The deposition of immune complexes, activation of complement and infiltration of the kidney by cells of the adaptive and innate immune systems have long been considered responsible for the induction of kidney damage in autoimmune, alloimmune and other inflammatory kidney diseases. However, emerging findings have highlighted the contribution of resident immune cells and of immune molecules expressed by kidney-resident parenchymal cells to disease processes. Several types of kidney parenchymal cells seem to express a variety of immune molecules with a distinct topographic distribution, which may reflect the exposure of these cells to different pathogenic threats or microenvironments. A growing body of literature suggests that these cells can stimulate the infiltration of immune cells that provide protection against infections or contribute to inflammation — a process that is also regulated by draining kidney lymph nodes. Moreover, components of the immune system, such as autoantibodies, cytokines and immune cells, can influence the metabolic profile of kidney parenchymal cells in the kidney, highlighting the importance of crosstalk in pathogenic processes. The development of targeted nanomedicine approaches that modulate the immune response or control inflammation and damage directly within the kidney has the potential to eliminate the need for systemically acting drugs.
Key points
Non-myeloid kidney parenchymal cells (KPCs) express molecules that are shared with immune cells; the expression of these molecules may have distinct topological associations and may increase in response to inflammation.
Kidney injury can induce the infiltration of immune cells; these cells may have protective or pro-inflammatory features depending on the phase of the disease process. In addition, kidney-resident immune cells may have a surveillance or regulatory role in the kidney but can accumulate in response to injury.
Components of the immune system, such as autoantibodies, cytokines and immune cells, can influence the metabolic profile of KPCs in the kidney.
Conversely, KPCs can contribute to inflammation by providing metabolites or through the secretion of chemokines and cytokines.
The cortex and the medulla of kidney tissue can contain distinct types of tertiary lymphoid organs, which may possess pathogenic or regulatory properties.
Targeted delivery of drugs to KPCs holds promise for preventing or reversing the inflammatory response in specific forms of kidney injury and disease.
In a randomized trial, letermovir was as effective as — but better tolerated than — valganciclovir.
Cytomegalovirus (CMV) seronegative recipients of kidney transplants from seropositive donors are at high risk for donor-to-recipient transmission of CMV and subsequent CMV disease. Universal prophylaxis with valganciclovir is highly effective in preventing CMV disease during the early post-transplant period, but leukopenia is common, resulting in discontinuation of prophylaxis or changes to the immunosuppressive regimen. Letermovir is a CMV-specific antiviral approved for prophylaxis after stem cell transplant. Now, researchers report results of a randomized noninferiority trial comparing letermovir to valganciclovir in CMV seronegative recipients of kidneys from seropositive donors.
In all, 601 participants received letermovir or valganciclovir for up to 200 days post-transplant. At 1 year, CMV disease developed in 10% (letermovir) versus 12% (valganciclovir) of recipients. No patient in the letermovir group developed letermovir resistance, compared with 12% valganciclovir resistance in the valganciclovir group. Drug discontinuation was more common in the valganciclovir arm (13% vs. 4%), primarily due to myelosuppression (64% vs. 26%).
Comment
When letermovir is used off-label to treat refractory or ganciclovir-resistant CMV, clinical failure and resistance have been observed (Transplantation 2020; 104:240. opens in new tab). Thus, it’s reassuring that letermovir resistance was not observed in this prophylaxis study. I plan to recommend letermovir for those recipients requiring CMV prophylaxis who cannot tolerate valganciclovir, although its high cost may limit its access. While this trial included only high-risk kidney recipients, extrapolating the results to other recipients of solid organ transplants is reasonable. Notably, on the basis of this study, the FDA recently approved letermovir for prevention of CMV disease in high-risk adult kidney transplant recipients. opens in new tab.
Person-centered care has been advanced as an effective framework for improving patient satisfaction. By considering biopsychosocial factors — including socioeconomic status, environment, intellectual development, health, cultural factors, and social interactions — such care can help optimize treatment outcomes, advance health equity, and decrease costs. However, these factors, adopted by the medical field and labeled social determinants of health, have been inconsistently evaluated, thereby missing an opportunity to truly understand the individual needing care. Furthermore, a balance of specific social determinants of health factors and assessments of cognition and functional status can improve understanding of a patient and their context. The authors explore new possibilities with a shift in assessment methodologies, using end-stage renal disease as a model, and present a vision for a more effective person-centered assessment model, which is increasingly possible — and needed — in the modern health care environment. A surprising finding from the qualitative interviews was the importance of social connections formed during in-center dialysis. Additional key considerations include financial barriers, transportation challenges due to financial and mobility limitation, housing insecurity, insufficient knowledge of kidney disease and treatment, and limited contact with nephrologists. This article proposes potential methods for improvement of care that can simultaneously improve patient engagement and outcomes.
Editors’ note: This case study is an early release from Volume 5, Issue 2 of NEJM Catalyst Innovations in Care Delivery. It will appear alongside other issue 5.2 articles in February 2024.
Person-centered care is particularly critical for those who experience chronic health conditions such as chronic kidney disease (CKD), which affects approximately 15% of adults in the United States and disproportionately affects people of low income and communities of color.1 Complicating care, up to 90% of people with CKD are unaware they have it. This is attributed to an absence of symptoms until later stages of the disease, which increases the likelihood of progression to kidney failure and end-stage renal disease (ESRD). Current treatments for ESRD include peritoneal dialysis, hemodialysis, and kidney transplant.
Total inflation-adjusted Medicare expenditures for patients with ESRD increased from $47.1 billion in 2010 to $53.0 billion in 2019.2 Between 2010 and 2020, inflation-adjusted per-patient-per-year spending for ESRD decreased from $96,451 to $79,439. The greatest decrease was in inpatient spending, to $25,313 in 2020 from $32,886 in 2010. Outpatient spending also decreased, to $27,973 in 2020 from $30,966 in 2010.
Although transplantation has the potential to significantly improve quality of life, reduce mortality, and decrease costs, only 13% of patients are deemed eligible for the transplant list, and there are no standardized protocols for selection, potentially revealing another selection bias in survival rates.2 Certain populations are disproportionately disadvantaged when it comes to being waitlisted. The following groups are significantly less likely to be listed for transplantation and hence many fewer receive transplants: older adults; Black, Latinx/Hispanic, Native American/Alaska Native, Native Hawaiian/Pacific Islander, and Asian American people; people of low income; and people with disabilities.3–6 In addition to these selection biases, such patients are also more likely to be dually eligible, that is, those who have insurance coverage by both Medicare and Medicaid, with low income (average less than $20,000 per year) and advanced age (≥65 years) or disability, and are likely to experience very different challenges than individuals covered by Medicare alone.
Needs-Finding in ESRD
In March 2023, the authors launched a quality improvement project focused on person-centered ESRD care delivery. This project was conducted as an independent study by researchers based at Stanford University’s Clinical Excellence Research Center in conjunction with DaVita Kidney Care. We developed a survey (Appendix) and worked from a list provided by DaVita Kidney Care of dually eligible patients who were receiving dialysis. We focused on dually eligible patients because there are approximately 12.3 million people7 in the United States who are dually eligible, and more than 30% of them experience CKD. In 2020, Medicare inflation-adjusted expenditures for ESRD beneficiaries with fee-for-service Medicare was $65,817, higher for Medicare Advantage beneficiaries at $75,263, and much higher for dually eligible beneficiaries at $94,532.2
Top themes identified by individuals undergoing dialysis treatment were related to food insecurity, low rates of home dialysis, transportation barriers, mobility limitations, housing insecurity, social isolation, and cognitive decline.
A semistructured survey was prepared with primarily open-ended questions that gauged patients’ dialysis experiences with respect to barriers to care they faced, knowledge barriers in ESRD/dialysis, perspectives on the practice of home dialysis, goals of care, and highlights in their care journey that could be used to shape improved care delivery. This approach was taken by examining the literature and adapting for qualitative surveys of patients’ experience in dialysis. From a list of 48, we successfully reached 28 patients, but only nine agreed to participate (Table 1). During interviews with this group, we found that the same general themes recurred and determined that we had reached a saturation of themes. This group included participants who resided in urban, suburban, or rural neighborhoods. Interviews were conducted via telephone. The duration of each interview ranged between 29 and 153 minutes (mean [standard deviation], 51.3 [40.3] minutes).
Table 1
Demographic Characteristics of ESRD Patient Interview Participants
Qualitative interviews with dually eligible ESRD patients were conducted to understand their multifaceted social needs. Interviews were conducted until saturation of themes was reached. Top themes identified by individuals undergoing dialysis treatment were related to food insecurity, low rates of home dialysis, transportation barriers, mobility limitations, housing insecurity, social isolation, and cognitive decline (Table 2).
Nearly all respondents expressed a belief that they were eating healthfully, while reporting diets consisting mostly of fast foods, frozen meals, and animal-based protein. Meal choices are often dictated by what individuals can afford with food assistance programs and/or can prepare with only a microwave or a limited cooking repertoire.8 However, all interviewees reported that they had been given “kidney-friendly” diet recommendations by clinicians, who often fail to consider the reality of the patient’s unique challenges, cultural factors, and preferences. Such a one-size-fits-all approach may limit the effectiveness of treatment plans, diminish rapport between patients and providers, and compound challenges, including limited patient engagement, fragmented care coordination, and suboptimal treatment outcomes.
Approximately 90% of all dually eligible patients in the United States receive dialysis in outpatient dialysis centers despite the goal of the U.S. Department of Health and Human Services of having 80% of patients with ESRD undergoing dialysis at home or receiving a transplant.9,10 In accordance with previous literature, we found that dually eligible patients were less likely to engage in home dialysis due to challenges related to social determinants of health (SDOH), such as housing instability, lack of resources or support systems, and limited health literacy.11,12 In addition, previously reported improved outcomes for home dialysis over in-center dialysis may be applicable only to specific subgroups of patients, such as those with significant support systems, stable housing, and those in better overall health, which often excludes dually eligible patients.13,14
As with nutrition recommendations, health care–centric assumptions about quality of life with different kidney care options might contradict an individual’s preferences; therefore, treatment options warrant tailoring to nuances not routinely captured in clinical settings.
Although in-center dialysis may pose a hardship, both in terms of time (three times a week, for several hours a day) and accessibility to patients who may have to travel 30–60 minutes in each direction to the nearest center, all of the dually eligible in-center interviewees stated that they preferred in-center dialysis for social connection; only one was open to in-home dialysis. Almost all (eight of nine) had to stop working due to dialysis, further limiting outside contact with other people. Interviewees expressed that they had formed strong friendships with staff and other patients through seeing them several times a week, over many years. For example, interviewees stated that staff would make ethnic, home-cooked meals to share; that talking with fellow dialysis patients was their social connection; and that seeing the same people multiple times a week for years was its own support group. Interviewees also stated that they utilized their dialysis time to learn about treatment options, or other tips, from fellow dialysis patients. As with nutrition recommendations, health care–centric assumptions about quality of life with different kidney care options might contradict an individual’s preferences; therefore, treatment options warrant tailoring to nuances not routinely captured in clinical settings. Ultimately, specific challenges and needs and preferences must be addressed if we are to advance kidney health for all patients.
Broadening Assessment to Include Cognitive and Functional Status
In addition to physical decline, CKD/ESRD has been linked to an increase in risk for cognitive decline, as have social isolation and loneliness, further emphasizing the importance of social engagement and the inclusion of cognitive and functional screening in addition to SDOH screening.15–17 Dually eligible individuals who experience cognitive challenges may have difficulty understanding their disease and treatment options. In interviews, some dually eligible patients (six of nine) expressed a lack of comprehension regarding what dialysis was or what dialysis entailed even after education by the dialysis center and/or clinicians, whereas others (two of eight) indicated that they preferred to be naive regarding their disease or treatments; many (six of nine) said that they hoped that providers would spend more time explaining procedures and treatments. Some (three of nine) patients expressed dismay at how dialysis has restricted their lives and daily activities. Persons living with a complicated disease such as ESRD and, in particular, those experiencing cognitive decline would uniquely benefit from increased time with clinicians so that the clinicians can check for comprehension and iterate the care plan, as needed and on a more timely basis.
A majority of interviewees (seven of nine) did not drive, which often was attributed to cognitive and mobility challenges, as well as financial and SDOH barriers. Functional difficulties with bathing, cooking, or other activities of daily living were also often reported (seven of nine). This was especially salient for those who lived alone or lacked support. Several of these patients (three of seven) relied on professional caregivers; some visited three or four times a week, which underscores the importance of understanding individual needs and barriers to engaging in critical health-promoting behaviors.
Understanding Context
Clinical, cognitive, and functional assessments can help to evaluate multidimensional risks for poor health outcomes, as well as provide opportunities for prevention and early intervention, especially for older adults who are more likely to experience a confluence of chronic conditions. Since December 2020, the Centers for Medicare & Medicaid Services (CMS) Advancing Interoperability and Improving Prior Authorization Processes Proposed Rule (85 FR 82586, which was later incorporated into the pending proposed rule CMS-0057-P), has called for accelerating the adoption of standards related to social risk factor data. In the wake of these calls to action, nearly one-quarter of hospitals are now screening for SDOH.18,19 When used in tandem with cognitive and functional assessments, these tools have shown enormous potential for identifying and serving complex, high-needs populations such as dually eligible patients with ESRD. For example, health technology companies have already effectively used functional and cognitive screening data to show how these factors are predictive of ED visits.20
One critical finding was the disparity between clinical recommendations and the lived realities of patients, especially in terms of diet and treatment options.
CMS has expressed interest in improving best practices for collecting functional, cognitive, and social risk data; new technologies should be leveraged to efficiently capture such data across a range of contexts.21 Rather than merely combining lengthy combinations of cognitive and functional assessments with SDOH indicators, new approaches aligned with the realities of telehealth, asynchronous care, and remote patient monitoring present exciting prospects for reimagining the assessment and triage process. For example, artificial intelligence–assisted telehealth, which includes routine wellness questions and evaluates responses, can easily capture important health data for patients with ESRD, potentially predicting future health issues. In addition, experimental wearable devices that assess social engagement could provide a more holistic and continuous picture of patient health, improving accuracy and outcomes without overburdening clinicians.22
To craft such integrated assessments, several prerequisites should be considered:
•
Instruments should capture functional, cognitive, and SDOH data across medical, social, and behavioral health domains, to improve health equity and promote shared decision-making.
•
Ease of use, workflow integration, and clinical and patient acceptability of these instruments must be considered and codesigned.
•
Streamlined screening instruments must be tied to modifiable outcomes of interest and be incentivized by informing standardized billing metrics.
•
Instruments must practically incorporate medical, social, and behavioral health needs to better inform clinician treatment planning.
Looking Ahead
Moving forward, the potential of this pilot qualitative study to shape care delivery for dually eligible patients with ESRD is noteworthy, particularly given the relative dearth of studies examining this unique clinical and demographic intersection. Despite the small number of interviews, the sessions lasted on average nearly 1 hour and encouraged open-ended input from participants on their experience of care. One critical finding was the disparity between clinical recommendations and the lived realities of patients, especially in terms of diet and treatment options. Individuals additionally face unique challenges such as financial limitations or lack of social support, which can hinder adherence to home-based care plans.
Based on these insights, we recommend that clinicians engage in conscientious, thorough discussions with patients at the outset of treatment — taking into account their social, cultural, and personal circumstances — to ultimately improve outcomes and drive down costs in the long term. For instance, dietary recommendations should be not only “kidney friendly,” but also realistic and achievable within the patient’s means. Similarly, decisions about dialysis modalities should involve a detailed discussion about the patient’s living conditions and support systems. These practices are not just suggestions, but important steps toward truly person-centered care, ensuring that treatment plans are medically sound as well as practically feasible and aligned with individual preferences. Thus, the findings from the current study may reinforce critical practices and ongoing shifts in kidney care, including an improved focus on the social determinants of kidney health. Further, it may open new vistas into opportunities to improve staffing, processes, or clinical/SDOH-related activities.
Our experience suggests that a thorough and empathetic understanding of the individual’s socioeconomic background, cultural influences, and personal preferences is critical.
In addressing the optimal mix of care delivery methods for patients with ESRD, it is important to consider the individualized needs of each patient, particularly those who are dually eligible. Our findings underscore the need for a more nuanced approach to care delivery. For instance, although at-home dialysis offers convenience and comfort, it may not be suitable for patients facing social isolation or financial barriers that may preclude ease of application in the home. In-clinic dialysis, on the other hand, may provide essential social interaction and support, but may present transportation and mobility challenges. Lastly, although kidney transplantation is the most desirable option for many, its limited availability and eligibility criteria make it an inaccessible choice for a significant portion of patients. Therefore, we recommend a person-centered framework in which care delivery is tailored based on a comprehensive assessment of each individual’s medical, social, and personal needs. This approach would enable more effective and personalized treatment plans, enhancing both outcomes and quality of life.
In implementing a person-centered care model for ESRD, particularly for dually eligible individuals, health care providers may encounter several challenges. First, accurately assessing and integrating individual needs and preferences into care plans can be complex, given the diverse and often underrepresented backgrounds of these individuals. Our experience suggests that a thorough and empathetic understanding of the individual’s socioeconomic background, cultural influences, and personal preferences is critical. This may require additional training for health care providers in cultural competence and communication skills. Furthermore, it is critical to measure what matters and to concretely identify the full breadth of the individual experience for those who engage in dialysis.
To this end, the creation of integrated assessment instruments that more effectively capture the whole person — including the full spectrum of lived experiences, context, and behaviors — offers much promise in building person-centered care models. For clinicians, improved assessments that consider clinical, cognitive, functional, and social determinants of health can improve the identification of clinical risks without additional burden and enable earlier, upstream intervention. For health plans and the government, standardized novel data collection instruments can foster progress toward value-based care and national policy goals. For individuals, such as those with ESRD, more holistic measures and new technologies can help with the efficient capture of the full depth and breadth of an individual’s experience and better align health care with what matters most to patients.
However, challenges lie in the adoption of new technologies for patient monitoring and data collection. Although these technologies offer promising avenues for enhancing care, their integration into existing health care systems can be hindered by logistical, financial, and technical barriers. To address these challenges, we recommend collaborative efforts involving multidisciplinary teams, including IT specialists, to ensure smooth technology integration and staff training. Health care organizations should consider pilot-testing these technologies in selected patient groups to identify and address potential issues before wider implementation. Finally, maintaining consistent and open communication throughout this process is vital to ensure that needs and concerns are continually addressed, fostering trust and engagement in the care journey.
Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.
Introduction
Chronic kidney disease (CKD) affects approximately 10% of the world’s population and is associated with substantial morbidity and mortality.1 Risks of kidney failure, acute kidney injury, heart failure, cardiovascular disease, and hospital admissions are all heightened in people with CKD.2 The Global Burden of Disease Consortium projects that CKD will be in the top five conditions contributing to years of life lost by 2040.3 However, CKD remains under-recognized by both patients and providers.1 A diverse entity, CKD is most commonly attributed to diabetes or high blood pressure, but many other causes exist, from genetic causes to adverse effects of drugs to autoimmune processes.2 In this review, we summarize the evidence for current paradigms of disease identification and classification, discuss new equations developed for estimating glomerular filtration rate (GFR) and harmonizing different measures of albuminuria, report major progress in individualized risk estimation of kidney failure and other adverse outcomes both for CKD in general and within specific disease entities, and describe longstanding and novel treatment strategies. Notable advances have been made in both general and cause specific therapies, including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists (MRA), and endothelin receptor antagonists. Finally, we describe major guidelines in CKD and highlight common themes as well as differences in their recommendations.
Sources and selection criteria
We searched PubMed for peer reviewed articles in the English language from 1 January 2010 to 14 July 2023 using the keywords listed in the web appendix. We additionally reviewed reference lists of selected articles, prioritizing randomized controlled trials, systematic reviews, and meta-analyses when possible but also including observational studies and reviews that were of high quality. We included older articles if we deemed them to be of high importance. Finally, we reviewed guidelines from websites of professional societies and advisory committees (for example, the National Institute for Health and Care Excellence (NICE), Kidney Disease: Improving Global Outcomes (KDIGO), US Centers for Disease Control and Prevention, US Department of Health and Human Services, and International Society of Hypertension).
Epidemiology
CKD is a global public health crisis. Recent estimates suggest that more than 700 million people have CKD, with greater burdens in low income and middle income countries.14 Determining the global, regional, and national burden of disease is challenging owing to inconsistent use of estimating equations for GFR, laboratory assay standardization, and albuminuria testing. Despite this, some important observations can still be made. The prevalence of CKD increases with age and is greatest in people over 70 years.2 In the US, compared with White people, Black people have substantially higher rates of kidney failure, followed by Native Americans, people of Hispanic ethnicity, and people of Asian descent.5
The most commonly reported risk factors for CKD are diabetes mellitus and hypertension.67 Social determinants of health are also important and likely contribute to racial disparities in kidney disease. Specific genetic variants increase risk of CKD, including variants in the APOL1 and HBB genes that are present in far greater proportions among people of African ancestry.891011 In Central America, Sri Lanka, Egypt, and Central India, defined geographic areas exist where many cases of CKD of unknown cause have been identified.12 Some experts postulate that heat stress or pesticides may contribute.
Whereas the incidence of CKD is difficult to estimate, reliant as it is on testing for GFR and albuminuria, the incidence of kidney failure with the receipt of replacement therapy (KFRT) is more readily captured. Many countries have developed national registries of patients with kidney failure, allowing comparison of incidence across ages and countries.13 For example, the countries with the highest incidence of treated kidney failure in 2020 were Taiwan, the US, and Singapore, whereas the countries with the highest prevalence were Taiwan, the Republic of Korea, and Japan.5
Definition and classification of CKD: cause, GFR, and albuminuria staging
CKD is defined as persistent abnormalities in kidney structure or function for more than three months, manifest as either low GFR or presence of a marker of kidney damage.2 Specifically, diagnosis requires one or more of the following: albuminuria, defined as an albumin-to-creatinine ratio (ACR) ≥30 mg per gram of creatinine (approximately ≥3 mg/mmol) or albumin excretion of ≥30 mg/day; GFR <60 mL/min/1.73 m2; abnormalities on urine sediment, histology, or imaging; electrolyte or other abnormalities attributed to tubular disorders; or history of kidney transplantation. The KDIGO heat map helps with understanding of overall risk (low, moderately increased, high, and very high) of patients according to level of albuminuria (A category), level of GFR (G category), and cause of disease (fig 1), such that people with normal estimated GFR but higher albuminuria have a similar risk to people with moderately reduced estimated GFR and no albuminuria.
Fig 1
Kidney Disease: Improving Global Outcomes heat map with guidance on monitoring.2 Numbers in boxes indicate recommended frequency of monitoring (number of times per year). Colors denote risk as follows: green (low risk), yellow (moderately increased risk), orange (high risk), and red (very high risk). CKD=chronic kidney disease; GFR=glomerular filtration rate
Albuminuria is often the first sign of kidney damage, and its detection drives many treatment decisions.2 The prevalence of albuminuria in people with diabetes or hypertension is estimated to be 32% and 22%, respectively.14 However, only a minority of patients receive urine screening tests.1415 For example, the mean albuminuria screening rates across health systems in the US were 35% among adults with diabetes and 4% among adults with hypertension.14
The gold standard for assessing albuminuria is either a sample collected mid-stream from an early morning urine void or a 24 hour urine collection; however, in situations where this is not possible, a spot collection is reasonable.2 Quantification of albumin is preferred over that of total protein.216 This preference is because the sensitivity of the total protein assay to different protein components can vary by laboratory, as well as the fact that proteinuria assessments do not easily discriminate A1 and A2 categories. Both urine albumin and urine protein are typically indexed to urine creatinine to account for differences in dilution, as urine ACR or urine protein-to-creatinine ratio (PCR). Dipstick protein assessment is generally more economical than both methods; however, like PCR, dipstick assessment can be insensitive in A1 and A2 categories. Although conversion calculators exist to aid in the harmonization of ACR and PCR measures; they do not work well at lower ranges of albuminuria.1718
GFR
The second axis for CKD classification focuses on GFR.2 The gold standard for assessing GFR is direct measurement from clearance of an exogenous filtration marker such as iohexol or iothalamate; however, this is relatively cumbersome and rarely done in clinical practice. Instead, GFR is usually estimated by using plasma or serum concentrations of endogenous filtration markers, such as creatinine and cystatin C, and demographic variables. Early equations for adults, such as Modification of Diet in Renal Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) 2009 equations, used filtration markers along with age, sex, and race (Black versus non-Black) to estimate GFR.192021 The newer European Kidney Function Consortium equation, which allows for seamless GFR evaluation from infancy to old age, uses a population specific divisor to adjust creatinine values (for example, separate values for Black European and White European populations).22 However, the use of race in GFR estimation has faced strong criticism and, in 2021, the US based American Society of Nephrology-National Kidney Foundation Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recommended immediate adoption of the race-free CKD-EPI 2021 estimating equations, which exist for creatinine alone (eGFRcr) as well as for creatinine and cystatin C (eGFRcr-cys).232425 Cystatin C has distinct confounders (non-GFR determinants) of its relation with GFR compared with creatinine (fig 2).226 Thus, eGFRcr-cys is a more accurate estimate of GFR than eGFRcr alone, irrespective of equation used, in most scenarios, including those in which large differences exist between eGFRcr and that estimated solely using cystatin C (eGFRcys).252728 However, the newest GFR estimating equations have not been tested extensively in Asian populations.2930
Fig 2
Common non-glomerular filtration rate (GFR) determinants of blood concentrations of creatinine and cystatin C.226 eGFR=estimated glomerular filtration rate
The third axis for classification is cause of CKD, which is generally ascertained through imaging, assessment of extrarenal manifestations and biomarkers, or kidney biopsy.2 Classification of cause typically hinges on the presence or absence of systemic disease (for example, obesity, diabetes, hypertension, systemic autoimmune disease) and the specific location of the kidney pathology (for example, glomeruli, tubulointerstitium, vasculature, or cystic/congenital abnormality). Unfortunately, the cause of CKD is often unknown, limiting its utility. Molecular phenotyping and genetic testing are increasingly being used to assign cause of disease. Targeted gene panels offered commercially may have high diagnostic yields in select populations, such as patients with glomerular disease, nephrotic syndrome, or congenital anomalies of the kidney and urinary tract.31 One study suggested that for appropriately selected patients, 34% had disease either reclassified or assigned on the basis of genetic testing, thus changing clinical management.32 The European Renal Association and the European Rare Kidney Disease Reference Network have issued a joint statement providing recommendations for how to provide genetic testing, including specific settings in which it may be considered (box 1).33
Box 1
European Renal Association and European Rare Kidney Disease Reference Network recommendations for settings in which genetic testing might be considered33
Most tubulopathies
Glomerulopathies:
Congenital nephrotic syndrome
Nephrotic syndrome refractory to standard steroid therapy
Multi-organ phenotypes suggestive of syndromic steroid resistant nephrotic syndrome
Identifying the cause of CKD is critical as different causes of CKD carry different prognoses and can have distinct treatments.2 For example, autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of CKD and is typically associated with faster progression than other disease entities.3234 Individualized prognosis is often determined by using disease specific risk classification or calculators (for example, the Mayo classification or the ADPKD Prognostic Tool), and screening and treatment recommendations such as increased fluid intake and tolvaptan are unique to this entity.35363738 IgA nephropathy, the most common type of glomerulonephritis worldwide, particularly in East Asian and Pacific Asian countries,39 has its own prognostic aids, such as the International IgA Nephropathy Prediction Tool,4041 and treatments specific to IgA nephropathy are in various stages of development.42 The APOL1 high risk genotypes confer about twofold higher risk of kidney failure in the general population and are common in people of African ancestry.8434445 A recently published phase 2A study of targeted therapy for APOL1 related disease showed promising reductions in albuminuria; the phase 3 study is ongoing.46 Other disease specific therapies are increasingly available, such as belimumab in lupus nephritis and lumasiran for primary hyperoxaluria type 1.4748
Individualized risk prediction is also available for more general populations of patients with CKD. The most widely known and validated is the kidney failure risk equation (KFRE), which is used in patients with GFR <60 mL/min/1.73 m2.49 Tested in more than 30 countries and 700 000 people, the tool provides probabilities of kidney failure at two years and five years based on age, sex, and estimated GFR and albuminuria levels.50 Like all risk equations, the KFRE may perform better with recalibration to absolute risk levels of local populations, but the discriminatory ability (that is, distinguishing people at high risk from those at low risk) has been extremely consistent across all studies. The KFRE has also been validated in recipients of kidney transplants.5152 Although the KFRE does not explicitly take into account the competing risk of death, estimates are quite accurate except among the members of the oldest segments of the population at the highest risk.53 One study suggested that the KFRE provides more accurate prediction of kidney failure than both patients and providers.54 Even within categories of GFR and urine ACR, the KFRE provides a wide estimate of risk prediction, which can be helpful in the counseling and referral of patients (fig 3). Some centers will refer patients with a two year risk of kidney failure greater than 20-40% for vascular access and kidney transplantation evaluation, on the basis that tools that incorporate albuminuria provide more accurate and unbiased time to kidney failure than does estimated GFR alone.55 Studies suggest that the KFRE is robust to different GFR equations (specifically, CKD-EPI 2009 and CKD-EPI 2021) and that many patients value being counseled using this information.5356
Fig 3
Range of predicted risk of kidney failure using the kidney failure risk equation (KFRE) within G and A categories of chronic kidney disease (CKD). The KFRE (ckdpcrisk.org/kidneyfailurerisk) was used to estimate two year risk of kidney failure in 350 232 patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 from the Optum Laboratories Data Warehouse (OLDW). OLDW is a longitudinal, real world data asset with deidentified administrative claims and electronic health record data. Patients with eGFR and albuminuria (urine albumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, or dipstick protein) within a two year window were included in this analysis. Different measures of albuminuria were harmonized to ACR levels for A categories (ckdpcrisk.org/pcr2acr)
Other risk equations exist to predict the risk of cardiovascular disease and death in CKD; some of these do consider the competing risk of death (www.ckdpcrisk.org). For example, the advanced CKD risk tool provides simultaneous estimates of kidney failure, cardiovascular disease, and death for patients with estimated GFR <30 mL/min/1.73 m2, which can inform decisions on access placement and reinforce the importance of cardiovascular risk reduction.57 Estimating risks of cardiovascular disease is particularly relevant given that many more patients with CKD have cardiovascular disease events than need KFRT.58 Other efforts incorporate estimated GFR and albuminuria into existing tools, such as SCORE2 and the pooled cohort equation for the prediction of cardiovascular disease.5960
Patient specific prognostic clues may stem from discrepant estimated GFR values between eGFRcr and eGFRcys.616263 When eGFRcys is substantially lower than eGFRcr, the risk for kidney related laboratory abnormalities (for example, anemia, hyperuricemia, and hyperphosphatemia) and subsequent adverse outcomes (for example, kidney failure, heart failure, and mortality) is higher.616465 By contrast, having a lower eGFRcr than eGFRcys is associated with lower risk of adverse outcomes.66 Risk factors for having a discrepancy between eGFRcr and eGFRcys include older age, female sex, higher body mass index, recent weight loss, and smoking.
General principles of management
The mainstays of therapy for patients with CKD include treating the underlying cause if known, and correcting risk factors (for example, albuminuria) for CKD progression and other CKD related complications (fig 4).2
Fig 4
Comprehensive care of patients with chronic kidney disease (CKD), irrespective of cause
The three major studies for evaluating the optimal blood pressure target in CKD were the Modification of Diet in Renal Disease Study (MDRD), African American Study of Kidney Disease and Hypertension (AASK), and Systolic Blood Pressure Intervention Trial (SPRINT).676869 In both MDRD and AASK, intensive blood pressure control did not slow GFR decline overall.6768 However, in MDRD, participants with baseline proteinuria of ≥3 g/day seemed to benefit from intensive blood pressure control, with slower mean rates of GFR decline compared with their counterparts in the usual blood pressure control group.67 Among SPRINT participants with baseline CKD (n=2646), aiming for a systolic blood pressure goal of <120 mm Hg versus <140 mm Hg did not significantly reduce the risk for a composite kidney outcome that included a ≥50% reduction in estimated GFR, long term dialysis, or kidney transplant.6970 However, benefits of intensive blood pressure control were seen with respect to prevention of the composite cardiovascular outcome (defined as myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes—hazard ratio 0.75, 95% confidence interval 0.64 to 0.89) and all cause mortality (hazard ratio 0.73, 0.60 to 0.90), regardless of CKD status.69 Blood pressure control can also reduce albuminuria, as shown in the Chlorthalidone in Chronic Kidney Disease (CLICK) trial of chlorthalidone in advanced CKD.71
Glycemic targets
Among patients with diabetes and CKD, glycemic control is an important component of comprehensive care.72 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was the largest trial of intensive glucose control to enroll patients with CKD.73 Among the 11 140 trial participants, 19% had an estimated GFR <60 mL/min/1.73 m2 and 31% had albuminuria at baseline.74 Compared with standard glucose control, intensive glucose control was associated with 9% (hazard ratio 0.91, 0.85 to 0.98), 30% (0.70, 0.57 to 0.85), and 65% (0.35, 0.15 to 0.83) lower risks of developing new onset ACR 30-300 mg/g, ACR >300 mg/g, and end stage kidney disease (ESKD), respectively.
Specific classes of therapy
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers
When choosing antihypertensive agents, those that act by inhibiting the renin-angiotensin-aldosterone system (RAAS) have particular relevance in CKD. A 2001 meta-analysis of 11 studies suggested that, for non-diabetic CKD, the use of angiotensin converting enzyme (ACE) inhibitors resulted in a 30% reduction in risk of KFRT or doubling of serum creatinine.75 Clinical trials in populations with CKD and diabetes (for example, IDNT, RENAAL) have also shown benefit of angiotensin receptor blockers (ARB) in preventing CKD progression (table 1).7778 RAAS inhibition also plays a role in prevention of cardiovascular disease. The Heart Outcomes Prevention Evaluation (HOPE) study showed that ACE inhibitors reduced the risks of myocardial infarction, stroke, and cardiovascular death in populations at high risk for cardiovascular disease, including those with diabetes and albuminuria.80 The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) showed that ACE inhibitors and ARB were generally equivalent in the prevention of cardiovascular events.81 Because of the increased risk of hyperkalemia and acute kidney injury, dual therapy with both an ACE inhibitor and an ARB is typically avoided.82
Table 1
Landmark randomized clinical trials on angiotensin converting enzyme inhibitors or angiotensin receptor blockers in chronic kidney disease
When GFR declines, providers often grapple with whether RAAS inhibitors should be continued. The Benazepril in Advanced CKD study showed that benazepril reduced the risk of the primary composite kidney endpoint by 43% compared with placebo, thus suggesting that RAAS inhibitors are beneficial even in advanced CKD (baseline serum creatinine 3.1-5.0 mg/dL).79 Three recent reports further explored this question, also examining the benefits in prevention of death and cardiovascular events associated with continuation of RAAS inhibitors.838485 A retrospective, propensity score matched study of patients with estimated GFR <30 mL/min/1.73 m2 showed higher risk of all cause mortality and major adverse cardiovascular events in those who stopped RAAS inhibitors compared with those who continued them,83 as did a Swedish trial emulation study.84 The risk of kidney replacement therapy associated with cessation of RAAS inhibitors was not statistically significant in the first study and lower in the second study.8384 In an open label randomized trial, cessation of RAAS inhibitors did not show significant between group differences in long term decline in estimated GFR or initiation of kidney replacement therapy, providing reassurance that RAAS inhibitors can be safely continued as GFR declines.85
SGLT-2 inhibitors
One of the biggest advancements in CKD management over the past decade was the discovery that SGLT-2 inhibitors have robust protective effects on the heart and kidneys in patients with and without diabetes. Recent trials showed an approximate 30% reduction in risk for diverse kidney outcomes among patients with baseline estimated GFR values as low as 20 mL/min/1.73 m2 (table 2).86888991 Importantly, the three trials designed with primary kidney outcomes (Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE), Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD), and Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY)) were terminated early because pre-specified efficacy criteria were met, with median follow-up times ranging from 2.0 to 2.6 years.888991 The overwhelming majority of trial participants were taking an ACE inhibitor or ARB before randomization, showing that the benefits of SGLT-2 inhibitors on slowing CKD progression are additive to those of RAAS inhibitors. One simulation study estimated that a 50 year old adult with non-diabetic albuminuric CKD would have seven extra years free from doubling of serum creatinine, kidney failure, or all cause mortality if treated with an SGLT-2 inhibitor and RAAS inhibitor.92
Table 2
Landmark randomized clinical trials on sodium-glucose co-transporter 2 inhibitors in chronic kidney disease (CKD)
Subgroup analyses of the DAPA-CKD and EMPA-KIDNEY trials have provided additional insights on the wide range of patients who are likely to benefit from SGLT-2 inhibitors.8991 In DAPA-CKD, dapagliflozin was favored over placebo in all pre-specified subgroups by baseline age, sex, race, diabetes status, systolic blood pressure, estimated GFR (<45 v ≥45 mL/min/1.73 m2), and ACR (≤1000 v >1000 mg/g or ≤113 v >113 mg/mmol).89 Similarly, in EMPA-KIDNEY, empagliflozin was associated with lower risk of the primary composite outcome compared with placebo regardless of baseline diabetes status or estimated GFR (<30 v ≥30 mL/min/1.73 m2 to <45 v ≥45 mL/min/1.73 m2).91 The risk of the primary outcome was not lower among patients with ACR ≤300 mg/g (approximately ≤30 mg/mmol). In exploratory analyses, however, empagliflozin was associated with slower annual rates of decline in estimated GFR compared with placebo among participants with ACR between 30 and 300 mg/g (approximately 3-30 mg/mmol) and slower chronic slope (from two months to the final follow-up visit) among all ACR subgroups.
The DAPA-CKD trial also showed that the kidney protective effects of SGLT-2 inhibitors extend to patients with IgA nephropathy and perhaps also those with focal segmental glomerulosclerosis (FSGS).9394 Among 270 participants with IgA nephropathy (mean estimated GFR 44 mL/min/1.73 m2; median ACR 900 mg/g (102 mg/mmol)), dapagliflozin was associated with a 71% lower risk of developing the primary outcome and a 70% lower risk of ESKD compared with placebo.93 Among the 104 participants with FSGS (mean estimated GFR 42 mL/min/1.73 m2; median ACR 1248 mg/g (141 mg/mmol)), dapagliflozin was not associated with a lower risk of the primary composite outcome, although this analysis was limited in power (only 11 events).94 In exploratory analyses, dapagliflozin was associated with slower chronic decline in estimated GFR in the FSGS population. Investigations on the use of SGLT-2 inhibitors in other patient populations, such as those with polycystic kidney disease and kidney transplant recipients, are ongoing (clinicaltrials.gov).
SGLT-2 inhibitors, which act at the level of the proximal tubule to block the reabsorption of glucose and sodium,95 are generally safe to use in patients with CKD. Early signals of heightened risks of volume depletion, serious genital infections, bone fractures, and need for limb amputation in the Canagliflozin Cardiovascular Assessment Study (CANVAS) were not observed in subsequent studies—CREDENCE, DAPA-CKD, and EMPA-KIDNEY—thus assuaging these concerns (table 3).86888991 A pooled analysis of 15 081 participants with type 2 diabetes and CKD G3-4 showed similar rates of serious adverse events for empagliflozin versus placebo, with a higher rate only of mild genital infections with the SGLT-2 inhibitor.96 A real world study of patients receiving SGLT-2 inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors found no increased risk of outpatient urinary tract infections or severe urinary tract infection events requiring hospital admission.97
Table 3
Adverse effects of SGLT-2 inhibitors* in CANVAS, CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials
GLP-1 receptor agonists have also been shown to improve kidney outcomes among patients with type 2 diabetes, albeit in trials that were designed for primary cardiac outcomes (table 4).9899100101102103104105106107108109 The reduction in risk of kidney outcomes, which included albuminuria, ranged from 15% to 36%. A large meta-analysis of approximately 44 000 participants from the six trials in table 4 reported that use of GLP-1 receptor agonists was associated with a 21% lower risk of developing the composite kidney outcome, defined as new onset albuminuria >300 mg/g, doubling of serum creatinine, ≥40% decline in estimated GFR, kidney replacement therapy, or death due to kidney causes, compared with placebo.100 This risk reduction seemed to be driven by the reduction in incident albuminuria >300 mg/g; associations between GLP-1 receptor agonists and CKD progression and kidney failure were not statistically significant. However, results were more promising in A Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease (AWARD-7), a clinical trial designed to evaluate change in glycated hemoglobin.110 Among 577 adults with type 2 diabetes and CKD G3-4 randomized to open label dulaglutide 1.5 mg once weekly, dulaglutide 0.75 mg once weekly, or insulin glargine daily, both dulaglutide groups had slower estimated GFR declines compared with the insulin glargine group; among participants with baseline albuminuria >300 mg/g, dulaglutide was associated with greater ACR reductions in a dose dependent manner over the one year follow-up.
Table 4
Landmark randomized clinical trials on associations of glucagon-like peptide-1 (GLP-1) receptor agonists with secondary kidney outcomes among patients with type 2 diabetes mellitus
Exact mechanisms by which the GLP-1 receptor agonists slow decline in estimated GFR and/or reduce albuminuria are not entirely clear, but proposed mechanisms include improved glycemic control, weight loss, increased natriuresis, and reduced inflammation and oxidative stress.111112113 Adverse effects observed with this class of drugs have included diarrhea, nausea, and vomiting.103104107109110
Mineralocorticoid receptor antagonists
Several MRAs are available and can be useful adjuncts to RAAS inhibitors, particularly among populations with albuminuria and/or diabetes. Two common steroidal non-selective MRAs, spironolactone and eplerenone, both lower albuminuria.72 In a meta-analysis of 372 participants from seven trials, combination therapy with a non-selective MRA and an ACE inhibitor and/or ARB was associated with a significant reduction in proteinuria, albeit with a higher risk of hyperkalemia.114 Finerenone, a non-steroidal selective MRA, was also recently approved.115 Compared with the steroidal non-selective MRAs, finerenone has a stronger selectivity for the mineralocorticoid receptor, a shorter half life, less of a blood pressure lowering effect, and a more favorable side effect profile, as well as potentially greater anti-inflammatory and antifibrotic effects.115116117 The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial were two complementary phase 3 clinical trials designed to investigate the kidney and cardiovascular benefits of finerenone, respectively, in people with albuminuria levels ≥30 mg/g and type 2 diabetes (table 5).116118 Both trials included patients taking maximally tolerated ACE inhibitor or ARB, with participants in FIDELIO-DKD generally having more severe baseline CKD. In a pooled analysis of the two trials, finerenone was associated with a 15-23% lower risk of developing the kidney composite outcomes and a 32% lower mean change in ACR from baseline to four months.119 Hyperkalemia was more frequent among patients randomized to finerenone (14%) compared with placebo (7%). In pre-specified analyses, baseline SGLT-2 inhibitor use (n=877) or GLP-1 receptor agonist use (n=944) did not modify the beneficial effect of finerenone on the kidney composite outcome, thus suggesting a potential role for dual therapy (for example, finerenone plus SGLT-2 inhibitor or GLP-1 receptor agonist) among patients with type 2 diabetes and CKD.
Table 5
Landmark randomized clinical trials on finerenone in chronic kidney disease
Endothelin receptor antagonists have emerged as novel treatments for a variety of kidney diseases. The Study of Diabetic Nephropathy with Atrasentan (SONAR) evaluated the effect of atrasentan on a composite kidney outcome (defined as a doubling of serum creatinine or ESKD) among adults with type 2 diabetes, estimated GFR 25-75 mL/min/1.73 m2, and urine ACR 300-5000 mg/g taking a stable dose of ACE inhibitor or ARB.120 After a six week enrichment period during which all participants received atrasentan 0.75 mg daily (n=5517), those who responded (defined as a ≥30% reduction in urine ACR without the development of substantial fluid retention or increase in serum creatinine by >0.5 mg/dL and 20% from baseline; n=2648) were randomized to receive atrasentan or placebo. Over a median follow-up of 2.2 years, the atrasentan group had a 35% lower risk of developing the composite kidney outcome compared with the placebo group, although fluid retention and anemia were more frequent in the former. Of note, the frequency of hyperkalemia was low (1%) in both treatment groups. Sparsentan, a dual endothelin and angiotensin II receptor antagonist, is also being investigated as a treatment for FSGS and IgA nephropathy.121122 In a phase 2, randomized, double blind, active control trial, 109 adults with biopsy proven FSGS (estimated GFR >30 mL/min/1.73 m2 and urine PCR ≥1 g/g) received varying doses of sparsentan (200, 400, or 800 mg daily) or irbesartan 300 mg daily.121 At eight weeks, participants receiving sparsentan had greater reductions in urine PCR compared with those receiving irbesartan. In an interim analysis of the PROTECT phase 3 trial, adults with biopsy proven IgA nephropathy (urine PCR ≥1 g/day) randomized to sparsentan 400 mg daily had a 41% greater reduction in urine PCR over 36 weeks and threefold higher odds of achieving complete remission of proteinuria at any point compared with their counterparts who were randomized to irbesartan 300 mg daily.122 Based in part on the results of this study, the US Food and Drug Administration (FDA) granted accelerated approval for the use of this drug in adults with primary IgA nephropathy considered to be at risk of rapid disease progression.123
Endothelin 1 has been implicated in the pathogenesis of kidney disease via various mechanisms including vasoconstriction, vascular hypertrophy, endothelial and podocyte injury, inflammation, cell proliferation, extracellular matrix accumulation, and fibrosis.124 Systemic and local kidney production of endothelin 1 is augmented in CKD.
Other nephroprotective and cardiovascular risk reduction strategies
A bidirectional association exists between CKD and cardiovascular disease: cardiovascular disease is both a risk factor for CKD and a common outcome in patients with CKD.125126 Thus, patients with CKD are likely to benefit from efforts at cardiovascular risk reduction including administration of a statin as well as the gamut of lifestyle changes.2127
Lipid management
The Study of Heart and Renal Protection (SHARP) trial evaluated the efficacy of ezetimibe and simvastatin combination therapy in patients with moderate to severe CKD (33% on dialysis; 67% not on dialysis with mean estimated GFR of 27 mL/min/1.73 m2).128 Treatment with these low density lipoprotein (LDL) cholesterol lowering agents led to a 17% risk reduction for development of a first major atherosclerotic event compared with placebo, although this benefit was seen only in the patients not requiring maintenance dialysis. Those at very high risk (for example, with previous major atherosclerotic cardiovascular disease events) may benefit from additional therapies to lower LDL cholesterol, including evolocumab.129 Evolocumab is a monoclonal antibody for proprotein convertase subtilisin/kexin type 9, which increases LDL cholesterol receptors and hence clearance of LDL; this novel therapy also seems to be safe and efficacious in patients with CKD.129130
Physical activity
Exercise has been shown to benefit patients with CKD. Several small, randomized trials have reported that exercise training programs in patients with moderate to severe CKD are safe, feasible, and effective in improving physical activity levels, cardiorespiratory fitness, and quality of life.131132133134135 Whether these interventions also slow CKD progression remains to be determined, as many of these studies were underpowered for this outcome.
Diet
For patients with obesity, weight loss may reduce the risk of CKD progression, whether it comes from intensive lifestyle intervention such as in the Look AHEAD (Action for Health in Diabetes) trial or, as in observational studies, from bariatric surgery.136137138 Micronutrient and macronutrient composition of diets may also matter.139
Traditional recommendations about diet in the setting of CKD have focused on limiting protein and dietary acid intake. Experimental evidence suggests that protein intake can increase intraglomerular pressure and cause glomerular hyperfiltration.140141142 Observational data from large cohort studies suggest that the type of protein may be important; a diet high in animal protein may increase risk, whereas protein from plant sources may be better tolerated.143144 For example, an observational study in Singapore found a strong correlation between red meat intake and risk of ESKD.145 Little clinical trial evidence for protein restriction exists. The MDRD study randomized patients to different levels of protein restriction but found no statistically significant difference in the rate of GFR decline.67
A second line of investigation has been into the benefits of increasing nutritional alkali intake, with a body of open label trials suggesting benefits on kidney function and prevention of starting dialysis.146 A phase 3 double blinded, placebo controlled trial reported that veverimer (a potent acid binder that acts in the intestine) was effective in raising or normalizing serum bicarbonate among patients with CKD and chronic metabolic acidosis.147 Other double blinded studies using veverimer suggested that treating acidosis in CKD improves quality of life and overall physical function.148 However, a recent trial evaluating veverimer in slowing progression of CKD was negative.149
Although patients with CKD are prone to hyperkalemia, potassium intake has a beneficial effect on blood pressure, cardiovascular disease, and death independent of and opposite to that of sodium intake.150151152153 One large randomized controlled trial suggested that substituting 25% of sodium chloride intake with potassium chloride reduced the risk of major adverse cardiovascular events by 13% in the general population.154 Similarly, small studies suggest that diets rich in potassium may be beneficial in CKD. A feeding trial in people with CKD G3 observed that 100 mmol compared with 40 mmol of dietary potassium per day increased serum potassium by 0.21 mmol/L,155 similar to the increase seen with finerenone.156 Many dietary studies have evaluated patterns of diet rather than potassium alone: for example, plant based diets tend to be rich in not only potassium but also alkali and fiber. Observational data from prospective cohorts suggest that plant based diets are associated with less CKD progression.143157158 Evidence is also emerging to suggest that increasing fiber intake benefits the gut microbiome, decreases inflammation, and possibly slows CKD progression.159
Appropriate drug dosing and nephrotoxin avoidance
An important component of care for patients with CKD is avoidance of additional insults. Many drugs are cleared by glomerular filtration or tubular secretion by the kidney, and reduced GFR can lead to accumulation of the drug or its metabolites resulting in adverse effects.160 Careful estimation of GFR is generally a first step in determining dosage for renally excreted drugs.161 The US FDA guidance to industry suggests that estimated GFR based on serum creatinine may be used in pharmacokinetic studies.162 If drugs are dosed on the basis of estimated GFR (rather than estimated creatinine clearance from the Cockcroft-Gault equation, an equation that is known to be flawed), estimated GFR must be “de-indexed” by multiplying the standardized estimated GFR by the individual’s calculated body surface area and dividing by 1.73 m2.163164165 This is because drug clearance is thought to be proportional to a person’s GFR and not the GFR standardized to body surface area. Antibiotics and antiviral agents, direct oral anticoagulants, drugs for diabetes mellitus, and chemotherapeutic agents are the most common drugs that require attention to dosing in CKD.2160164
Some drugs should be avoided or minimized in CKD because of their potential to worsen kidney function. For example, non-steroidal anti-inflammatory drugs (NSAIDs) can exacerbate hypertension, cause fluid retention, and contribute to the risk of acute kidney injury.166 Particularly when used with RAAS inhibitors and diuretics, NSAIDs are ideally avoided.167 In select patients with CKD, however, some clinicians will prescribe an abbreviated course of NSAIDs given that the most common alternative, opioids, also have significant adverse effects.168 Proton pump inhibitors can lead to acute or chronic interstitial nephritis and have been associated with incident CKD, progression of CKD, and ESKD.169170 Although the mechanism by which proton pump inhibitors contribute to CKD remains unclear, most experts agree that these agents should be used judiciously.
Emerging treatments
Many phase 3-4 clinical trials are ongoing to evaluate emerging treatments for kidney disease (clinicaltrials.gov). These include, but are not limited to, investigations on the use of dapagliflozin in advanced CKD (for example, estimated GFR <25 mL/min/1.73 m2, on maintenance dialysis with residual daily urine output of >500 mL, and kidney transplant recipients with estimated GFR ≤45 mL/min/1.73 m2; NCT05374291); finerenone in non-diabetic CKD (NCT05047263); and monteluklast (NCT05362474) and pentoxyifylline (NCT03625648) in diabetic CKD. Several therapies are also being tested for rarer causes of kidney disease: obinutuzumab (NCT04629248), zanubrutinib (NCT05707377), and SNP-ACTH (1-39) gel (NCT05696613) in membranous nephropathy; voclosporin (NCT05288855), atacicept (NCT05609812), anifrolumab (NCT05138133), inanalumab (NCT05126277), secukinumab (NCT04181762), obinutuzumab (NCT04221477), and ACTHar gel (NCT02226341) in lupus nephritis; VX-147 in APOL1 related kidney disease (NCT05312879); imlifidase in antiglomerular basement membrane disease (NCT05679401); sparsentan in focal segmental glomerulosclerosis (NCT03493685); and pegcetacoplan (NCT05067127) in immune complex glomerulonephritis. IgA nephropathy, in particular, is an area of high interest, as recent work suggests that disease activity may be driven by the overproduction of galactose deficient IgA antibodies that are recognized as autoantigens, triggering glomerular deposition of immune complexes.171 Monoclonal antibodies to signaling molecules that enhance IgA production are in phase 3 trials, as are immunosuppressive and non-immunosuppressive agents (for example, those acting on the endothelin-1 and angiotensin II pathways): budesonide (NCT03643965), sparsentan (NCT03762850), atrasentan (NCT04573478), LNP023 (NCT04578834), RO7434656 (NCT05797610), atacicept (NCT04716231), and sibeprenlimab (NCT05248646; NCT05248659).
Guidelines
Major guidelines in CKD are issued by the international KDIGO group (https://kdigo.org/), and locally in the UK by NICE (www.nice.org.uk/guidance/ng28/chapter/Recommendations#chronic-kidney-disease), with the most recent issuances primarily from 2023 (currently in public review) and 2021, respectively. KDIGO publishes guidelines on the evaluation and management of patients with CKD in general, as well as myriad other aspects (for example, diabetes, blood pressure, lipids, anemia, mineral and bone disease, hepatitis C, ADPKD, glomerular diseases). With the expansion of therapeutic options, both organizations are updating recommendations frequently. Other guideline producing organizations such as the American College of Cardiology, the American Heart Association, the European Society of Cardiology, the European Society of Hypertension, the International Society of Hypertension, and the American Diabetes Association (ADA) provide more limited statements of recommendation for the specific aspects of the management of patients with CKD.172173174175
Annual screening for CKD (including testing for albuminuria) is widely recommended in people with diabetes.72174175176177 Guidelines in hypertension are less clear.178 The 2020 Global Hypertension Practice Guideline from the International Society of Hypertension is a notable exception and now recommends routine assessment of albuminuria in addition to estimated GFR in people with hypertension.173 KDIGO and NICE also recommend testing anyone who is at risk for CKD, which includes those with hypertension, cardiovascular disease, diabetes, and previous acute kidney injury, along with multiple other, less common conditions.179 For CKD, the KDIGO guidelines recommend at least annual albuminuria testing with greater frequency in higher risk categories (fig 1).2 The NICE guidelines, on the other hand, recommend annual ACR testing with individualization based on clinical characteristics, risk of progression, and whether a change in ACR would lead to a change in management.16
KDIGO guidelines and those from NICE differ slightly on staging CKD. KDIGO recommends using a validated equation for GFR estimation and suggests that using “race as a distinct variable in the computation of GFR” is not appropriate.179 NICE recommends using the CKD-EPI 2009 equation, which did include race, but using the computed value for non-Black people for everyone, a position that is also endorsed by other European groups.16180181 The KDIGO guidelines recommend staging CKD by eGFRcr-cys when cystatin C is available, as well as when precise estimates of GFR are needed for clinical decision making.2179 The NICE guidelines recommend direct measurement of GFR rather than the use of cystatin C in clinical situations requiring additional precision.16
Both KDIGO and NICE emphasize the importance of risk assessment in patients with CKD. The NICE guidelines suggest that primary care providers should counsel patients using the KFRE five year risk estimate, with referral to a specialist if risk is greater than 5%.16 KDIGO 2023 additionally suggests that the two year risk estimate can drive referral for multidisciplinary care (>10%) and preparation for kidney replacement therapy, including vascular access planning and referral for transplantation (>40%).179 The KDIGO 2023 guidelines also emphasize the importance of cardiovascular risk assessment using equations developed in people with CKD or that encompasses estimated GFR and albuminuria and the use of disease specific tools in IgA nephropathy and ADPKD.179
Multiple guidelines comment on target blood pressures in the setting of CKD. The NICE guidelines recommend a target of <140/90 mm Hg, or <130/80 mm Hg if ACR is ≥70 mg/mmol (approximately 700 mg/g).16 Guidelines from the American College of Cardiology, American Heart Association, European Society of Cardiology, and European Society of Hypertension recommend a systolic blood pressure target of <130 mm Hg as a best practice target, with the European Society of Cardiology and European Society of Hypertension specifically advising against lower targets.172 The KDIGO guidelines on hypertension in CKD advocate for a systolic blood pressure goal of <120 mm Hg, as assessed using standardized office measurements.182 This recommendation is based largely on data from SPRINT and the observed benefits in cardiovascular endpoints and survival rather than benefits in kidney endpoints.70
Of note, disparate guideline recommendations may reflect different emphasis on standardized blood pressure measurement techniques, which can result in measured blood pressure that is substantially lower than measurement in an uncontrolled setting.183 Joint statements from several international groups including KDIGO stress the importance of proper technique when assessing blood pressure.184 Both NICE and KDIGO recommend RAAS inhibitors (either ACE inhibitor or ARB) as first line antihypertensive treatment for people without diabetes but with albuminuria (NICE: urine ACR >70 mg/mmol; KDIGO: A3) as well as those with diabetes and CKD G1-G4, A2-A3.16182 KDIGO 2023 suggests continuation of RAAS inhibitors even when estimated GFR is <30 mL/min/1.73 m2.179
For patients with diabetes and CKD not treated with dialysis, KDIGO recommends a hemoglobin A1c target ranging from <6.5% to <8%.72 NICE does not provide specific recommendations for people with CKD, instead emphasizing shared decision making but a general goal of hemoglobin A1c <7% for people with diabetes treated with drugs associated with hypoglycemia and <6.5% for people with diabetes managed by lifestyle or a single drug not associated with hypoglycemia.185
KDIGO and ADA guidelines recommend SGLT-2 inhibitors as first line drug therapy for all people with type 2 diabetes, CKD, and an estimated GFR ≥20 mL/min/1.73 m2 (fig 5).72174175179 The NICE guidelines recommend that an SGLT-2 inhibitor should be offered when ACR is >30 mg/mmol (approximately >300 mg/g) and considered when ACR is between 3 and 30 mg/mmol (approximately 30 to 300 mg/g) in patients with type 2 diabetes and CKD who are already taking an ACE inhibitor or ARB and meet estimated GFR thresholds.185 The NICE guidelines further specify that dapagliflozin should also be considered in people with estimated GFR 25-75 mL/min/1.73 m2 and ACR ≥22.6 mg/mmol (approximately 200 mg/g) regardless of diabetes status186; KDIGO is broader and recommends SGLT-2 inhibitors in general in people with ACR ≥200 mg/g and estimated GFR ≥20 mL/min/1.73 m2, as well as in those with CKD and heart failure.179 KDIGO further specifies that once started, a SGLT-2 inhibitor can be continued even if the estimated GFR drops below 20 mL/min/1.73 m2, as long as it is tolerated and kidney replacement therapy has not yet been started.72179 The KDIGO and ADA guidelines recommend the use of GLP-1 receptor agonists in patients with type 2 diabetes and CKD who are unable to tolerate metformin or an SGLT-2 inhibitor or do not meet their individualized glycemic target with these drugs.72174175179
Fig 5
Kidney Disease: Improving Global Outcomes/American Diabetes Association recommendations on the management of diabetes in populations with chronic kidney disease.72174 ACR=albumin-to-creatinine ratio; ASCVD=atherosclerotic cardiovascular disease; BP=blood pressure; CCB=calcium channel blocker; CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; GLP-1 RA=glucagon-like peptide-1 receptor agonist; HTN=hypertension; MRA=mineralocorticoid receptor antagonist; PCSK9i=proprotein convertase subtilisin/kexin type 9 inhibitor; RAS=renin-angiotensin system; SGLT2i=sodium-glucose cotransporter-2 inhibitor
In patients with diabetes and CKD, the KDIGO and ADA guidelines recommend that finerenone should be used as add-on therapy to maximally tolerated ACE inhibitor or ARB if ACR is ≥30 mg/g (approximately ≥3 mg/mmol) and potassium is within normal limits (that is, ≤4.8 mmol/L based on trial and ≤5.0 mmol/L as per FDA).72174175179 More specifically, the starting dose should be 10 mg daily when estimated GFR is 25-59 mL/min/1.73 m2 and 20 mg daily when it is ≥60 mL/min/1.73 m2. The guidelines also recommend that potassium concentration should be checked at four weeks after starting treatment, with each dose change, and routinely during treatment. If potassium is >5.5 mmol/L, the drug should be stopped and restarted at the lower dose of 10 mg daily when potassium is ≤5.0 mmol/L. Additionally, finerenone need not be stopped when estimated GFR falls below 25 mL/min/1.73 m2 as long as the patient is normokalemic.174175
With respect to cardiovascular risk reduction, the KDIGO guidelines suggest that all patients aged over 50 with CKD G3-G5 but not treated with chronic dialysis or kidney transplantation should be treated with a statin, irrespective of cholesterol concentrations or a statin/ezetimide combination.179187 The NICE recommendation is broader, recommending starting atorvastatin 20 mg for all people with CKD.188 KDIGO recommends regular physical activity for people with CKD, for at least 150 minutes a week of moderate intensity exercise.179 NICE simply suggests providing lifestyle advice, including encouragement of exercise, maintenance of healthy weight, and smoking cessation, and specifically recommends against offering low protein diets (defined as dietary protein intake <0.8 g/kg/day).16 KDIGO recommends maintaining sodium intake <2 g/day and a protein intake of 0.8 g/kg/day but no higher than 1.3 g/kg/day.179
Conclusion
People with CKD face high risks of many adverse outcomes, including requirement for kidney replacement therapy, cardiovascular events, and death. Fortunately, major advances have been made in the field of CKD over the past decade. Estimating equations for GFR and ACR have evolved for more precise classification of disease. Individualized risk prediction tools exist to assist in the counseling, referral, and treatment of patients. Novel therapies build on the fundamentals—a healthy lifestyle, blood pressure and glucose control, and statin therapy and RAAS blockade—to provide effective preventive strategies for CKD progression and cardiovascular events.
eGFRcr—estimated glomerular filtration rate using creatinine
eGFRcr-cys—estimated glomerular filtration rate using creatinine and cystatin C
eGFRcys—estimated glomerular filtration rate using cystatin C
ESKD—end stage kidney disease
FDA—Food and Drug Administration
FSGS—focal segmental glomerulosclerosis
GFR—glomerular filtration rate
GLP-1—glucagon-like peptide-1
KDIGO—Kidney Disease: Improving Global Outcomes
KFRE—kidney failure risk equation
KFRT—kidney failure with replacement therapy
LDL—low density lipoprotein
MDRD—Modification of Diet in Renal Disease
MRA—mineralocorticoid receptor antagonists
NICE—National Institute for Health and Care Excellence
NSAID—non-steroidal anti-inflammatory drug
PCR—protein-to-creatinine ratio
RAAS—renin-angiotensin-aldosterone system
SGLT-2—sodium-glucose cotransporter-2
Questions for future research
How do the race-free estimating equations perform in global populations?
Where can genetic testing add value in patient care?
Can cause of chronic kidney disease be incorporated into risk prediction tools?
How can medical therapy be best tailored for the individual patient with chronic kidney disease?
Patient perspective
Increasing awareness of chronic kidney disease is key to empowering patients to make lifestyle changes and seek treatments to improve their health outcomes. We are pleased to offer our perspective as husband and wife, and as physicians, who have been affected by kidney disease. Roberta M Falke is a patient with autosomal dominant polycystic kidney disease (ADPKD), a kidney transplant recipient, and a retired hematologist-oncologist. Andrew S Levey is a kidney donor and a nephrologist. Our knowledge of Roberta’s family history enabled early diagnosis and treatment.189 Although we have benefited from our training and positions in the healthcare system, all patients can benefit from early diagnosis.
RMF—My ADPKD was diagnosed when I developed pyelonephritis at age 22 years. Thereafter, I had prophylaxis and prompt treatment of recurrent urinary tract infections and, as the disease progressed, complications of kidney and liver cysts, hypertension, hyperparathyroidism, vitamin D deficiency, acidosis, hyperkalemia, and ultimately kidney failure, with fatigue, dietary restrictions, and a long list of medications to take every day. I had always known that living donor kidney transplantation would be the best treatment for my kidney failure. Over time, family members without ADPKD donated to others, and when I was ready at age 60 years no family members were available. Fortunately, Andy stepped up. I felt better immediately after the transplant, and in the 13 years since then I have continued to take medications daily but have had few complications. I am grateful to all those who have cared for me for many years and enabled me to make the best choices I could to help myself, and I’m especially grateful to Andy who gave me the gift of life.
ASL—I knew that Roberta would develop kidney failure and hoped that a living kidney donor would be available for her. I wanted to donate, but our blood group incompatibility was an obstacle, so it was exciting when paired donor exchange was conceived and implemented in our region. I believe that kidney donors benefit from donation, not only by fulfilling their spirit of altruism but by improving their own lives. In my case, donating has been life changing. Roberta and I have been able to have an active, fulfilling life for more than a decade after the transplant, without the demands and complications of kidney failure or dialysis. I hope that we will have many more years together. I am also grateful to all those who enabled me to achieve my goal and to Roberta, who always takes full responsibility for caring for her kidney disease.
Risk of all-cause mortality, MAKE, and MACE were significantly reduced
SGLT2 inhibitors significantly lowered the risk of death, major adverse kidney events (MAKE), and major adverse cardiovascular events (MACE) in people with type 2 diabetes and acute kidney disease, according to a cohort study.
Compared with nonusers, SGLT2 inhibitor users had a 5-year all-cause mortality rate of 9.0% versus 18.7%, which translated into a 31% lower risk of mortality (adjusted HR 0.69, 95% CI 0.62-0.77) over a median 2.3-year follow-up, Vin-Cent Wu, PhD, of the National Taiwan University Hospital in Taipei, and colleagues found.
SGLT2 users also had significantly lower rates for MAKE (9.5% vs 21%) and MACE (13.5% vs 25.8%), which yielded 38% (aHR 0.62, 95% CI 0.56-0.69) and 25% lower risks (aHR 0.75, 95% CI 0.65-0.88), respectively, the researchers noted in JAMA Network Openopens in a new tab or window.
“Given that the current management of acute kidney disease primarily relies on conservative approaches, such as monitoring, medication adjustments, and minimizing kidney-stressing procedures or treatments, there has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” Wu told MedPage Today. He added that this class of drugs has already been well-established to slow kidney function decline and the risk of death in those with chronic kidney disease. At the moment, a few FDA approved SGLT2 inhibitors have diabetes, kidney, and cardiovascular protection indications, including empagliflozin (Jardiance)opens in a new tab or window, dapagliflozin (Farxiga)opens in a new tab or window, and canagliflozin (Invokana).
The current findings add to the argument that this medication class also holds benefits for patients with acute kidney disease, said Wu. “Given the potential contribution of acute kidney disease to the rise in the burdens of MACEs and MAKEs, it is crucial for clinicians to consider using SGLT2 inhibitors to address this growing public health concern.”
Researchers identified 230,366 patients with acute kidney disease (average age 67.1) from the TriNetX global healthcare database who were admitted to targeted healthcare organizations. Among this patient population, only 5,319 (2.3%) were on an SGLT2 inhibitor, which Wu called a “relatively low” number, particularly given the fact that current guidelinesopens in a new tab or window recommend the use of SGLT2 inhibitors in patients with existing kidney disease. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making,” he pointed out.
Inclusion criteria included a type 2 diabetes diagnosis and having received dialysis during hospitalization. Those who received postdischarge redialysis or who died within 3 months were excluded. MAKEs were defined as redialysis, dialysis dependence, or mortality, and MACEs were defined as cerebral infarction, hemorrhagic stroke, acute myocardial infarction, cardiogenic shock, or mortality.
At baseline, people on SGLT2 inhibitors had slightly higher average HbA1c levels (8.4% vs 7.9%), eGFR (76.9 vs 73.9 mL/min/1.73m2), and BMI (32.3 vs 30.4). More SGLT2 users were also on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
Despite the many protective benefits of SGLT2 inhibitors in this population, the researchers did find a higher risk for diabetic ketoacidosis (AHR 1.36, 95% CI 1.00-1.85) and osteoporotic fractures (AHR 1.39, 95% CI 1.04-1.85).
When the researchers looked at specific subgroups, they found the reduction in mortality risk was seen regardless of whether patients were also on insulin, renin-angiotensin aldosterone system blockers, or diuretics. Patients with more advanced kidney disease, no hypertension, and those not taking other diabetic agents had greater reduction of mortality and MAKE risk.
When discussing the thinking behind this study, Wu explained that this group recently conducted a network meta-analysisopens in a new tab or window and found that the use of empagliflozin or dapagliflozin yielded superior renal protection in patients with diabetes and also significantly reduced the risk of acute kidney injury. “The incidence of acute kidney disease following acute kidney injury is approximately 33.6% and it can occur without identifiable preceding acute kidney injury. The development of acute kidney disease is associated with increased risks of chronic kidney disease, dialysis, and mortality.”
The researchers noted that most patients included were white, which could limit how generalizable the findings are to other racial and ethnic groups. Also, the baseline differences in SGLT2 users’ comorbidities and medication use also may have biased the findings.
When health problems affect your kidneys, they can cause CKD. This is permanent damage that may get worse over time. If they’re so damaged that they stop working, it’s called kidney failure, or end-stage renal disease (ESRD). The treatment is usually either dialysis — when a machine does the work your kidneys normally do, or a transplant — when you get a new healthy kidney from a donor.
Diabetes
2/13
This leading cause of kidney failure damages the organs’ small blood vessels and filters. That makes it difficult for them to clean your blood. Your body holds on to more salt and water than it should, and there’s more waste in your system. Nerve damage caused by the disease can make urine back up and harm your kidneys through pressure or infection.
Anorexia Nervosa
3/13
People who have this have an unrealistic body image, and they don’t eat enough to stay at a healthy weight. (They weigh at least 15% less than they should.) That can lead to a lack of water, electrolytes, and salt in the body, which can cause chronic kidney disease and, eventually, kidney failure. This is especially true for people who binge-eat and purge (vomit or use laxatives) to get rid of calories.
High Blood Pressure
4/13
If the force of blood flow through your body is too high, it can stretch and scar — and weaken — your blood vessels, including the ones in your kidneys. This can keep them from getting rid of waste the way they should, and the extra fluid in your blood vessels can raise your blood pressure even more, leading to a dangerous cycle. It’s treated with medication and changes to things like your diet, exercise habits, and stress level.
High Cholesterol
5/13
If you have too much bad cholesterol, it can build up in the vessels that carry blood into and out of your kidneys, and that can affect how well they work. It also makes you more likely to have high blood pressure and diabetes. A blood test can tell you if your cholesterol level is too high.
Lupus
6/13
This is a disease that makes your immune system attack certain parts of your body. When it affects your kidneys, it’s called lupus nephritis. It causes inflammation and scarring of the small blood vessels that filter waste out of your kidneys, and sometimes in your kidneys as well. It’s treated with different medications: Some affect your immune system, while others help control your blood pressure or get rid of swelling and excess fluid.
Multiple Myeloma
7/13
This kind of cancer involves the white blood cells (plasma) that help you fight infection. The cancer cells build up in your bone marrow, where they crowd out healthy blood cells and make abnormal proteins that can cause kidney problems. More than half the people with multiple myeloma also end up with kidney problems.
Hemolytic Uremic Syndrome
8/13
This happens when small blood vessels in the kidney and other organs get damaged. That can eventually cause kidney failure. It happens after 5 to 10 days of diarrhea, usually brought on by an infection, like from E. coli bacteria. Most people recover if it’s treated quickly. See your doctor if you have several days of diarrhea, aren’t peeing often, and are very tired. You also may get bruises or unusual bleeding.
ANCA Vasculitis
9/13
This is when your own antibodies — which usually fight germs — attack the small blood vessels in your kidneys and other organs. It may lead to blood and protein in your urine and can cause kidney failure. You may have fever, body aches, joint and muscle pain, and brown, tea-colored pee.
Urine Blockage
10/13
If you can’t pee, that can mean urine is backed up, and that can damage your kidneys. It can cause pressure and lead to infection in your kidneys and other parts of your body. An enlarged prostate, prostate cancer, kidney stones, bladder cancer, urinary tract blood clots, and colon cancer are some of the things that can cause this. See your doctor if you’re peeing much less or much more often than usual or if you see blood in your urine.
Blood Clots
11/13
Many conditions can cause blood clots, but a blood disorder — thrombotic thrombocytopenic purpura — is commonly linked to kidney problems. It causes clots in tiny blood vessels that also can affect your brain and heart. Symptoms include fever, bleeding from your nose or gums, diarrhea, chest pain, confusion, headache, bruising, and feeling very tired. It can be serious if it’s not treated quickly, so see a doctor if you have any of these signs.
Scleroderma
12/13
This is a group of rare diseases that make your skin and connective tissues hard and tight. It can sometimes also harm other things, like blood vessels and organs. If it affects your kidneys and they don’t work the way they should, they can let protein escape through your urine. It also can cause a sudden increase in blood pressure that can lead to rapid kidney failure.
Polycystic Kidney Disease
13/13
This causes cysts — small sores often filled with fluid — to grow inside your kidneys. That makes them much larger than they should be and damages their tissue. It’s caused by problem genes you get from one of your parents. If it’s not diagnosed and managed soon enough, it can lead to chronic kidney disease and, eventually, to end-stage renal disease.
Sodium–glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.
Methods
EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.
Findings
Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83–2·41) reduction in eGFR, equivalent to a 6% (5–6) dip in the first 2 months. After this, it halved the chronic slope from –2·75 to –1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42–58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36–136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19–38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001).
Interpretation
Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.
Discussion
Our analyses showed that, in this cohort of patients with chronic kidney disease at risk of progression, allocation to empagliflozin caused a small dip in kidney function of approximately 2 mL/min per 1·73 m2 (or 6%) and then halved the subsequent rate of long-term loss of kidney function. This overall result complements the 29% (95% CI 19–38) reduction in risk of kidney disease progression when assessed with the categorical composite outcome of end-stage kidney disease, a sustained decrease from baseline in eGFR of at least 40% or to less than 10 mL/min per 1·73 m2, or death from kidney failure. The beneficial effects of empagliflozin on the progression of chronic kidney disease varied by diabetes status and eGFR, but most prominently by albuminuria, where relative benefits might in fact be larger among participants with lower albuminuria. These findings are consistent with observations in other trials of SGLT2 inhibitors in chronic kidney disease, although these trials focused on patients with diabetes, significant levels of albuminuria, or both.
The broad range of patients included in the large EMPA-KIDNEY trial has allowed this to be explored in a more diverse population than those included in other large trials of SGLT2 inhibition in chronic kidney disease; in particular, EMPA-KIDNEY included participants with an eGFR of less than 25 mL/min per 1·73 m2 and with a uACR of less than 200 mg/g who were excluded from these previous trials.
The acute dip in eGFR when empagliflozin was initiated in EMPA-KIDNEY was modest (in all participant subgroups; it was on average ❤ mL/min per 1·73 m2 or <10% of baseline eGFR) and was largely reversible when treatment was discontinued. The acute effect was larger among participants with diabetes than in those without (on both absolute and relative scales), which might reflect the greater prevalence and degree of hyperfiltration in this group. The acute effect of SGLT2 inhibition on kidney function was recognised early in the development of this drug class (although not in all studies
) and is believed to be due to the acute reduction in intraglomerular pressure caused by afferent arteriolar vasoconstriction stimulated by increased sodium delivery to the macula densa.
Our exploratory analyses suggest that the reduction in albuminuria might be the most important measured determinant of the benefits observed in EMPA-KIDNEY, explaining a fifth of the effect on chronic slopes and two-fifths of the effect on the primary composite outcome of kidney disease progression, consistent with analyses from other trials in chronic kidney disease.
These analyses need to be interpreted with some caution because they could have been subject to bias due to measurement error and residual mediator–outcome confounding. Whether this association is due to avoidance of direct toxic effects of albumin on tubular function, a reduction in intraglomerular pressure, or another unmeasured correlate of urinary albumin is not clear. However, these analyses also suggest that other mechanisms unrelated to albuminuria, blood pressure, or glycaemic control contribute to the benefit of SGTL2 inhibition on kidney function.
Our analyses focused on chronic slopes. Although effects on total slope correlate strongly with effects on clinical outcomes over short (2–3-year) follow-up periods,
the chronic slope is likely to be more informative for longer time periods. When the magnitude of the acute dip correlates with the relative reduction in the chronic slope (which is plausible because they share causal mechanisms, such as reduced intraglomerular pressure), this reduces variation between subgroups in total slope when measured over 2–3 years. However, this would not be the case with longer follow-up (see appendix p 29 for an explanatory example). Clinicians seeking to delay or avoid kidney failure would usually consider such longer time periods for which the chronic slope is most relevant. Furthermore, the limited variation in total slopes between patient subgroups reduces the ability to explore any such differences in treatment effect that might exist between those subgroups. This is shown by the apparent consistency of treatment effect on total slope in EMPA-KIDNEY versus the evidence of effect modification when using chronic slopes.
When comparing chronic slopes, we have reported both the absolute and relative differences but have emphasised the latter. Absolute differences are determined by both the background annual rate of change in eGFR and the relative effect of treatment, so any heterogeneity observed could be due to either of these components. This is demonstrated in the analysis by baseline uACR: the absolute difference in the chronic slope among participants with a uACR of 2000 mg/g or higher was 1·82 mL/min per 1·73 m2 per year, whereas the background chronic slope among participants with a uACR of less than 30 mg/g was 0·88 mL/min per 1·73 m2 per year, so it was impossible for the absolute difference in the latter subgroup to be similar to that observed in the highest uACR subgroup. Indeed, the absolute difference in the chronic slope was positively associated with baseline uACR; however, the relative difference was inversely associated such that participants with the lowest baseline uACR had the largest relative reduction (86% [95% CI 36–136] in those with uACR <30 mg/g vs 29% [19–38] in those with uACR ≥2000 mg/g). There was no strong evidence that this association was importantly modified by the presence or absence of diabetes. Contrary to some international guidelines that only suggest (rather than recommend) using SGLT2 inhibitors in patients without diabetes and without significant albuminuria (uACR <200 mg/g),
these analyses suggest that patients with low albuminuria (with or without diabetes) are likely to gain substantial benefit in terms of preservation of kidney function from SGLT2 inhibition, in addition to the other benefits of reductions in risk of acute kidney injury and cardiovascular disease.
Given the short follow-up in EMPA-KIDNEY (median 2 years) it would be expected that a treatment that causes a 2 mL/min per 1·73 m2 acute dip in eGFR in the subgroup of patients with uACR <30 mg/g (progressing at only 1 mL/min per 1·73 m2 per year) would not demonstrate definitive benefits on the categorical outcome (by contrast with subgroups with higher uACR progressing faster than 2 mL/min per 1·73 m2 per year). These analyses of the chronic slope suggest that important benefits would likely emerge with longer treatment (see appendix p 29 for an example).
These analyses are limited by the characteristics of patients included in EMPA-KIDNEY.
Few patients with type 1 diabetes were included, and patients with autosomal dominant polycystic kidney disease or with a kidney transplant were not eligible for the trial. In a companion paper, we assess whether the effects of allocation empagliflozin vary in different types of kidney disease.
The trial deliberately excluded patients at low risk of chronic kidney disease progression (ie, those with an eGFR of ≥45 mL/min per 1·73 m2 and uACR <200 mg/g), but demonstrated that the relative benefit on the chronic slope was inversely proportional to predicted risk of kidney failure. Participants only received study treatment for 2 years on average because the trial was stopped earlier than planned owing to clear evidence of benefit. A further 2 years of off-treatment follow-up is underway to assess the longer-term effects of an average of 2 years of treatment.
In summary, in EMPA-KIDNEY, allocation to empagliflozin compared with placebo caused a modest acute dip in eGFR, and then substantially slowed the longer-term progression of chronic kidney disease. The longer-term benefits varied by diabetes status, eGFR, and most prominently uACR (and related characteristics such as predicted risk of kidney failure). Although the trial stopped early because of clear benefits emerging based on results in patients at highest risk, these analyses show that patients at lower risk such as those with lower levels of albuminuria—many of whom in their lifetime would otherwise develop kidney failure—could benefit in terms of preservation of kidney function, in addition to other proven cardiovascular and mortality benefits.
Renal congestion is an issue of cardiorenal syndrome in patients with heart failure. Recent clinical and basic studies suggest a renoprotective potential of sodium–glucose cotransporter (SGLT) 2 inhibitors. However, the effect on renal congestion and its mechanism is not fully understood. Thus, we aimed to clarify the effect of SGLT inhibition in a renal congestion model. Renal congestion was induced in the left kidney of male Sprague-Dawley rats by ligation of the inferior vena cava between the renal veins. The SGLT2 inhibitor tofogliflozin or vehicle was orally administered daily from the day before IVC ligation until two days after surgery. On the third postoperative day, both the right control kidney and the left congested kidney were harvested and analyzed. Kidney weight and water content was increased, and renal injury and fibrosis were observed in the left congested kidney. Kidney weight gain and hydration were improved with tofogliflozin treatment. Additionally, this treatment effectively reduced renal injury and fibrosis, particularly in the renal cortex. SGLT2 expression was observed in the congested kidney, but suppressed in the damaged tubular cells. Molecules associated with inflammation were increased in the congested kidney and reversed by tofogliflozin treatment. Mitochondrial dysfunction provoked by renal congestion was also improved by tofogliflozin treatment. Tofogliflozin protects against renal damage induced by renal congestion. SGLT2 inhibitors could be a candidate strategy for renal impairment associated with heart failure.
Discussion
The present study showed that SGLT2 protein was still expressed in the apical membrane of non-injured proximal tubules after renal congestion and that an SGLT2 inhibitor tofogliflozin showed renoprotective effects against renal damage induced by renal congestion. Renal interstitial fibrosis, inflammation and mitochondrial dysfunction were reversed by tofogliflozin treatment. These results suggest that SGLT2 inhibitors are responsible for renal damage induced by renal congestion.
The expression of SGLT2 was decreased in the proximal tubules of the congested kidney in the present study. The expression pattern of SGLT2 differs in different types of kidney disorders. SGLT2 expression is upregulated in diabetic patients and animal models [34,35,36,37]. In contrast to diabetic nephropathy, its expression is decreased in models of the ischemia-reperfusion acute kidney injury [38], unilateral ureteral obstruction [39], and calcium-oxalate nephrolithiasis [28]. Furthermore, double-labeling immunofluorescence analysis revealed that SGLT2 expression was abolished or decreased in KIM1-positive damaged proximal tubules of the congested kidney, which is consistent with our previous report in calcium-oxalate nephrolithiasis rats [28]. Tubular injury causes loss of renal tubular transporters, including SGLT2 [39]. These results may suggest that the renoprotective potential of SGLT2 inhibitors may be limited in the injured proximal tubules. However, SGLT2 inhibitors show renoprotective ability in patients with chronic kidney disease with and without diabetes [21, 40]. Renoprotective effects are also observed in mice that started SGLT2 inhibitor treatment after ischemia-reperfusion [38]. Therefore, further investigation may be needed to clarify what level of renal function is required to obtain the renoprotective effect of SGLT2 inhibitors.
Renal congestion forms a vicious cycle of several factors including hormonal activation, inflammation, oxidative stress, sodium reabsorption, and volume overload [41, 42]. Several approaches are necessary to dissect the pathophysiological mechanisms relating to renal congestion. The IVC pressure on day 3 was approximately 10 mmHg in our renal congestion model [14, 15]. This pressure is comparable to the other renal congestion model in Dahl salt-sensitive rats fed high salt, in which the IVC pressure reached 12.2 mmHg [11]. In contrast to Dahl salt-sensitive rats, our rats with renal congestion have a contralateral control kidney that exhibits unchanged morphology and function as compared to sham-operated kidney [14]. Therefore, our model could have the potential to clarify the direct impact of renal congestion, without the influence of neuro/hormonal transmitters.
Increased kidney weight and water content, and progression of renal injury and fibrosis were observed in the congested kidney in the present study. They were reversed by tofogliflozin treatment. This may reflect renal decongestion and subsequent renoprotection by the SGLT2 inhibitor. SGLT2 inhibitors show renoprotective properties in Dahl salt-sensitive rats with high salt diet [43, 44]. SGLT2 inhibitors relieved renal congestion by removing excess fluid from both intravascular and renal medullary interstitial space, and suppressed renal intra-tubular cast formation in Dahl salt-sensitive rats fed high salt [43]. In contrast to Dahl salt-sensitive rats, the renoprotective effects of tofogliflozin treatment on medullary regions were limited by molecular and histological analysis in this study. Furthermore, tofogliflozin treatment recovered the upregulation of inflammatory molecules and mitochondrial dysfunction, which were reported in diabetic conditions but not in renal congestion including Dahl salt-sensitive rats fed high salt [45, 46]. Thus, the direct effect of SGLT2 inhibitors on the proximal tubules may be preferential in our renal congestion model.
The molecules associated with renal injury and fibrosis were upregulated in the left congested kidney and reversed by tofogliflozin treatment. Among them, OPN is a marker reflecting tubular injury and dramatically upregulated in the cortex of the congested kidney [14]. OPN is a secreted glycoprotein and expresses in the ascending lib of loop of Henle and distal tubules in normal kidneys in both humans and animals [47]. After several damages, its expression is highly upregulated in the proximal tubules in humans and rodents [48, 49]. OPN is also essential for TGFB1-mediated myofibroblast differentiation and activity [50]. In addition, SGLT2 inhibitors suppress the transcriptional activity of OPN by inhibiting glucose uptake in damaged proximal tubules [27]. Therefore, OPN and its suppression by SGLT2 inhibitors may be crucial targets to regulate fibrosis and the TGFB1 driven inflammatory cascade in the injured proximal tubular cells.
Myofibroblasts have a pivotal role in renal fibrosis, but the origin of these cells is still debated. Myofibroblasts are a heterogeneous population with a variety of origins, including tubular epithelial cells by epithelial-mesenchymal transition [51, 52], endothelial cells by endothelial-mesenchymal transition (EndoMT) [53] and pericyte cells by PMT [14, 15, 18, 54]. Indeed, suppression of PMT by inhibition of the PDGFR pathway reduced renal congestion-induced renal interstitial fibrosis in our previous study [15]. Furthermore, macrophage-myofibroblast transition is another source of myofibroblasts [55]. Approximately one-third of the myofibroblasts are derived from bone marrow cells in the unilateral ureteral obstruction model [56] and the renal allograft [57]. However, the macrophage marker (CD68) and myofibroblast marker (ACTA2) did not colocalize in the congested kidney of the present study. The contribution of macrophage-myofibroblast transition seems to be limited in renal fibrosis after renal congestion.
Mitochondrial dysfunction, previously observed in this model of renal congestion by transmission electron microscopy [14], was reversed by tofogliflozin treatment. The kidneys are enriched in mitochondria, second only to the heart [58, 59]. SGLT2 inhibitors recovered mitochondrial dysfunction in diabetic patients and mice [37, 45]. Glucose-induced toxicity leads to oxidative stress and mitochondrial dysfunction, which impar tubular function in diabetic kidney [60]. SGLT2 inhibitors improve mitochondrial number and mitophagy in cardiomyocytes [61]. Thus, SGLT2 inhibitors may also exert renoprotective effects by reversing mitochondrial dysfunction in renal congestion.
There are several limitations. First, the duration of treatment is important in assessing the therapeutic potential of SGLT2 inhibitors. It is difficult to start therapeutic intervention before the onset of renal congestion in patients. We started tofogliflozin treatment before IVC ligation surgery and evaluated it 3 days after the induction of renal congestion, which was a semi-acute phase. Because the formation of collateral circulation and attenuation of renal venous congestion occurred within 7 days after IVC ligation [14, 62], our model may not be suitable for chronic phase experiments. Further experiments using other models of renal congestion including Dhal salt-sensitive rats with high salt loading and deoxycorticosterone acetate (DOCA)-salt rats may be needed to evaluate the effects of SGLT2 inhibitors on long-term renal congestion and after renal congestion has occurred. Second, the mixed anesthesia, which is recommended for animal experiments in our animal facility, transiently increases serum glucose, hematocrit, and hemoglobin levels and decreases total protein levels and white blood cell counts, with most of these parameters returning to normal within 24 h [32]. In the present study, rats treated with and without tofogliflozin had blood glucose levels of approximately 140 mg/dL before being anesthetized for sacrifice, which is consistent with previous reports using tofogliflozin in normal rats [30, 33]. However, because these factors are closely related to the effects of SGLT2 inhibitors, anesthesia may influence the results of this study.
Conclusion
Tofogliflozin treatment suppressed renal interstitial fibrosis, inflammation, and mitochondrial dysfunction after renal venous congestion, especially in the renal cortex. Therefore, SGLT2 inhibitors could be a therapeutic candidate for renal impairment associated with heart failure.
When health problems affect your kidneys, they can cause CKD. This is permanent damage that may get worse over time. If they’re so damaged that they stop working, it’s called kidney failure, or end-stage renal disease (ESRD). The treatment is usually either dialysis — when a machine does the work your kidneys normally do, or a transplant — when you get a new healthy kidney from a donor.
Diabetes
2/13
This leading cause of kidney failure damages the organs’ small blood vessels and filters. That makes it difficult for them to clean your blood. Your body holds on to more salt and water than it should, and there’s more waste in your system. Nerve damage caused by the disease can make urine back up and harm your kidneys through pressure or infection.
Anorexia Nervosa
3/13
People who have this have an unrealistic body image, and they don’t eat enough to stay at a healthy weight. (They weigh at least 15% less than they should.) That can lead to a lack of water, electrolytes, and salt in the body, which can cause chronic kidney disease and, eventually, kidney failure. This is especially true for people who binge-eat and purge (vomit or use laxatives) to get rid of calories.
High Blood Pressure
4/13
If the force of blood flow through your body is too high, it can stretch and scar — and weaken — your blood vessels, including the ones in your kidneys. This can keep them from getting rid of waste the way they should, and the extra fluid in your blood vessels can raise your blood pressure even more, leading to a dangerous cycle. It’s treated with medication and changes to things like your diet, exercise habits, and stress level.
High Cholesterol
5/13
If you have too much bad cholesterol, it can build up in the vessels that carry blood into and out of your kidneys, and that can affect how well they work. It also makes you more likely to have high blood pressure and diabetes. A blood test can tell you if your cholesterol level is too high.
Lupus
6/13
This is a disease that makes your immune system attack certain parts of your body. When it affects your kidneys, it’s called lupus nephritis. It causes inflammation and scarring of the small blood vessels that filter waste out of your kidneys, and sometimes in your kidneys as well. It’s treated with different medications: Some affect your immune system, while others help control your blood pressure or get rid of swelling and excess fluid.
Multiple Myeloma
7/13
This kind of cancer involves the white blood cells (plasma) that help you fight infection. The cancer cells build up in your bone marrow, where they crowd out healthy blood cells and make abnormal proteins that can cause kidney problems. More than half the people with multiple myeloma also end up with kidney problems.
Hemolytic Uremic Syndrome
8/13
This happens when small blood vessels in the kidney and other organs get damaged. That can eventually cause kidney failure. It happens after 5 to 10 days of diarrhea, usually brought on by an infection, like from E. coli bacteria, or certain medications. Most people recover if it’s treated quickly. See your doctor if you have several days of diarrhea, aren’t peeing often, and are very tired. You also may get bruises or unusual bleeding.
ANCA Vasculitis
9/13
This is when your own antibodies — which usually fight germs — attack the small blood vessels in your kidneys and other organs. It may lead to blood and protein in your urine and can cause kidney failure. You may have fever, body aches, joint and muscle pain, and brown, tea-colored pee.
Urine Blockage
10/13
If you can’t pee, that can mean urine is backed up, and that can damage your kidneys. It can cause pressure and lead to infection in your kidneys and other parts of your body. An enlarged prostate, prostate cancer, kidney stones, bladder cancer, urinary tract blood clots, and colon cancer are some of the things that can cause this. See your doctor if you’re peeing much less or much more often than usual or if you see blood in your urine.
Blood Clots
11/13
Many conditions can cause blood clots, but a blood disorder — thrombotic thrombocytopenic purpura — is commonly linked to kidney problems. It causes clots in tiny blood vessels that also can affect your brain and heart. Symptoms include fever, bleeding from your nose or gums, diarrhea, chest pain, confusion, headache, bruising, and feeling very tired. It can be serious if it’s not treated quickly, so see a doctor if you have any of these signs.
Scleroderma
12/13
This is a group of rare diseases that make your skin and connective tissues hard and tight. It can sometimes also harm other things, like blood vessels and organs. If it affects your kidneys and they don’t work the way they should, they can let protein escape through your urine. It also can cause a sudden increase in blood pressure that can lead to rapid kidney failure.
Polycystic Kidney Disease
13/13
This causes cysts — small sores often filled with fluid — to grow inside your kidneys. That makes them much larger than they should be and damages their tissue. It’s caused by problem genes you get from one of your parents. If it’s not diagnosed and managed soon enough, it can lead to chronic kidney disease and, eventually, to end-stage renal disease.
Pathway Project results were presented for the first time at ASN Kidney Week, revealing three new best practices for end-of-life care, specific to the kidney community.
“Although there’s an increasing body of evidence outside of nephrology that says care practices can improve quality of life, confidence in end-of-life decision-making and bereavement, there is a lag in translating these findings into practice,” Manjula Kurella Tamura, MD, MPH, director of the Geriatric Research and Education Clinical Center at the Veterans Affairs Palo Alto Health Care System and professor of medicine at Stanford University, said.
The Pathway Project identified and presented 14 evidence-based best practices that could be incorporated into kidney care to dialysis organizations, then refined the final package to prioritize three best practices. These practices focused on seriously ill patients.
The first best practice of the Pathway Project encourages nephrologists to screen patients by asking themselves the “surprise” question: “Would I be surprised if this patient died in the next 6 or 12 months?” Answering no would mean that the patient is seriously ill. The second best practice is to prioritize goals of care conversations with seriously ill patients. The third best practice is offering palliative care pathways that allow patients to transition to less frequent dialysis, hospice or dialysis discontinuation based on their goals of care.
Ten hemodialysis centers voluntarily adopted and implemented these practices after two learning sessions. The serious illness screening was implemented and sustained, even after the beginning of the COVID-19 pandemic, in early 2020 throughout all the centers.
“In terms of the next best practice, conducting goals of care conversations, sites monitored the implementation of this practice by tracking the percent of seriously ill patients who had a goals of care conversation within 30 days of hospital discharge,” Kurella Tamura said. “What they found is that goals of care discussions were implemented, but unevenly, over the course of the implementation.”
She said a few reasons that implementation was challenging were scheduling issues, lack of confident caregivers to have these conversations and some patients felt they could continue putting off the conversation.
The third best practice, the palliative care pathway, was implemented the least, and no centers developed protocols to transition patients to hospice or dialysis withdrawal. A given reason for this was the CMS payment structure and that removing a patient from dialysis could negatively affect paid caregivers.
When interviewed 18 months after implementing the Project Pathway practices, many caregivers involved expressed positive thoughts about the practices.
“We found that all of the sites encountered challenges, but also found this experience incredibly rewarding both for their own individual practice, as well as the practice for their center as a whole,” Kurella Tamura said. “While there were many successes, there were still some hurdles that couldn’t be overcome in the project, particularly the policy and resource barriers that are inherent in our current health care system. So, in some ways, it’s not surprising that a learning collaborative just by itself was not able to overcome these barriers. Maybe one of our takeaways is that the learning collaborative needs to be coupled with changes at the policy and health care structure level to be able to see meaningful changes in health care utilization and patient experience near the end of life.”
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