Claire C. Sharpe

Prevalence and Factors Associated with Hyperkalemia in Predialysis Patients Followed in a Low-Clearance Clinic

BACKGROUND AND OBJECTIVES Recent studies evaluated the prevalence of hyperkalemia and related risk factors in patients with CKD of various stages, but there is limited relevant information in predialysis patients. This study aimed to examine the prevalence and factors associated with hyperkalemia in the structured environment of a low-clearance clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cross-sectional fashion over a prespecified period of 4 months, information on serum potassium and relevant laboratory variables, comorbidities, medications, and dietician input in patients with advanced CKD under follow-up in the low-clearance clinic of our department was recorded. Univariate and multiple logistic regression analyses were used to identify factors associated with serum potassium ≥ 5.5 meq/L. RESULTS The study population consisted of 238 patients aged 66.2 ± 4.2 years with estimated GFR of 14.5 ± 4.8 ml/min per 1.73 m(2). The prevalence of hyperkalemia. defined as potassium > 5.0, ≥ 5.5, and ≥ 6.0 meq/L., was at 54.2%, 31.5%, and 8.4%, respectively. In univariate comparisons, patients with potassium ≥ 5.5 meq/L had significantly higher urea and lower estimated GFR and serum bicarbonate; also, they were more often using sodium bicarbonate and had received potassium education and attempts for dietary potassium lowering. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was not associated with hyperkalemia. In multivariate analyses, estimated GFR<15 ml/min per 1.73 m(2) and sodium bicarbonate use were independently associated with hyperkalemia. CONCLUSIONS The prevalence of hyperkalemia in predialysis patients with CKD is high. Even at this range of renal function, low estimated GFR seems to be the most important factor associated with hyperkalemia among the wide range of demographic, clinical, and laboratory characteristics studied.

Association between hemolysis and albuminuria in adults with sickle cell anemia

Studies have questioned whether renal dysfunction in sickle cell disease is linked to hemolysis-associated vasculopathy. We have investigated renal function and markers of hemolysis in a cohort of 424 adult African-British patients with sickle cell disease. While significant associations were found in HbSS and HbSβ0 (sickle cell anemia) patients with and without controlling for covariates between hemolytic markers and albuminuria, the associations were not significant in patients with HbSC. Estimated glomerular filtration rate, a marker of renal function, correlated significantly with reticulocyte count and bilirubin. Alpha thalassemia, present in 34% of the sickle cell anaemia patients, had a protective effect against albuminuria in this group. Altogether, the incidence of hyperfiltration was 71% and microalbuminuria 37%, making nephropathy a common complication of sickle cell anemia.

Signaling: Focus on Rho in Renal Disease

Control of glomerular blood flow is complex, crucial in renal pathophysiology, and an attractive target for therapeutic intervention. In this issue of JASN , Cavarape et al. ([1][1]) observe that inhibition of Rho-kinase leads to a decrease in basal tone of the glomerular afferent and efferent

Sickle cell nephropathy – a practical approach

Despite its apparently simple molecular aetiology, sickle cell disease (SCD) has long been known to have a remarkably variable clinical course, with complications involving many organs including the kidneys. Whilst many affected individuals show no evidence of renal involvement into late adulthood, others develop renal dysfunction in childhood or early adult life with a significant proportion eventually requiring renal replacement therapy. This review explores the pathophysiology and clinical manifestations of sickle cell nephropathy (SCN) and discusses how each complication can be investigated, monitored and managed in the outpatient setting. We summarize current knowledge of genetic modulation of sickle‐related renal dysfunction. We outline the evidence for various treatment options and discuss others for which little evidence currently exists.

Rho isoforms have distinct and specific functions in the process of epithelial to mesenchymal transition in renal proximal tubular cells

Epithelial to mesenchymal transition (EMT) is involved in embryological development, cancerous metastatic spread and organ fibrosis, including the kidney. This process is largely driven by transforming growth factor-beta and recent evidence has implicated Rho as a key intracellular signalling molecule. In this study we have used RNA interference to silence the genetically distinct Rho (A, B and C) isoforms to define their individual functions in human kidney epithelial cells undergoing EMT. We demonstrate that the downregulation of the epithelial cell marker E-cadherin is dependent upon the Rho effector, Rho-kinase. However, silencing RhoA or RhoC expression also results in E-cadherin loss, though each by different mechanisms. Loss of RhoA leads to an upregulation of Snail1 and a reduction in the transcription of E-cadherin whereas loss of RhoC upregulates its breakdown via proteasomal degradation. During EMT, the upregulation of alpha-smooth muscle actin can be blocked by inhibiting the expression of RhoA, but not by that of RhoB or RhoC. This effect is independent of Rho-kinase activity. RhoC is the isoform solely responsible for stress fibre formation and inhibiting its expression reduces EMT-induced migration by 50%. RhoB appears to play a role in cell survival as inhibiting its expression leads to >300% increase in cell apoptosis and a relocalization of focal adhesion kinase. We conclude that Rho is a key signalling molecule in the process of EMT but that each isoform has a distinct and specific role.

Expression of voltage-gated K+ channels in human atrium.

Abstract. Voltage-gated K+ channels underlie repolarisation of the cardiac action potential and represent a potential therapeutic target in the treatment of cardiac dysrhythmias. However, very little is known about the relative expression of K+ channel subunits in the human myocardium. We used a semi-quantitative RT-PCR technique to examine the relative expression of mRNAs for the voltage-gated K+ channel subunits, Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, Kv4.3, KvLQT1, HERG and IsK in samples of human atrial appendage. Data were expressed as a percentage expression density relative to an 18S ribosomal RNA internal standard. The most abundant K+ channel mRNAs were Kv4.3 (80.7 ± 10.1 %), Kv1.5 (69.7 ± 11.2 %) and HERG (55.9 ± 21.5 %). Significant expression of KvLQT1 (33.5 ± 5.5 %,) and Kv1.4 (26.7 ± 9.6 %) was also detected. Levels of mRNAs for Kv1.2 and IsK were very low and neither Kv2.1 nor Kv4.2 mRNA were detected in any experiments. Whole-cell patch-clamp techniques were used to examine the outward currents of isolated human atrial myocytes at 37 °C. These recordings demonstrated the existence of transient (Ito1) and sustained (Iso) outward currents in isolated human atrial myocytes. Ito1, and not Iso, showed voltage-dependent inactivation during 100 ms pre-pulses. Both Ito1 and Iso were inhibited by high concentrations (2 mM) of the K+ channel blocker, 4-aminopyridine (4-AP). However, lower concentrations of 4-AP (10 μM) inhibited Iso selectively. Ito1 recovered from inactivation relatively rapidly (t ∼21 ms). These data, with published information regarding the properties of expressed K+ channels, suggest that Kv4.3 represents the predominant K+ channel subunit underlying Ito1 with little contribution of Kv1.4. The sensitivity of Iso to very low concentrations of 4-aminopyridine and the relatively low expression of mRNA for Kv1.2 and Kv2.1 is consistent with the major contribution of Kv1.5 to this current. The physiological significance of the expression of KvLQT1 and Kv1.4 mRNA in the human atrium warrants further investigation.

How I treat renal complications in sickle cell disease.

Renal disease is one of the most frequent and severe complications experienced by patients with sickle cell disease; its prevalence is likely to increase as the patient population ages. We recommend regular monitoring for early signs of renal involvement and a low threshold for the use of hydroxyurea as preventative measures for end-stage renal disease. Once renal complications are detected, a careful assessment of the patient is required to rule out other causes of renal disease. Proteinuria and hypertension should be managed aggressively and the patient referred to a specialist nephrology center when progressive decline in renal function is noted. For the few patients who develop advanced chronic kidney disease, timely planning for dialysis and transplantation can significantly improve outcome, and we recommend an exchange blood transfusion policy for all patients on the transplant waiting list and for those with a functioning graft. Alongside the invasive treatment regimes, it is important to remember that renal failure in conjunction with sickle cell disease does carry a significant burden of morbidity and that focusing on symptom control has to be central to good patient care.

Prevalence, Patterns of Treatment, and Control of Hypertension in Predialysis Patients with Chronic Kidney Disease

Background/Aims: Data on the prevalence, treatment and control of hypertension in patients with advanced chronic kidney disease (CKD) are limited. This study aimed to examine the above factors in a cohort of predialysis patients. Methods: During a period of 4 months, we recorded information on blood pressure (BP), comorbidities, medications and related parameters of patients followed up in the Low-Clearance Clinic of our Department. Control rates of hypertension were calculated at two thresholds: <130/80 and <140/90 mm Hg. Univariate and multiple linear regression analyses were employed to assess factors associated with BP control. Results: In the population studied [n = 238, males 58.4%, age 66.21 ± 4.2 years (mean ± SD), estimated glomerular filtration rate 14.5 ± 4.8 ml/min/1.73 m2], the prevalence of hypertension was 95.0%. Treatment rate among hypertensives was at 99.1%. On average, 3.04 ± 1.32 antihypertensive drugs were used, ranging from 1 to 7 agents. BP control rates at the <130/80 and <140/90 mm Hg thresholds were 26.5% and 48.2%, respectively. The systolic goal was achieved in 31.0% and 50.4%, whereas the diastolic goal was achieved in 67.7% and 91.2% of patients, respectively. In multivariate analysis, only black race was independently and inversely related with hypertension control (β = –0.187, p = 0.030). No specific antihypertensive class showed independent associations with control. Conclusions: Hypertension is highly prevalent in predialysis CKD patients. An almost universal treatment, employing a multi-agent regime, can help towards improved rates of control. Systolic BP is the main barrier to successful control and black race is associated with poorer control rates.

Antisense knockdown of Kras inhibits fibrosis in a rat model of unilateral ureteric obstruction.

Tubulointerstitial fibrosis is the hallmark of chronic kidney disease and is characterized by an increase in the number and activity of interstitial fibroblasts and by excessive matrix deposition. Ras is an intracellular signaling molecule involved in cell proliferation and differentiation. It has recently been implicated in the pathogenesis of renal fibrosis. Of the three different isoforms of Ras (Kirsten, Harvey, and Neural), we previously demonstrated that the Kirsten isoform is key in the control of renal fibroblast proliferation in vitro. In this study, we used gene therapy in the form of antisense oligonucleotides (ASOs) specifically to silence Kras (alias Ki-ras) expression in a rat model of renal fibrosis caused by unilateral ureteric obstruction. We demonstrate that renal Kras expression increases by 70% in this model compared with sham-operated animals and that treatment with ASOs can reduce total renal Kras by >90% to levels well below basal. This silencing is associated with a dramatic inhibition of interstitial fibrosis, a fivefold reduction in α-smooth muscle actin expression, and a 2.4-fold reduction in collagen I deposition. This inhibition was observed despite histologic evidence of marked interstitial inflammation. These findings demonstrate that silencing Kras expression can markedly inhibit renal fibrosis. This strategy should be considered as a new potential therapeutic avenue.

Prenylation is not necessary for endogenous Ras activation in non-malignant cells.

Ras monomeric GTPases are pivotal to many core cellular processes such as proliferation and differentiation. The post‐translational prenylation of Ras with a farnesyl or a geranylgeranyl moiety is thought to be critical for its membrane binding and consequent signaling activity. Inhibitors of Ras prenylation have an anti‐proliferative effect in some Ras‐transformed cells. We present a study of the effects of prenylation inhibitors on endogenous, wild‐type Ras in three renal cell types, namely primary adult human renal fibroblasts, primary adult human mesangial cells, and a primate renal fibroblast cell line (Vero cells). We have previously demonstrated that Ras is necessary for normal proliferation in these cells. Here we show that Ras is farnesylated and not geranylgeranylated in all three cell types. Furthermore, inhibiting Ras farnesylation has no effect on cell proliferation or Ras activation. Although inhibiting geranylgeranylation in these cells does inhibit proliferation, this is through an Ras‐independent mechanism. Non‐prenylated Ras is able to localize to the plasma membrane, bind Raf when cells are stimulated by epidermal growth factor or platelet‐derived growth factor, and activate the Ras downstream effectors mitogen‐activated protein kinase and phosphotidylinositol 3‐kinase. We conclude that in wild‐type cells, endogenous Ras does not need to be prenylated to be active. J. Cell. Biochem.