1 The present study investigated the effect of streptozotocin-induced diabetes on alpha(1)-adrenoceptor subtypes in rat renal resistance vessels. 2 Studies on renal haemodynamics were carried out 7 days after the last streptozotocin. Changes in renal blood flow were recorded in response to electrical stimulation of the renal nerve (RNS) and a range of adrenergic agonists; noradrenaline (NA), phenylephrine (PE) and methoxamine (MTX), either in the absence or the presence of nitrendipine (Nit), 5-methylurapidil (MEU), chlorethylclonidine (CEC) or BMY 7378. 3 In non-diabetic animals, Nit, MEU and BMY 7378 significantly attenuated renal vasoconstriction induced by adrenergic agonists, while CEC showed a significant accentuation in RNS-induced responses without having a significant effect on responses to adrenergic agonists. In diabetic rats, renal vasoconstriction was also significantly reduced in Nit-, MEU- and BMY 7378-treated groups and CEC potentiated RNS-induced contractions caused a change similar to that observed in non-diabetic rats. BMY 7378 significantly (P < 0.05) attenuated the PE- and MTX-induced vasoconstrictions but did not cause any significant (P > 0.05) alteration in the RNS- and NA-induced responses. 4 The results showed functional co-existence of alpha(1A)- and alpha(1D)-adrenoceptors in the renal vasculature of SD rats irrespective of the presence of diabetes. A possible minor contribution of prejunctional alpha-adrenoceptor subtype has also been suggested in either experimental group, particularly possible functional involvement of alpha(1B)-adrenoceptor subtypes in non-diabetic SD rats.
Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
We report a case of renal cell carcinoma diagnosed after a patient was treated successfully with intravenous cyclophosphamide for her active proliferative lupus nephritis (classes III and V). After the intravenous cyclophosphamide regimen, the patient was asymptomatic with persistent microscopic haematuria, and no proteinuria. The renal cell carcinoma was located on the left kidney; incidentally, this was where the initial renal biopsy was done to diagnose lupus nephritis.
To measure plasma pro-apoptotic and pro-necrotic activity in severe acute kidney injury (AKI) patients within a randomized controlled trial of continuous veno-venous hemofiltration with high cut-off filters (CVVH-HCO) versus standard filters (CVVH-Std).
There is evidence that in chronic renal failure, the sympathetic nervous system is activated. This study investigated the role of the renal innervation in suppressing high- and low-pressure baroreflex control of renal sympathetic nerve activity and heart rate in cisplatin-induced renal failure.
Although hemodialysis treatment has greatly increased the life expectancy of end stage renal disease patients, low quality of life among hemodialysis patients is frequently reported. This cross-sectional study aimed to determine the relationship between medical history, hemodialysis treatment and nutritional status with the mental and physical components of quality of life in hemodialysis patients. Respondents (n=90) were recruited from Hospital Kuala Lumpur and dialysis centres of the National Kidney Foundation of Malaysia. Data obtained included socio-demography, medical history, hemodialysis treatment and nutritional status. Mental and physical quality of life were measured using the Mental Composite Summary (MCS) and Physical Composite Summary (PCS) of the Short-Form Health Survey 36-items, a generic core of the Kidney Disease Quality of Life Short Form. Two summary measures and total SF-36 was scored as 0-100, with a higher score indicating better quality of life. Approximately 26 (30%) of respondents achieved the body mass index (24 kg/m(2)) and more than 80% (n=77) achieved serum albumin level (>35.0 mg/dL) recommended for hemodialysis patients. The majority of respondents did not meet the energy (n=72, 80%) and protein (n=68,75%) recommendations. The total score of SF-36 was 54.1 ± 19.2, while the score for the mental and physical components were 45.0 ± 8.6 and 39.6 ± 8.6, respectively. Factors associated with a higher MCS score were absence of diabetes mellitus (p=0.000) and lower serum calcium (p=0.004), while higher blood flow (p=0.000), higher serum creatinine (p=0.000) and lower protein intake (p=0.006) were associated with a higher PCS score. To improve the overall quality of life of hemodialysis patients, a multidisciplinary intervention that includes medical, dietetic and psychosocial strategies that address factors associated with mental and physical quality of life are warranted to reduce further health complications and to improve quality of life.
Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY) rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA) levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione S-transferase (GST) were significantly downregulated while total antioxidant status (TAS) and activities of GST and catalase (CAT) were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.
The kidney is one of the critical target organs for chronic cadmium toxicity. Cadmium is a cumulative nephrotoxicant, and preferentially accumulates and persists in the kidneys. The natriuretic and antidiuretic effects of methyl alcohol extracts of Chelidonium majus L. (C. majus) leaves were evaluated in kidney of cadmium-intoxicated rats. Ninety-six male Sprague-Dawley Albino rats were divided into two major groups (toxicity and biochemical, 60 and 36 rats, respectively). There was a decrease in kidney weight and serum electrolytes, but an increase in urinary volume, excretion of electrolytes, serum urea and creatinine, after 9 weeks of cadmium chloride intoxication. Treatment of C. majus methyl alcohol extract for 10 weeks starting 1 week before cadmium administration shifted the above parameters towards the normal values. These results were supported by molecular and histological investigations. Treatment with C. majus methyl alcohol extract has natriuretic and antidiuretic effects against cadmium-induced nephrotoxicity in rats.
Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.
Hyperglycemia-induced increase in oxidative stress is implicated in diabetic complications. This study investigated the effect of metformin and/or glibenclamide in combination with honey on antioxidant enzymes and oxidative stress markers in the kidneys of streptozotocin (60 mg/kg; intraperitoneal)-induced diabetic rats. Diabetic rats were randomized into eight groups of five to seven rats and received distilled water (0.5 mL); honey (1.0 g/kg); metformin (100 mg/kg); metformin (100 mg/kg) and honey (1.0 g/kg); glibenclamide (0.6 mg/kg); glibenclamide (0.6 mg/kg) and honey (1.0 g/kg); metformin (100 mg/kg) and glibenclamide (0.6 mg/kg); or metformin (100 mg/kg), glibenclamide (0.6 mg/kg) and honey (1.0 g/kg) orally once daily for four weeks. Malondialdehyde (MDA) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significantly elevated while catalase (CAT) activity, total antioxidant status (TAS), reduced glutathione (GSH), and GSH:oxidized glutathione (GSSG) ratio was significantly reduced in the diabetic kidneys. CAT, glutathione reductase (GR), TAS, and GSH remained significantly reduced in the diabetic rats treated with metformin and/or glibenclamide. In contrast, metformin or glibenclamide combined with honey significantly increased CAT, GR, TAS, and GSH. These results suggest that combination of honey with metformin or glibenclamide might offer additional antioxidant effect to these drugs. This might reduce oxidative stress-mediated damage in diabetic kidneys.
Renal calculi disease or known as kidney stone disease is the most common urological disorder in both men and women, although it is more prevalent in men. The lifetime chance for an individual to develop renal calculi is approximately 10% whereas the risk of recurrence in a 10-year period is 74%. Therefore, a diagnostic tool for screening or detecting renal calculi is greatly needed. In this study, we analyze urinary protein profiles from patients with renal calculi for the first time (RC), healthy subjects (HS), and patients with recurrent renal calculi (RRC) to identify a biomarker for detecting the disease. Urinary proteins were isolated by salt precipitation and the proteins resolved by SDS-PAGE. Target proteins were analyzed with LC/MS/MS. Thirty-two proteins were identified from healthy subjects and patients. Uromodulin was the most abundant urinary protein in HS but was a very faint band if detected at all from those that formed renal calculi for the first time (p < 0.05). Yet the excreted levels of urinary uromodulin in RRC were similar to those of the HS suggesting that uromodulin is a reliable biomarker for only RC. In addition, a few immunoglobulins that were commonly found in the urine of both RC and RRC, which include Ig alpha heavy chain 1, Ig gamma-2 c region, Ig gamma-3 heavy chain disease protein, Ig heavy chain variable region, Ig heavy constant region gamma 4, and Ig heavy chain. Ig heavy chain Fab frag and antibody a5b7 chain B may serve as potential biomarkers for renal calculi disease.
The aims of this retrospective analysis were (i) to examine the trends of quality of life (QoL) scores and (ii) to identify the risk factors for QoL scores among 6908 dialysis patients entering dialysis between 1997 and 2002. The Spitzer QoL Index was the instrument used by the National Renal Registry of Malaysia to assess the QoL amongst dialysis patients. Demographic and biochemical data were analysed to identify risk factors for poor QoL. The median QoL-index score ranged between 9 and 10. Significant risk factors for poor QoL were female gender, age > 40, diabetes, cohort starting dialysis 2001-2002, haemodialysis modality, body mass index < 18.5, albumin < 30g/dL, cholesterol < 3.2 mmol/L, haemoglobin < 10 g/dL, diastolic blood pressure of > 90 mHg, iPTH < 100 pg/ml. The overall QoL of dialysis patients is satisfactory. The negative impact of diabetes and haemodialysis on QoL warrants further evaluation as each factor involves 50% and 90% of our dialysis population.
A 20-year-old, previously healthy woman, presented with high fever, headache and myalgia 3 days after her return from a holiday in Southeast Asia. Laboratory data on admission demonstrated a pronounced increase in plasma creatinine, marked thrombocytopenia and moderately elevated liver aminotransferases. After having ruled out malaria, dengue fever was primarily suspected and supportive intravenous fluid therapy was initiated. Still, 1 day after admission, platelet counts dropped even further and she became anuric although she did not appear hypovolemic. On day 2 after admission, urine production commenced spontaneously and the patient slowly recovered. All laboratory test results had returned to normal approximately 2 months later. Serological analysis for dengue fever was negative. It turned out that the patient had been trekking in the jungle while in Thailand and we, therefore, analyzed serology for Leptospira spirochetes which was clearly positive. The patient was diagnosed with leptospirosis which is a serious condition associated with a high mortality when complicated by acute renal failure. Differential diagnoses in patients with acute renal failure and tropical infections are reviewed. The importance of early recognition of leptospirosis, and prompt treatment with antibiotics in suspected cases, is emphasized.
The effects of indomethacin and nabumetone on urine and electrolyte excretion in conscious rats were examined. Male Sprague-Dawley rats were housed individually for a five-week duration, consisting of acclimatization, control, experimental, and recovery phases. During the experimental phase, rats were given either indomethacin (1.5 mg . kg(-1) body weight . day(-1) in 0.5 ml saline, n = 10), nabumetone (15 mg . kg(-1) body weight . day(-1) 0.5 ml saline, n = 10), or 0.5 ml saline alone (n = 10) for a period of two weeks. Water and food intake, body weight, urine output, and electrolyte excretions were estimated. Data were analyzed using two-way ANOVA. Urine output in the indomethacin- and nabumetone-treated groups was not different from the controls, but was significantly different between the drug-treated groups (P<0.01). Sodium, potassium, calcium, and magnesium excretions were not different between nabumetone-treated and control rats. However, sodium and potassium excretion was significantly lower in rats receiving indomethacin when compared to the control rats. Calcium and magnesium outputs, although did not differ from the controls, nevertheless decreased significantly with indomethacin (P<0.01). It appears that indomethacin and nabumetone when given at maximum human therapeutic doses may affect urine and electrolyte output in conscious rats.
An analysis of 1000 consecutive, adequate renal biopsies from patients of the University Hospital Kuala Lumpur between 1982 and 1991 revealed: minimal change nephritis (20.7%), focal glomerulosclerosis (2.9%), proliferative glomerulonephritides (16.0%), membranous glomerulonephritis (5.5%), IgA nephropathy (18.5%), lupus nephritis (24.9%), end stage nephropathy (3.1%) and others (8.4%). Compared with the previous decade, IgA nephropathy has emerged as a common entity. Lupus nephritis forms the largest diagnostic entity and is probably related to the selected referral of SLE patients to this hospital.
A patient with severe hyponatreamia secondary to chronic renal failure was treated with peritoneal dialysis (PD). On the third day of admission, she developed progressive obtundation. Neurological examination showed bilateral brisk reflexes with intact brain stem reflexes. Magnetic resonance imaging demonstrated patchy demyelination of the pontine area indicating central pontine myelinolysis (CPM). Despite supportive measures, the patient died on the fifteenth day of admission. The rate of correction of hyponatraemia with peritoneal dialysis can be rapid and detrimental to hyponatraemic chronic renal failure patients and careful monitoring of serum sodium level is advocated.
Two forms of abnormal fibrillary protein deposition are considered: amyloidosis and fibrillary (immunotactoid) glomerulonephritis. Amyloid is characterised by an antiparallel, beta-pleated configuration which imparts to it a unique apple-green birefringence after Congo red staining. Inspite of its fairly constant physical properties, the chemical composition of amyloid fibrils is amazingly diverse, encomposing AA protein, light chain fragments, transthyretin, procalcitonin, islet amyloid polypeptide, atrial natriuretic peptides, beta-amyloid protein, beta-2-microglobulin, cystatin C, gelsolin, apolipoprotein A1, lyzozyme and their mutant variants. Amyloid P component and heparan sulphate proteoglycan are ubiquitous non-fibrillary amyloid components which have significant roles in the amyloidogenetic process, as do also precursor fibril proteins. Different amyloid fibril proteins relate to different amyloidosis syndromes and different histological patterns, and provide the basis for new diagnostic approaches to this disorder. Glomerular deposits in fibrillary glomerulonephritis (FGN), although often mistaken for amyloid, differ from it in its negative Congophilia, wider fibril width and highly organised, microtubular-tactoidal appearance ultrastructurally. FGN is essentially a primary glomerulopathy resulting in progressive renal failure. Despite certain differences, intriguing similarities between both entities of fibrillary deposition pose a challenge to researchers as to the mechanisms of abnormal protein crystallization and fibril formation in tissues.