) and 3.95 (1.62-9.62) for urinary protein (+/-), (+), (2+) and (3+), respectively]. Subgroup analyses showed proteinuria was especially associated with post-operative AKI among subjects with renin-angiotensin system inhibitors, other anti-hypertensives, hypoalbuminemia or impaired renal function (P for interaction = 0.05, 0.003, 0.09 or 0.02, respectively)., Conclusions: In noncardiac surgery, pre-operative proteinuria was independently associated with post-operative AKI. Subjects with proteinuria should be managed with caution to avoid AKI peri-operatively., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objectives: The aim of this study was to describe the causes, clinicopathologic features and outcomes of feline protein-losing nephropathy (proteinuria secondary to glomerular disease [PLN])., Methods: Kidney biopsy/necropsy samples from proteinuric cats submitted to the International Veterinary Renal Pathology Service were retrospectively reviewed. Diagnoses based on histopathology were categorized by primary disease compartment. Clinicopathologic variables at diagnosis, development of hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema, and survival were compared between cats with immune-complex glomerulonephritis (ICGN) and other causes of PLN., Results: Fifty-eight percent (n = 31/53) of proteinuric cats had ICGN and 74% (n = 31/42) of cats with PLN had ICGN. Cats with glomerular diseases other than ICGN had a higher median urine protein:creatinine ratio than ICGN cats (14.5 vs 6.5; P <0.001). Onset of PLN occurred at a young age; median age at diagnosis was 3.5 years in ICGN cats vs 1.3 years in cats with other glomerular diseases ( P  = 0.026). Development of complications such as hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema were common, regardless of the cause of PLN, and were not different between ICGN and cats with other glomerular diseases. Male cats were over-represented in the ICGN group ( P  = 0.003). Median survival time (MST) for all cats with PLN was 94 days (range 3-1848 days). Survival was not different between cats with ICGN and cats with other glomerular diseases. MST in ICGN cats that developed effusion was shorter (94 days) than cats that did not (700 days; P  = 0.035). MST in IGCN cats that received immunosuppressive medications was longer (244 days) than cats that did not (17 days, P  = 0.039)., Conclusions and Relevance: Taken together, these data suggest that clinical suspicion for glomerular proteinuria should increase in young, male cats with higher degrees of proteinuria, and immune-mediated disease is common. Further studies are needed to determine the effect of immunosuppression on morbidity and mortality in cats with ICGN.

Background: Since the Coronavirus Disease 2019 (COVID-19) outbreak, there is accumulating data on the clinical characteristics, treatment strategies and prognosis of COVID-19 in patients with concurrent renal disease. Postmortem investigations reveal renal involvement in COVID-19, and most recently, several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy such as collapsing glomerulopathy were common histological findings. However, to our best knowledge, there is limited data regarding IgA nephropathy in the setting of COVID-19., Case Presentation: In the present case, we report a 65-year old Chinese woman who presented with dark-colored urine, worsening proteinuria and decreased renal function after COVID-19 infection. She received a renal biopsy during COVID-19 infection. The renal biopsy revealed IgA nephropathy without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities were a consequence of exacerbation of this patient's underlying glomerular disease after COVID-19 infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up., Conclusions: It is important to consider the underlying glomerular disease exacerbation as well as virus induced injury when dealing with renal abnormalities in patients with COVID-19. A kidney biopsy may be indicated to exclude a rapidly progressive glomerular disease.

Recent advances in neonatal care have improved the survival rate of those born premature. But prenatal conditions, premature birth and clinical interventions can lead to transient and permanent problems in these fragile patients. Premature birth (<36 gestational weeks) occurs during critical renal development and maturation. Some consequences have been observed but the exact pathophysiology is still not entirely known. This experimental animal study aims to investigate the effect of premature birth on postnatal nephrogenesis in premature neonatal rabbits compared to term rabbits of the same corrected age. We analyzed renal morphology, glomerular maturity and functional parameters (proteinuria and protein/creatinine ratio) in three cohorts of rabbit pups: preterm (G28), preterm at day 7 of life (G28+7) and term at day 4 of life (G31+4). We found no significant differences in kidney volume and weight, and relative kidney volume between the cohorts. Nephrogenic zone width increased significantly over time when comparing G31 + 4 to G28. The renal corpuscle surface area, in the inner cortex and outer cortex, tended to decrease significantly after birth in both preterm and term groups. With regard to glomerular maturity, we found that the kidneys in the preterm cohorts were still in an immature state (presence of vesicles and capillary loop stage). Importantly, significant differences in proteinuria and protein/creatinine ratio were found. G28 + 7 showed increased proteinuria (p = 0.019) and an increased protein/creatinine ratio (p = 0.023) in comparison to G31 +4. In conclusion, these results suggest that the preterm rabbit kidney tends to linger in the immature glomerular stages and shows signs of a reduced renal functionality compared to the kidney born at term, which could in time lead to short- and long-term health consequences., Competing Interests: The authors have declared that no competing interests exist.

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1 BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1 BN Add3 KO ( Add3 KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3 KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3 KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3 KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3 KO rats. The degree of renal injury was greater in Add3 KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3 KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3 KO rats.

Objectives: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre-eclampsia (PE) in pregnancies with COVID-19, and to assess their accuracy to differentiate between PE and the PE-like features associated with COVID-19., Design: A prospective, observational study., Setting: Tertiary referral hospital., Participants: Singleton pregnancies with COVID-19 at >20 +0  weeks., Methods: Forty-two consecutive pregnancies were recruited and classified into two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms-like tyrosine kinase-1/placental growth factor [sFlt-1/PlGF]) were assessed in women with suspected PE., Main Outcome Measures: Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt-1/PlGF., Results: Thirty-four cases were classified as non-severe and 8 as severe COVID-19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID-19 cases (62.5%). However, abnormal sFlt-1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE-like syndrome., Conclusions: Pregnant women with severe COVID-19 can develop a PE-like syndrome that might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre-eclampsia with caution., Tweetable Abstract: This study shows that a pre-eclampsia-like syndrome could be present in some pregnancies with severe COVID-19., (© 2020 Royal College of Obstetricians and Gynaecologists.)

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.