Tissue kallikrein and kinins in renal disease

The renal kallikrein-kinin system is involved in sodium and water homeostasis, blood pressure regulation and inflammation. Tissue kallikrein and kinin levels were measured in the urine of patients with renal disease and in the urine of living related kidney donors prior to uninephrectomy who served as controls. Tissue kallikrein and kinin B1 and B2 receptors were immunolocalised by confocal microscopy in renal biopsy material from patients with renal disease and controls (fresh autopsy material and normal kidney tissue from nephrectomies for malignancy). Urinary tissue kallikrein excretion was significantly decreased in patients with mild renal disease (16.6 +/- 6.7 ng tissue kallikrein (TK)/ng protein; p < 0.05) and more markedly so (1.8 +/- 0.7 ng TK/microg protein; p < 0.01) in patients with severe renal failure requiring dialysis compared to normal controls (78.9 +/- 31.7 ng TK/microg protein). Basal kinin values were unchanged in patients with renal disease (14 +/- 0.8 ng/ml) compared to controls (13.3 +/- 0.56 ng/ml). In control kidney tissue kallikrein was immunolocalised in the distal connecting tubules and collecting ducts whereas decreased immunolabelling was observed with renal disease. Kinin B2 receptor labelling was present in the entire nephron in the normal control kidney but was reduced with renal disease. While kinin B1 receptor immunolabelling was not observed in the control kidneys, labelling of distal tubules and collecting ducts was noted in renal disease, suggesting an upregulation of B1 receptors in renal parenchymal disease.     

Preparation and protein conjugation of a divinyl sulphone derivatized bifunctional chelating agent

A new bifunctional chelating agent with a novel linking arm, 2-[p-?N-benzyl-N-(2-vinylsulfoethyl)?- (aminobenzyl)?-1,3-propane-diamine-N,N,N',N'-tetraacetic acid (VS-PDTA) was synthesized and was conjugated to protein for the purpose of attaching radiometals to monoclonal antibodies (MAbs). The effect of various parameters such as ligand concentration, protein concentration, pH, temperature and reaction period on the conjugation have been examined using chromatographic (SE and TLC) analysis after labeling with 111In. The parameters and chemical variables studied have significant effects on the efficiency and rate of protein conjugation.     

The Role of Uric Acid in Preeclampsia: Is Uric Acid a Causative Factor or a Sign of Preeclampsia?

Purpose of Review

Because of the significant discrepancies on this topic, this review will focus on the role of uric acid in PE, uric acid as a predictor of preeclampsia and fetal growth retardation. We considered eligible review and original articles relevant to the research question.

Recent Findings

Hypertensive disorders of pregnancy such as preeclampsia (PE) are a major cause of both maternal and fetal morbidity and mortality worldwide. Uric acid has been reported as a key factor contributing to the pathogenesis of PE. Some studies have indicated that serum uric acid levels increase with the severity of PE, while several studies have shown contradictory results. Some studies suggested high uric acid levels lead to PE, while others state that PE causes an increase in uric acid levels.

Summary

Despite the strong association of uric acid in the pathogenesis of preeclampsia, current data is still contradictory hence genetic and high-end laboratory investigations may clarify this enigma.

     

Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system

Bedaquiline (BDQ) is the first-in-class United States Food and Drug Administration (US FDA) approved anti-tuberculosis (anti-TB) drug, which is a novel diarylquinoline antibiotic that has recently been utilized as an effective adjunct to existing therapies for multidrug-resistant tuberculosis (MDR-TB). BDQ is especially promising due to its novel mechanism of action, activity against drug-sensitive and drug-resistant tuberculosis (TB) in addition to having the potential to shorten treatment duration. Drug delivery to the central nervous system (CNS) is a major concern in TB chemotherapy, especially with the increasing cases of CNS-TB. In this study, we investigated the CNS penetration of BDQ in healthy rodent brain. Male Sprague-Dawley rats (n = 27; 100 ± 20 g) received a single 25 mg kg⁻¹ b.w dose of BDQ via intraperitoneal (i.p.) administration, over a 24 h period. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine whole tissue drug concentrations and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) was utilized to evaluate drug distribution in the brain. BDQ reached peak concentrations (C_max) of 134.97 ng mL⁻¹ in the brain at a T_max of 4 h, which is within the range required for therapeutic efficacy. BDQ was widely distributed in the brain, with a particularly high intensity in the corpus callosum and associated subcortical white matter including the striatal, globus pallidus, corticofugal pathways, ventricular system, basal forebrain region and hippocampal regions. Using MALDI MSI, this study demonstrates that due to BDQ''s distribution in the brain, it has the potential to target TB reservoirs within this organ.

Bedaquiline (BDQ) was administered to healthy Sprague-Dawley rats in order to determine its localisation in the brain using mass spectrometry imaging (MSI). This study shows that BDQ has the potential for targeting TB reservoirs in the CNS.     

The effects of antihistamines with varying anticholinergic properties on voluntary and involuntary movement

ObjectiveRecent evidence indicates that antihistamines can affect movement, which is most likely due to altered neurotransmission in cholinergic and histaminergic pathways. The purpose of this study was to determine if antihistamines with varying anticholinergic properties differentially affect voluntary and involuntary movement control.MethodsEleven healthy subjects were enlisted into a human double blind, placebo-controlled, five-way crossover study. Drowsiness, reaction time, and physiological tremor were examined 1-, 2-, and 3-hr post-ingestion of antihistamines with known anticholinergic profiles. These were the first-generation promethazine, and second-generation loratadine, desloratadine, and fexofenadine. Hyoscine butylbromide was used in an additional experiment to determine how a peripheral antimuscarinic drug influenced neuromotor function.ResultsPromethazine, desloratadine and fexofenadine increased drowsiness. Promethazine increased simple and choice reaction time and reduced tremor. Desloratadine increased choice reaction time and tremor, while loratadine slowed simple and choice reaction time.ConclusionCentral anticholinergic and antihistaminergic properties of antihistamines potentially contribute to movement dysfunction.SignificanceSecond-generation antihistamines have provided the consumer with a safer alternative to the first-generation sedating antihistamine. However, the results of this study suggest that loratadine and desloratadine have the potential to affect movement control, and further research is warranted to understand the clinical relevance of these findings.     

Nutritional problems associated with end-stage renal disease in the developing world

Protein-energy malnutrition is a major problem in dialysis patients. There is increased morbidity and mortality in dialysis patients with malnutrition. There are very few published studies on nutritional parameters and adequacy of dialysis from the developing world and especially from Africa. There was a significant improvement in neuromuscular function and nutrition in 22 hemodialysis patients in Egypt with optimization of dialysis dose and nutritional status. In a study of 82 continuous ambulatory peritoneal dialysis (CAPD) patients in Durban, South Africa, there was a reduction in the number of hospital admissions in adequately dialyzed patients (achieving Kt/V of >2.1). In another study of 84 CAPD patients from the same center, 76.2% of patients were assessed as being malnourished, with loss of appetite being an important etiological factor. Strategies to optimize dialysis dose, together with services of a renal dietician, will assist in improving the nutrition of patients with chronic renal failure.     

The pathogenesis of membranoproliferative glomerulonephritis in KwaZulu-Natal,South Africa is unrelated to hepatitis C virus infection

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a well-defined clinicopathological entity with a poor prognosis, with 50% of patients progressing to end stage renal disease (ESRD) within 10 years. It was reported in about 36% of adult Black patients with nephrotic syndrome in our center previously [Seedat et al. 1988]. Hepatitis C virus (HCV) infection has been shown to be associated with cryoglobulinemic as well as non-cryoglobulinemic (or idiopathic glomerulonephritis). The aim of this study was to determine whether an association exists between HCV infection and idiopathic MPGN in a population with a relatively high prevalence of MPGN. We studied adult patients referred with glomerular disease over a two-year period, 104 patients had primary glomerulonephritis. All 23 (22%) patients with idiopathic MPGN were enrolled, as well as 32 age-matched patients presenting with other primary glomerular diseases. We examined serum from all 55 patients for evidence of HCV antibodies and HCV RNA. None of the 55 patients showed evidence of HCV infection. Chronic renal failure was present in 82.6% of the patients with idiopathic MPGN and it was advanced in 52,2%, who either were dialysis-requiring at presentation or progressed to ESRD soon thereafter; 30.4% had moderate chronic renal failure, while only 17.4% had normal renal function. HCV infection is not associated with idiopathic MPGN in our patients. Idiopathic MPGN remains an idiopathic disease, possibly with a poor prognosis in our population.