Treatment-resistant hypertension (RH), defined as uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with ≥3 medications of different classes (including diuretics) at optimal doses, is associated with poor prognosis and an elevated risk of end-organ damage. In areas where HIV is endemic, such as sub-Saharan Africa, the risk of hypertension is high in people living with HIV. It remains unknown if HIV infection further increases the risk of RH. This study seeks to determine the association between HIV and RH as well as investigate other factors associated with RH in hypertensive Malawian adults.A case–control study will be conducted among adult hypertensive patients attending a clinic at a referral hospital in Malawi. The cases will be hypertensive patients with a confirmed diagnosis of RH. For each case, two controls (hypertensive patients without RH), frequency matched for age group and sex, will be selected from among hospital clients attending the same hypertension clinic as the case. In both groups, HIV status will be ascertained. Additionally, information on other potential risk factors of RH, such as chronic kidney disease, obesity, hypercholesteraemia, diabetes, smoking, alcohol use, antiretroviral therapy regimen and duration, will be collected in both cases and controls. For each of the potential risk factors, ORs will be calculated to quantify the strength of their association with RH. In a multivariate analysis, conditional logistic regression will be used to assess the independent association between HIV and RH as well as the influence of the other potential drivers of RH.This protocol has been approved by the College of Medicine Research Ethics Committee (COMREC) in Malawi (P.05/22/3637). Findings from this study will be disseminated through a peer-reviewed publication in an open-access international journal. Furthermore, anonymised data will be available on request from the authors. A key strength of the case–control design is that it will allow the investigation of multiple exposures that could drive treatment-resistant hypertension in people living with HIV.To the best of our knowledge, this is the first study in Malawi to understand drivers of treatment-resistant hypertension and will generate important knowledge to inform future cohort studies in settings where HIV is highly prevalent.The study will only recruit participants from one large hypertension clinic at a referral public hospital. This has the potential to exclude other adults that could be otherwise eligible  leading to selection bias.Over the last 20 years, sub-Saharan Africa (SSA) has faced a rise in the prevalence of non-communicable diseases (NCDs) because of an increase in cardiovascular risk factors such as poor diet, little to no physical activity, hypertension, obesity, diabetes and dyslipidaemia.2 5Despite its high global burden, most people who suffer from hypertension, including those living with HIV, fail to achieve adequate blood pressure control and are usually unaware of their disease status, until faced with end-organ disease. In SSA, only 27% of people with hypertension are aware of their disease, 18% are receiving treatment and yet only 7% of those suffering from hypertension have well-controlled blood pressure.3RH is defined as uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with ≥3 medications of different classes (including diuretics) at optimal doses. RH is associated with poor prognosis and elevated risk of end-organ damage which can lead to premature deaths. The global burden of RH has been estimated to be around 10.3%,Malawi, like most SSA countries, has a high burden of HIV: 10.6%A case–control study will be conducted at the outpatient hypertension clinic at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. QECH is the largest tertiary hospital in Malawi that receives referrals from across the country. It is a free public hospital hence it serves mainly the low-income to middle-income class. A case–control study design has been chosen for three reasons. First, treatment-RH is a relatively rare disease, and a case–control study will allow research on this outcome. Second, it will reduce the time constraint that a prospective cohort study would present due to the need for a longer follow-up period. Third, it will allow the investigation of multiple factors associated with RH.Cases will be defined as hypertensive patients with a confirmed diagnosis of treatment-RH. In this study, treatment-RH will be defined as a blood pressure of ≥140/90 mm Hg measured using an ambulatory blood pressure monitor (ABPM) over 4 hours in patients with hypertension and who are on at least three different medications including a diuretic. The 4 hour ABPM will be adopted in this study since previous studies have shown and validated a 4 hour ABPM as an accurate proxy of daytime (24 hours) blood pressure.Suspected RH cases will be patients who have elevated blood pressure of ≥140/90 mm Hg on the day of recruitment and who are taking any three classes of antihypertensive medication including a diuretic. The investigators will measure the blood pressure of both cases and controls using a digital blood pressure cuff. After 30 min of the participants’ rest and while the participant is seated, the investigators will collect three blood pressure readings 5 min apart. This method was used in previous studies to measure blood pressure in Malawian adults.The controls will be sex and age-group-matched individuals who have well-controlled blood pressure (BP<140/90 mm Hg). After obtaining consent in both groups, HIV status will be ascertained. Other factors such as chronic kidney disease, obesity, hypercholesteraemia, diabetes, smoking, alcohol use, ART regimen and duration will be assessed through the collection of medical history, review of notes in health passport books and blood tests.Non-pregnant adults (≥18 years)Patients taking at least 3 classes of antihypertensive medication including a diuretic for at least a month.Patients with high blood pressure readings of ≥140/90 mm Hg on the last two hospital visits.Patients with a blood pressure reading of ≥140/90 mm Hg on the date of enrollment.Patients over 18 years with blood pressure readings of ≥140/90 mm Hg who are taking no more than two classes of antihypertensive medication.Patients taking at least three classes of antihypertensive medication but not including a diuretic on their drug regimen.Non-pregnant adults (≥18 years) who have well-controlled blood pressure (BP<140/90 mm Hg) taking any classes of antihypertensive medication.Patients must have had well-controlled blood pressure (BP<140/90 mm Hg) on their last two hospital visits.Patients over 18 years with blood pressure readings of ≥140/90 mm Hg.Patients over 18 years with well-controlled blood pressure (BP<140/90 mm Hg), who are not taking any antihypertensive medication.Details of the data that will be collected are outlined in In a private environment, participants will first be asked if they are aware of their HIV status. HIV status will be deemed positive if the individual is on ART or has a documented positive result in their health passport. Those who have been taking ART will provide more information on regimen(s) and how long they have been taking the drugs. This includes asking if they have been switched on ART previously.Individuals with documented negative HIV test results in their health passports within the last 3 months will be marked as negative. Three months have been employed in tandem with the window period for HIV infection. Rapid antibody tests (which is what will be used in this study) can accurately detect HIV infection 90 days after exposure. An HIV test following the testing algorithm that is stipulated in the Malawi HIV Clinical GuidelinesIn previous studies,The primary outcome of the study is the adjusted OR, with a 95% CI, of the association between RH and HIV. This will be defined as the odds of HIV in RH patients divided by the odds of HIV in hypertensive patients without RH.The secondary outcome measures are the ORs, with 95% CIs, of the independent association between the covariates representing other potential risk factors: cholesterol, obesity, kidney disease and RH.In calculating the sample size, a threefold relative difference in the odds of HIV infection in cases compared with controls was considered clinically significant. Assuming an HIV prevalence of 10.6% among controls, as is seen in the general population,All data in the study will be collected and managed using the Open-Data Kit software platform. Data will be entered by the study team, and the data accuracy will be verified by the study principal investigator. Only study team members will have access to protected health information. All study-related information will be stored securely at the study site. Tablet computers used to collect the data will be password protected. Any physical participant information will be stored in locked file cabinets in areas with limited access. Patients will not be identified by name in any reports on this study. The study PI and coinvestigators will have access to the final dataset of the study.The number and percentages of cases and controls identified, and those recruited into the study and participants included in the final analysis will be reported. Additionally, the median (range) of baseline continuous variables  will be described for both cases and controls. Furthermore, the prevalence of other risk factors, HIV, obesity, hypercholesteraemia and chronic kidney disease in both RH cases and non-RH controls, will be described. In participants living with HIV, different ART regimens and documented viral load and/or CD4 counts, in both controls and cases, will be compared.To determine the primary and secondary outcomes, two main steps will be carried out. First, the crude ORs of the association between RH and exposure characteristics of interest: HIV, obesity, chronic kidney disease and hypercholesteraemia will be computed in univariate analysis with conditional logistic regression models. Similarly, the relationships between other exposure variables: smoking, alcohol intake and diabetes and RH will be established. In participants living with HIV, we will explore the relationship between the different ART regimens and RH. Point estimates, their CIs and statistical significance, assessed at a 5% level of significance, will be used to determine the strength of the association. Except for HIV, only covariates that show narrow CIs in this univariate analysis will be carried on to the next step.2 test will be used to compare categorical data between cases and controls, while the Wilcoxon Rank Sum test will be used for continuous data. Reporting of results will be in line with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.Second, using a backward stepwise approach in a conditional logistic regression model, the adjusted association between RH and HIV will be ascertained. Covariates to be adjusted for will be those that show a narrow CI for the crude OR in the first step above. For all analyses, the χPatients and the public were not involved in setting the research priorities, defining the research question or determining the outcomes of this study.This study has been approved by the College of Medicine Research Ethics Committee (COMREC) with approval number P.05/22/3637. Written consent will be sought from participants before enrolment into the study. Findings from this study will be disseminated through submission for publication in an international, open-access, peer-reviewed journal. Anonymised data from the study will be made available on request from the authors.


Neoadjuvant nivolumab and cabozantinib in locally advanced renal cell carcinoma in a horseshoe kidney is a novel therapeutic approach in the preoperative setting.We report a case of a 52-year old male who presented with a large inoperable tumor of the horseshoe kidney and achieved major partial radiologic response after neoadjuvant therapy with nivolumab and cabozantinib leading to radical resection of the tumor. The patient remains tumor free on the subsequent follow-up and his renal function is only mildly decreased. The systemic treatment was complicated by hepatotoxicity leading to early nivolumab withdrawal.Currently, the combination therapy based on immune checkpoint inhibitors and tyrosine kinase inhibitors represents the treatment of choice in treatment-naïve patients with metastatic renal cell carcinoma in any prognostic group. The neoadjuvant treatment approach is being tested in prospective clinical trials and results are eagerly awaited. Renal cell carcinoma in a horseshoe kidney is an uncommon finding that is always challenging. Additionally, management guidance in this patient population is lacking. In some patients neoadjuvant therapy could be the only way to preserve kidney function. The initial treatment strategy should be individualized to patient needs aiming at the radical resection of the primary tumor as the only chance of getting the tumor under control in the long term.Herein, we highlight the feasibility of neoadjuvant systemic therapy with nivolumab and cabozantinib allowing the subsequent performance of radical tumor resection with negative margins in a patient with advanced renal cell carcinoma in a horseshoe kidney, removing the primary tumor while sparing the patient from lifelong dialysis. In recent years, the use of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of metastatic renal cell carcinoma (mRCC) –5. UndouThe current first line strategy in mRCC comprises mainly a combination of an ICI plus tyrosine-kinase inhibitor (TKI) based on prior demonstration of the benefit of these combinations. One such example is the combination of an anti-PD1 antibody nivolumab with TKI cabozantinib which has shown superior efficacy compared with sunitinib monotherapy in the first-line setting in patients with mRCC regardless of their prognosis according to the International Metastatic Database Consortium (IMDC) Risk Score for RCC, introducing a shift in the common therapeutical practice of the first-line treatment . MoreoveLocalized renal cell carcinoma (RCC) can be inoperable for several reasons including solitary kidney or locally advanced disease. Data on optimal therapeutic strategy in this patient population are scarce. The potential of the neoadjuvant treatment approach in this patient population lies in downsizing the primary tumor, enabling radical tumor resection .We describe a case of a patient with locally advanced inoperable RCC of a horseshoe kidney treated with neoadjuvant nivolumab and cabozantinib leading to radical resection of the primary tumor 7 months later.A 52-year-old Caucasian male, non-smoker, with an Eastern Cooperative Oncology Group (ECOG) status 0 with no serious comorbidities presented in October 2021 with anemia and hematuria. The abdominal CT scan revealed a horseshoe kidney, a bulky tumor at the junction of the lower kidney poles affecting a large part of the right kidney. The dimensions of the tumor were 150x120x100 mm (The combination therapy with nivolumab (240 mg intravenously every two weeks) and cabozantinib 40 mg orally daily was started in December 2021. In January 2022, 6 weeks after therapy initiation, the patient developed grade 3 hepatotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 manifested by elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with bilirubin levels within normal limits. Other potential causes of hepatotoxicity including infections or obstruction were ruled out. The therapy was stopped immediately and corticosteroid administration with prednisolone 1mg/kg orally was initiated with close monitoring of liver enzymes and other related parameters. Within a week of therapy, slow lowering of corticosteroid dose was possible because of a decrease in AST and ALT levels to grade 1 suggesting immune-related toxicity. In February 2022, the restaging CT scan was performed showing tumor size reduction to 90x60x100 mm, i.e. partial regression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 was achieved  was reported only in anecdotal case reports , 9. In sAntitumor response promoted by ICIs via PD-1/PD-L1 inhibition potentially induces a long-term effect by eliminating of metastatic clones. Concerning immunotherapy in the preoperative setting, in 2021 Gorin et al. published data on high-risk nonmetastatic RCC patients given preoperative nivolumab  with only 1 patient out of 17 having pathological response with immune-related features in the removed kidney . ResultsThe therapy preference should always be carefully considered and discussed in patients with a solitary kidney or significantly impaired renal function where kidney function preservation is at risk. Regarding the large inoperable tumor mass in this case, we decided to initiate the combination strategy of nivolumab with cabozantinib to attempt downsizing the tumor. One of the critical moments of the whole process is finding a strategy that would preserve maximum of functional renal parenchyma, and failure to do this adversely affects the patient´s prognosisThe tumor size reduction was rapid at the beginning of the therapy when the combination of both drugs was given. The tumor diameter decreased by 30% after 2 months of cabozantinib therapy with nivolumab, while an additional 4% decrease was obtained during single-agent cabozantinib therapy. The pathologist described the tumor as 85x87x50 mm in size, but only a small portion of the tumor consisted of viable tumor cells. The discrepancy between the radiological and actual tumor size has been previously described as viable tumor cells might represent only a small proportion of the remaining mass .Management guidance on tumors arising from a horseshoe kidney remains anecdotal owing to the rarity of this presentation. Only case reports or small case series provide clinical data on therapeutic management specific to this particular presentation. The variable anatomy of a horseshoe kidney, aberrant vasculature with accessory arteries and branches arising from arteries other than the aorta, and the complexity of the tumor renders surgery highly demanding . In ordeVarious histopathological subtypes of renal abnormalities have been described in association with renal tumors in a horseshoe kidney, hence a tumor biopsy preceding the operation is warranted.In the current case, no complications associated with the surgery or wound healing disturbances were noted. Wound healing problems resulting from TKI therapy have been previously published , as wereNot only efficacy but also safety is of concern when we manage a patient with localized disease considering a future surgical procedure. Identifying the optimal therapy at the very beginning is crucial as novel potent therapies emerge. The patient in the present case experienced grade 3 hepatotoxicity leading to ICI termination followed by single agent TKI. In the Checkmate-9ER trial 5.6% patients discontinued both agents and nearly 20% patients permanently stopped the combination therapy and continued with single agent therapy due to adverse events . AdverseThe present report demonstrates the potential of neoadjuvant nivolumab and cabozantinib therapy to downsize an initially inoperable RCC leading to subsequent radical surgical resection. The neoadjuvant approach with nivolumab and cabozantinib may be a viable option for patients with initially inoperable RCC, including patients with a solitary kidney.The original contributions presented in the case report are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the case report in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentiall identifiable images or data included in the article.AZ: writing and revision of the manuscript, collected data. HS: conceptualization, supervision, writing and revision of the manuscript. AK: collected data, revision of the manuscript. TT: revision of the manuscript. VS: revision of the manuscript. BM: revision of the manuscript. All authors contributed to the article and approved the submitted version.