Clinical Outcomes of Dialysis Catheter–Related Candidemia in Hemodialysis Patients

Background and objectives: Candidemia is a rare complication in catheter-dependent hemodialysis patients. As a result, there is uncertainty about its optimal medical management. The goal of this retrospective study was to compare the clinical outcomes of catheter-related candidemia managed with two different strategies: Guidewire exchange of the infected catheter versus removal with delayed replacement.Design, setting, participants, & measurements: We retrospectively queried a prospective, computerized vascular access database to identify 40 hemodialysis patients with catheter-related candidemia. All patients underwent treatment with antifungal medications for 2 wk, in conjunction with guidewire catheter exchange or catheter removal with delayed replacement. The primary outcomes were major complications, recurrent candidemia, and patient survival.Results: Candidemia represented approximately 2% of all cases of catheter-related bloodstream infections. Of the 40 patients with candidemia, 27 underwent guidewire catheter exchange and 13 had prompt catheter removal with delayed replacement. The two treatment groups were similar in demographic, clinical, and catheter characteristics. Only 1 (2.5%) patient developed a serious complication (endophthalmitis). Recurrence of candidemia within 3 mo was observed in 15% of each treatment group. Patient survival at 6 mo was similar in both groups.Conclusions: Catheter-related candidemia is rare in hemodialysis patients and has a low complication rate. Catheter exchange over a guidewire in conjunction with antifungal therapy is an effective and safe treatment regimen.Candidemia is a widely recognized nosocomial infection in non-neutropenic hospitalized patients with intravascular catheters (1,2). It can be complicated by osteomyelitis, septic arthritis, endocarditis, central nervous system candidiasis, and endophthalmitis (3). Systemic antifungal agents do not eradicate the Candida catheter biofilm (4), suggesting that the central vein catheter should be removed in patients with catheter-related candidemia. Several large, prospective studies observed a shorter duration of candidemia, better clinical outcomes, and lower mortality when the central vein catheter was removed or replaced (1,2,5–7). These observations form the basis of the current guidelines, which recommend removing the intravascular catheter to eradicate the source of candidemia (3).Candidemia is a relatively uncommon complication of hemodialysis catheters; therefore, there are no large series describing its frequency, complications, or optimal medical management. Dialysis catheter–related candidemia is typically treated with an antifungal drug in conjunction with catheter removal and delayed placement of a new, tunneled dialysis catheter. This strategy creates hardship in managing the patient''s dialysis, because it requires placement of a temporary dialysis catheter. In patients with dialysis catheter–related bacteremia, exchange of the infected tunneled catheter for a new one over a guidewire can achieve a high cure rate while simplifying access management (8–12). It is unknown whether this strategy is effective and safe for management of dialysis catheter–related candidemia.The goal of this study was to evaluate the frequency and medical complications of dialysis catheter–related candidemia. In addition, we evaluated whether guidewire exchange of the infected tunneled catheter is a viable alternative to catheter removal with delayed replacement.     

Cilostazol Improves Long-Term Patency after Percutaneous Transluminal Angioplasty in Hemodialysis Patients with Peripheral Artery Disease

Background and objectives: Peripheral artery disease (PAD) is common in patients on hemodialysis (HD). Recently, cilostazol has been reported to reduce target lesion revascularization (TLR) after percutaneous transluminal angioplasty (PTA) for PAD in the general population. This study aimed to clarify the effects of cilostazol administration on long-term patency after PTA in HD patients.Design, setting, participants, & measurements: Three-hundred seventy-two consecutive lesions in 193 HD patients successfully undergoing PTA were enrolled in the study and divided into two groups: patients receiving 100 mg cilostazol twice daily in conjunction with standard therapy (130 lesions in 71 patients) and those not administered cilostazol (242 lesions in 122 patients). Effects of cilostazol on preventing restenosis after PTA in these patients were investigated.Results: Kaplan-Meier analysis demonstrated the 5-yr patency rate was significantly higher in the cilostazol group than in the control group [52.4 versus 32.9%, hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.39 to 0.77, P = 0.0005]. Cox multivariate analysis revealed that administration of cilostazol was an independent predictor of preventing restenosis (HR 0.56, 95% CI 0.36 to 0.87, P = 0.010). In 102 lesions matched after propensity score analysis, cilostazol had a beneficial effect on preventing restenosis (58.4 versus 34.7%, HR 0.47, 95% CI 0.30 to 0.75, P = 0.0017) and was an independent predictor of preventing restenosis (HR 0.50; 95% CI 0.26 to 0.87, P = 0.014) after multivariate Cox analysis.Conclusions: Cilostazol administration improves long-term patency after PTA in HD patients with PAD.Accelerated atherosclerosis is a major risk for long-term survivors receiving maintenance HD (1,2). Furthermore, cardiovascular disease is a leading cause of morbidity and mortality in patients with renal disease receiving HD (1–5). It has been reported that PAD is commonly seen in patients on HD (6). In this day and age, PTA has become a common therapeutic standard for PAD in non-HD patients (7,8), and PTA is reported to be effective in patients on HD (9). However, vascular calcification and diffuse lesions may make the PTA procedure difficult to perform (10).On the other hand, it has been reported that cilostazol, which has antiplatelet action and vasodilatory effects, significantly reduces the risk of restenosis after percutaneous coronary intervention (PCI) in many patients (11–15). Furthermore, chronic cilostazol treatment prevents TLR after PTA of the femoropopliteal artery in the general population (16). However, it is unclear whether this extends to high-risk individuals, such as those receiving HD. In the study presented here, we compared clinical events after PTA in a series of patients on chronic maintenance HD with and without an additional treatment of cilostazol.     

Hepatitis C Is Less Aggressive in Hemodialysis Patients than in Nonuremic Patients

Background and objectives: The severity of liver disease among hepatitis C patients on hemodialysis is controversial. The aim of this study was to compare the clinical, biochemical, and liver histologic characteristics of hepatitis C virus (HCV) in hemodialysis patients and in those with normal renal function.Design, setting, participants, & measurements: A case-control study was carried out with 36 HCV patients on hemodialysis and 37 HCV patients with normal renal function matched for gender, age at infection, and estimated time of infection.Results: HCV patients on hemodialysis had lower levels of alanina aminotransferase and lower viral load. Hepatic fibrosis was significantly higher in the patients with normal renal function (73%) than in hemodialysis patients (47.2%, P < 0.025); the same was observed for inflammatory activity (control group 59.5% versus hemodialysis patients 27.7%, P = 0.003). In addition, the risk of tissue inflammation was four times lower in hemodialysis patients (odds ratio = 0.23, P < 0.004), and severe inflammatory activity on biopsy was the only independent risk factor for fibrosis (P < 0.001).Conclusions: The lower biochemical and inflammatory activities observed in hemodialysis patients suggest that hemodialysis and uremia may have a protective role against progression of the disease caused by HCV.Hepatitis C is the main cause of chronic liver disease in patients with end-stage renal disease (ESRD). The prevalence of hepatitis C virus antibody (anti-HCV) is high, between 3.4% and 32.1%, among hemodialysis (HD) patients and potential kidney transplant candidates (1). Despite the decrease in the incidence of newly acquired HCV infections observed in recent years, which may be attributable to the efficient serologic HCV tests used in blood transfusions and to the use of erythropoietin to treat anemia, contamination by HCV still occurs in HD units (2).Patients infected with HCV who undergo renal transplantation show a higher risk for progression to severe liver disease, death, and graft failure after transplantation compared with anti-HCV negative recipients (3). Liver disease should consequently be staged at the time of kidney transplantation because patients with cirrhosis or advanced fibrosis will have a poorer prognosis (4).The natural history of chronic liver disease caused by HCV in HD patients remains unknown (4–6). HCV infection increases mortality rates in uremic patients, and cirrhosis and other liver-related deaths are more frequent in HCV-infected dialysis patients than in those without the virus (5–7).Results from liver biopsies of HCV-infected dialysis patients are limited (1,2), and the rate of bridging hepatic fibrosis and liver cirrhosis ranges from 5% to 32% (8–15). Whether the liver disease caused by HCV shows a different clinical course in HD patients and in patients with normal renal function is still controversial. Barril (8) reported that progression time to cirrhosis can be much shorter in HCV-infected HD patients than in patients with normal renal function. However, other studies suggest that HCV-infected HD patients present a lower degree of inflammatory activity and a lower stage of liver fibrosis compared with HCV-infected patients with normal renal function (9,12,15). Indeed, the effects of chronic uremia and HD on HCV-related liver disease and on the progression of liver fibrosis in HCV-infected patients with ESRD remain unknown.To investigate the impact of chronic renal failure and HD on the progression of hepatitis C in patients awaiting kidney transplantation, we compared clinical, biochemical, virologic, and histologic findings in HCV-infected patients with ESRD receiving HD treatment and in HCV-infected patients with normal renal function. Our results showed that HCV-infected patients on HD presented lower levels of alanine aminotransferase (ALT), lower viral load, and less inflammatory activity and fibrosis in their liver biopsies. Moreover, severe inflammatory activity was the only independent risk factor for liver fibrosis. Taken together, our results strongly suggest that chronic hepatitis C is less aggressive in HD patients than in nonuremic patients.     

Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Mutations that lead to Huntington’s disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M₄ subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M₄ positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M₄ PAMs could provide a therapeutic strategy for the treatment of HD.Huntington’s disease (HD) is a rare and fatal neurodegenerative disease caused by an expansion of a CAG triplet repeat in Htt, the gene that encodes for the protein huntingtin (1, 2). HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3–7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6–16).Striatal spiny projection neurons (SPNs) receive large glutamatergic inputs from the cortex and thalamus, as well as dopaminergic innervation from the substantia nigra. In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17, 18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12–14) and could contribute to synaptic changes observed in later stages of HD (19, 20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.Muscarinic acetylcholine receptors (mAChRs), particularly M₄, can inhibit transmission at corticostriatal synapses (21–25). Therefore, it is possible that selective activation of specific mAChR subtypes could normalize excessive corticostriatal transmission in HD. Interestingly, previous studies also suggest that HD is associated with alterations of striatal cholinergic markers, including mAChRs (26–29). We now provide exciting new evidence that M₄-mediated control of corticostriatal transmission is increased in young asymptomatic HD mice and that M₄ positive allosteric modulators (PAMs) may represent a new treatment strategy for normalizing early changes in corticostriatal transmission and reducing the progression of HD.     

Circulating Bacterial-Derived DNA Fragments and Markers of Inflammation in Chronic Hemodialysis Patients

Background and objectives: Bacterial-derived DNA fragments (BDNAs) have been shown to be present in dialysis fluid, to pass through dialyzer membranes, and to induce IL-6 (IL-6) in mononuclear cells. The present study aimed at assessing the eventual presence of BDNAs in the blood of hemodialysis (HD) patients and if this is associated with markers of chronic inflammation.Design, setting, participants, & measurements: Fifty-eight HD patients and 30 controls were included in the study. A blood sample was collected from a peripheral vein and from the central venous catheter (CVC) or the arteriovenous fistula (AVF) and examined for presence of BDNAs by 16S rRNA gene PCR amplification, bacterial growth, and measurement of C-reactive protein and IL-6. Thirty minutes after the start of HD, a sample of dialysis fluid was collected before the entry into and at the exit of the dialyzer and examined for presence of BDNAs.Results: Controls had negative blood cultures and absence of blood BDNAs. All HD patients had negative blood cultures, but in 12 (20.7%), BDNAs were present in the whole blood. In five of the latter, BDNAs were also found in the dialysis fluid. C-reactive protein serum levels (mg/L) were significantly higher in patients with than in those without BDNAs. Likewise, IL-6 serum levels (pg/ml) were significantly higher in patients with BDNA than in those without.Conclusions: Circulating BDNAs are associated with higher levels of C-reactive protein and IL-6 in HD patients.Chronic inflammation is highly prevalent in end-stage renal disease patients receiving maintenance hemodialysis, with approximately 30% to 50% of them exhibiting evidence of an inflammatory response (1–2).Inflammation in dialysis patients may be related to processes associated with renal failure itself such as oxidative stress, may be dialysis related, or may be attributable to infectious causes (1–4). Among the dialysis-related causes of chronic inflammation, exposure of blood to bioincompatible dialysis membranes seems to play an important role. Bioincompatible membranes, such as cellulosic membranes, activate white blood cells and complement (1–2). Other investigators have suggested that even dialysis with biocompatible membranes may pose risks for activation of the acute-phase response (1–2).The quality of water used to prepare the dialysis fluid may also contribute to inflammation (3–4). Mounting evidence suggests that the use of less-than-sterile dialysis fluid or back-leakage of lipopolysaccharide through the dialysis membranes can cause dialysis-related inflammation (3–4). Several groups recently prepared ultrapure, endotoxin-free water by membrane filtration of the dialysis fluid and observed reduced levels of cytokines (3–4), which suggests either that monocytes may be activated by endotoxin that remains on the dialysis fluid side of the membrane or that endotoxin can directly cross the dialysis membrane.Recently, Schindler et al. (5) demonstrated that short bacterial-derived DNA fragments are present in clinically used fluids such as dialysis fluid, and that these fragments are of sufficiently small size to pass through dialyzer membranes. DNA fragments are thought to be derived from microorganisms inhabiting hemodialysis water and fluid (6). Most of these microorganisms that include potential pathogens might subsist in a “viable but not culturable” state or may need specific culture media (7). In addition, it has been shown that short bacterial-derived DNA fragments are able to induce IL-6 in human mononuclear cells (5) and that in vitro they promote the survival of inflammatory cells from patients with chronic kidney diseases, suggesting that this action may contribute to perpetuate inflammation in these patients (8). On these bases, it has been suggested that bacterial DNA fragments may be an overlooked factor contributing to inflammation in hemodialysis patients (5,8). However, there is no evidence in patients receiving chronic hemodialysis that circulating bacterial-derived DNA fragments, when present, are associated with enhanced inflammatory response (9). This is an important issue, because elucidating the association between bacterial-derived DNA fragments and markers of inflammation may facilitate the development of effective treatment strategies for chronic inflammation in such patients. The primary end-point of the present study was to assess whether bacterial-derived DNA fragments are present in the blood of end-stage renal disease patients on maintenance hemodialysis and to determine whether this eventual presence is associated with markers of chronic inflammation.     

D-Dimer Level and the Risk for Thrombosis in Systemic Lupus Erythematosus

Background and objectives: Patients who have systemic lupus erythematosus (SLE) and manifest antiphospholipid antibodies (APA) are at increased risk for thrombosis; however, it is difficult to predict who will clot. This study tested the hypothesis that peak D-dimer level measured routinely during follow-up identifies whether a hypercoagulable state is developing and, therefore, the patient is at increased risk for thrombosis.Design, setting, participants, & measurements: One hundred consecutive patients who had SLE with recurrent activity (71% renal SLE) and were evaluated for or enrolled in the Ohio SLE Study were studied. D-dimer testing was done annually and usually at SLE flare or other serious illness. When D-dimer was elevated, evaluation for thrombosis (large vessel, small vessel, or Libman-Sacks) was undertaken. Mean follow-up was 37.5 ± 15 SD months.Results: Of those with peak D-dimer <0.5 μg/ml (n = 46), 0% thrombosed, 33% had APA. Of those with peak D-dimer 0.5 to 2.0 μg/ml (n = 19), 6% thrombosed, 44% had APA. Of those with peak D-dimer >2.0 μg/ml (n = 36), 42% thrombosed, 76% had APA. The most common causes of elevated D-dimer in the absence of demonstrable thrombosis were SLE flare and systemic infection. D-dimer levels were usually elevated for several months before thrombosis.Conclusions: Patients with SLE and normal D-dimer levels are at low risk for thrombosis, irrespective of APA status. Those with persistent unexplained elevated D-dimer levels, particularly when >2.0 μg/ml, are at high risk for thrombosis.Thrombosis is an important manifestation of human systemic lupus erythematosus (SLE). Virtually any organ can be involved. The thrombosis can occur in large or small vessels (1–3) or can involve the cardiac valves (Libman-Sacks) (4,5). When large-vessel thrombosis occurs, usually it involves the deep veins (DVT) of the lower extremities (2). Large-vessel thrombosis can also involve arteries as a consequence of thromboembolism (e.g., from thrombi on the mitral or aortic valve in those with Libman-Sacks, “paradoxical embolism” through an atrial-septal defect) (6). Arterial thrombosis can also occur in situ, apparently as successive layers of clot accumulate until the lumen is stenosed or completely occluded (7).When small-vessel thrombosis occurs and the predominant site is arteriolar, the usual manifestation is a thrombotic microangiopathic hemolytic anemia (1,8). The lung can also be involved in small-vessel thrombosis. This process is independent of DVT and pulmonary embolism (9,10). At autopsy, these cases show noninflammatory fibrin microthrombi in pulmonary vessels (10–16). This thrombotic process in its mildest form may represent the unexplained reversible hypoxia of SLE flare (10,17). In its more severe and chronic form, it may manifest as restrictive lung disease that can progress to severe pulmonary hypertension (8–11,15). The small-vessel thrombotic lung disease of SLE may be analogous to that seen in primary pulmonary hypertension (18). Small-vessel thrombosis in SLE can also affect the kidney with a characteristic arteriopathy that shows, side by side, acute thromboses and chronic vascular lesions. The latter include arterial fibrous intimal hyperplasia, arteriosclerosis, and organized thromboses with or without recanalization (19).The most common risk factors for thrombosis in SLE are antiphospholipid antibodies (APA), including anticardiolipin antibodies (ACL; IgG or IgM) or the lupus anticoagulant (LAC) (2). Collectively, these are referred to as APA. The clotting disorder associated with APA is referred to as the antiphospholipid syndrome (2). ACL is present in approximately 39% and LAC in approximately 22% of patients with SLE. These estimates are the median of the reported values described in a systematic review of the literature (2). ACL in high titer (>5 SD above the mean; e.g., IgG ACL >40 GPL units) (20–22) increases the risk for clotting by approximately two-fold; LAC increases clotting risk approximately six-fold (23). The absolute risk for clotting in untreated patients who have SLE with ACL, LAC, or both has not been well established (24); however, in patients who had SLE with APA and previously thrombosed but were not currently receiving anticoagulation therapy, the risk for recurrent thrombosis was 19 to 29 per 100 patient-years (24).When thrombosis occurs in patients with SLE and APA, long-term warfarin therapy, perhaps for a lifetime, is generally recommended (2,23,25–27). Less clear is how to treat patients who have SLE and APA but have not yet thrombosed (20,24). This study tested the hypothesis that periodic measurement of D-dimers can identify whether the patient with SLE is becoming hypercoagulable and, therefore, is at increased risk for thrombosis regardless of their ACL/LAC status.D-dimer is a cross-linked peptide derived from fibrin thrombus (28). In vivo, fibrin clot normally undergoes fibrinolysis by plasmin, which releases D-dimer as a specific fibrin-splitting product. Thus, D-dimers are elevated in patients who have formed clots. Elevated D-dimer can also be present in those who are forming and degrading fibrin at an abnormally high rate but who do not have evidence of a clinically significant clot. In such patients, elevated D-dimers have been used to predict the risk for recurrent DVT (29–31), pulmonary embolus (32), myocardial infarction (33), progression of primary pulmonary hypertension (18), or death in patients with peripheral arterial disease (34). Normal D-dimer levels have also been used to exclude clinically significant clot burden to exclude DVT or pulmonary embolism (35–37). The association of D-dimer level and risk for clotting has not been reported in patients with SLE. This work addresses that unmet need.     

Encapsulating Peritoneal Sclerosis in the New Millennium: A National Cohort Study

Background and objectives: The study aim was to establish the incidence and characterize all encapsulating peritoneal sclerosis (EPS) cases in patients treated by peritoneal dialysis (PD).Design, setting, participants, & measurements: The patient cohort, which started PD from January 1, 2000, to December 31, 2007, was identified from the Scottish Renal Registry (n = 1238). Possible EPS cases were identified by the ten adult Scottish renal units. Patient records were examined to ensure cases met diagnostic criteria.Results: Forty-six cases were identified; 19 had their first PD exposure after January 1, 2000. The rate was 1.5%, an incidence of 4.9 per 1000 person-years. The incidence increased with PD duration, with rates of 0, 0.6, 2.0, 3.5, 8.1, 8.8 and 5% at <1, 1 to 2, >2 to 3, >3 to 4, >4 to 5, >5 to 6 and >6 yr PD exposure, respectively. The median PD duration of EPS cases was 5.1 yr (interquartile range [IQR] 3.4 to 6.1 yr). At diagnosis, 12 (26%) were on PD and 33 (72%) were diagnosed <2 yr after PD stopped. The cases had a median of 3.3 episodes of peritonitis (range 0 to 20, IQR 1 to 4.5). Thirty (65%) had used 3.86% dextrose dialysate and 45 (98%) had used Extraneal. The mortality was 42% at 1 yr postdiagnosis with a median survival of 149 d (IQR 61 to 408 d).Conclusions: The incidence reported in this study may be used to inform patients of the minimum risk of developing EPS on PD.Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), first described in 1980 (1). EPS is thought to result from chronic intra-abdominal inflammation that is multifactorial in origin. Prolonged PD represents the most consistent “risk factor” identified (2–6).EPS is uncommon, but the incidence is unknown. A UK series identified 27 EPS cases, indicating a rate of 3.3% over 7 yr (7). An Australian study identified 54 cases in 14 yr, giving a rate of 0.7% (4). Japanese and Korean studies describe rates of 0.8 to 2.5% (2,3,5,6). Kawanishi et al. published a 2 yr follow-up of a PD cohort in 2001, suggesting an incidence of 0.8% (2). They published a further analysis in 2004 reporting an incidence of 2.5%, which may reflect the longer follow-up inherent to the study design rather than a true incidence increase (3). These studies include incident and prevalent patients on PD, which does not allow accurate calculation of incidence (2–7). To calculate a true incidence of EPS, a cohort of patients must be followed from the start of PD to identify all cases diagnosed thereafter.The clinical features of EPS have been described previously (2–9). Onset may occur on PD, but most cases become apparent after stopping PD, including after renal transplantation (2–8). Clinical, radiologic and pathologic criteria for EPS diagnosis were defined by the International Society for Peritoneal Dialysis (ISPD) in 2000 (10).There is little evidence to guide management of EPS patients. In Japan, enterolysis (surgical division of adhesions) is recommended but there are few European reports on EPS surgery (11–15). Case series have assessed total parenteral nutrition, immunosuppression and tamoxifen, and some have shown encouraging results (3,7,16- 26). There are no reliable biochemical or radiologic screening tests to identify patients at risk or in the early stages of EPS (27,28).The primary aim of this study was to report the EPS incidence in patients using PD for end-stage renal failure (ESRF) in Scotland between January 1, 2000, and December 31, 2007. A secondary aim was to characterize these cases.     

Coagulase Negative Staphylococcal Peritonitis in Peritoneal Dialysis Patients: Review of 232 Consecutive Cases

Background and objectives: Coagulase-negative Staphylococcus species is the most common cause of peritoneal dialysis–related peritonitis; however, the optimal treatment strategy of coagulase-negative Staphylococcus species peritonitis remains controversial.Design, setting, participants, & measurements: All of the coagulase-negative Staphylococcus species peritonitis in a dialysis unit from 1995 to 2006 were reviewed. During this period, there were 2037 episodes of peritonitis recorded; 232 episodes (11.4%) in 155 patients were caused by coagulase-negative Staphylococcus species.Results: The overall primary response rate was 95.3%; the complete cure rate was 71.1%. Patients with a history of recent hospitalization or recent antibiotic therapy had a higher risk for developing methicillin-resistant strains. Episodes that were treated initially with cefazolin or vancomycin had similar primary response rate and complete cure rate. There were 33 (14.2%) episodes of relapse and 29 (12.5%) episodes of repeat peritonitis; 12 (60.6%) of the repeat episodes developed within 3 mo after completion of antibiotics. Relapse or repeat episodes had a significantly lower complete cure rate than the other episodes. For relapse or repeat episodes, treatment with effective antibiotics for 3 wk was associated with a significantly higher complete cure rate than the conventional 2-wk treatment.Conclusions: Coagulase-negative Staphylococcus species peritonitis remains a common complication of peritoneal dialysis. Methicillin resistance is common, but the treatment outcome remains favorable when cefazolin is used as the first-line antibiotic. A 3-wk course of antibiotic can probably achieve a higher cure rate in relapse or repeat episodes.Peritonitis is a serious complication of peritoneal dialysis (PD) and probably the most common cause of technique failure in PD (1–5). In the United States, 18% of the infection-related mortality in PD patients is the result of peritonitis (6). Although fewer than 4% of the peritonitis episodes resulted in death (7), peritonitis is a “contributing factor” in 16% of deaths of patients who are on PD (8). In Hong Kong, peritonitis is the direct cause of death in >16% of PD patients (9).Gram-positive organisms remain the most common bacteriologic cause of PD-related peritonitis (1,5,10); coagulase-negative Staphylococcus species (CNSS) accounted for nearly half of all Gram-positive episodes (11,12), although it is less common a cause of mortality as compared with Gram-negative peritonitis (12). It is commonly believed that CNSS peritonitis is primarily due to touch contamination and is generally a mild form of peritonitis that responds readily to antibiotic therapy (13). Current guideline for the management of CNSS peritonitis by the Ad Hoc Advisory Committee on Peritonitis Management recommends single effective antibiotics therapy, for example, cefazolin or vancomycin, for 2 wk (13). In methicillin-sensitive organisms, cefazolin has been shown to have equivalent results to vancomycin (14,15) and is usually the agent preferred so that excessive use of vancomycin could be minimized (13); however, the optimal treatment strategy of CNSS peritonitis remains controversial. The current treatment recommendation by the Ad Hoc Advisory Committee was largely based on small studies and expert opinion (13). Many dialysis programs have a high rate of methicillin-resistant organisms (16–18). Using cefazolin as the first-line antibiotic for Gram-positive organisms may theoretically result in delaying the use of effective treatment, and vancomycin is often considered the only appropriate first-line coverage for Gram-positive organisms in centers with a high incidence of methicillin resistance (12,18). In this study, we reviewed the clinical course and therapeutic outcome of 232 consecutive episodes of CNSS peritonitis in a large unselected cohort of PD patients over 12 yr. We aimed to identify key factors that could improve the treatment outcome of this common complication of PD.     

A Phase III,Randomized, Double-Blind,Placebo-Controlled Study of Tenecteplase for Improvement of Hemodialysis Catheter Function: TROPICS 3

Background and objectives: Despite widespread use of tunneled hemodialysis (HD) catheters, their utility is limited by the development of thrombotic complications. To address this problem, this study investigated whether the thrombolytic agent tenecteplase can restore blood flow rates (BFRs) in dysfunctional HD catheters.Design, setting, participants, & measurements: In this randomized, double-blind study, patients with dysfunctional tunneled HD catheters, defined as a BFR <300 ml/min at −250 mmHg pressure in the arterial line, received 1-hour intracatheter dwell with tenecteplase (2 mg) or placebo. The primary endpoint was the percentage of patients with BFR ≥300 ml/min and an increase of ≥25 ml/min above baseline 30 minutes before and at the end of HD. Safety endpoints included the incidence of hemorrhagic, thrombotic, and infectious complications.Results: Eligible patients (n = 149) were treated with tenecteplase (n = 74) or placebo (n = 75). Mean baseline BFR was similar for the tenecteplase and placebo groups at 151 and 137 ml/min, respectively. After a 1-hour dwell, 22% of patients in the tenecteplase group had functional catheters compared with 5% among placebo controls (P = 0.004). At the end of dialysis, mean change in BFR was 47 ml/min in the tenecteplase group versus 12 ml/min in the placebo group (P = 0.008). Four catheter-related bloodstream infections (one tenecteplase, three placebo) and one thrombosis (tenecteplase) were observed. There were no reports of intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications.Conclusions: Tenecteplase improved HD catheter function and had a favorable safety profile compared with placebo.Effective hemodialysis (HD) requires reliable vascular access. Arteriovenous fistulas and grafts are preferred over catheters for their higher patency rates, prolonged survival, and lower complication rates (1–3). However, HD catheters are used by most dialysis patients to provide temporary access or to allow maturation of surgically placed fistulas (4). Tunneled catheters may also be used because of comorbidities or exhaustion of all graft and fistula sites (5,6).HD catheters must be carefully managed to mitigate a high complication rate. For example, catheter thrombosis is estimated to occur at a frequency of 0.5 to 3.0 events/1000 catheter-days (7–9). Among patients who experience access loss, catheter thrombosis is the precipitating event in 30% to 40% (1). Thrombotic obstruction of the catheter lumen reduces blood flow rate (BFR), frequently impeding the delivery of adequate HD. Treatment of partial occlusions of catheter lumens is often postponed by catheter line reversal, contributing to recirculation without addressing the underlying thrombus. The National Kidney Foundation''s Kidney Disease Outcomes Quality Initiative guidelines for HD vascular access advise against regular use of line reversal to manage low BFR (1).Maintenance of catheter patency is critical because many patients rely on catheter access for HD, and catheter insertion sites are limited. Administration of a thrombolytic directly into a dysfunctional HD catheter lumen may provide a way to salvage catheters with suboptimal BFRs while minimizing the risk of adverse events (AEs) associated with systemic delivery of these agents and avoid the need for catheter replacement. Previous studies evaluating the efficacy of alteplase or reteplase for clearance of HD catheters have yielded conflicting results (10–25). Limitations of prior studies include differences in trial design, sample size, thrombolytic dose, and definitions of treatment success. Until now there have been no large-scale, randomized, double-blind controlled trials using well defined efficacy and safety endpoints. As a result, many questions remain regarding the efficacy and safety of thrombolytics in the treatment of dysfunctional HD catheters.Tenecteplase is a recombinant serine protease that binds to fibrin and converts thrombus-bound plasminogen to plasmin, thereby stimulating local fibrinolysis. Tenecteplase has three engineered amino acid changes, resulting in greater fibrin specificity and an increased resistance to plasminogen activator inhibitor-1 compared with alteplase (26,27). When injected systemically, tenecteplase has a plasma half-life of approximately 22 minutes (28) and is primarily cleared by the liver (29). However, when tenecteplase is administered intraluminally for HD catheter dysfunction and subsequently withdrawn, circulating tenecteplase levels are not expected to reach detectable concentrations (30). Tenecteplase maintained clot lysis ability for 72 hours in a catheter in in vitro studies (Genentech data on file). In this study, we compared the efficacy of tenecteplase with placebo in improving BFR in dysfunctional HD catheters.     

Comparison of Early versus Late Use of Antibiotic Locks in the Treatment of Catheter-Related Bacteremia

Background and objectives: This retrospective study compared the effectiveness of the timing of the antibiotic locks to clear catheter-related bacteremia in children on chronic hemodialysis.Design, setting, participants, & measurements: The early antibiotic lock group received antibiotic locks along with systemic antibiotics from the very beginning of catheter-related bacteremia. The late antibiotic lock group was given only systemic antibiotics initially, and antibiotic locks were used late in the infection if the catheter-related bacteremia could not be cleared after resolution of symptoms.Results: There were 264 catheter-related bacteremias in 79 children during 6 yr of observation. Early antibiotic locks were able to clear catheter-related bacteremia and resolve the symptoms more effectively without the need for catheter exchange when compared with late antibiotic locks. A total of 84 catheter-related bacteremias required wire-guided exchange of the catheters. Late antibiotic locks required wire-guided catheter exchange more frequently than the early antibiotic locks. The post–catheter-related bacteremia infection–free survival of the catheters after wire-guided exchange were significantly longer than those of both antibiotic lock groups. Recurrence of catheter-related bacteremia within 45 d after wire-guided exchange occurred at similar rates compared with the antibiotic lock groups.Conclusion: Antibiotic locks are significantly more effective in clearing catheter-related bacteremia when used early in infection, diminishing the need for catheter exchange. Wire-guided exchange has a late-onset advantage for infection-free survival compared with catheter in situ treatment. The recurrence rates in the first 45 d after catheter-related bacteremia are similar regardless of the treatment strategy.Antibiotic lock solutions (ABL) are high concentration of antibiotic with or without anticoagulant agent that is dwelled (locked) in the catheter lumen, exposing the internal lumen of the catheter to persistent antibacterial action. Biofilms that harbor microorganisms are demonstrated on external and internal surfaces of the indwelling catheters within as early as 24 h after their placement (1,2). The fibrinous-proteinous ultrastructure of the biofilm gives both protection and antimicrobial resistance to the microorganisms. Because the intraluminal concentrations of the systemic antibiotics never reach high enough concentrations above the minimal inhibitory concentration, treatment failure as well as the loss of the catheter becomes inevitable during treatment of catheter-related bacteremias (CRB). Clinical series involving tunneled-cuffed catheters used for hemodialysis or nutrition reported 44 to 100% success rates for clearing CRB with ABL along with systemic antibiotics (3–9). The success of these studies has led to the recommendation of the use of ABL for the management of uncomplicated catheter-related bacteremias from a consensus panel (10).Despite the current recommendations for long-term vascular access in hemodialysis patients being arteriovenous (AV) fistula or AV graft, still in 60% of the newly diagnosed and 30% of the prevalent hemodialysis patients, tunneled cuffed long-term central venous catheters are used as vascular access because of the difficulties in creating and maintaining AV fistulas and grafts (11–17). This is even more prominent for the pediatric ESRD population (18–20). CRB that lead to septic shock and metastatic infections are the most feared complications of long-term catheter use, and systemic antibiotics cannot satisfactorily clear the infected catheters, requiring early catheter exchange, as recommended in the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (11).The aim of this study was to investigate the effect of timing of the use of ABL along with systemic antibiotics for CRB treatment on children who were receiving long-term hemodialysis. The tested hypothesis was that ABL would act synergistically with the systemic antibiotics in eradicating the CRB when used early in the course of CRB rather than when systemic antibiotics fail to control CRB initially. The infection-free outcomes of the two ABL groups were compared with the outcomes of the catheters that were submitted to wire-guided exchange (WGE) as a result of CRB. The WGE catheters did not receive any ABL but only systemic antibiotics. These new catheters had no reason to have intraluminal biofilm formation. The second tested hypothesis was that ABL can successfully clear the intraluminal space of an infected catheter. If so, then post-CRB infection–free survival of the catheters treated in situ should be similar to WGE catheters as a result of CRB. The study was designed as a retrospective chart review protocol.     

Structure-based cleavage mechanism of Thermus thermophilus Argonaute DNA guide strand-mediated DNA target cleavage

We report on crystal structures of ternary Thermus thermophilus Argonaute (TtAgo) complexes with 5′-phosphorylated guide DNA and a series of DNA targets. These ternary complex structures of cleavage-incompatible, cleavage-compatible, and postcleavage states solved at improved resolution up to 2.2 Å have provided molecular insights into the orchestrated positioning of catalytic residues, a pair of Mg²⁺ cations, and the putative water nucleophile positioned for in-line attack on the cleavable phosphate for TtAgo-mediated target cleavage by a RNase H-type mechanism. In addition, these ternary complex structures have provided insights into protein and DNA conformational changes that facilitate transition between cleavage-incompatible and cleavage-compatible states, including the role of a Glu finger in generating a cleavage-competent catalytic Asp-Glu-Asp-Asp tetrad. Following cleavage, the seed segment forms a stable duplex with the complementary segment of the target strand.Argonaute (Ago) proteins, critical components of the RNA-induced silencing complex, play a key role in guide strand-mediated target RNA recognition, cleavage, and product release (reviewed in refs. 1–3). Ago proteins adopt a bilobal scaffold composed of an amino terminal PAZ-containing lobe (N and PAZ domains), a carboxyl-terminal PIWI-containing lobe (Mid and PIWI domains), and connecting linkers L1 and L2. Ago proteins bind guide strands whose 5′-phosphorylated and 3′-hydroxyl ends are anchored within Mid and PAZ pockets, respectively (4–7), with the anchored guide strand then serving as a template for pairing with the target strand (8, 9). The cleavage activity of Ago resides in the RNase H fold adopted by the PIWI domain (10, 11), whereby the enzyme’s Asp-Asp-Asp/His catalytic triad (12–15) initially processes loaded double-stranded siRNAs by cleaving the passenger strand and subsequently processes guide-target RNA duplexes by cleaving the target strand (reviewed in refs. 16–18). Such Mg²⁺ cation-mediated endonucleolytic cleavage of the target RNA strand (19, 20) resulting in 3′-OH and 5′-phosphate ends (21) requires Watson–Crick pairing of the guide and target strands spanning the seed segment (positions 2–2′ to 8–8′) and the cleavage site (10′–11′ step on the target strand) (9). Insights into target RNA recognition and cleavage have emerged from structural (9), chemical (22), and biophysical (23) experiments.Notably, bacterial and archaeal Ago proteins have recently been shown to preferentially bind 5′-phosphoryated guide DNA (14, 15) and use an activated water molecule as the nucleophile (reviewed in ref. 24) to cleave both RNA and DNA target strands (9). Structural studies have been undertaken on bacterial and archaeal Ago proteins in the free state (10, 15) and bound to a 5′-phosphorylated guide DNA strand (4) and added target RNA strand (8, 9). The structural studies of Thermus thermophilus Ago (TtAgo) ternary complexes have provided insights into the nucleation, propagation, and cleavage steps of target RNA silencing in a bacterial system (9). These studies have highlighted the conformational transitions on proceeding from Ago in the free state to the binary complex (4) to the ternary complexes (8, 9) and have emphasized the requirement for a precisely aligned Asp-Asp-Asp triad and a pair of Mg²⁺ cations for cleavage chemistry (9), typical of RNase H fold-mediated enzymes (24, 25). Structural studies have also been extended to binary complexes of both human (5, 6) and yeast (7) Agos bound to 5′-phosphorylated guide RNA strands.Despite these singular advances in the structural biology of RNA silencing, further progress was hampered by the modest resolution (2.8- to 3.0-Å resolution) of TtAgo ternary complexes with guide DNA (4) and added target RNAs (8, 9). This precluded identification of water molecules coordinated with the pair of Mg²⁺ cations, including the key water that acts as a nucleophile and targets the cleavable phosphate between positions 10′-11′ on the target strand. We have now extended our research to TtAgo ternary complexes with guide DNA and target DNA strands, which has permitted us to grow crystals of ternary complexes that diffract to higher (2.2–2.3 Å) resolution in the cleavage-incompatible, cleavage-compatible, and postcleavage steps. These high-resolution structures of TtAgo ternary complexes provide snapshots of distinct key steps in the catalytic cleavage pathway, opening opportunities for experimental probing into DNA target cleavage as a defense mechanism against plasmids and possibly other mobile elements (26, 27).     

Predictive Value of Brain Natriuretic Peptides in Patients on Peritoneal Dialysis: Results from the ADEMEX Trial

Background and objectives: Natriuretic peptides have been suggested to be of value in risk stratification in dialysis patients. Data in patients on peritoneal dialysis remain limited.Design, setting, participants, & measurements: Patients of the ADEMEX trial (ADEquacy of peritoneal dialysis in MEXico) were randomized to a control group [standard 4 × 2L continuous ambulatory peritoneal dialysis (CAPD); n = 484] and an intervention group (CAPD with a target creatinine clearance ≥60L/wk/1.73 m²; n = 481). Natriuretic peptides were measured at baseline and correlated with other parameters as well as evaluated for effects on patient outcomes.Results: Control group and intervention group were comparable at baseline with respect to all measured parameters. Baseline values of natriuretic peptides were elevated and correlated significantly with levels of residual renal function but not with body size or diabetes. Baseline values of N-terminal fragment of B-type natriuretic peptide (NT-proBNP) but not proANP(1–30), proANP(31–67), or proANP(1–98) were independently highly predictive of overall survival and cardiovascular mortality. Volume removal was also significantly correlated with patient survival.Conclusions. NT-proBNP have a significant predictive value for survival of CAPD patients and may be of value in guiding risk stratification and potentially targeted therapeutic interventions.Plasma levels of cardiac natriuretic peptides are elevated in patients with chronic kidney disease, owing to impairment of renal function, hypertension, hypervolemia, and/or concomitant heart disease (1–7). Atrial natriuretic peptide (ANP) and particularly brain natriuretic peptide (BNP) levels are linked independently to left ventricular mass (3–5,8–16) and function (3,6–17) and predict total and cardiovascular mortality (1,3,8,10,12,18) as well as cardiac events (12,19). ANP and BNP decrease significantly during hemodialysis treatment but increase again during the interdialytic interval (1,2,4,6,7,14,17,20–23). Levels in patients on peritoneal dialysis (PD) have been found to be lower than in patients on hemodialysis (11,24–26), but the correlations with left ventricular function and structure are maintained in both types of dialysis modalities (11,15,27,28).The high mortality of patients on peritoneal dialysis and the failure of dialytic interventions to alter this mortality (29,30) necessitate renewed attention into novel methods of stratification and identification of patients at highest risk to be targeted for specific interventions. Cardiac natriuretic peptides are increasingly considered to fulfill this role in nonrenal patients. Evaluations of cardiac natriuretic peptides in patients on PD have been limited by small numbers (3,9,11,12,15,24–26) and only one study examined correlations between natriuretic peptide levels and outcomes (12). The PD population enrolled in the ADEMEX trial offered us the opportunity to evaluate cardiac natriuretic peptides and their value in predicting outcomes in the largest clinical trial ever performed on PD (29,30). It is hoped that such an evaluation would identify patients at risk even in the absence of overt clinical disease and hence facilitate or encourage interventions with salutary outcomes.     

Evidence for Pathogenicity of Atypical Splice Mutations in Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by locus and allelic heterogeneity, large multi-exon gene structure and duplication in PKD1, and a high level of unclassified variants. Comprehensive screening of PKD1 and PKD2 by two recent studies have shown that atypical splice mutations account for 3.5% to 5% of ADPKD. We evaluated the role of bioinformatic prediction of atypical splice mutations and determined the pathogenicity of an atypical PKD2 splice variant from a multiplex ADPKD (TOR101) family.Design, setting, participants, & measurements: Using PubMed, we identified 17 atypical PKD1 and PKD2 splice mutations. We found that bioinformatics analysis was often useful for evaluating the pathogenicity of these mutations, although RT-PCR is needed to provide the definitive proof.Results: Sequencing of both PKD1 and PKD2 in an affected subject of TOR101 failed to identify a definite mutation, but revealed several UCVs, including an atypical PKD2 splice variant. Linkage analysis with microsatellite markers indicated that TOR101 was PKD2-linked and IVS8 + 5G→A was shown to cosegregate only with affected subjects. RT-PCR of leukocyte mRNA from an affected subject using primers from exons 7 and 9 revealed six splice variants that resulted from activation of different combinations of donor and acceptor cryptic splice sites, all terminating with premature stop codons.Conclusions: The data provide strong evidence that IVS8 + 5G→A is a pathogenic mutation for PKD2. This case highlights the importance of functional analysis of UCVs.Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder worldwide, affecting approximately one in 500 live births. It is characterized by focal development and progressive enlargement of renal cysts, leading to end-stage renal disease (ESRD) in late middle age. Typically, only a few renal cysts are detected in most affected subjects before 30 yr of age. However, by the fifth decade of life, hundreds to thousands of renal cysts are found in most patients. Overall, ADPKD accounts for 5% to 8% of end-stage renal disease (ESRD) in developed countries (1,2). Extrarenal complications of ADPKD are variable and include inguinal hernias, colonic diverticulae, valvular heart disease, and intracranial arterial aneurysms (1).Mutations of two genes, PKD1 (MIM 601313) and PKD2 (MIM 173910), account for approximately 85% and 15% of all cases of ADPKD in linkage-characterized European populations (3,4). Although the clinical manifestations of PKD1 and PKD2 overlap completely, a strong locus effect on renal disease severity is evident with more severe renal disease in PKD1 than PKD2 (median age at ESRD: 54 yr versus 74, respectively) (5). PKD1 is a large gene consisting of 46 exons with an open reading frame of approximately 13 kb and is predicted to encode a protein of 4302 amino acids. Its entire 5′ region up to exon 33 has been duplicated six times proximally on chromosome 16p, and the presence of these highly homologous pseudogenes has made genetic analysis of PKD1 difficult (1,2). Recent availability of protocols for long-range and locus-specific amplification of PKD1 has enabled the complete mutation screening of this complex gene (6–9). In contrast, PKD2 is a single-copy gene consisting of 15 exons with an open reading frame of approximately 3 kb and is predicted to encode a protein of 968 amino acids (1,2).The diagnosis of ADPKD is straightforward in affected subjects with a positive family history and enlarged kidneys with multiple cysts (6). Renal ultrasound is a useful method for this purpose, and age-dependant criteria based on cyst number have been derived for subjects born with 50% risk of PKD1 or PKD2 (6,10). However, ultrasound diagnosis of ADPKD in younger at-risk subjects with equivocal or negative findings and in subjects affected by PKD2 or de novo disease remains a challenge (6). For these reasons, molecular screening is a useful tool in the clinical setting. However, marked allelic heterogeneity is evident, with over 200 different PKD1 and over 50 different PKD2 mutations reported to date (2,6–9,11–13). The majority of these mutations are unique and scattered throughout both genes. Although the majority of these mutations are predicted to be protein truncating (frame-shift deletion/insertion, nonsense or canonical splice changes), a large number of unclassified variants (UCVs; in-frame deletions, mis-sense and atypical splice changes) has also been reported (7–9). Comprehensive screening of both PKD1 and PKD2 by two recent studies identified definitive and probable mutations in 42% to 63% and 26% to 37% of patients, respectively (8,9). These two studies also reported that atypical splice mutations account for approximately 3.5% to 5% of ADPKD (8,9). In the current study, we performed and evaluated the utility of bioinformatics analysis on 17 reported atypical PKD1 and PKD2 splice mutations. We also determine the pathogenicity of an atypical splice variant found in a family affected by PKD2 and highlight the importance of functional analysis of UCVs in molecular diagnostic testing.     

Self-assembly of alkynylplatinum(II) terpyridine amphiphiles into nanostructures via steric control and metal–metal interactions

A series of mono- and dinuclear alkynylplatinum(II) terpyridine complexes containing the hydrophilic oligo(para-phenylene ethynylene) with two 3,6,9-trioxadec-1-yloxy chains was designed and synthesized. The mononuclear alkynylplatinum(II) terpyridine complex was found to display a very strong tendency toward the formation of supramolecular structures. Interestingly, additional end-capping with another platinum(II) terpyridine moiety of various steric bulk at the terminal alkyne would lead to the formation of nanotubes or helical ribbons. These desirable nanostructures were found to be governed by the steric bulk on the platinum(II) terpyridine moieties, which modulates the directional metal−metal interactions and controls the formation of nanotubes or helical ribbons. Detailed analysis of temperature-dependent UV-visible absorption spectra of the nanostructured tubular aggregates also provided insights into the assembly mechanism and showed the role of metal−metal interactions in the cooperative supramolecular polymerization of the amphiphilic platinum(II) complexes.Square-planar d⁸ platinum(II) polypyridine complexes have long been known to exhibit intriguing spectroscopic and luminescence properties (1–54) as well as interesting solid-state polymorphism associated with metal−metal and π−π stacking interactions (1–14, 25). Earlier work by our group showed the first example, to our knowledge, of an alkynylplatinum(II) terpyridine system [Pt(tpy)(C ≡ CR)]⁺ that incorporates σ-donating and solubilizing alkynyl ligands together with the formation of Pt···Pt interactions to exhibit notable color changes and luminescence enhancements on solvent composition change (25) and polyelectrolyte addition (26). This approach has provided access to the alkynylplatinum(II) terpyridine and other related cyclometalated platinum(II) complexes, with functionalities that can self-assemble into metallogels (27–31), liquid crystals (32, 33), and other different molecular architectures, such as hairpin conformation (34), helices (35–38), nanostructures (39–45), and molecular tweezers (46, 47), as well as having a wide range of applications in molecular recognition (48–52), biomolecular labeling (48–52), and materials science (53, 54). Recently, metal-containing amphiphiles have also emerged as a building block for supramolecular architectures (42–44, 55–59). Their self-assembly has always been found to yield different molecular architectures with unprecedented complexity through the multiple noncovalent interactions on the introduction of external stimuli (42–44, 55–59).Helical architecture is one of the most exciting self-assembled morphologies because of the uniqueness for the functional and topological properties (60–69). Helical ribbons composed of amphiphiles, such as diacetylenic lipids, glutamates, and peptide-based amphiphiles, are often precursors for the growth of tubular structures on an increase in the width or the merging of the edges of ribbons (64, 65). Recently, the optimization of nanotube formation vs. helical nanostructures has aroused considerable interests and can be achieved through a fine interplay of the influence on the amphiphilic property of molecules (66), choice of counteranions (67, 68), or pH values of the media (69), which would govern the self-assembly of molecules into desirable aggregates of helical ribbons or nanotube scaffolds. However, a precise control of supramolecular morphology between helical ribbons and nanotubes remains challenging, particularly for the polycyclic aromatics in the field of molecular assembly (64–69). Oligo(para-phenylene ethynylene)s (OPEs) with solely π−π stacking interactions are well-recognized to self-assemble into supramolecular system of various nanostructures but rarely result in the formation of tubular scaffolds (70–73). In view of the rich photophysical properties of square-planar d⁸ platinum(II) systems and their propensity toward formation of directional Pt···Pt interactions in distinctive morphologies (27–31, 39–45), it is anticipated that such directional and noncovalent metal−metal interactions might be capable of directing or dictating molecular ordering and alignment to give desirable nanostructures of helical ribbons or nanotubes in a precise and controllable manner.Herein, we report the design and synthesis of mono- and dinuclear alkynylplatinum(II) terpyridine complexes containing hydrophilic OPEs with two 3,6,9-trioxadec-1-yloxy chains. The mononuclear alkynylplatinum(II) terpyridine complex with amphiphilic property is found to show a strong tendency toward the formation of supramolecular structures on diffusion of diethyl ether in dichloromethane or dimethyl sulfoxide (DMSO) solution. Interestingly, additional end-capping with another platinum(II) terpyridine moiety of various steric bulk at the terminal alkyne would result in nanotubes or helical ribbons in the self-assembly process. To the best of our knowledge, this finding represents the first example of the utilization of the steric bulk of the moieties, which modulates the formation of directional metal−metal interactions to precisely control the formation of nanotubes or helical ribbons in the self-assembly process. Application of the nucleation–elongation model into this assembly process by UV-visible (UV-vis) absorption spectroscopic studies has elucidated the nature of the molecular self-assembly, and more importantly, it has revealed the role of metal−metal interactions in the formation of these two types of nanostructures.