Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.  Howev2) , identif2) –11.Establishing novel biomarkers that predict progression and represent biologically relevant pathways in DKD could improve the care of patients with diabetes. To identify novel biomarkers, we recently performed an untargeted urine metabolomics study in patients with T2D and impaired estimated GFR (eGFR) from the Chronic Renal Insufficiency Cohort (CRIC) study , and we 2. The top tertile of baseline urine adenine/creatinine ratio (UAdCR) was found to identify the participants with diabetes who were at high risk for ESKD and all-cause mortality  (https://doi.org/10.1172/JCI170341DS1).The baseline clinical characteristics of the participants with diabetes from the CRIC and Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) study are shown in tertile) , and a stertile) . The top2) in a American Indian cohort with more than a 20-year follow-up (n = 42 of the 54 participants), the association of UAdCR with longitudinal progression to ESKD was presented in this nonmacroalbuminuric cohort. ESKD was associated with the top UAdCR tertile    . UAdCR w 0.0001) . Similar 0.0001) . Of note 0.0001) . Of the To determine if UAdCR could be modified in nonmacroalbuminuric participants with normal or elevated measured GFR by glycemia or a therapeutic intervention with an SGLT2 inhibitor, the UAdCR was measured during euglycemia or hyperglycemia before and after empagliflozin in patients with T1D  and performed on kidney biopsies from individuals acting as healthy controls and patients with diabetes  and an unbiased pathway analysis were performed based on differentially regulated genes. The top pathway identified was the ribosomal nucleoprotein biogenesis pathway in patients without macroalbuminuria and low eGFR  study , a small-molecule-specific inhibitor of methylthioadenosine phosphorylase (MTAP), was administered to db/db mice, a model of obese T2D. MTAP converts methylthioadenosine to adenine and is responsible for approximately 80% of adenine production in mammalian cells . MTDIA wThe results from this study demonstrate a role for endogenous adenine in kidney disease progression in the context of DKD. Urine levels of the AdCR identified patients with diabetes at high risk of kidney failure and all-cause mortality at all levels of albuminuria in the CRIC study, and this was verified in a cohort study from Singapore. The UAdCR could also identify patients who will develop ESKD even in the setting of normal or elevated GFR without macroalbuminuria across ethnicities. Spatial metabolomics localized adenine to regions of vascular, tubular, and glomerular pathology in patients with diabetes who have normoalbuminuria and GFR. Adenine appears to be in the causal pathway of kidney fibrosis, as adenine was demonstrated to stimulate matrix molecules in proximal tubular cells via mTOR and was causative of kidney matrix production in mice, and inhibiting adenine production was protective in diabetic mice.Biomarkers in the potentially causal pathways have not previously been identified for kidney disease progression in nonmacroalbuminuric patients with diabetes to our knowledge. Microalbuminuria is clearly a risk factor for kidney disease progression; however, as microalbuminuria can revert to normoalbuminuria  the depeAdenine is known to cause kidney pathology as an exogenous toxin in mouse  and rat The UAdCR measurement was closely associated with DKD progression in the nonmacroalbuminuric diabetic American Indian, the CRIC study, and SMART2D cohorts. As nonmacroalbuminuric DKD leads to ESKD in many patients with CKD and diabetes , 8, 33, Strengths of our study included multiple analysis of several independent cohorts across different ages, ethnicities, and stages of DKD. Additional strengths include application of spatial metabolomics and single-cell transcriptomics to identify a pathway linking adenine to mTOR in human kidney disease pathology and progression. A limitations of our study is that the role of adenine was not demonstrated in type 1 DKD and other causes of CKD.In conclusion, urine samples from independent well-characterized cohorts of patients with diabetes identified the UAdCR as a robust predictor of ESKD and mortality independent of albuminuria and baseline eGFR, and spatial metabolomic and single-cell-transcriptomic studies from human kidney biopsies identified a potential role for endogenous adenine and the mTOR pathway in DKD. Studies in cells and mice identified a causative role for adenine, and a small-molecule therapeutic was found to block adenine production and was nephroprotective in a mouse model of T2D. Our results thus demonstrate that endogenous adenine could contribute to progressive kidney disease in the context of T2D.2 and sample and outcome data available. SMART2D is an ongoing prospective cohort study of Southeast Asian participants with T2D recruited between 2011 and 2014  to evaluate the effects of empagliflozin   . EuglyceUrine samples from the American Indian, CRIC, SMART2D cohorts and ATIRMA urines were all analyzed using Zip-Chip (908 Devices) coupled with mass spectrometry . A rapidHuman kidney samples were obtained via the KPMP  and the CROCODILE studies –41. SampZDF rat kidney and urine samples were provided by Epigen Inc. to verify that kidney spatial adenine correlated with the targeted urine adenine assay. C57BL/6J, db/m, and db/db mice were obtained from The Jackson Laboratory. C57BL/6J mice were administered adenine for 4 weeks in drinking water before sacrifice, and tissues and blood samples were harvested at University of Texas Health Science Center at San Antonio. db/m and db/db mice were administered vehicle or MTDIA MTAP inhibitor for a period of 8 weeks from week 10 to week 18. An Albumin ELISA kit  and creatinine colorimetric kit  were used for the urinary ACR. Serum cystatin C was measured by the Quantikine ELISA kit . Plasma creatinine and metabolites in kidney tissue were measured by Zip-Chip-mass spectrometry as previously described . Urine aA multimodal imaging approach was developed to investigate regional localization of metabolites in kidney sections. Bright-field and autofluorescence microscopy outlined glomeruli and tubules, and PAS-H staining revealed regions of pathology in serial sections. MALDI-MSI was performed with a Thermo Fisher Scientific Q Exactive HF-X hybrid quadrupole-Orbitrap mass spectrometer in combination with a novel elevated pressure MALDI/ESI interface (Spectroglyph LLC) . MetabolHuman kidney proximal tubular (HK-2) cells were purchased from the ATCC and were cultured as previously described . Murine Single-cell transcriptomics and spatial metabolomics data sets generated from healthy kidney tissue, unaffected tissue in kidney nephrectomy, and biopsy samples (KPMP and CROCODILE) were analyzed as recently described –41. The 2, or more than 50% GFR or eGFR decline from baseline level. All-cause mortality included death from any cause before reaching the ESKD endpoint. Urine adenine was normalized to urine creatinine concentrations and log2 transformed. In the CRIC and SMART2D cohorts, the association of urine adenine levels (tertile) with clinical endpoints was studied by multivariable Cox proportional hazard regression models with adjustment for age, sex, ethnicity and race, body mass index, hemoglobin A1c, mean arterial pressure, baseline eGFR, and urine ACR  as covariates. The group with a UAdCR in the lowest tertile was used as reference. Due to the limited number of cases in the American Indian cohort, we only reported univariate Cox proportional hazards analysis for this cohort. To evaluate the pretreatment and posttreatment effect of empagliflozin on urine adenine in the ATIRMA cohort, we performed a linear regression analysis for repeated measures. Two-tailed Student’s t test was used for comparisons of features between 2 groups. A P value of less than 0.05 was considered significant.A composite kidney endpoint was defined as sustained kidney replacement therapy, progression to GFR or eGFR of less than 15 mL/min/1.73 mFor the CRIC study, informed consent was obtained from participants. Protocols were approved by IRBs and Scientific and Data Coordinating Center . The SMART2D study was approved by the Singapore National Healthcare Group, and all participants provided written informed consent. The KPMP and CROCODILE studies were approved by the Institutional Review Board at Washington University, St. Louis, Missouri, and the University of Colorado, respectively, and written consent was obtained from all patients. The American Indian study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases, and all participants gave written informed consent. Mouse studies were carried out after IACUC approval from the University of Texas Health Science Center at San Antonio.Values for all data points in graphs are reported in the The first 9 coauthors each made unique and critical contributions to this manuscript, and authorship order was determined after discussion among writing group members. KS, PB, SCL, JJL, RI, RGN, MK, and GZ designed the study. KS, PB, SCL, DC, and RGN acquired funding for the study. GZ, J Hansen, HJL, RM, PB, JJL, HLH, LH, AF, PB, MAV, LK, and FCT acquired or generated the data. GZ, J Hansen, HJL, JJL, HLH, VS Sridhar, BYC, RF, MAV, LK, JBH, and JG analyzed the data. KS, GZ, PB, KRT, MK, RGN, and RI wrote the manuscript. KS, PB, MK, SCL, LN, JZ, VS Sharma, B Kwan, SSW, J Himmelfarb, KRT, B Kestenbaum, TF, HIF, IHB, J Sedor, HCL, J Schaub, RM, EAO, CRA, TA, SCL, RGN, JG, and RI provided scientific guidance and insights. All authors reviewed, edited, and approved the manuscript.


The contribution of large vessel stenosis to the development of white matter hyperintensities (WMHs) has not been fully elucidated. This study aims to explore the correlation between ipsilateral white matter hyperintensities (WMHs) and the severity of large vessel stenosis in the anterior circulation and cerebral perfusion level, as well as analyze the factors influencing WMHs.A cross‐sectional study of 150 patients with unilateral anterior circulation large vessel stenosis of ≥50% was conducted. The severity of ipsilateral WMHs was assessed by Fazekas scale on T2‐weighted image and/or fluid‐attenuated inversion recovery MR imaging, vascular stenosis severity was evaluated on computed tomography angiography images, and the level of cerebral perfusion was rated according to a staging system for abnormal cerebral perfusion based on CTP results. The relationships between the stenosis severity, cerebral perfusion level and ipsilateral WMHs severity were analyzed. A multivariate logistic regression analysis was performed to determine the factors independently influencing WMHs.p < .001; Gamma = 0.600, p < .001), and a positive correlation between cerebral perfusion level and the severity of vascular stenosis .While, there was no statistically significant correlation between the severity of vascular stenosis and the severity of DWMHs and PWMHs . The multivariate logistic regression analysis results demonstrated that age , stroke/TIA history  and stage II of cerebral perfusion  were independent influencing factors on ipsilateral DWMHs. Age , and stage II of cerebral perfusion  were factors independently influencing ipsilateral PWMHs.Among 150 patients , there was a statistically significant positive correlation between cerebral perfusion level and the severity of DWMHs and PWMHs (Gamma = 0.561, White matter hyperintensities may be attributed to cerebral hypoperfusion secondary to vascular stenosis but not directly to the severity of stenosis in the large vessels of anterior circulation. Moreover, longitudinal studies with sequential imaging exams may further reveal the impact of cerebral perfusion secondary to vascular stenosis on the development and progression of WMHs.  WMHs were divided into periventricular WMHs (PWMHs) and deep WMHs (DWMHs) based on the distance between lesions and the lateral ventricular wall, both of which were scored by the Fazekas scale, respectively. PWMHs were scored as follows: 0 points, no lesions; 1 point, cap‐shaped or pencil‐like thin‐layer lesions; 2 points, smooth halo‐like lesions; 3 points, irregular paraventricular hyperintensities. DWMHs were scored as follows: 0 points, no lesions; 1 point, punctate small lesions; 2 points, initially fused lesions; 3 points, extensively fused lesions. 1 point represented mild WMHs, 2 points represented moderate WMHs, and 3 points represented severe WMH. The total score (0–6 points) was the sum of PWMH and DWMH scores . The scanning was performed under the following parameters: Tube voltage of 120 kV, effective milliampere‐second of 200 mAs, collimator width of 64 mm × 0.6 mm, the pitch of 1.0, rotation speed of 0.4 s, original image acquisition slice thickness of 1.0 mm, reconstruction slice thickness of 0.5 mm, and slice spacing of 0.5 mm. Based on the calculation method related to warfarin‐aspirin symptomatic intracranial disease (WASID)  was used to perform scanning examinations. The 6‐cm layer adjacent to the basal ganglia was selected. The scanning was performed under tube voltage of 80 kV and tube current of 150 mAs. During the examination, 50 mL of iohexol (iodine content: 350 mg/mL) was injected from the median cubital vein with a high‐pressure syringe at a flow rate of 5.0 mL/s, and then flushed with 50 mL of normal saline. Subsequently, 60 s of continuous dynamic scanning was started with a delay of 5 s and a sampling interval of 2 s. As a result, the images with 480 frames were obtained. Standard reconstruction was performed under the slice thickness of 4 mm, the slice spacing of 4 mm, and the FOV of 190 mm × 190 mm. The postprocessing of cerebral perfusion imaging was performed by CT Brain Perfusion on the Philips IntelliSpace Portal workstation (v6.0. 5.02900). The pseudo‐color images related to such perfusion parameters as cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and time to peak (TTP) were obtained. The region of interest (ROI) was plotted on the perfusion image after avoiding blood vessels and calcification. The lesion area and contralateral mirror area parameters were automatically generated by software to perform a quantitative analysis. Based on the staging system proposed by Yin et al. , abnormaAll the above images were independently interpreted by two senior neuroimaging doctors. The third doctor would participate in discussion and consultation in case of any disagreement. There was excellent interobserver agreement in evaluating the vascular stenosis, DWMHs, PWMHs, and cerebral perfusion with kappa values of 0.856, 0.874, 0.893, and 0.866, respectively.2.4x¯± s), and an independent sample t‐test was performed to compare these data between groups. The data that did not conform to a normal distribution were expressed by median (quartile). The classification and counting data were expressed by the number of cases (percentage), and the χ2 test was performed to compare these data between groups. The relationships between the stenosis severity, cerebral perfusion level and ipsilateral WMHs severity were tested by Gamma correlation analysis, as they are both ordinal level variables. Logistic regression analysis enabled the analysis of factors influencing WMHs. The Wilcoxon signed‐rank test was applied to evaluate the differences in WMH scores between the ipsilateral hemisphere of vascular stenosis and the contralateral hemisphere. p < .05 indicated the threshold for a statistically significant difference.Statistical analysis was performed by the SPSS 26.0 software. Normally distributed data were expressed as mean ± standard deviation (33.1p < .05) (Table p < .05) (Table p < .05)  Table . Among t5) Table . Additio5) Table .3.2p > .05), and the proportion of stage II patients was significantly higher in the moderate‐severe DWMH and moderate‐severe PWMH groups than in the nonmild DWMH and nonmild PWMH groups (p < .05) , and a positive correlation between cerebral perfusion level and the severity of vascular stenosis . While, there was no statistically significant correlation between the severity of vascular stenosis and the severity of DWMHs and PWMHs . Figures According to univariable analysis, there was no difference in the severity of stenosis and site of stenosis between patients in the nonmild DWMH and moderate‐severe DWMH groups, as well as in the nonmild PWMH and moderate‐severe PWMH groups (5) Table . The rel3.3p < .05 for all of these variables, they were included as covariates in the subsequent binary logistic regression. Age , stroke/TIA history , and stage II of cerebral perfusion  were independent influencing factors on ipsilateral DWMHs. (Table p = .018), and stage II of cerebral perfusion  were factors independently influencing ipsilateral PWMHs.In the univariate analysis, age, smoking history, hypertension, stroke/TIA history, Hcy, and cerebral perfusion level were strongly associated with ipsilateral DWMHs. Since 3.4p < .001 for both; Table The Wilcoxon signed‐rank test on WMH severity between the ipsilateral and contralateral sides of the stenosis revealed that the scores of DWMHs and PWMHs were higher in the ipsilateral hemisphere of stenosis than in the contralateral hemisphere , glial activation, and apoptosis, thus leading to the progression of WMHs  can be determined using the software. CBV is defined as the volume occupied by intravascular blood within a particular quantity of brain tissue (including capillaries and large vessels). A drop in CBV denotes poor cerebral microcirculation. On the other hand, CBF is defined as the amount of blood flow through certain cerebral vascular structures  in a unit interval. A decline in CBF delineates an impairment of the cerebral microcirculation. Meanwhile MTT is defined as the average time for contrast media to pass through the ROI. The prolonged MTT indicates decreased cerebral perfusion pressure and impaired perfusion reserve. Similarly, TTP is defined as the time duration from the beginning of injection of contrast media to reaching the peak concentration in the ROI. The prolonged TTP is mainly caused by the slow blood flow or collateral blood supply (Tao et al., In this study, we discovered that DWMHs and PWMHs were more severe on the ipsilateral side of the stenosis than on the contralateral side. This may be related to their anatomy since DWMHs are supplied by deep penetrating arteries branching from the intracranial soft meningeal arteries. These arteries have relatively short vascular pathways and it is difficult for ischemia to occur in this region when the collateral circulation is good or perfusion is normal. Thus, ischemic changes only happen when perfusion is inadequate or when cerebral blood flow self‐regulation is reduced. Blood supply to the PWMHs is derived from the choroidal artery of the inferior ventricular artery or from the terminal branches of the striatum arteriosus, which has a sparse or absent anastomosis with vessels originating from the cerebral surface (Song et al., The current findings on the impact of cerebral hypoperfusion on the severity of WMHs may have clinical implications for the management of patients with vascular stenosis. Improving cerebral perfusion could be highly beneficial to patients with WMHs and cerebrovascular stenosis. It has been demonstrated in a prospective study (Chuang et al., Limitations of our study: First, this study is a single‐center retrospective study, which could not evaluate the causality of the association between cerebral perfusion and WMHs. Therefore, it is still necessary to conduct multicenter, large‐sample and prospective studies to further verify the findings reported in this study. However, the results of the relationships between the severity of large vessel stenosis, the level of cerebral perfusion, and the severity of ipsilateral WMHs may provide important clues for the direction of future research in this area. Second, most patients in our study were symptomatic, a heterogeneous group with different presentations, so sample selection bias was inevitable, a multicenter study including both symptomatic and asymptomatic patients would reduce this error. Third, many patients without stenosis may also have WMHs, and since few patients without stenosis are clinically assessed for cerebral perfusion, patients without stenosis were excluded from this study. Our study has some strengths. First, we combine CTA with CTP, and the vascular stenosis can be more fully represented morphologically and functionally. Second, two experienced radiologists assessed the severity of stenosis, WMH, and cerebral perfusion without knowledge of clinical demographics, which minimized the expected bias. Third, this is a retrospective study, and it is much easier and cheaper to conduct a review of medical records, and valuable information can often be found this way.In summary, white matter hyperintensities may be attributed to cerebral hypoperfusion secondary to vascular stenosis but not directly to the severity of stenosis in the large vessels of anterior circulation. We need to actively treat and intervene in factors that cause cerebral hypoperfusion in order to delay the development of WMHs. However, further investigations are required to verify these findings and identify potential pathophysiological mechanisms.FF, RD, WK, and HY conceived and designed the study. FF, WK, and HY acquired the data. FF, RD, WK, and HY analyzed and interpreted the data. All authors contributed to the writing of the manuscript, read and approved the final version.The authors have no conflicts of interest to declare.This study was approved by the Ethics Committee of the affiliated Hospital of Xuzhou Medical University.https://publons.com/publon/10.1002/brb3.2932.The peer review history for this article is available at


Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke and thromboembolism. Anticoagulation therapy can reduce this risk, but the optimal choice of anticoagulant in patients with AF and renal dysfunction is challenging. Renal dysfunction is a common comorbidity seen in patients with AF. Renal dysfunction would affect the pharmacokinetics and pharmacodynamics of anticoagulants and make the patient more prone to bleeding complications. This complicates the assessment of the risks, benefits, and ratio for starting anticoagulant drugs in patients with renal dysfunction. Therefore, there is always a therapeutic conundrum due to the increased risk of bleeding and thromboembolic events in AF patients with renal dysfunction.We conducted a systematic review to summarize the current literature and identify the challenges of anticoagulation strategies in AF with renal dysfunction. We examined 180 articles from reputable journals published from 2018 to June 2023 and selected eight papers for detailed analysis.The studies we chose included a variety of drug treatments, such as traditional therapies like vitamin K antagonists, factor Xa inhibitors, heparins, and direct thrombin inhibitors. This systematic review will provide comprehensive information on the latest data on the effectiveness of various pharmacological treatments (anticoagulation strategies) in AF patients with renal dysfunction. The aim is to help doctors and other healthcare decision-makers choose the best anticoagulation strategy in AF patients with renal dysfunction and to overcome their dilemma between bleeding risk and systemic thromboembolic events. Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and systemic embolism. Compared to those with normal or near-normal kidney function, patients with renal dysfunction or chronic kidney disease (CKD) are at very high risk for cardiovascular morbidity and mortality, including AF. AF is less common in the general population, with less than 2% prevalence. However, those with CKD have a much higher prevalence of AF, with more than 10 times the occurrence rate. Patients with moderate (stage 3) CKD have almost 20% of AF prevalence. For individuals with more advanced CKD (stage 4 or 5), especially those requiring dialysis, the incidence of AF is even higher, with some studies indicating that nearly 33% of all patients have AF [Having CKD increases the possibility of developing health conditions that usually need anticoagulation such as venous thromboembolic events and AF. However, it also significantly raises the likelihood of experiencing complications related to anticoagulation, particularly major bleeding . AssessiThere are conflicting reports on the effectiveness of oral anticoagulants in lowering the risk of stroke in patients with advanced renal dysfunction and AF. While a large study in Denmark found a reduced risk of ischemic stroke, another analysis of patients treated with warfarin showed a two-fold increase in stroke risk .For the treatment of venous thromboembolism (VTE) and AF in CKD patients, vitamin K antagonists (VKA) have traditionally been used. However, VKAs have certain drawbacks in this population, such as difficulty maintaining therapeutic levels, regular monitoring needs, potential risks of vascular calcification, and the rare condition of calciphylaxis . Direct This systematic review will help with anticoagulation on the available evidence of the effectiveness and risks of anticoagulation strategies in AF patients with renal dysfunction.MethodsThis review focuses on clinical research involving the administration of anticoagulants to patients with AF and renal disease. Animal studies and articles that presented no clinical data but rather discussed the methods of anticoagulation regimens in AF with renal failure were omitted. The review adheres to the standards outlined in Figure Systematic Literature Search and Study SelectionWe used PubMed, MEDLINE, and Google Scholar to search for pertinent papers thoroughly. On PubMed, we looked for research that was cited in reviews, editorials, and commentaries. But even so, we kept looking for further papers that met our inclusion standards.We independently evaluated a list of abstracts for inclusion according to predetermined standards. The requirements included using anticoagulant techniques, concentrating on AF with renal failure, and including a clinical cohort in the study that was precisely characterized. Review articles and animal research were not included. A dual review was performed by six reviewers, and any disputes were settled through conversation.Inclusion and Exclusion CriteriaIn order to accomplish our research objectives, we defined precise inclusion and exclusion criteria. Table Search TechniquesA complete literature review was conducted using the population, intervention/condition, control/comparison, and outcome (PICO) criteria. Acute anticoagulation strategies, AF, and renal dysfunction were used as relevant keywords in the search on databases like PubMed (including MEDLINE) and Google Scholar libraries. A thorough search strategy was created using the medical subject heading (MeSH) approach for PubMed (including MEDLINE) and Google Scholar, as shown in Table Quality AppraisalWe made use of a variety of quality assessment tools to ensure the validity of the papers we chose. For systematic reviews and meta-analyses, we used the PRISMA checklist and Cochrane bias tool assessment for randomized clinical trials. The Newcastle-Ottawa tool scale was used to evaluate clinical studies that were not randomized. Using the Critical Appraisal Skills Program (CASP) checklist, we evaluated the caliber of the qualitative investigations, as shown in Table ResultsAfter selecting databases such as PubMed, MEDLINE, and Google Scholar, we retrieved 22719 articles in July 2023. These papers were then carefully scrutinized, applying specific criteria to exclude 8164 articles. Out of the remaining 14555 papers, 14375 were eliminated due to inadequate titles or abstracts. We evaluated the remaining 180 papers and disqualified 172 articles as they did not meet our inclusion criteria. Finally, we conducted a thorough quality check on the remaining eight papers, which all fulfilled our criteria. Our systematic review includes these eight articles, and Table DiscussionAs far as we are aware, this study has been done thus far comparing several oral anticoagulants throughout the spectrum of kidney function. The study discovered that as patients' renal function deteriorates, direct oral anticoagulants (DOACs) are taken progressively less frequently than warfarin. To assist in clinical decision-making, there are no firm clinical guidelines generated from RCTs, and the results of observational research are inconsistent .Pathophysiology of the Thromboembolic Event in AF Patients With Renal DysfunctionThe increased risk of thromboembolism in individuals with concurrent CKD and AF is a result of changes to the three elements of Virchow's triad. A hypercoagulable condition is brought on by altered prothrombotic blood elements and elevated platelet activity. Deranged hemodynamics are caused by changes in arterial wall contractility as a result of inflammation, changes in atrial architecture and contractility, and activation of the renin-angiotensin-aldosterone system (RAAS). The production of thrombi is predisposed by damage to the dysfunction of the heart muscle and vascular endothelium. The separate effectors and the elements of the triad interact significantly .There are kidney tests like serum creatine test, cystatin c, glomerular filtration rate (GFR), blood urea nitrogen (BUN), kidney ultrasound, kidney biopsy, etc. The best overall indicator of the glomerular function is the GFR. The glomerular filtration rate shows how well the kidneys are filtering; the lower value means the kidneys are not working properly. The staging of CKD based on the GFR is as follows  - Stage Classification of AnticoagulantsFigure Mechanism of Action of AnticoagulantsUnfractionated heparin (UFH): UFH is a mixture of polysaccharide chains that enhance the activity of antithrombin, a natural inhibitor of coagulation that blocks thrombin, and FXa, two key factors in the coagulation cascade. UFH binds to antithrombin through a pentasaccharide sequence and increases its anticoagulant effect .LMWH: LMWHs are anticoagulant drugs that are derived from UFH by chemical splitting. LMWHs have a similar mechanism of action as UFH but with fewer side effects and more predictable responses. LMWHs can be injected subcutaneously without constant monitoring and allow for outpatient treatment of some VTE patients.VKA: VKAs block the enzyme that recycles vitamin K, which is needed for several coagulation factors to become active. VKAs can be taken orally, and warfarin is the most commonly used VKA for preventing thromboembolic events.Fondaparinux, argatroban, and bivalirudin: Fondaparinux, argatroban, and bivalirudin are anticoagulant drugs that are designed to target specific clotting factors or enzymes. Fondaparinux is based on the active component of heparins and inhibits FXa; argatroban is derived from L-arginine and blocks thrombin; and bivalirudin is based on hirudin from leeches and also inhibits thrombin.Direct oral anticoagulants: Direct oral anticoagulants (DOACs) are anticoagulant drugs that are taken orally and act quickly by blocking FXa or thrombin. DOACs have replaced VKAs in the clinic as they do not need the heparin bridging period, have a wider therapeutic window, and have fewer drug interactions. Ximelagatran was the first DOAC that was designed by computer modeling, but it was withdrawn from the market due to liver toxicity. Dabigatran is a direct thrombin inhibitor, which is derived from a compound that inhibits serine proteases, and it is used as an oral prodrug. FXa DOACs are anticoagulant drugs that target FXa, which was identified as a promising target in the 1980s. Some FXa DOACs are derived from natural compounds from leeches.Side Effects of Anticoagulant DrugsThe side effects of the anticoagulant drugs are detailed below:Warfarin: Warfarin has several adverse effects that are not related to bleeding, such as interference with vitamin K-dependent enzymes, acceleration of vascular calcification, heightened risk of calciphylaxis, and warfarin-related nephropathy . WarfariDabigatran: Dabigatran is a direct thrombin inhibitor that is mainly eliminated by the kidneys and has low protein binding. It has a higher risk of bleeding and lower efficacy in patients with end-stage kidney disease (ESKD) compared with warfarin. Dabigatran can be removed by dialysis, which may increase the risk of thromboembolic events or bleeding depending on the patient’s adherence to dialysis sessions. It may also cause kidney injury by inducing microvascular bleeding and tubular obstruction, similar to warfarin-related nephropathy.Rivaroxaban: Patients bleeding from rivaroxaban also did not have an antagonist drug available, which may explain why there was an even higher observed risk for bleeding complications, which may lead to death in severe renal dysfunction patients as compared with warfarin. Andexanet alfa, a reversal agent for factor Xa inhibitors, was approved by the FDA in 2018.Apixaban: It is the least reliant on kidney function for clearance and is minimally affected by dialysis. Apixaban has shown safety and efficacy in patients with advanced renal dysfunction down to a CrCl of 25 mL/min but not in ESKD patients. Apixaban has a lower risk of bleeding and stroke than warfarin and aspirin in patients with CKD but not in ESKD patients. Apixaban has a higher plasma concentration in ESKD patients than in healthy controls but is well tolerated. The FDA approved a dose reduction for ESKD patients.Edoxaban: Edoxaban is eliminated by the kidneys and the liver, and its dose should be reduced in patients with moderate to severe kidney impairment. It is not approved for patients with ESKD or CrCl greater than 95 mL/min as it may cause higher bleeding or stroke risk. It is non-inferior to warfarin in preventing stroke and systemic embolism and superior in reducing bleeding and cardiovascular mortality.Various anticoagulation strategies are being used to prevent thromboembolic events in AF patients with renal dysfunctions mostly VKAs and direct-acting oral anticoagulants.In Individuals With CrCl of 15-30 mL/minAccording to the AF guideline update, decreased dosages of apixaban, dabigatran, rivaroxaban, or edoxaban may be an option for people with CrCl of 15-30 mL/min . AccordiIn Individuals With End-Stage Renal Disease and Dialysis (CrCl < 15 mL/min)Dialysis-dependent patients with severe renal dysfunction had a higher risk of stroke than the normal functioning kidney population, but the increased risk of intracerebral hemorrhage is much higher than the increased risk of ischemic stroke . AccordiIn Individuals With CrCl of More Than 30 mL/minDOACs are generally safer and more effective than warfarin, especially when it comes to serious bleeding. DOACs cause half as much life-threatening bleeding as warfarin, and they are also more convenient than warfarin because they do not require frequent blood monitoring and can be given safely in fixed doses . In the Exposure to VKA damages kidney function in patients with AF and advanced renal dysfunction, leading to a decline in eGFR values . In addiSubstitutes for AnticoagulationFor patients with AF and advanced renal dysfunction who cannot tolerate anticoagulation, one very effective anticoagulation substitute is left atrial appendage closure . Recent LimitationsWe have constraints with our literature review. We especially restricted our research to English articles published during the last five years. Our research was restricted to English-language papers on anticoagulation, AF, and renal dysfunction, and we only used free articles. For more particular information, more study is required.Renal dysfunction and AF often coexist; this systematic review highlights the appropriate anticoagulation strategies in AF patients with renal dysfunction. In patients with coexisting AF and renal dysfunction, the anticoagulation strategy should be based on the patient's renal function or CKD stage. With decreased major bleeding and comparable efficacy, DOACs may be preferable to warfarin in patients with VTE or AF and a CrCl ≥ 30 ml/min. In those patients (CrCl < 15 ml/min), there are not enough pieces of evidence that suggest what to use in this situation. However, we should avoid using warfarin in these patients and use other anticoagulants. We can also use the left atrial appendage to prevent them from bleeding-side effects of anticoagulant drugs. Future randomized clinical trials are required to give more conclusive data, particularly in individuals with severely impaired kidney function, on the comparative efficacy and safety of various oral anticoagulant medications.


BackgroundHypertensive disorders of pregnancy are the leading causes of both maternal morbidity and maternal mortality. Hypertensive disorders are acute obstetric emergencies, which refer to various life-threatening medical challenges known to develop during pregnancy, labor, and delivery, requiring urgent attention to reduce blood pressure (BP) for the benefit of the affected mothers and infants. Hydralazine and labetalol have been widely used as the first-line medications in the management of severe hypertension during pregnancy. However, the choice between these two drugs lacks clear evidence regarding their safety and superiority. Several studies have attempted to study intravenous (IV) labetalol versus hydralazine, but very few such comparison studies have been conducted in Africa. ObjectiveTo compare the effectiveness of IV labetalol and IV hydralazine in reducing systolic and diastolic BP in pregnant women with severe hypertension. Also, to determine the time required for hydralazine and labetalol to lower BP to ≤150/100 mmHg, the number of doses needed for each drug, and evaluating maternal and perinatal outcomes.Study designThis study employed an open-label randomized clinical trial design conducted in the labor, delivery, and antenatal ward of the Central and Stella Obasanjo Hospital in Benin City. A total of 120 women with severe pregnancy-induced hypertension were randomly assigned to two groups: Group X, consisting of 60 pregnant women, received IV hydralazine at a slow rate of 5 mg for five minutes, repeated every 20 minutes (maximum of five doses) until a blood pressure of ≤150/100 mmHg was achieved. Group Y, also consisting of 60 pregnant women, received IV labetalol in escalating doses of 25, 50, 75, 75, and 75 mg (maximum of 300 mg) every 20 minutes until the blood pressure reached ≤150/100 mmHg. Statistical analysis was performed using SPSS version 23 .ResultIV hydralazine achieved the target BP in an average time of 45.80 +/- 25.17 minutes, while IV labetalol took an average of 72.67 +/- 41.80 minutes (p=0.001). The number of doses required to reach the target BP differed significantly between the two drugs. Hydralazine required an average of 1.72 +/- 0.904 doses, whereas labetalol required an average of 3.72 +/- 1.782 doses (p=0.0001). While 45% of women in the hydralazine group attained the target BP with a single dose of hydralazine, only 31.1% of women in the labetalol group were able to attain the target BP with a single dose of labetalol (p=0.02). Overall, target BP was achieved in 55 out of 60 women (91.7%) who were randomized to receive IV hydralazine, whereas 45 out of 60 women (75%) who received IV labetalol achieved the target blood pressure. While hydralazine demonstrated more favorable results in terms of achieving target blood pressure, there were higher incidences of maternal adverse effects in the hydralazine group compared to the labetalol group. However, these adverse effects were not severe enough to warrant discontinuation of the medication.ConclusionIV hydralazine showed faster achievement of the target BP and a lower number of doses required compared to IV labetalol. Additionally, a higher percentage of women in the hydralazine group achieved the target BP with a single dose. However, there were more maternal adverse effects associated with hydralazine, although they were not severe. Perinatal outcomes did not differ significantly between the two groups. Gestational hypertension is a medical disorder in pregnancy marked by high blood pressure (BP) levels that develop during pregnancy, specifically after ≥20 weeks of gestation, in the absence of organ dysfunction, signs of preeclampsia, and proteinuria. After parturition, the BP typically returns to normal . GestatiDeveloping effective strategies for the prevention and treatment of gestational hypertension has been challenging due to the elusive understanding of its underlying mechanisms. Hypertension in a normal pregnancy follows a dynamic pattern: BP decreases during the first trimester are attributed to pregnancy hormones, including estrogen, relaxin, and progesterone, which dilate the vascular smooth muscles of the endothelium . SubsequHypertensive disorders in pregnancy can be categorized as follows: (a) gestational hypertension, occurring in previously normotensive women after 20 weeks of gestation, without significant proteinuria; (b) severe hypertension, defined by a systolic BP of ≥160 mmHg or diastolic BP of ≥110 mmHg, and mainly diagnosed in previously hypertensive women or when hypertension occurs prior to 20 weeks of the gestation period, without molar pregnancy and connective tissue disease; (c) preeclampsia is the pregnancy-specific disorder that is marked by the extensive vasospasm and endothelial dysfunction that normally occur after 20 weeks of gestation, in addition to presenting as late as four weeks postpartum; and (e) eclampsia, which involves convulsions along with hypertension . AdditioTo prevent these complications, rapid-acting antihypertensive drugs are often administered with the objective of reducing and controlling the BP without having any adverse effects such as hypotension and fetal distress on the fetus and mother. Once BP is adequately controlled, the decision to deliver the baby depends on gestational age and the presence or absence of complications. Near-term or term pregnancies are typically delivered immediately through the fastest and safest route. However, in cases of extreme prematurity without complications but with well-managed BP, conservative management may be considered in selected centers to improve fetal outcomes .Antihypertensive pharmacology during pregnancyThere are several classes of antihypertensive medications available for reducing BP. Currently, while several studies and clinical trials have been conducted in Nigeria in relation to the choice of antihypertensive drugs for managing severe hypertension in pregnant women, many clinicians still rely on the findings of studies conducted in Europe for guidance. Hydralazine, nifedipine, and labetalol have been suggested as the first-line medication for a quick reduction of BP. However, there is no consensus on which of these drugs is superior in this specific setting . At CentPhysiological changes associated with hypertension in pregnancy and choice of antihypertensiveThe physiological changes that occur during pregnancy can have significant effects on the pharmacokinetics of drugs, including absorption, distribution, metabolism, protein binding, and excretion. Pregnancy is often marked by an increment in the heart rate (HR) alongside stroke volume (SV), which causes general increments in cardiac outputs (CO) (CO = HR x SV). However, despite this increase, arterial BP decreases due to a reduction in total peripheral vascular resistance in the mid-trimester .The hemodilution and volume expansion in pregnancy result in a progressive decrease in albumin concentration, which in turn reduces the plasma protein binding of certain antihypertensive medications that are albumin binding. Additionally, the increment in cardiac output during pregnancy leads to the increment of the effectual renal plasma flow (about 60-70%), the rate of glomerular filtration (about 50%), and clearance of creatinine, leading to increased clearance of drugs eliminated through the kidneys , 11. To Considering the metabolic changes during pregnancy is crucial when prescribing rapid-acting antihypertensive drugs and determining the appropriate dosage for treatment. The dosing frequency may need to be increased for drugs with shorter durations of action. The beta-adrenoceptor blockers medications' therapeutic effects may be assessed by monitoring the drug's serum levels and indirectly by observing the patient's heart rate. By understanding the fundamental pharmacology of drugs in pregnancy and considering clinical observations of adverse effects, healthcare providers can make informed adjustments to the dose and dosing interval to achieve the desired therapeutic effect. A thorough comprehension of the physiological changes during pregnancy and the gestation-specific pharmacology of different antihypertensives is essential for effective treatment and minimizing risks to both the mother and the fetus. For instance, in the management of severe pregnancy-related hypertension, avoiding hypotension is vital, given that the degree of regulation of placental blood flow has not been aptly established, and excessively aggressive reduction of BP might lead to fetal distress -21.The adrenergic receptor antagonist labetalol peripheral actingExtensive utilization of beta-blockers occurs during pregnancy. Despite the observation that numerous randomized trials have compared beta-blockers to other agents and placebo -29, a nuLabetalol is an adrenergic receptor antagonist that exhibits both non-selective and selective beta-adrenergic receptor-blocking action. Its beta-blockade/alpha-blockade ratio is seven to one -37. StimLabetalol is considered safe during pregnancy as it crosses the placenta in small amounts and does not seem to present any teratogenic side effects on the basis of a significant body of evidence , 37. TheDirect vasodilators Direct vasodilators, specifically hydralazine, are potent antihypertensive drugs known for their rapid action. Hydralazine, a hydrazine derivative, selectively relaxes smooth muscles in arterioles. However, the precise mechanism of its action remains unknown , 37. ThiThe adverse effects of hydralazine primarily stem from excessive vasodilation and sympathetic stimulation. Immediate side effects may include palpitations, headaches, flushing, and nausea. Lengthy usage can result in pyridoxine-responsive polyneuropathy and rare immunological reactions, such as lupus syndrome that is drug-induced. Administration of hydralazine has occurred in every pregnancy trimester without evidence of teratogenicity, although there have been reports on cases of lupus syndrome and neonatal thrombocytopenia . Even asTiming for IV hydralazine and labetalol to achieve 150/100 mmHg or below target BPThe American College of Obstetricians and Gynecologists  maintainThe dosages required to achieve BP levels below or equal to 150/100 mmHg Limited research has been conducted on the number of doses required for labetalol and hydralazine to achieve a BP level of 150/100mmHg or lower , 58-61. Hydralazine and labetalol failure ratesIn a study conducted by Deka , it was Numbur et al. , on the Adverse effects of hydralazine and labetalolA meta-analysis , 14 compContrarily, a recent Cochrane analysis , which oVigil De Gracia et al. , Numbur Although criticized for their small sample size, Khan, Hafeez, and Farah  observedStudy justificationHypertensive disorder during pregnancy is considered a key cause of maternal mortality and morbidity at Central Hospital Benin City . GloballAt our center, IV hydralazine was the favored drug for managing acute hypertension during pregnancy until the introduction of IV labetalol in 2011. However, the cost of a 300mg dose of labetalol is approximately 35 times higher than a 40mg dose of hydralazine. Central Hospital Benin switched from IV hydralazine to IV labetalol without considering its cost-effectiveness in this context. Labetalol is expensive, and in Sub-Saharan Africa, many women require affordable and effective antihypertensive drugs. This is because over 70% of healthcare expenses in this region are covered through out-of-pocket payments . As a reThis study is necessary due to the decision to switch from IV hydralazine to IV labetalol at our hospital without any evidence-based rationale. Consequently, the hospital's pharmacy department reduced the procurement of IV hydralazine and gradually shifted to stocking only IV labetalol. To determine the most effective drug with limited side effects on the study population between the two drugs, we conducted a randomized clinical trial that compared IV hydralazine to labetalol in relation to the management of acute hypertension in pregnancy.Aims and objectiveThe aim of the study was to compare the efficiency of IV labetalol and hydralazine with regard to the management of acute gestational hypertension in pregnant women at a tertiary healthcare facility in Sub-Saharan Africa. The specific objectives of the research are as follows: 1) to determine the time required for IV hydralazine and IV labetalol to achieve a 150/100mmHg BP or below; 2) to determine the number of doses of labetalol and hydralazine needed to achieve a BP level of less than or equal to 150/100mmHg; 3) to record any adverse effects experienced by the mother; and 4) to document any adverse effects on the fetus.The research hypothesis is as follows: null hypothesis - there was no statistically significant difference in BP control for women with severe gestational hypertension when comparing IV hydralazine and IV labetalol. Alternate hypothesis - there is a significant difference in the BP control in acute gestational hypertension patients when comparing IV hydralazine and IV labetalol.Study design and settingThis study employed a prospective open-label randomized clinical trial to investigate acute hypertension control in pregnant women admitted at Central Hospital Benin, Benin City, Nigeria. The research was conducted in the labor and maternity wards of Central Hospital and Stella Obasanjo Hospital in Benin City, Edo State. These hospitals are tertiary care centers and serve as referral facilities for several states, including Ondo, Edo, Kogi, and Delta. The Central Hospital has a total of 60 obstetric beds and 42 gynecological beds and has an average delivery rate of 4,000 infants per year. Consequently, Stella Obasanjo Hospital is equipped with 22 gynecological beds and 32 obstetric beds and has an average delivery rate of 3,500 infants per year. The prevalence of gestational hypertension in this center is 9% . AccordiThe trial was conducted from October 2018 to March 2019 in the labor and maternity wards of the Department of Obstetrics and Gynecology unit at Central Hospital and Stella Obasanjo Hospital in Benin City. The study duration involved 247 pregnant women with gestational hypertension who were admitted to the labor and maternity ward for conservative management, stabilization, and delivery. Of the 247 women, 120 women satisfied the study inclusion criteria leading to their enrolment in the study, averaging approximately 24 women per month, six women per week, and one to two women per day in both centers.Inclusion CriteriaThe study included consenting adults aged 18-45 years with ≥28 weeks gestational age. The gestational age of ≥28 weeks was chosen given that pre-eclampsia mainly occurs during the second half of pregnancy . The fetus had to have a normal heart rhythm of 110 to 160mmHg, along with the participant having a normal maternal heart rate of >60 bpm to <120 bpm. Given that this study sought to compare the efficiency of IV hydralazine to IV labetalol, the participants were placed in one class of antihypertensives, either hydralazine or labetalol. Additional antihypertensives were not evaluated, and no women on them were included in the study.Exclusion CriteriaParticipants with recognized and diagnosed drug allergies, asthma, extant heart block and congestive cardiac failure history, maternal co-morbidities, including renal failure, chronic hypertension, diabetes, and hemoglobinopathy, as well as acute pre-eclampsia, fetal distress, eclampsia, and various abnormalities disclosed during laboratory assessment were excluded.Sample SizeFor the present study, the sample size was determined through the use of comparative study formula. The equation used was N = 2.Z^2.P.Q / d^2, where N represents the desired minimum sample size per group.In the formula, Z corresponds to a confidence level of 95% and is taken as 1.96. P represents the prevalence of severe gestational hypertension in Nigeria, which was reported as 1.9% in a previous study. Q is computed as 100 - P. The desired accuracy level is set at 5%, and indicated by d. That is, the calculation is presented as follows: N = (2 * (1.96^2) * (1.9/100) * (98.1/100) / (0.05^2)). Simplifying further: N = 2 * 3.841 * 0.018 * 0.981 / 0.0025. This leads to N = 1431.848 / 25, resulting in N = 57.27. Rounded up, the minimum sample size per group is 57. Considering a 5% attrition rate, 60 subjects were recruited for each group, totaling to 120 study participants.The study included women admitted to the labor and maternity ward with severe pregnancy-induced hypertension. Eligible participants underwent a detailed medical history assessment, physical examination , and various investigations such as a full blood count, peripheral blood film, liver function test, serum electrolyte analysis, urea and creatinine measurement, urine dipsticks for significant proteinuria, and serum uric acid assessment. These measures were taken to select suitable participants for the study.After counseling, eligible participants provided written informed consent and were randomly allocated to either of the two groups: the intravenous hydralazine group (group X) or the intravenous labetalol group (group Y). Randomization was performed using computer-generated numbers assigned to each participant. The sequential placing of the numbers in opaque envelopes by the researcher, and the subsequent sealing and requesting of the participants to select one enabled unbiased allocation of the participants to the groups. This process continued until all participants were allocated to a group. Following group assignment, intravenous access was established using a green cannula (18G), and the appropriate medication was administered to each group.For group X , a slow bolus of 5mg of intravenous hydralazine was administered over a period of five minutes. To prepare the dosage, 0.5ml of hydralazine was withdrawn using a 5ml syringe and diluted with 4.5ml of sterile water. The diluted solution was then administered at a rate of 1ml per minute. In instances where the preferred blood pressure levels were not realized within 20 minutes following the administration of the first dose, a second dose of 5mg of intravenous hydralazine was administered slowly over five minutes. If the target blood pressure was still not attained after the second dose, a maximum of five doses (5mg each) were given slowly over five minutes. If the desired blood pressure was not reached after this point, a combination of antihypertensive drugs (crossover therapy) was employed to control blood pressure. The specific brand of hydralazine used was Mack-hydralazine hydrochloride, which contains 20mg of hydralazine in a 2ml vial manufactured in New Delhi, India. The drugs were purchased from the Central Hospital Benin pharmacy in one batch to ensure continuous availability throughout the study.Within the Y group, the administration of intravenous labetalol was performed as follows: a slow 25mg bolus dose of labetalol administration over five minutes (1ml per minute), followed by the administration of 50mg (2ml per minute) in instances where no efficiency is reported in 20 minutes. If necessary, an additional dose of 75mg (3ml/minute) was given every 20 minutes, with 300mg being the maximum. In case the target blood pressure level (BP ≤150/100mmHg) was not realized, a mixture of antihypertensive agents was administered. Blood pressure measurements were taken every 10 minutes, starting from the time of drug administration, and continued for up to two hours after the last dose or until the target blood pressure was reached. The time of drug initiation and the duration it took to achieve the desired BP were recorded using a stopwatch.The specific brand of labetalol used was called Labet, which is manufactured in Bangladesh and comes in a 10ml container containing 50mg of labetalol. The drug was obtained from the hospital pharmacy in a similar manner as hydralazine. Throughout the entire process, all patients were actively monitored, with Bp measurements taken every 10 minutes and fetal heart rate measurements taken every 15 minutes for up to two hours after the last dose. The general condition of the participants was also taken into consideration.The monitoring of the intermittent fetal heart rate occurred during the treatment using a handheld Doppler device. If an abnormal fetal heart rate/rhythm or a compromised maternal condition was detected, the trial protocol was discontinued, and appropriate standard interventions were carried out to ensure the safety of the mother and baby. Participants with uncontrollable blood pressure or near-term gestational age underwent labor induction, even as participants with aptly controlled blood pressure levels at a distance from term were placed under observation in the maternity ward, receiving oral antihypertensive medications, corticosteroids, and fetal kick charts. At the end of the study protocol, the participants were required to complete the provided questionnaire on the potential side effects we may have missed that they experienced during the trial period.OutcomesThe principal outcome evaluated in the present study concentrated on aspects that included the duration required for intravenous administration of labetalol and hydralazine to lower BP to 150/100mmHg or below, the number of doses essential to realizing the targeted blood pressure level, and the failure rate of both drugs. The secondary outcome measures centered on evaluating the adverse effects of the drugs on the mothers, fetuses, and newborns delivered during the study period.Data collectionTo ensure accurate data collection, a structured data collection form was utilized to document all measurements and biodata of the participating individuals. Section A involved recording their biodata and socio-demographic parameters, including BP at enrollment and drug history. Section B contained information on the timing, the dosage of the trial drugs administered, as well as the corresponding blood pressure readings at the time of administration. Section C documented the number of doses required, failure rate, APGAR score at one and five minutes, adverse effects, mode of delivery, neonatal admission, and early neonatal death.The research assistants involved in this study underwent a comprehensive training program lasting a minimum of two days (two hours per day). The training encompassed various aspects, such as obtaining consent, BP measurement techniques, questionnaire completion, reconstitution of drugs, and drug administration.Prior to the initial BP measurement, women were granted a five-minute quiet rest. The initial BP was then measured with the individual in a seated position, ensuring that the cuff was placed at the level of the heart. Subsequent measurements of BP were recorded while the patient was lying in the left lateral position, even as diastolic and systolic BB were indicated using Korotkoff sounds I (first sound) and V (sound disappearance), correspondingly. In cases where a notable discrepancy existed between the fourth (muffling) and fifth (disappearance) Korotkoff sounds, with the fifth sound approaching zero, the fourth sound was regarded as indicative of diastolic BP. The BP cuff was deflated and left on the upper arm for subsequent BP measurements.Data analysisFor this study, we conducted data analysis through the use of SPSS v. 23 statistical software . The data analysis was carried out on the basis of the intent-to-treat concept. The data distribution normality was evaluated through the use of the Kolmogorov-Smirnov test. Further, the presentation of categorical variables was mainly in percentages and numbers, even as the expression of continuous was done in the form of standard deviation and mean. The non-normal data was mainly described using the median. Additionally, we utilized independent sample t-tests in comparing normally distributed data means alongside the Mann-Whitney U test that we utilized for the analysis of ordinal data. Fisher's exact and Chi-square tests were also employed in analyzing categorical variables. Each test was two-sided, and a p-value of <0.05 was regarded as statistically significant.Ethical considerationsThe study's approval was obtained from the Central Hospital Benin's ethical committee, approval number HMB10092018. We adhered to the various ethical considerations in this study, including the general ethical principles that are applicable to human study subjects . The patThe uniformity of the study population for the two groups is reflected by the baseline characteristics presented in Table Table Table Intravenous hydralazine also demonstrated a lower requirement for doses (1.72 ± 0.904) compared to intravenous labetalol (3.72 ± 1.782) (p=0.008). Furthermore, persistent hypertension, despite receiving the maximum dose of the assigned medication, was observed in 8.3% of patients within the hydralazine group and 25% in the labetalol group (p=0.0143). In the hydralazine subset, 27 patients (45%) achieved BP control with a single dose, whereas in the labetalol group, this was the case for 14 patients (23.3%) (p=0.02). Additionally, 24 subjects (40%) in the hydralazine group and 11 (18.3%) in the labetalol group required two to three doses of their respective drugs to achieve BP control (p=0.0004). Moreover, four subjects (6.7%) in the hydralazine group and 20 (33.3%) in the labetalol group needed four to five doses of their respective drugs to reach the target BP (p=0.00003). In total, five patients in the hydralazine group and 15 in the labetalol subset experienced persistent hypertension despite receiving five doses of the assigned antihypertensive agent, resulting in a failure rate of 8.3% and 25%, respectively.Table Table Table Table According to this study, intravenous hydralazine demonstrated faster efficacy than intravenous labetalol in treating acute onset severe hypertension during pregnancy. It requires fewer doses to reach the desired BP level, although it does come with more adverse effects compared to intravenous labetalol. The time taken to achieve the target BP in this clinical trial aligns with previous studies conducted in Port Harcourt by Mmom et al. , in PakiIt is widely accepted that pregnant women with severe pregnancy-induced hypertension should receive antihypertensive medication promptly, within 40-60 minutes of diagnosis, to minimize the risk of cerebrovascular accidents , 61. In The effectiveness of antihypertensive medication can also be evaluated based on the dosage required to normalize blood pressure , 45-59. In this study, the failure rate of treatment was 8.3% (five cases) in the hydralazine group and 25% (15 cases) in the labetalol group (p=0.0143). This finding aligns with a study conducted in Port Harcourt, Nigeria, by Mmom et al., where 40% of patients in the labetalol group and 13.33% in the hydralazine group required crossover therapy due to persistent hypertension . HoweverThe difference in results between this study and previous research could be attributed to variations in drug potency and racial differences in the study population. Labetalol has been found to be more effective in controlling hypertension among White individuals compared to Black individuals , 51, 52.In this study, the rate of cesarean section was 19.9% higher in the labetalol group compared to the hydralazine group. This is not surprising, as failure to achieve blood pressure control often leads to emergency cesarean section, which is considered the fastest and safest delivery method in the study environment. Additionally, vaginal delivery was more common in the hydralazine group, as those who achieved the target blood pressure during labor were allowed to have a vaginal birth. These findings are consistent with previous studies , althougThe primary goal of treating acute, severe hypertension is to gradually reduce blood pressure to a safe level for both the mother and fetus while avoiding a rapid drop in blood pressure that can cause complications. In this study, maternal hypotension, dizziness, nausea, vomiting, and headache were significantly higher in the hydralazine group compared to the labetalol group. However, there were no cases of abruptio placenta. These findings align with documented side effects of hydralazine in previous studies , 55, 66.There was no statistically significant difference in the first- and fifth-minute AGPAR scores between the hydralazine and labetalol groups. Two newborns from the hydralazine group and one newborn from the labetalol group were admitted to the special care baby unit due to birth asphyxia. It is noteworthy that there were no perinatal deaths reported in either group, which aligns with previous studies , 54, 55.Based on the findings of this research, it was determined that the current price for a 40mg dose of hydralazine at the local hospital pharmacy is N200.00, equivalent to approximately $0.48 USD for two doses. In contrast, the price for a 300mg dose of labetalol is N7000.00, approximately $17 USD for four doses. These figures indicate a significant increase of approximately 94% in the cost of medication.Prior to the year 2003, intravenous hydralazine was commonly prescribed as the initial treatment option -45, 66. Strengths, challenges, and limitationsThe initial characteristics of the participants in both groups were similar. Despite a number of previous studies -20 suggeDuring the study, patients were closely monitored for a duration of two hours following the initial control of blood pressure or administration of the maximum dose. Extending the patient follow-up to 24 hours could potentially identify more cases of rebound hypertension and maternal adverse effects. Unfortunately, we did not evaluate urinary output in this study. It is worth noting that previous research has indicated a potential association between hydralazine usage and reduced renal blood flow.Throughout the trial period, continuous electronic fetal monitoring was not employed for all the participants, which may have limited our ability to identify more adverse outcomes in newborns. Furthermore, it's important to acknowledge that the study was not conducted in a blind manner, leaving room for observer bias. We were unable to exclude fast acetylators who could have rapidly metabolized hydralazine, leading to reduced drug bioavailability. However, it is crucial to mention that individuals with a history of allergy to any of the drugs were excluded from the study.Furthermore, the research study posed significant challenges in terms of drug procurement, patient recruitment involving travel between Central Hospital and Stella Obasanjo Hospital, and the need to await results of electrolytes, urea, and creatinine (E/U/Cr) test and liver function tests (LFT) before selecting patients for inclusion. In some cases, patients had already been started on antihypertensive medication before arriving at the labor ward without undergoing the necessary investigations to determine their eligibility for participation in the study. Such patients, upon arrival, who met eligibility criteria were included following the principal investigator's approval.RecommendationsAlthough the study findings have indicated that IV hydralazine was effective in attaining the target BP in a shorter time and with fewer dosages compared to IV labetalol, IV hydralazine presented more adverse maternal side effects than IV labetalol. These findings highlight the need for careful consideration when selecting the appropriate medication. Considering the rapid control of blood pressure in women with severe gestational hypertension, who do not have allergies to intravenous hydralazine, it may be advisable to consider hydralazine as the preferred initial medication. Nevertheless, it is essential to conduct further research to explore alternative options to intravenous hydralazine. This should involve large-scale community-based studies with adequate statistical power, encompassing a wider age range of participants. In addition, conducting multi-centered double-blind trials will enhance the search for a suitable alternative. To ensure robust results, future trials should implement stratified randomization based on individual blood pressure values. It is crucial to analyze subgroups of women with chronic hypertension, non-proteinuric hypertension, and pre-eclampsia separately. Moreover, women who achieve blood pressure control through intravenous hydralazine should be transitioned to oral hydralazine and monitored until delivery, while those who achieve blood pressure control through intravenous labetalol should be transitioned to oral labetalol for comparative purposes.This study, therefore, concludes that intravenous hydralazine acts faster than intravenous labetalol and requires fewer doses of drugs than intravenous labetalol for acute control of blood pressure in women with severe gestational hypertension. However, intravenous hydralazine was associated with more maternal side effects such as hypotension, dizziness, nausea, vomiting, and headache compared to intravenous labetalol, but no final dose reduction or drug discontinuation was required due to major side effects. Furthermore, intravenous hydralazine has no significant adverse effect on the baby.


Escherichia coli was the most common isolated pathogen in both urine (28.4%) and kidney cultures (42.4%), followed by Proteus mirabilis in bladder urine cultures (6.3%) and Klebsiella pneumoniae (7.6%) in kidney cultures. Extended-spectrum beta-lactamases producing bacteria were reported in 6% of the bladder urine cultures. On multivariable analysis, urosepsis, recurrent urinary tract infections, increased creatinine, and disease extension to perirenal and pararenal space were independent factors associated with positive bladder urine cultures. On multivariable analysis, only the presence of anemia was significantly more frequent in patients with positive kidney cultures. Our results can help urologists counsel XGP patients undergoing nephrectomy.Xanthogranulomatous pyelonephritis (XGP) is an uncommon chronic granulomatous infection of renal parenchyma. XGP is often associated with long-term urinary tract obstruction due to stones and infection. We aimed to analyze the clinical, laboratory, and microbial culture profiles from bladder and kidney urine of patients who were diagnosed with XGP. Databases of patients with histopathological diagnosis of XGP from 10 centers across 5 countries were retrospectively reviewed between 2018 and 2022. Patients with incomplete medical records were excluded. A total of 365 patients were included. There were 228 (62.5%) women. The mean age was 45 ± 14.4 years. The most common comorbidity was chronic kidney disease (71%). Multiple stones were present in 34.5% of cases. Bladder urine culture results were positive in 53.2% of cases. Kidney urine culture was positive in 81.9% of patients. Sepsis and septic shock were present in 13.4% and 6.6% of patients, respectively. Three deaths were reported.  It is estimated that the number of microbes in and on the human body is 10 times the total number of human cells, and collectively these influence our physiology during health and illness. Humans are seen as “superorganisms” where human and microorganisms live symbiotically . The impXGP peak of incidence is at age 50–70 years, with a 2:1 female:male ratio. XGP has an incidence of 1.4 cases per 100,000 people per annum .Escherichia coli and Proteus mirabilis, but sometimes uncommon and opportunistic pathogens too ), recurrent urinary tract infections (UTI) , increased creatinine , disease extension to perirenal , and pararenal space  were independent factors associated with positive bladder urine cultures   .XGP was first described in 1916 by Schlagenhaufer. Oberling coined its current name in 1939, identifying the characteristic yellowish coloration of the affected kidney due to abundant lipid deposits within the cytoplasm of macrophages (xanthoma cells) on histopathological examination . XGP is The challenge in treating renal infections with stones involves emergent intervention by percutaneous nephrostomy or double J stent to relieve an often-obstructed system , followeIn our series, the mean age was 45 years and 62.5% of patients were women. This was similar to previous reports . OverallThis association of recurrent UTI, female gender, KSD, and XGP is well known to precipitate sepsis, intensive care admission, the need for earlier nephrectomy, and often ensuing renal failure . It is dA possible diagnosis of XGP or emphysematous pyelonephritis must be considered in immunocompromised patients, especially whenever clinical presentation is atypical, current antibiotic therapy is not effective, and imaging shows features of dubious interpretation, since these patients have a very high risk of morbidity and mortality ,20. 71% A 36.9% transfusion rate in our study reiterates its importance in perioperative planning. On multivariable analysis of factors associated with positive kidney cultures, anemia has a significant association. Whether this is incidental or has a prognostic significance and how this information can be better utilized for the management of renal infections remains to be ascertained.Computed tomography is the gold-standard imaging modality for XGP staging. Classic findings include a loss of normal renal parenchyma, an enlarged kidney, paradoxical contracted scarred renal pelvis, and dilated calyces resulting in a multiloculated appearance. This combination resembles the paw print of a bear (bear’s paw sign) and is often associated with the presence of staghorn stones . In someOverall, 52.6% of patients in our series needed an early nephrectomy. Presence of a positive urine culture, indicating a higher probability of a septic patient, was directly and significantly associated with a higher probability of developing Clavien–Dindo grade 3 and above complications. Whilst not significant, a higher proportion of patients with positive kidney cultures had Clavien–Dindo grade 3 and above complications (30.5% vs. 23.1%) vis à vis those with a negative culture at surgery. This could be because our complications included all patients undergoing nephrectomy (early and delayed) and they might have already been on a higher antibiotic regimen. However, as surgical intervention itself is an independent predictive factor for complications and morbidity, it becomes imperative to look at all parameters that may aid in counseling patients before surgery .Proteus mirabilis or Escherichia coli infection, and Pseudomonas species have also been implicated [Escherichia coli was the most common isolated pathogen in both bladder and kidney urine cultures. This finding was in line with 16 of 20 included studies in Harley’s review, where Proteus species were most commonly cultured microorganisms in the remaining ones [Understanding pathogenesis and its impact on a disease process is essential for developing proper management strategies. In an era of antibiotic resistance and superbugs , if we cplicated ,25. In oing ones . There iing ones . We alsoProteus mirabilis and Escherichia coli are usually sensitive to various antibiotics, including first-generation cephalosporins and trimethoprim–sulfamethoxazole. Pseudomonas species have a narrower spectrum to which they are sensitive and may require the use of aminoglycosides, third-generation cephalosporins, or fluoroquinolones. In our study, the presence of Pseudomonas aeruginosa had a 4% incidence in bladder urine culture and 6.3% in kidney urine cultures. Whilst ours was a real-world practice where surgeons might have used different antibiotic regimens, we found that ESBL bacteria were present in 6.08% of bladder urine cultures. There were no reported ESBL producing bacteria in kidney urine cultures. Perhaps, coupled with the absence of an antibiotic regime, a limitation inherent to the retrospective nature of this study precludes further subset analysis to recommend the ideal antibiotic treatment to start at presentation, even before a culture is obtained. However, there was microbiological concordance in 76.7% of those patients who had both cultures with growing pathogens. This reiterates the importance of having a bladder urine culture in all XGP patients before starting antibiotics, since it commonly harbors the actual pathogen.An insight into the clinical presentation from this large, global, multicenter real-world XGP study highlights for the first time the need to obtain both bladder and kidney urine cultures and importance of using Malek’s classification. Together with microbiological and clinical findings, our results can help urologists to counsel the prognostic expectations in patients undergoing nephrectomy.


Loin pain hematuria syndrome (LPHS) is a rare clinical syndrome with a reported prevalence of 1 in 10,000. The syndrome is characterized by severe pain localized to the kidney in the absence of identifiable urinary tract disease. Because of an inadequate understanding of the pathophysiology of the disease, the goal of management has been limited to symptomatic pain management. Through detailed phenotype and genotype assessment we sought to identify possible underlying etiologies.COL4A3, COL4A4, and COL4A5) gene sequencing in 14 patients with loin pain hematuria recruited from a single center.We completed a chart review, ultrasound imaging, kidney biopsy, and type IV collagen  was normal in 11 patients and thickened in 1 patient. Staining for IgA kappa was present in 1 patient. C3 deposition without any inflammation was present in 7 patients. Arteriolar hyalinosis was present in 4 patients and endothelial cell injury was present in 6 patients. No pathogenic Conventional histopathology and genetic testing for type IV collagen variants failed to identify the cause of hematuria in 14 patients with LPHS.  Since its first description by Little and colleagues in 1967, the etiology of LPHS remains poorly understood.COL4A3, COL4A4, and COL4A5) have increasingly been recognized as common causes of glomerular hematuria. Hemizygous severe pathogenic variants in COL4A5 lead to classical Alport syndrome in boys and young men with hematuria, proteinuria, and rapid decline in estimated glomerular filtration rate as well as extrarenal manifestations of ocular and hearing abnormalities. Nevertheless, the population prevalence of heterozygous type IV collagen variants was about 1 in 1000 in the UK biobank, which is 5 to 16 times more frequent than historic prevalence estimates of Alport syndrome.For glomerular hematuria to occur, red blood cells need to pass a 3-layered barrier consisting of glomerular endothelial cells, GBM, and podocytes.et al..,,,The mechanism of pain in LPHS is also unclear. There is a consensus that the hematuria is glomerular in origin but it remains uncertain if the pain is interrelated with the hematuria. In 1996, Hebert COL4A3, COL4A4, and COL4A5.Because there are gaps in our understanding, we sought to assess the histopathological features on kidney biopsy in 14 patients with loin pain hematuria, and specifically, to evaluate the correlation of GBM alterations by electron microscopy with hematuria. Further, in keeping with the recent advances in our understanding of type IV collagen’s role in hematuria, we performed targeted sequencing of Eighteen consecutive patients referred to nephrology clinic (run by the corresponding author) were approached by a study coordinator and 14 agreed to participate in the study . BecauseDemographic data, including sex, age, and self-reported ethnicity, was gathered. Phenotype information including age of onset of symptoms, comorbidities , weight, height, smoking status, and current medications was reported by patients. Morphine milligram (mg) equivalent per day was determined by using an equivalency factor to calculate a dose of morphine that is equivalent to the used opioid. Family history of LPHS, kidney stones, chronic kidney disease or end-stage kidney disease, or chronic pain was collected.After enrollment, serum creatinine and electrolytes; complete blood count; and urine dip, microscopy, and albumin-to-creatinine ratio were measured. All patients underwent a cystoscopy, ultrasound assessment of the kidneys and urinary tract, triphasic computed tomography of the abdomen and pelvis with delayed images, and split function mercaptoacetyltriglycine scan to assess the relative function of the kidneys. All patients had a negative urological assessment for causes of pain and hematuria .Patients underwent kidney biopsies from December 2020 to May 2021 at the Regina General Hospital, Saskatchewan, Canada. Kidney biopsies were performed by an interventional radiologist under realtime ultrasound guidance. Three cores were taken with a spring-loaded biopsy gun using an 18-gauge needle . All biopsies were read by a single kidney pathologist (PD) at the Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. The samples obtained were divided into 3 portions for light microscopy, immunofluorescence, and electron microscopy (EM). The sample for light microscopy was fixed in formalin and embedded in a paraffin block. Sections of 1 to 3 mm thickness were cut and stained with hematoxylin and eosin, periodic acid–Schiff, Masson trichrome, and periodic acid silver methenamine special stains. The prepared slides were assessed using Nikon Eclipse Ci  microscope, using magnifications from 40 to 600 times. Each case was assessed and scored for global and segmental glomerulosclerosis, tubular injury, interstitial fibrosis and tubular atrophy, arteriosclerosis, arterial intimal fibrosis, and presence of red blood cells or degenerated red cell casts in tubules.Direct immunofluorescence was performed by adding fluorescein-conjugated antibodies against immunoglobulin heavy chains , light chains (kappa and lambda), complement components , and albumin using Benchmark ULTR system from Roche Diagnostics following the manufacturer’s instructions. Samples were then examined under blue laser light using an immunofluorescent microscope.et al.Ultrathin sections were stained with uranyl acetate and lead citrate before examination under the transmission electron microscope . GBM thickness was measured digitally using an EM image analysis system after calibration. Measurements were obtained in properly oriented open peripheral glomerular capillaries, with a minimum of 3 measurements evenly distributed per loop. GBM measurements were obtained in a minimum of 10 glomerular capillary loops of at least 2 viable glomeruli when possible. Mean and range of GBM thickness were then calculated and recorded for each sample. For standardization, mean and range of GBM thickness were reported for each sample, as previously reported.COL4A3, COL4A4, and COL4A5 was captured using hybridization probes. Captured DNA was pair end sequenced (150 × 2) on NovaSeq6000 using Illumina’s reversible dye terminator technology. The Clinical Laboratory Improvement Act certified laboratory used the following quality control metrics: >98% of targeted bases covered at >20× and mean coverage of target bases >100×. Copy number evaluation defined as single exon or larger deletions or duplications (Del/Dups) were detected from the sequencing data by the Clinical Laboratory Improvement Act laboratory using their proprietary bioinformatics pipeline. All sequencing results were reviewed and interpreted by clinical molecular geneticists. All sequencing results were reviewed and interpreted by clinical molecular geneticists. Sequence variants were categorized as “pathogenic”, “likely pathogenic”, “benign”, “likely benign”, and “variant of uncertain significance” as per American College of Medical Genetics Guidelines.Genetic testing was performed at Clinical Laboratory Improvement Act certified clinical laboratory approved by Saskatchewan Health Authority. DNA was extracted from leukocytes obtained from whole blood specimens. Sequencing included coding regions and 10 bases of exon flanking region. DNA corresponding to Descriptive statistics were used to report baseline characteristics and histology findings. Results were expressed as count (%) for categorical variables and median (interquartile range) for continuous variables.Among 18 patients who were approached, 14 agreed to participate and their baseline characteristics are in 2). We were unable to assess GBM thickness on EM for 1 patient because of inadequate sample. Red blood cells or red cell casts were present in the tubules or glomerular space of 10 patients (71%)  c.Table 2COL4A3, COL4A4, and COL4A5 genes in all 14 participants, there were no identified “pathogenic” or “likely pathogenic” variants. There was no evidence of copy number variations identifiable in the sequencing data.After successful sequencing of the COL4A3, COL4A4, or COL4A5 variants in this cohort of patients with loin pain hematuria. Based on these results, conventional histopathology and genetic testing for type IV collagen variants failed to identify the cause of hematuria in 14 patients with LPHS.We present kidney biopsy results and type IV collagen sequencing in 14 unrelated patients with LPHS. Eleven of 14 had a normal appearing GBM, whereas 1 of 14 had a thick GBM and 1 of 14 had evidence of IgA deposition. Red blood cells (10/14) or red cell casts (7/14) were present in multiple tubules in the majority of patients consistent with a glomerular source of bleeding. We did not identify any pathogenic et al.If a biopsy is performed in a patient with isolated hematuria, examination of the GBM using EM is usually viewed as the most important component. A case series of 7 patients in 1996 reported an absence of GBM abnormalities but presence of red cells in multiple cross-sections of renal tubules, indicating that the hematuria was glomerular in origin.COL4A5 variants,COL4A3 or COL4A4,COL4A3 or COL4A4 variants, or heterozygous COL4A5 in women can present with a range of histological and phenotype features variably, including hematuria, proteinuria, focal segmental glomerulosclerosis, and chronic kidney disease.COL4A3, COL4A4, and COL4A5 genes leading to a reclassification of Alport syndrome and thin basement membrane nephropathy as type IV collagen nephropathies.Increasing access to genetic testing has improved our understanding of the spectrum of phenotypes associated with type IV collagen nephropathy and a recognition that thin basement membrane disease and Alport syndrome share a common molecular basis.Deposition of C3, presence of arterial sclerosis, and endothelial cell injury were present in patients in this LPHS cohort but similar abnormalities have been reported in studies of healthy kidney donors. Of 102 transplant donors who underwent a kidney biopsy before transplant, 74.5% showed nonspecific IgM or C3 deposits, intimal fibrosis of small arteries (44%), interstitial fibrosis (8%), and arteriolar hyalinosis (29%).,et al.It remains possible that yet unidentified defects in the endothelium and GBM lead to the leakage of red cells from the vasculature into the urinary filtrate. Red cell transit through the GBM has been associated with a transient 2.25 μm wide gaps in the endothelium and underlying basement membrane.LPHS is likely not a distinct clinical entity but a common end point for a diverse group of underlying disease processes that manifest clinically with loin pain and hematuria. The histological changes identified in our study offer no consistent explanation for the genesis of the hematuria or pain or further basis for patient subclassification. Pathogenic type IV collagen variants are unlikely to explain a significant proportion of patients with LPHS but future genomic studies investigating additional genes that code for the GBM, proteins important for glomerular endothelial cell function, or the remainder of the exome and genome may provide additional clues. Given its rarity, genetic and genomic efforts will focus on families with multiple affected individuals.N = 420) that code for transduction, conduction, synaptic transduction, and modulation.Incapacitating, debilitating, opioid requiring pain remains a prominent feature of LPHS and its pathophysiology remains a mystery. The transmission of pain from the viscera to the brain involves a pathway that is controlled by an intricate series of genes (Limitations of the current study include the small sample size conducted in a single center, which limits generalizability. However, LPHS is a rare condition and as a regional referral center, we have attempted to capture as many patients as possible. All the patients were female and majority were of European heritage. Additional studies are on-going and collaboration is welcome.In conclusion, LPHS remains a disabling chronic condition primarily impacting women of reproductive age whose pathophysiology remains unknown. Kidney biopsy histology and sequencing of the type VI collagen genes in our cohort of 14 patients did not provide additional clues to the mechanism of hematuria or pain in patients with LPHS.This research was supported partially with a generous grant by The Hospitals of Regina Foundation. BP reports speaker and advisory fees from Bayer, Otsuka, Glaxo Smith Kline, Astra Zeneca, and Medtronic. MBL reports speaker and advisory fees from Otsuka, Bayer, Reata, and Sanofi. All authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.