Cardiovascular Manifestations and Management in ADPKD.

Cardiovascular disease (CVD) is the major cause of mortality in autosomal dominant polycystic kidney disease (ADPKD) and contributes to significant burden of disease. The manifestations are varied, including left ventricular hypertrophy (LVH), intracranial aneurysms (ICAs), valvular heart disease, and cardiomyopathies; however, the most common presentation and a major modifiable risk factor is hypertension. The aim of this review is to detail the complex pathogenesis of hypertension and other extrarenal cardiac and vascular conditions in ADPKD drawing on preclinical, clinical, and epidemiological evidence. The main drivers of disease are the renin-angiotensin-aldosterone system (RAAS) and polycystin-related endothelial cell dysfunction, with the sympathetic nervous system (SNS), nitric oxide (NO), endothelin-1 (ET-1), and asymmetric dimethylarginine (ADMA) likely playing key roles in different disease stages. The reported rates of some manifestations, such as LVH, have decreased likely due to the use of antihypertensive therapies; and others, such as ischemic cardiomyopathy, have been reported with increased prevalence likely due to longer survival and higher rates of chronic disease. ADPKD-specific screening and management guidelines exist for hypertension, LVH, and ICAs; and these are described in this review.

Efficacy of beetroot juice on reducing blood pressure in hypertensive adults with autosomal dominant polycystic kidney disease (BEET-PKD): study protocol for a double-blind, randomised, placebo-controlled trial.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD) impaired nitric oxide (NO) synthesis, in part, contributes to early-onset hypertension. Beetroot juice (BRJ) reduces blood pressure (BP) by increasing NO-mediated vasodilation. The aim of this double-blind, randomised, placebo-controlled study is to test the hypothesis that BRJ reduces systolic and diastolic clinic BP in hypertensive adults with ADPKD. METHODS: Participants with ADPKD and treated hypertension (n = 60) will be randomly allocated (1:1) to receive a daily dose of either nitrate-replete (400 mg nitrate/day) or nitrate-deplete BRJ for 4 weeks. The co-primary outcomes are change in mean systolic and diastolic clinic BP before and after 4 weeks of treatment with daily BRJ. Secondary outcomes are changes in daily home BP, urinary albumin to creatinine ratio, serum and salivary nitrate/nitrite levels and serum asymmetric dimethylarginine levels before and after 4 weeks of BRJ. DISCUSSION: The effect of BRJ in ADPKD has not been previously tested. BRJ is an accessible, natural dietary supplement that, if effective, will provide a novel adjunctive approach for treating hypertension in ADPKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05401409. Retrospectively registered on 27th May 2022.

A case of minimal change disease during pregnancy - benefits of early diagnosis and use of corticosteroids.

Nephrotic syndrome presenting in pregnancy is rare and poses a diagnostic and therapeutic challenge. Timing of renal biopsy is important given the increased risk of bleeding and miscarriage, and the choice of immunosuppression is limited due to the teratogenicity profiles of standard drugs. We report and discuss a case of minimal change disease diagnosed by renal biopsy during early pregnancy and treated with corticosteroids throughout the pregnancy. Prompt diagnosis and treatment of glomerular disease in pregnancy are vital to prevent poor maternal and fetal outcomes.

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.

Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 µg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 µg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.

Increased water intake reduces long-term renal and cardiovascular disease progression in experimental polycystic kidney disease.

Polycystic kidney disease (PKD) is the most common inherited cause of kidney failure and currently has limited treatment options. Increasing water intake reduces renal cyst growth in the pck rat (a genetic ortholog of autosomal recessive PKD) but it is not clear if this beneficial effect is present in other models of PKD. In this study, we tested the hypothesis that high water intake (HWI) reduces the progression of cystic renal disease in Lewis polycystic kidney (LPK) rats (a genetic ortholog of human nephronophthisis-9). Groups of female and male LPK (n = 8-10 per group) and Lewis (n = 4 per group) rats received water ad libitum supplemented with or without 5% glucose [to simulate HWI or normal water intake (NWI) respectively] from postnatal weeks 3 to 16. Water intake increased ~1.3-fold in the LPK+HWI group compared to LPK+NWI rats between weeks 3 to 10 but the differences were not significant at later timepoints. In LPK rats, HWI reduced the increases in the kidney to body weight ratio by 54% at week 10 and by 42% at week 16 compared to NWI (both p<0.01). The reduction in kidney enlargement was accompanied by decreases in the percentage renal cyst area, percentage renal interstitial collagen and proteinuria (all p<0.05). At week 16, HWI reduced systolic blood pressure and the heart to body to weight ratio by 16% and 21% respectively in males LPK rats (both p<0.01). In conclusion, a modest increase in water intake during the early phase of disease was sufficient to attenuate renal cystic disease in LPK rats, with secondary benefits on hypertension and cardiovascular disease. These data provide further preclinical evidence that increased water intake is a potential intervention in cystic renal diseases.

Effect of dimethyl fumarate on renal disease progression in a genetic ortholog of nephronophthisis.

Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) ( n = 8-9 each) dimethyl fumarate in drinking water for eight weeks. Age-matched Lewis control rats were also studied ( n = 4 each). Nuclear factor erythroid-derived factor 2 was quantified by whole-slide image analysis of kidney sections. Renal nuclear factor erythroid-derived factor 2 activation was partially reduced in vehicle-treated Lewis polycystic kidney disease rats compared to Lewis control (21.4 ± 1.7 vs. 27.0 ± 1.6%, mean ± SD; P < 0.01). Dimethyl fumarate upregulated nuclear factor erythroid-derived factor 2 in both Lewis Polycystic Kidney Disease (D10: 35.9 ± 3.8; D30: 33.6 ± 3.4%) and Lewis rats (D30: 34.4 ± 1.3%) compared to vehicle-treated rats ( P < 0.05). Dimethyl fumarate significantly reduced CD68+ cell accumulation in Lewis polycystic kidney disease rats (V: 31.7 ± 2.4; D10: 23.0 ± 1.1; D30: 21.5 ± 1.9; P < 0.05). In Lewis polycystic kidney disease rats, dimethyl fumarate did not alter the progression of kidney enlargement (V: 6.4 ± 1.6; D10: 6.9 ± 1.2; D30: 7.3 ± 1.3%) and the percentage cystic index (V: 59.1 ± 2.7; D10: 55.7 ± 3.5; D30: 58.4 ± 2.9%). Renal dysfunction, as determined by the serum creatinine (Lewis + V: 26 ± 4 vs. LPK + V: 60 ± 25 P < 0.01; LPK + D10: 47 ± 7; LPK + D30: 47 ± 9 µmol/L), and proteinuria were also unaffected by dimethyl fumarate treatment. In conclusion, the upregulation of nuclear factor erythroid-derived factor 2 by dimethyl fumarate reduced renal macrophage infiltration in nephronophthisis without adverse effects, suggesting that it could potentially be used in combination with other therapies that reduce the rate of renal cyst growth. Impact statement This is the first study to investigate the effects of dimethyl fumarate in a model of cystic kidney disease. The study assessed the therapeutic efficacy of dimethyl fumarate in upregulating renal nuclear factor erythroid-derived factor 2 expression, reducing macrophage accumulation and cyst progression in a Lewis polycystic kidney disease rat model. This study demonstrates that dimethyl fumarate significantly upregulated renal nuclear factor erythroid-derived factor 2 expression and attenuates renal macrophage infiltration, but had no effect on renal cyst progression, cardiac enlargement, and improving renal function.

Utility of penicillin allergy testing in patients presenting with a history of penicillin allergy.

BACKGROUND: Current statistics show that approximately 10% of patients claim to be allergic to penicillin yet only 10% of these have demonstrable allergy. The most appropriate and cost-effective antibiotics are sometimes withheld on the basis of patient history of drug allergy. OBJECTIVE: Investigation of IgE hypersensitivity and delayed hypersensitivity in patients with a history of penicillin allergy to a teaching hospital allergy clinic. METHODS: Patients underwent skin prick and intradermal testing (IDT) with major and minor penicillin determinants. Those with negative skin tests were administered a three-day oral challenge. Demographic and clinical details about the reactions were noted. RESULTS: One hundred twenty eight patients underwent testing, of these, one hundred and ten had self-reported histories of penicillin allergy and eighteen were referred because of other antibiotic allergies. Seventeen patients with self-reported penicillin allergy had either positive skin tests or oral challenge results, corresponding to 15% of patients having proven allergy. None reacted on skin prick testing, four reacted to IDT, thirteen reacted to oral challenge (five immediate and eight delayed). Analysis of clinical histories showed that patients with a well-defined history of allergy and a history of anaphylaxis were more likely to have a positive test compared to patients with vague histories. Skin testing proved to be less sensitive than oral challenge. CONCLUSION: A minority of patients presenting with a history of penicillin allergy have evidence of immune-mediated hypersensitivity (17/110, 15%) in this study. Of these, eight out of seventeen (47%) had delayed reactions, demonstrating the usefulness and discriminating power of objective testing, which must include three-day oral challenge. Discriminating factors for immune-mediated allergy from patient history were a clear description of the original reaction and a history of anaphylaxis. Negative allergy testing enables the use of penicillin as first-line treatment when necessary and this can significantly reduce costs of antibiotics.