Potential utility of renal functional reserve testing in clinical nephrology

PURPOSE OF REVIEW: The aim of this review is to discuss the concept of renal functional reserve (RFR) and its potential relevance in clinical practice. RECENT FINDINGS: The RFR is a measure of the change in glomerular filtration rate (GFR) from baseline to a peak value when the kidney is stimulated to increase its function. This concept has a strong physiologic basis in nephrology and the presence, magnitude or absence of RFR capacity may have prognostic significance in many clinical scenarios where individuals are at risk of hyperfiltration or kidney dysfunction. Unlike in other medical specialties, where organ reserve function is reliably measurable and used routinely, measurement of RFR in nephrology has not been integrated into clinical care. Methodologic challenges including standardization of methods to stimulate GFR and the ability of measures of GFR to discriminate acute dynamic changes in GFR upon kidney stimulation have hampered the robustness and use of RFR measurements in research and clinical care. SUMMARY: Given the emergence of many new disease-modifying therapies in nephrology, it is imperative that we move forward and develop more robust tools to further our understanding of kidney physiology and pathophysiology, such as the RFR, which should be integrated into research and clinical care to support optimal personalization of therapeutic kidney care strategies

Impact of early life development on later onset chronic kidney disease and hypertension and the role of evolutionary trade-offs

NEW FINDINGS What is the topic of this review? In this report, we summarize the latest clinical evidence linking developmental programming in the kidney to later life blood pressure and kidney disease. What advances does it highlight? Population-level studies now show convincingly that low birth weight, fetal growth restriction and preterm birth are associated with and have a synergistic impact on the risk of kidney disease in later life. A new approach also considers how evolutionary selection pressure might fail to select for long-term robustness of kidney function. ABSTRACT The global burden of kidney disease is high and rising. The risk of kidney disease among individuals is highly variable, in part related to genetic and environmental factors, but also likely to be modulated by developmental programming of the number of nephrons and kidney function in fetal life. The number of nephrons varies widely across the population and is lower among those who were born small or preterm. Population registry evidence clearly shows an association between these birth circumstances and later-life risk of hypertension and kidney disease, not only for chronic kidney disease but also for acquired kidney disease, demonstrating an inherent susceptibility to kidney disease in these individuals. Gestational stressors impact kidney development, a process that is likely to be layered upon the evolutionary history of the kidney and how the organ has developed in response to selection pressure to support reproductive capacity in early adulthood, but not to withstand multiple stresses later in life. Reducing the global burden of kidney disease in future generations will require both individual- and population/environment-level risks to be addressed

Low Nephron Number and Its Clinical Consequences

Epidemiologic studies now strongly support the hypothesis, proposed over two decades ago, that developmental programming of the kidney impacts an individual’s risk for hypertension and renal disease in later life. Low birth weight is the strongest current clinical surrogate marker for an adverse intrauterine environment and, based on animal and human studies, is associated with a low nephron number. Other clinical correlates of low nephron number include female gender, short adult stature, small kidney size, and prematurity. Low nephron number in Caucasian and Australian Aboriginal subjects has been shown to be associated with higher blood pressures, and, conversely, hypertension is less prevalent in individuals with higher nephron numbers. In addition to nephron number, other programmed factors associated with the increased risk of hypertension include salt sensitivity, altered expression of renal sodium transporters, altered vascular reactivity, and sympathetic nervous system overactivity. Glomerular volume is universally found to vary inversely with nephron number, suggesting a degree of compensatory hypertrophy and hyperfunction in the setting of a low nephron number. This adaptation may become overwhelmed in the setting of superimposed renal insults, e.g. diabetes mellitus or rapid catch-up growth, leading to the vicious cycle of on-going hyperfiltration, proteinuria, nephron loss and progressive renal functional decline. Many millions of babies are born with low birth weight every year, and hypertension and renal disease prevalences are increasing around the globe. At present, little can be done clinically to augment nephron number; therefore adequate prenatal care and careful postnatal nutrition are crucial to optimize an individual’s nephron number during development and potentially to stem the tide of the growing cardiovascular and renal disease epidemics worldwide

Preventing CKD in Developed Countries

Chronic kidney disease (CKD) is an important public health concern in developed countries because of both the number of people affected and the high cost of care when prevention strategies are not effectively implemented. Prevention should start at the governance level with the institution of multisectoral polices supporting sustainable development goals and ensuring safe and healthy environments. Primordial prevention of CKD can be achieved through implementation of measures to ensure healthy fetal (kidney) development. Public health strategies to prevent diabetes, hypertension, and obesity as risk factors for CKD are important. These approaches are cost-effective and reduce the overall noncommunicable disease burden. Strategies to prevent nontraditional CKD risk factors, including nephrotoxin exposure, kidney stones, infections, environmental exposures, and acute kidney injury (AKI), need to be tailored to local needs and epidemiology. Early diagnosis and treatment of CKD risk factors such as diabetes, obesity, and hypertension are key for primary prevention of CKD. CKD tends to occur more frequently and to progress more rapidly among indigenous, minority, and socioeconomically disadvantaged populations. Special attention is required to meet the CKD prevention needs of these populations. Effective secondary prevention of CKD relies on screening of individuals at risk to detect and treat CKD early, using established and emerging strategies. Within high-income countries, barriers to accessing effective CKD therapies must be recognized, and public health strategies must be developed to overcome these obstacles, including training and support at the primary care level to identify individuals at risk of CKD, and appropriately implement clinical practice guidelines

Climate change and its influence in nephron mass

PURPOSE OF REVIEW The consequences of climate change, including heat and extreme weather events impact kidney function in adults and children. The impacts of climate change on kidney development during gestation and thereby on kidney function later in life have been poorly described. Clinical evidence is summarized to highlight possible associations between climate change and nephron mass. RECENT FINDINGS Pregnant women are vulnerable to the effects of climate change, being less able to thermoregulate, more sensitive to the effects of dehydration, and more susceptible to infections. Exposure to heat, wildfire smoke, drought, floods and climate-related infections are associated with low birth weight, preterm birth and preeclampsia. These factors are associated with reduced nephron numbers, kidney dysfunction and higher blood pressures in offspring in later life. Exposure to air pollution is associated with higher blood pressures in children and has variable effects on estimated glomerular filtration rate. SUMMARY Climate change has important impacts on pregnant women and their unborn children. Being born too small or too soon is associated with life-time risk of kidney disease. Climate change may therefore have a dual effect of impacting fetal kidney development and contributing to cumulative postnatal kidney injury. The impact on population kidney health of future generations may be significant

Eculizumab in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: a systematic review

BACKGROUND: Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS. METHODS: PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively. RESULTS: A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations. DISCUSSION: Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients

Hemodialysis versus peritoneal dialysis in resource-limited settings

PURPOSE OF REVIEW To assess the use, access to and outcomes of hemodialysis and peritoneal dialysis in low-resource settings. RECENT FINDINGS Hemodialysis tends to predominate because of costs and logistics, however services tend to be located in larger cities, often paid for out of pocket. Outcomes of dialysis-requiring acute kidney injury and end-stage kidney disease may be similar with hemodialysis and peritoneal dialysis, and therefore choice of therapy is dominated by availability, accessibility and patient or physician choice. Some countries have implemented peritoneal dialysis-first policies to reduce costs and improve access, because peritoneal dialysis requires less infrastructure, can be scaled up more easily and can be cheaper when fluids are manufactured locally. SUMMARY Access to both hemodialysis and peritoneal dialysis remains highly inequitable in lower-resource settings. Although challenges associated with dialysis in low-resource settings are similar, and there are more adults who require dialysis in low-resource settings, addressing hemodialysis and peritoneal dialysis needs of children in low-resource settings requires attention as the global inequities are greatest in this area. Lower-income countries are increasingly seeking to improve access to dialysis through various strategies, but meeting the costs of the entire dialysis population continues to be a major challenge

Bedside rationing and moral distress in nephrologists in sub- Saharan Africa

Background Kidney diseases constitute an important proportion of the non-communicable disease (NCD) burden in Sub-Saharan Africa (SSA), though prevention, diagnosis and treatment of kidney diseases are less prioritized in public health budgets than other high-burden NCDs. Dialysis is not considered cost-effective, and for those patients accessing the limited service available, high out-of-pocket expenses are common and few continue care over time. This study assessed challenges faced by nephrologists in SSA who manage patients needing dialysis. The specific focus was to investigate if and how physicians respond to bedside rationing situations. Methods A survey was conducted among a randomly selected group of nephrologists from SSA. The questionnaire was based on a previously validated survey instrument. A descriptive and narrative approach was used for analysis. Results Among 40 respondents, the majority saw patients weekly with acute kidney injury (AKI) or end-stage kidney failure (ESKF) in need of dialysis whom they could not dialyze. When dialysis was provided, clinical compromises were common, and 66% of nephrologists reported lack of basic diagnostics and medication and > 80% reported high out-of-pocket expenses for patients. Several patient-, disease- and institutional factors influenced who got access to dialysis. Patients’ financial constraints and poor chances of survival limited the likelihood of receiving dialysis (reported by 79 and 78% of nephrologists respectively), while a patient’s being the family bread-winner increased the likelihood (reported by 56%). Patient and institutional constraints resulted in most nephrologists (88%) frequently having to make difficult choices, sometimes having to choose between patients. Few reported existence of priority setting guidelines. Most nephrologists (74%) always, often or sometimes felt burdened by ethical dilemmas and worried about patients out of hospital hours. As a consequence, almost 46% of nephrologists reported frequently regretting their choice of profession and 26% had considered leaving the country. Conclusion Nephrologists in SSA face harsh priority setting at the bedside without available guidance. The moral distress is high. While publicly funded dialysis treatment might not be prioritized in essential health care packages on the path to universal health coverage, the suffering of the patients, families and the providers must be acknowledged and addressed to increase fairness in these decisions

Understanding Similarities and Differences in CKD and Dialysis Care in Children and Adults

In lower-income settings there is often a dearth of resources and nephrologists, especially pediatric nephrologists, and individual physicians often find themselves caring for patients with chronic kidney diseases and end-stage kidney failure across the age spectrum. The management of such patients in high-income settings is relatively protocolized and permits high-volume services to run efficiently. The basic principles of managing chronic kidney disease and providing dialysis are similar for adults and children, however, given the differences in body size, causes of kidney failure, nutrition, and growth between children and adults with kidney diseases, nephrologists must understand the relevance of these differences, and have an approach to providing quality and safe dialysis to each group. Prevention, early diagnosis, and early intervention with simple therapeutic and lifestyle interventions are achievable goals to manage symptoms, complications, and reduce progression, or avoid kidney failure in children and adults. These strategies currently are easier to implement in higher-resource settings with robust health systems. In many low-resource settings, kidney diseases are only first diagnosed at end stage, and resources to pay out of pocket for appropriate care are lacking. Many barriers therefore exist in these settings, where specialist nephrology personnel may be least accessible. To improve management of patients at all ages, we highlight differences and similarities, and provide practical guidance on the management of children and adults with chronic kidney disease and kidney failure. It is important that children are managed with a view to optimizing growth and well-being and maximizing future options (eg, maintaining vein health and optimizing cardiovascular risk), and that adults are managed with attention paid to quality of life and optimization of physical health