In the early stages of kidney damage, individuals may not experience noticeable symptoms. Kidney disease can progress silently, and symptoms may only become apparent as the condition progresses.
Chronic kidney disease, also called chronic kidney failure, involves a gradual loss of kidney function. Your kidneys filter wastes and excess fluids from your blood, which are then removed in your urine. Advanced chronic kidney disease can cause dangerous levels of fluid, electrolytes and wastes to build up in your body.
In the early stages of chronic kidney disease, you might have few signs or symptoms. You might not realize that you have kidney disease until the condition is advanced.
Treatment for chronic kidney disease focuses on slowing the progression of kidney damage, usually by controlling the cause. But, even controlling the cause might not keep kidney damage from progressing. Chronic kidney disease can progress to end-stage kidney failure, which is fatal without artificial filtering (dialysis) or a kidney transplant.
However, one of the first main symptoms that may indicate kidney damage is often:
1. **Proteinuria:** – Presence of excess protein in the urine. Healthy kidneys filter waste products, including excess protein, from the blood. When the kidneys become damaged, they may allow protein to leak into the urine.
It is important to understand that proteinuria can be detected through a urine test and is not usually something you can see visually. Regular checkups with a health care professional and regular urine tests can help identify early signs of kidney damage.
As kidney disease progresses, other symptoms may emerge, including:
2. **Changes in urination:** – Increased or decreased frequency of urination. – Change in color of urine or appearing foamy.
3. **Swelling (Oedema):** – Swelling, especially around the feet, ankles or eyes. This may result from fluid retention due to poor kidney function.
4. **Fatigue:** – Generalized tiredness and weakness.
5. **High Blood Pressure:** – High blood pressure (hypertension) is a common complication of kidney disease and can develop or worsen.
6. **Back Pain:** – Pain in the lower back, especially around the kidney area.
It is important to note that these symptoms may also be associated with various other health conditions, and their presence does not necessarily indicate kidney damage. Regular health checkups including blood pressure measurement and urine tests are important for early detection of kidney-related problems.
If you have special concerns about your kidney health or notice any of these symptoms, it is advisable to consult a health care professional for a comprehensive evaluation and appropriate guidance. Early intervention can help slow the progression of kidney disease and improve outcomes.
Adults with a higher self-reported salt intake were more likely to have a diminished eGFR.
Participants who reported “always” adding salt had an 11% increased risk for CKD.
A higher frequency of adding salt to food may be associated with an increased risk of chronic kidney disease in the general population, according to a recently published study.
Researchers led by Rui Tang, MS, MPH, of the department of epidemiology at Tulane University in New Orleans, led a trial to “prospectively examine the association of self-reported frequency of adding salt to foods with incident CKD,” they wrote in the report. “The association of high sodium consumption with hypertension has been well established in previous studies. … Although many studies to date have investigated the association of dietary sodium intake with the risk of CKD, most have only included participants who have already received a diagnosis of hypertension, diabetes or other chronic conditions.”
Participants who reported ‘always’ adding salt had an 11% increased risk for CKD.
Investigators evaluated 465,288 adults (aged 37 to 73 years) from the UK Biobank and who were enrolled from 2006 to 2010 and free of CKD at baseline. Patients were prospectively followed up for diagnosis, and researchers examined data from 2022 to 2023. The UK Northwest Multicenter Research Ethics Committee is a national, population-based cohort study designed to improve the prevention, diagnosis and treatment of various illnesses.
The study aimed to evaluate potential links between adding salt to foods and the risk of incident CKD in a general population. Participants self-reported their frequency of salt addition to foods and were categorized into four groups: “never or rarely,” “sometimes,” “usually” and “always.” The main outcome was incident CKD, identified through diagnostic codes.
During a median follow-up of 11.8 years, researchers found 22,031 incident cases of CKD.
Results showed that patients with a higher self-reported frequency of salt intake were more likely to have a higher BMI and diminished eGFR compared to those with a lower frequency of adding salt. In addition to likely being a current smoker or drinker or having diabetes or cardiovascular disease at baseline, patients with higher salt intake frequency were also more likely to have a higher Townsend Deprivation Index score, a composite measure of deprivation based on unemployment and socioeconomic status.
Participants who reported “sometimes” adding salt to food had a 4% increased risk, those who reported “usually” adding salt had a 7% increased risk and those who reported “always” adding salt had an 11% increased risk for CKD vs. those who “never or rarely” did.
The links were greater in patients with a higher eGFR, lower BMI and lower physical activity.
“These findings suggest that reducing the frequency of adding salt to foods at the table might be a valuable strategy to lower CKD risk,” Tang and colleagues wrote.
New findings led to boxed warning on drug’s labeling for advanced CKD patients
Many women on dialysis quickly developed severe hypocalcemia after starting denosumab (Prolia) for osteoporosis, Medicare data showed.
During the first 12 weeks of treatment, 41.1% of women on denosumab developed severe hypocalcemia compared with 2.0% of those taking oral bisphosphonates, reported a group of largely FDA researchers led by Steven Bird, PhD, PharmD, of the agency offices in Silver Spring, Maryland.
This translated to more than a 20-times higher risk for incident severe hypocalcemia with denosumab (weighted risk ratio 20.7, 95% CI 13.2-41.2), according to the retrospective cohort study in JAMAopens in a new tab or window.
Supported by these new findings, the FDA on Friday added a boxed warningopens in a new tab or window over the risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD) taking denosumab for osteoporosis.
The study revealed a sharp decline in calcium levels within the first week of denosumab administration that continued for up to 10 weeks after.
The same was seen in regards to the 12-week weighted cumulative incidence of very severe hypocalcemia, which occurred in 10.9% of denosumab-treated patients versus only 0.4% of those on oral bisphosphonates (weighted RR 26.4, 95% CI 9.7-449.5).
“Stable serum calcium levels observed in this cohort during the 6 months prior to denosumab administration, coupled with the rapid onset and high incidence of severe hypocalcemia post administration, suggest that this association might be causal,” they posited. Because of this, the authors said denosumab should only be administered “after careful patients selection and with plans for frequent monitoring.”
“This may be due to a confluence of nephrology practice patterns, inadequate communication between physicians, and lack of guidance on osteoporosis management in patients undergoing dialysis,” commented accompanying editorialopens in a new tab or window authors Pascale Khairallah, MD, of Baylor College of Medicine in Houston, and Thomas Nickolas, MD, MS, of Columbia University Irving Medical Center in New York.
These findings also weren’t totally unexpected, Khairallah and Nickolas said, as other global studies reported rates of denosumab-related hypocalcemia of up to 42%.
“The lack of guidance on managing osteoporosis in CKD is shared between the nephrology community and drug regulatory agencies,” the editorialists argued. “The broad range of anti-fracture medications being used in patients and the emerging postmarketing adverse event data should prompt medical societies, in conjunction with the … FDA, to produce relevant guidance on management strategies, including restrictions on drug class usage if warranted by drug safety profiles.”
The FDA had issued a safety alertopens in a new tab or window back in November 2022 over denosumab’s potential hypocalcemia risk in dialysis-dependent women. In that safety alert, the agency referred to interim results from maker Amgen’s ongoing safety study of denosumab, which suggested an increased risk of hypocalcemia in patients with advanced kidney disease. That safety study — required upon denosumab’s initial approval — was conducted in men and postmenopausal women with osteoporosis.
Bird’s group looked at Medicare data on women 65 and older who initiated treatment with denosumab 60 mg (n=1,523) or oral bisphosphonates (n=1,281) including alendronate (Fosamax), risedronate (Actonel, Atelvia), or ibandronate (Boniva) from 2013 through 2020. All women were undergoing long-term hemodialysis or peritoneal dialysis and had a diagnosis of osteoporosis or were receiving treatment for low bone mass after therapy with aromatase inhibitors, gonadotropin-releasing hormone agonists, or high-intensity glucocorticoids. Nearly all had osteoporosis and hyperparathyroidism.
The vast majority of these drugs were prescribed by primary care clinicians, followed by endocrinologists and rheumatologists. Less than 3% of scripts were written by nephrologists.
Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis, while very severe hypocalcemia was considered a serum calcium below 6.5 mg/dL (1.63 mmol/L) or emergent care. Almost all severe hypocalcemia cases were identified based on albumin-corrected serum calcium levels rather than based on emergency department or hospital diagnosis.
Medication people with type 2 diabetes use to manage their blood sugar also appear to protect their hearts and kidneys, according to a new study in JAMA Network Open.
These pills, known as sodium-glucose cotransport protein 2 (SGLT2) inhibitors, reduce the amount of blood sugar in a kidney by causing more glucose to be excreted in urine.
Chronic kidney disease (CKD) cannot be cured and often leads to renal failure. SGLT2 inhibitor drugs can help stave off this possibility. Acute kidney disease (AKD), on the other hand, is potentially reversible. It typically occurs after an acute kidney injury, lasts for up to 90 days, and can progress to CKD if left unchecked.
“T here has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” said Vin-Cent Wu, MD, PhD, a nephrologist at National Taiwan University Hospital in Taipei, and an author of the study.
For the retrospective analysis, Wu and his colleagues looked at data from more than 230,000 adults with type 2 diabetes whose health records were gathered into a research tool called the TriNetX, a global research database. Patients had been treated for AKD between 2002 and 2022. Major adverse kidney events were noted for 5 years after discharge, which were defined as events which required regular dialysis, major adverse cardiovascular events such as a heart attack or stroke, or death.
To determine the effects of SGLT2 inhibitors, Wu and colleagues compared outcomes among 5317 patients with AKD who received the drugs with 5317 similar patients who did not. Members of both groups had lived for at least 90 days after being discharged from the hospital and did not require dialysis during that period.
After a median follow-up of 2.3 years, more patients who did not receive an SGLT2 inhibitor had died (994 compared with 481) or had endured major stress to their kidneys (1119 compared with 504) or heart (612 compared with 295). The relative reduction in mortality risk for people in the SGLT2-inhibitor arm was 31% (adjusted hazard ratio, 0.69; 95% CI, 0.62-0.77).
Only 2.3% of patients with AKD in the study were prescribed an SGLT2 inhibitor.
In the United States, approximately 20% of people with type 2 diabetes and CKD receive a SGLT2 inhibitor, according to 2023 research.
“Our study reveals that the prescription rate of SGLT2 inhibitors remains relatively low in clinical practice among patients with type 2 diabetes and AKD,” Wu told Medscape Medical News. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making.”
Wu said that AKD management tends to be conservative and relies on symptom monitoring. He acknowledged that confounders may have influenced the results, and that the use of SGLT2 inhibitors might only be correlated with better results instead of producing a causation effect.
This point was raised by Ayodele Odutayo, MD, DPhil, a nephrologist at the University of Toronto, who was not involved in the study. But despite that caution, Odutayo said that he found the study to be encouraging overall and broadly in line with known benefits of SGLT2 inhibitors in CKD.
“The findings are reassuring that the medications work even in people who’ve already had some kidney injury beforehand,” but who are not yet diagnosed with CKD, Odutayo said.
“There is vast underuse of these medications in people for whom they are indicated,” perhaps due to clinician concern that the drugs will cause side effects such as low blood pressure or loss of salt and fluid, Odutayo said. Though those concerns are valid, the benefits of these drugs exceed the risks for most patients with CKD.
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.
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.
Today is World Kidney Day, and the National Kidney Foundation is emphasizing its effort with the Coalition for Kidney Health to nominate targeted screening or case finding for chronic kidney disease based on risk conditions, like diabetes.
Joseph A. Vassalotti
The NKF is nominating these screenings to the United States Preventive Service Task Force (USPSTF) to re-evaluate the current absence of a recommendation. This reassessment is overdue and increasingly urgent, given significant racial and ethnic inequities in the diagnosis and treatment of kidney disease that have been worsened by the COVID-19 pandemic and socioeconomic depravation.
Source: Adobe Stock
Screening efforts
Current evidence supports testing individuals with diabetes, hypertension and other conditions, as recommended by clinical practice guidelines from the American Diabetes Association, the Kidney Diseases Improving Global Outcomes and the Kidney Disease Outcomes Quality Initiative. The major barrier in the United States is the limited use of the quantitative urine albumin-creatinine ratio (uACR), with annual testing rates of approximately 40% for diabetes and less than 10% for hypertension in national data, supporting the need for interventions to improve targeted albuminuria testing.
The absence of a current CKD screening recommendation contributes to the low rates of testing and, in turn, suboptimal CKD diagnosis in the primary care setting. It is a necessary action if we want to address this year’s World Kidney Day theme, Kidney Care For All.
More than 90% of Americans with kidney disease are unaware they have it. Health services research and the United States Renal Data System show Americans with CKD have more than 50% uncontrolled diabetes and hypertension, low rates of disease-modifying medication use, suboptimal interdisciplinary care and 80% hemodialysis catheter use at dialysis initiation.
Health inequities
Kidney health inequities by race and ethnicity have been documented since the 1980s. For example, African American individuals are three to four times more likely than white individuals to experience kidney failure, even though white individuals are more likely to have diabetes and hypertension.
Hispanic, Asian, Hawaiian, Pacific Islander and American Indian individuals also have documented kidney health disparities with nuances across the groups. Americans living with kidney failure have low rates of preemptive and early kidney transplantation and low access to home dialysis, particularly among socioeconomically disadvantaged populations.
Randomized trials have demonstrated kidney and cardiovascular protection using new CKD therapeutics that increase the potential outcome and cost benefits of CKD diagnosis. Overwhelming evidence from CREDENCE, DAPA-CKD and other trials shows the SGLT2 inhibitor drug class has efficacy in slowing CKD progression and reducing risk of cardiovascular events, particularly heart failure hospitalization in patients with CKD and type-2 diabetes mellitus (T2DM), as well as those without diabetes.
Mortality benefits were also shown in the SGLT2 inhibitor trials. Elevated albuminuria by uACR is an evidence-based indication for SGLT2 inhibitor therapy even if the eGFR is normal, emphasizing the need for testing. A non-steroidal mineralocorticoid antagonist (MRA) has also demonstrated reduction in CKD progression and heart failure hospitalization for the T2DM and CKD population.
Moreover, observational studies have shown interdisciplinary care that may include a primary care clinician, registered dietitian, pharmacist and nephrologist is also associated with improved outcomes for T2DM with CKD.
In addition to kidney protection, there are several interventions that do not necessarily modify CKD progression, but reduce risk of CVD, including statin-based therapies and the glucagon-like peptide receptor agonists (GLP-1RA) drug class for T2DM. Multiple additional studies of the SGLT2 inhibitor, non-steroidal MRA and GLP-1RA classes on kidney protective efficacy are ongoing.
Finally, prioritizing the development of a USPSTF CKD screening recommendation is foundational to achieving health equity. In September 2021, the NKF-American Society of Nephrology Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases recommended the adoption of a new race-free Chronic Kidney Disease Epidemiology Collaboration 2021 creatinine equation to estimate kidney function. The aim of the new equation was to minimize potential consequences that disproportionately affect any one group of individuals. Removing race correction from clinical algorithms is important to society to avoid implying a biologic cause for race, which is a social construct.
NKF is working with large clinical laboratories across the United States to uniformly implement the new eGFR calculation. Kidney health equity will require targeted testing and improved access to care, including disease-modifying medications. Kidney disease typically does not have symptoms, so eGFR and uACR case finding are required among high-risk populations rather than general or mass population screening.
The evidence-base supporting targeted screening in high-risk populations has grown since 2012, tipping the scales in favor of the USPSTF to revisit the recommendation.
Joseph A. Vassalotti, MD, is the chief medical officer for the NKF and a clinical professor at the Icahn School of Medicine at Mount Sinai Hospital, New York.
“Just because it comes in pairs, doesn’t mean you may value one less,” as the saying goes. This is especially true when it comes to one’s kidneys. Despite the fact that the human body is blessed with two critical organs, kidney failure and other kidney disorders are common and seem to be on the rise.
The main focus for medical professionals around the world on this World Kidney Day is to educate people and raise awareness about the fact that illnesses are more common than one might think, and that even minor lifestyle changes and decisions can result in major setbacks in one’s kidney health and condition.
How common are chronic kidney diseases?
According to studies, Chronic Kidney Disorder (CKD) is becoming more common, and reportedly 1 in 7 adults suffer from it. The major function of the kidneys is to filter blood and regulate the salt, potassium, and acid content of the body by removing waste and excess fluid. CKD is a dangerous and progressive disorder defined by diminishing kidney function in those who have Type 2 diabetes, high blood pressure, or a family history of kidney disease.
Despite its high frequency, CKD is a ‘silent’ disease, meaning most people don’t notice symptoms until it has progressed to more advanced stages. Patients with CKD may be at higher risk for various illnesses such as heart disease, stroke, and more, in addition to kidney function decline. End-stage kidney disease (ESKD) is caused by a reduction in kidney function that can only be treated with dialysis (a therapy that helps eliminate waste products, excess fluid, and potassium) or a kidney transplant to keep the body working after the kidneys fail.
How does one diagnose kidney disorders?
Because CKD symptoms may not develop until later in the disease’s progression, it’s critical to have continuing conversations with your doctor so you’re aware of your risk factors. It’s also crucial to monitor your blood work on a regular basis to assess how well your kidneys are working. Particular blood and urine tests can determine whether or not you have CKD.
Knowing your eGFR, or estimated Glomerular Filtration Rate, which is a measure of how well your kidneys filter waste from the body, is one indicator of renal health and a key aspect of managing CKD. This test is performed as part of normal blood work. The urine albumin-to-creatinine ratio test, which examines for excess protein (albumin) in the urine, is another crucial test to confirm CKD. Kidney disease is indicated by a high urine albumin-to-creatinine ratio.
How to go about with treatments once diagnosed with kidney disease?
In case of risk factors such as diabetes, high blood pressure (hypertension), heart disease, or a family history of kidney failure, it’s critical to detect and treat CKD as soon as possible. Early intervention has been demonstrated to halt disease development, preserve renal function, and lower the risk of developing other CKD-related diseases.
CKD treatments are now available to assist decrease renal disease progression and delay end-stage kidney disease, thanks to the advancement of contemporary therapeutics. Traditionally, CKD has been treated by addressing the underlying risk factors, taking particular medications if there is protein in the urine and high blood pressure, and discontinuing certain medications that may be causing kidney damage. People with CKD risk factors, such as diabetes and high blood pressure, should study their blood test findings and speak with their doctor about their eGFR score and the best treatment options for them.
Patients who received 3 months of individualized nutritional counseling reaped a variety of benefits, including better adherence to dietary recommendations, decreased BMI and improved kidney function.
“In spite of the reported benefits of intensive individualized nutrition counseling for advanced CKD patients, insurance policies for such intervention are still limited in several countries, including Korea,” Hosun Lee, CCD, MS, of the department of nutrition care at Severance Hospital, Yonsei University Health System, and colleagues wrote. “Dietary patterns depend deeply on ethnicity and cultural background. For instance, the typical Asian diet is composed of less protein and more [sodium] Na. Therefore, the effect of nutrition counseling would also vary depending on the region and culture.”
Contending that most studies on nutrition counseling have been focused on Western countries, the researchers here studied its impact on “a single nation Asian ethnic group,” recruiting 59 patients with stage 3 and 4 CKD from a tertiary hospital outpatient clinic in Korea (81% were men).
Patients were randomized to an intensive care group or a control group. While all patients first received one 45-minute group session regarding nutritional information, diet management practices to prevent complications, and meal plans, those in the intervention received 3 monthly sessions of individualized intensive nutrition counseling.
“For intensive individualized nutrition counseling, a trained clinical dietitian calculated each patient’s nutritional requirements according to ideal body weights based on the [Kidney disease: Improving Global Outcomes] KDIGO guidelines,” the researchers wrote.
In addition, patients in the individualized counseling group kept food diaries and were provided tailored nutritional information.
The most common nutritional diagnoses were excessive intake of sodium (97.6%), potassium (78.6%), protein (52.4%) and phosphorus (31%).
After 3 months of counseling, Lee and colleagues observed that while potassium and phosphorous intakes decreased significantly in both groups, protein, sodium and energy intakes only decreased in the intensive group.
Further findings indicated BMI decreased and eGFR improved for patients in the intensive group but not the control group.
“Although dietary modification is a critical component of CKD management, patients’ compliance is still far from satisfactory,” Lee and colleagues concluded.
“It should be noted that multiple intensive nutrition counseling sessions, although provided for only 3 months, resulted in improved dietary adherence and clinical improvement in CKD patients.”
Supplementation of Vitamin D improves vascular function and reduces inflammation in patients with early stage of chronic kidney disease, according to a new study.
Simple identification and correction of Vitamin D deficiency has the potential to improve the outcomes among kidney patients, said the study conducted by researchers from the George Institute for Global Health, New Delhi and the Postgraduate Institute of Medical Education and Research, Chandigarh. The study has been presented at the ongoing American Society of Nephrology Kidney Week 2015 (November 3-8) in San Diego.
In a randomised controlled trial, under direct supervision, the researchers gave two doses of 300,000 units of Vitamin D to one group (consisting of 60 patients) eight weeks apart whereas the patients in the other group (60 patients) received matching placebo. “Several parameters of vascular function and biomarkers to measure status of inflammatory and immune activation were studied at baseline and after 16 weeks, Vitamin D levels increased in patients in the active treatment group whereas there was no change in the control arm.
“About 70 per cent of patients receiving Vitamin D demonstrated significant improvement in their vascular functions and improvement in biomarkers indicating reduction in the level of inflammatory and immune activation,” said Professor Vivekanand Jha, the Executive Director of the George Institute for Global Health who led the study. In the placebo arm only five per cent patients showed improved vascular function and there was no change in the inflammatory and immune markers, Jha said.
Vitamin D deficiency is common in patients with chronic kidney disease. Our study shows that simply identifying and correcting this abnormality has the potential to improve the outcomes in these patients, said Dr Vivek Kumar, Nephrologist, Postgraduate Institute of Medical Education and Research, Chandigarh and the first author of the study.
“About one in 10 persons suffer from chronic kidney disease around the world. Most of these patients are destined to develop premature cardiovascular disease, hence mitigation of this risk is an important therapeutic goal,” added Jha.
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