Kidney care in low- and middle-income countries.

Optimal kidney care requires a trained nephrology workforce, essential healthcare services, and medications. This study aimed to identify the access to these resources on a global scale using data from the multinational survey conducted by the International Society of Nephrology (ISN) (Global Kidney Health Atlas (GKHA) project), with emphasis on developing nations. For data analysis, the 125 participating countries were sorted into the 4 World Bank income groups: low income (LIC), lower-middle income (LMIC), upper-middle income (UMIC), and high income (HIC). A severe shortage of nephrologists was observed in LIC and LMIC with < 5 nephrologists per million population. Many LIC were unable to access estimated glomerular filtration rate (eGFR) and albuminuria (proteinuria) tests in primary-care levels. Acute and chronic hemodialysis was available in most countries, although acute and chronic peritoneal dialysis access was severely limited in LIC (24% and 35%, respectively). Most countries had kidney transplantation access, except for LIC (12%). HIC and UMIC funded their renal replacement therapy (RRT) and renal medications primarily through public means, whereas LMIC and LIC required private and out-of-pocket contributions. In conclusion, this study found a huge gap in the availability and access to trained nephrology workforce, tools for diagnosis and management of CKD, RRT, and funding of RRT and essential medications in LIC and LMIC.

Impact of Ramadan fasting on kidney function and related outcomes in patients with chronic kidney disease: a systematic review protocol.

INTRODUCTION: Fasting during the month of Ramadan is a significant Islamic religious practice that involves abstinence from food, drink and medication from dawn to dusk. As just under a quarter of the world's population identifies as Muslim, the effect of fasting on chronic conditions, such as chronic kidney disease (CKD) is a topic of broad relevance. To date, the information in this area has been mixed, with many limitations of previous studies. This study aims to synthesise the evidence of the effect of Ramadan fasting on changes on kidney function, risk factors, episodes of acute kidney injury and impact on the quality of life in patients with CKD or kidney transplant. METHODS AND ANALYSIS: A systematic review of the literature will be conducted, using electronic databases such as MEDLINE, Embase, Global Health, CINAHL and Scopus. Original research and grey literature on the effect of Ramadan fasting in adult patients with CKD or renal transplantation will be included. Two reviewers will independently screen articles for inclusion in the review and independently assess the methodology of included studies using a customised checklist. Mean difference or risk ratio will be reported for continuous or dichotomous outcomes and results will be pooled using a random-effects model where heterogeneity is reasonable. If possible, subgroups (CKD status, setting, season and risk of bias) will be analysed for effect modification with fasting and the outcomes of interest. Risk of bias will be assessed using the Downs and Black checklist. ETHICS AND DISSEMINATION: The results will be disseminated using a multifaceted approach to engage all stakeholders (patients, practitioners and community leaders). Research ethics board approval is not required as this is a systematic review of previously published research. PROSPERO REGISTRATION NUMBER: CRD42018088973.

Guidelines, policies, and barriers to kidney care: findings from a global survey.

An international survey led by the International Society of Nephrology in 2016 assessed the current capacity of kidney care worldwide. To better understand how governance and leadership guide kidney care, items pertinent to government priority, advocacy, and guidelines, among others, were examined. Of the 116 responding countries, 36% (n = 42) reported CKD as a government health care priority, which was associated with having an advocacy group (χ2 = 11.57; P = 0.001). Nearly one-half (42%; 49 of 116) of countries reported an advocacy group for CKD, compared with only 19% (21 of 112) for AKI. Over one-half (59%; 68 of 116) of countries had a noncommunicable disease strategy. Similarly, 44% (48 of 109), 55% (57 of 104), and 47% (47 of 101) of countries had a strategy for nondialysis CKD, chronic dialysis, and kidney transplantation, respectively. Nearly one-half (49%; 57 of 116) reported a strategy for AKI. Most countries (79%; 92 of 116) had access to CKD guidelines and just over one-half (53%; 61 of 116) reported guidelines for AKI. Awareness and adoption of guidelines were low among nonnephrologist physicians. Identified barriers to kidney care were factors related to patients, such as knowledge and attitude (91%; 100 of 110), physicians (84%; 92 of 110), and geography (74%; 81 of 110). Specific to renal replacement therapy, patients and geography were similarly identified as a barrier in 78% (90 of 116) and 71% (82 of 116) of countries, respectively, with the addition of nephrologists (72%; 83 of 116) and the health care system (73%; 85 of 116). These findings inform how kidney care is currently governed globally. Ensuring that guidelines are feasible and distributed appropriately is important to enhancing their adoption, particularly in primary care. Furthermore, increasing advocacy and government priority, especially for AKI, may increase awareness and strategies to better guide kidney care.

Global access of patients with kidney disease to health technologies and medications: findings from the Global Kidney Health Atlas project.

Access to essential medications and health products is critical to effective management of kidney disease. Using data from the ISN Global Kidney Health Atlas multinational cross-sectional survey, global access of patients with kidney disease to essential medications and health products was examined. Overall, 125 countries participated, with 118 countries, composing 91.5% of the world's population, providing data on this domain. Most countries were unable to access eGFR and albuminuria in their primary care settings. Only one-third of low-income countries (LICs) were able to measure serum creatinine and none were able to access eGFR or quantify proteinuria. The ability to monitor diabetes mellitus through serum glucose and glycated hemoglobin measurements was suboptimal. Pathology services were rarely available in tertiary care in LICs (12%) and lower middle-income countries (45%). While acute and chronic hemodialysis services were available in almost all countries, acute and chronic peritoneal dialysis services were rarely available in LICs (18% and 29%, respectively). Kidney transplantation was available in 79% of countries overall and in 12% of LICs. While over one-half of all countries publicly funded RRT and kidney medications with or without copayment, this was less common in LICs and lower middle-income countries. In conclusion, this study demonstrated significant gaps in services for kidney care and funding that were most apparent in LICs and lower middle-income countries.

The effect of socioeconomic status on access to primary care: an audit study.

BACKGROUND: Health care office staff and providers may discriminate against people of low socioeconomic status, even in the absence of economic incentives to do so. We sought to determine whether socioeconomic status affects the response a patient receives when seeking a primary care appointment. METHODS: In a single unannounced telephone call to a random sample of family physicians and general practices (n = 375) in Toronto, Ontario, a male and a female researcher each played the role of a patient seeking a primary care physician. Callers followed a script suggesting either high (i.e., bank employee transferred to the city) or low (i.e., recipient of social assistance) socioeconomic status, and either the presence or absence of chronic health conditions (diabetes and low back pain). We randomized the characteristics of the caller for each office. Our primary outcome was whether the caller was offered an appointment. RESULTS: The proportion of calls resulting in an appointment being offered was significantly higher when the callers presented themselves as having high socioeconomic status than when they presented as having low socioeconomic status (22.6% v.14.3%, p = 0.04) and when the callers stated the presence of chronic health conditions than when they did not (23.5% v. 12.8%, p = 0.008). In a model adjusted for all independent variables significant at a p value of 0.10 or less (presence of chronic health conditions, time since graduation from medical school and membership in the College of Family Physicians of Canada), high socioeconomic status was associated with an odds ratio of 1.78 (95% confidence interval 1.02-3.08) for the offer of an appointment. Socioeconomic status and chronic health conditions had independent effects on the likelihood of obtaining an appointment. INTERPRETATION: Within a universal health insurance system in which physician reimbursement is unaffected by patients' socioeconomic status, people presenting themselves as having high socioeconomic status received preferential access to primary care over those presenting themselves as having low socioeconomic status.

Ca2+-dependent induction of TRPM2 currents in hippocampal neurons.

TRPM2 is a Ca(2+)-permeable member of the transient receptor potential melastatin family of cation channels whose activation by reactive oxygen/nitrogen species (ROS/RNS) and ADP-ribose (ADPR) is linked to cell death. While these channels are broadly expressed in the CNS, the presence of TRPM2 in neurons remains controversial and more specifically, whether they are expressed in neurons of the hippocampus is an open question. With this in mind, we examined whether functional TRPM2 channels are expressed in this neuronal population. Using a combination of molecular and biochemical approaches, we demonstrated the expression of TRPM2 transcripts and proteins in hippocampal pyramidal neurons. Whole-cell voltage-clamp recordings were subsequently carried out to assess the presence of TRPM2-mediated currents. Application of hydrogen peroxide or peroxynitrite to cultured hippocampal pyramidal neurons activated an inward current that was abolished upon removal of extracellular Ca(2+), a hallmark of TRPM2 activation. When ADPR (300 microM) was included in the patch pipette, a large inward current developed but only when depolarizing voltage ramps were continuously (1/10 s) applied to the membrane. This current exhibited a linear current-voltage relationship and was sensitive to block by TRPM2 antagonists (i.e. clotrimazole, flufenamic acid and N-(p-amylcinnamoyl)anthranilic acid (ACA)). The inductive effect of voltage ramps on the ADPR-dependent current required voltage-dependent Ca(2+) channels (VDCCs) and a rise in [Ca(2+)](i). Consistent with the need for a rise in [Ca(2+)](i), activation of NMDA receptors (NMDARs), which are highly permeable to Ca(2+), was also permissive for current development. Importantly, given the prominent vulnerability of CA1 neurons to free-radical-induced cell death, we confirmed that, with ADPR in the pipette, a brief application of NMDA could evoke a large inward current in CA1 pyramidal neurons from hippocampal slices that was abolished by the removal of extracellular Ca(2+), consistent with TRPM2 activation. Such a current was absent in interneurons of CA1 stratum radiatum. Finally, infection of cultured hippocampal neurons with a TRPM2-specific short hairpin RNA (shRNA(TRPM2)) significantly reduced both the expression of TRPM2 and the amplitude of the ADPR-dependent current. Taken together, these results indicate that hippocampal pyramidal neurons possess functional TRPM2 channels whose activation by ADPR is functionally coupled to VDCCs and NMDARs through a rise in [Ca(2+)](i).

Activation of pannexin-1 hemichannels augments aberrant bursting in the hippocampus.

Pannexin-1 (Px1) is expressed at postsynaptic sites in pyramidal neurons, suggesting that these hemichannels contribute to dendritic signals associated with synaptic function. We found that, in pyramidal neurons, N-methyl-d-aspartate receptor (NMDAR) activation induced a secondary prolonged current and dye flux that were blocked with a specific inhibitory peptide against Px1 hemichannels; knockdown of Px1 by RNA interference blocked the current in cultured neurons. Enhancing endogenous NMDAR activation in brain slices by removing external magnesium ions (Mg2+) triggered epileptiform activity, which had decreased spike amplitude and prolonged interburst interval during application of the Px1 hemichannel blocking peptide. We conclude that Px1 hemichannel opening is triggered by NMDAR stimulation and can contribute to epileptiform seizure activity.

TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations.

Exposure to low Ca(2+) and/or Mg(2+) is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca(2+) overload and cell death. This phenomenon has been called the "Ca(2+) paradox" of ischemia-reperfusion. The mechanism by which a decrease in extracellular Ca(2+) and Mg(2+) is "detected" and triggers subsequent cell death is unknown. Transient periods of brain ischemia are characterized by substantial decreases in extracellular Ca(2+) and Mg(2+) that mimic the initial condition of the Ca(2+) paradox. In CA1 hippocampal neurons, lowering extracellular divalents stimulates a nonselective cation current. We show that this current resembles TRPM7 currents in several ways. Both (i) respond to transient decreases in extracellular divalents with inward currents and cell excitation, (ii) demonstrate outward rectification that depends on the presence of extracellular divalents, (iii) are inhibited by physiological concentrations of intracellular Mg(2+), (iv) are enhanced by intracellular phosphatidylinositol 4,5-bisphosphate (PIP(2)), and (v) can be inhibited by Galphaq-linked G protein-coupled receptors linked to phospholipase C beta1-induced hydrolysis of PIP(2). Furthermore, suppression of TRPM7 expression in hippocampal neurons strongly depressed the inward currents evoked by lowering extracellular divalents. Finally, we show that activation of TRPM7 channels by lowering divalents significantly contributes to cell death. Together, the results demonstrate that TRPM7 contributes to the mechanism by which hippocampal neurons "detect" reductions in extracellular divalents and provide a means by which TRPM7 contributes to neuronal death during transient brain ischemia.