new chronic kidney disease guidelines

 A new clinical guideline by the Kidney Disease: Improving Global Outcomes (KDIGO) on the evaluation and management of chronic kidney disease: see ckd kdigo guidelines AnnIntMed2025 in dropbox, or doi:10.7326/ANNALS-24-01926

 

Overview:

-- these guidelines pertain to all patients with chronic kidney disease (CKD) who are not on kidney replacement therapy (KRT), with the current synopsis referring to their highest recommendations and some upgraded practice points that have evolved since 2012 (these practice points are based on expert opinion)

-- the guidelines emphasize a tailored-care approach, which does vary over the life course from infants to old age

-- they note that these guidelines will only be feasible in higher-resource settings, despite being from a "global" organization

 

Recommendations:

-- staging CKD:

    -- they encourage routine testing for patients at risk, including those with hypertension, diabetes, multisystem diseases, or exposure to potentially nephrotoxic drugs

        -- I would add the importance of testing people with cardiovascular disease, heart failure, or on medications that require renal dosing. 

            -- one particular concern not in the guidelines is the presence of apolipoprotein L1, a variant found in patients who have a West African background (ie lots of the Black American population), which can be present as homozygous (2 alleles, the highest risk group) or heterozygous (1 allele), who develop CKD (84% increased risk of focal segmental glomerulosclerosis (FSGS) in those with 2 alleles and 61% in those with one allele) and CKD. the prevalence of apo L1 in sub-Saharan Africa varies from 0 to 45% for those with 1 allele and 0 to 24% for 2 alleles. These variants developed evolutionarily likely because they conferred protection from lethal African sleeping sickness from Trypanosoma ( https://www.nejm.org/doi/full/10.1056/NEJMoa2404211 , and  https://www.ajkd.org/article/S0272-6386(24)00597-3/fulltext ), as well as perhaps HIV, salmonella and leishmaniasis. and FSGS is found at a mean age of 12 for those with 2 alleles and age 5 in those with one. there may also be increased risk of HIV-associated nephropathy and hypertension-attributed end-stage kidney disease

                -- which means that we should perhaps be testing kids/teens of African ancestry for renal disease at a much younger age and aggressively treat CKD risk factors (especially hypertension), since there is currently no specific apo L1 treatment.

    -- for blood tests to assess renal function, they strongly recommend checking cystatin C levels along with creatinine

        -- there are well-recognized concerns with both of these measurements:

            -- creatinine is influenced by the extremes of muscle mass, malnutrition, dietary intake, and drugs that impair tubular secretion of creatinine (which is quite a long list, including trimethoprim-sulfamethoxazole, salicylates, vitamin D derivatives, cimetidine, famotidine, dolutegravir, cobicistat)

            -- cystatin C is influenced by smoking, chronic inflammation, adiposity, cancer, chemotherapy, thyroid function, and glucocorticoid excess

            -- for a review of this as well as a Swedish study finding that cystatin C, but not creatinine, was the best predictor of bad clinical outcomes: https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html (this blog also highlights some of the drug interactions,  more info in Table 2 of this KDIGO document)

        -- they have not changed their position that the most accurate predictor of the measured GFR is their easy-to-use calculator that combines both creatinine and cystatin: https://www.kidney.org/professionals/gfr_calculator

            -- this approach has been validated by a few large-scale studies of general population cohorts and clinical populations in North America and Europe

        -- they also note that the higher cost of cystatin measurement would be “mitigated by an evidence-driven approach to its use, which reduces misdiagnosis, improves accurate dosing of medications, and reduces adverse events due to medication errors”

-- they also strongly recommend the importance of incorporating urine albumin-to-creatinine ratio (uACR) in the CKD analysis

-- they support point-of-care testing for creatinine and uACR measurement when available, since these are easier to use and might be done more regularly, though they do note that these may be less accurate than laboratory testing

 

-- they recommend a kidney failure risk calculator (https://kidneyfailurerisk.com/), validated in 60 cohorts in 30 different countries from around the world, that reliably predicts both the two- and the five-year estimates of the probability of kidney failure requiring kidney replacement therapy in those with an eGFR<60 (this risk calculator requires only a few variables: age, sex, North America vs other regions, GFR, and urine albumin: creatinine ratio). the use of this risk calculator provides a personalized, tailored approach to treatment and care plans, ”a shift from a GFR based to a risk-based approach to CKD care and advanced care planning”

 

-- Delaying CKD progression and managing its associated complications:

    -- they highlight the importance of SGLT2 inhibitors in both patients with and without diabetes, based on several studies

        -- their recommendation for treating adults with CKD is to begin SGLT2s as long as their eGFR>20 with uACR>200, or heart failure irrespective of the level of albuminuria

    -- SGLT2s reduce the risk for kidney disease progression by 37%, acute kidney injury by 23% (regardless of diabetes status), and kidney failure

    -- a less strong recommendation (grade 2B) was to use SGLT2s in patients with eGFR 20-45 with uACR <200. Studies have found that the benefit to cardiovascular outcomes and hospitalization risk occurs regardless of level of albuminuria

    -- one of their practice points (expert opinion) is that patients whose eGFR falls below 20 should still continue with the SGLT2 inhibitors

 

-- treatment for hyperuricemia

    -- hyperuricemia is quite common as CKD progresses. However, the American College of Rheumatology as well as these guidelines do not recommend prescribing meds in patients with asymptomatic hyperuricemia with the of goal delaying CKD progression. This has been shown in several studies. However, those with symptomatic hyperuricemia should be treated (though it is important to realize that in those with significant CKD, we should start allopurinol at lower doses and slowly titrate upwards as tolerated to the goal uric acid level)

 

-- statin use

    -- given the increased risk of cardiovascular disease in those with CKD, lipids need to be treated aggressively

        -- I would add that uACR is another cardiovascular disease risk factor in and of itself; also statins themselves lower the level of albuminuria

    -- they recommend using a statin or a statin-ezetimibe combination in adults age 50 or older with an eGFR <60 (but not in those on chronic dialysis or who had kidney transplantation), and with a more tepid recommendation to treat those with eGFR even at stages 1 (where eGFR is normal but there is proteinuria) and stage 2 (eGFR 60-90)

    -- they concur with the more aggressive CKD management in younger patients (but those without being on dialysis or kidney transplant) who have known coronary artery disease, diabetes, prior ischemic stroke, or 10-year calculated risk of greater than 10%

        -- I would argue here that CKD is a rather profound cardiovascular risk factor, and especially since it rarely presents itself without other cardiovascular risk factors (e.g. hypertension), so we should view atherosclerotic disease as a progressive disease that starts in people in their late teens and that it is best to prevent the continuing accretion of atherosclerosis earlier than trying to deal with this highly morbid/mortal condition at age 50…

            -- and, most notably, the most common cause of death in patients with CKD is cardiovascular disease: https://pmc.ncbi.nlm.nih.gov/articles/PMC10034498/

 

-- there were several practice points of note (ie expert opinion):

    -- consider using meds with or without dietary intervention to prevent acidosis (eg if serum sodium bicarbonate is <18 mmol/L)

    -- for the risk calculator:

        -- 5-year kidney failure risk: consider nephrology referral if 3%-5% risk in addition to criteria based on eGFR or other clinical considerations

        -- 2-year kidney failure risk:

            -- if >10%, consider multidisciplinary care in addition to criteria based on eGFR or other clinical considerations

            -- if >40%, time to discuss kidney replacement therapy, eg planning for vascular access or referral for transplantation, in addition to criteria based on eGFR or other clinical considerations

        -- avoid the use of race to compute eGFR

        -- use an externally validated cardiovascular risk prediction model that incorporates eGFR and albuminuria to guide preventive therapy in patients

            -- there are a slew of non-eGFR/uACR included cardiovascular factors in the commonly used cardiovascular risk calculators: https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html

            -- CKD stage 3-5 is included in the QRISK3 risk calculator: https://gmodestmedblogs.blogspot.com/2017/08/a-new-atherosclerosis-risk-calculator_2.html 

            -- both CKD and albuminuria are included in the new PREVENT risk calculator (though albuminuria is an optional one): https://gmodestmedblogs.blogspot.com/2024/07/prevent-new-cardiac-risk-factor.html   

 

Limitations:

-- one big one is the limitation of not having important studies to justify some of their practice principles as well as to provide important data on CKD risk, including specifically, as they mentioned, “studies do not account sufficiently for cause of CKD, sex, gender, age, socioeconomic status, and urinary ACR in all cohorts and involve patients with CKD throughout the research process". these make it difficult to just look at the eGFR, for example, since that may reflect kidney damage from a quite diverse set of causes and be associated with diverse findings of CKD trajectory and be able to optimize interventions to help abate that trajectory

    -- also many studies do not include either very old or very young patients, those who are pregnant and lactating, and persons with advanced CKD

-- there are also knowedge gaps in testing strategies for CKD, the optimal combination and timing of therapies, decision-making, and processes of care

-- though the kidney failure risk calculator above seems to be pretty accurate, are there others that might perhaps are even better? for example, a single eGFR value (ie a static value in an evolving condition) plugged into this calculator may actually have little relevance to the long term. perhaps assessing the trajectory of renal function is more useful (eg, the faster, the worse the prognosis), eg see https://pubmed.ncbi.nlm.nih.gov/26728745/. and this kidney failure risk calculator does not include some well-known conditions that seem to accelerate CKD progression, especially hypertension.

    -- and even a single value of eGFR may actually change from one day to the next, and it is clearly affected by certain meds, or hydration status, or exercise

 

so,

--these new KDIGO recommendations support a few important conclusions for primary care providers:

    -- there is important utility to measuring creatinine and cystatin-C and calculating eGFR in the combination equation, since it more accurately reflects the measured GFR. and that should be the basis for decisions about when to adjust medication doses depending on renal function (and we could be really under- or over-treating people without this; eg, this more accurate eGFR could avoid adverse effects associated with over-dosing)

        -- this also means that drug companies should use this creatinine/cystatin C calculation instead of a creatinine-based one in computing the appropriate renal dosing for their meds

        -- and the correct eGFR from the creatinine/cystatin one would standardize our approach to treating the different stages of CKD

        -- as noted above, a Swedish study found that when there was a discordance between the creatinine- vs cystatin-based CKD stage, the cystatin-based one was the only of the two that predicted adverse outcomes (https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html )

    -- the 2- and 5-year risks of CKD, per the kidney failure risk calculator, adds to our ability to interpret the likely effects of a given eGFR for an individual patient, to be able to inform the patient of their current medical situation and prepare them better for their likely future, and even to help enforce the importance of aggressive care to reduce the progression of CKD (and especially to convince patients to the real necessity to have very well-controlled blood pressure)

        -- these KDIGO guidelines put front-and-center the role of SGLT2 inhibitors in those with pretty much any degree of CKD, and that those on SGLT2s should continue even if their eGFR descends to <20 (the latter being expert opinion and without definitive data)

        -- though not mentioned in these guidelines, there also seems to be a significant role for GLP-1 receptor agonists for renal protection, even in those without diabetes: https://www.ajkd.org/article/S0272-6386(24)00975-2/fulltext

    -- it is important to be aggressive with statins/ezetimibe in lipid management. this goes against a couple of early studies that did not find benefit (though these studies did not lower LDL levels a lot)

 

geoff

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