Chronic Kidney Disease and End-Stage Kidney Disease

Chronic kidney disease (CKD) is defined by the presence of kidney damage or decreased kidney function or a progressive decline in the glomerular filtration rate (GFR) for at least 3 months. CKD has important cardiovascular and survival implications and is associated with increased morbidity and mortality.

Glomerular filtration rate (GFR) varies by age, sex, and dietary protein intake. In clinical practice, GFR is typically estimated (eGFR) from the serum concentration of creatinine (or increasingly, cystatin C) using one of several calculators with CKD defined as an eGFR below 60 mL/min per 1.73 m².

• eGFR calculation in the Black population:

  • For many years, a correction for Black race-ethnicity had been included in most eGFR calculations. This “correction factor” is based on an assumption, without hard evidence, that Black adults have higher muscle mass than non-Blacks.

  • This unsubstantiated approach generally overestimates GFR in Blacks and misclassifies Black patients with CKD to an earlier stage of disease.

  • Consequently, many Black patients may not receive timely evaluation, therapy, and care, compounding or contributing to reported disparities in the Black population associated with higher morbidity and mortality.

  • In a recent cross-sectional nationally representative study, removal of the coefficient for Black race from one equation increased the estimated prevalence of CKD among the US Black population. New and more accurate formulas for estimating eGFR using cystatin C have been developed and are increasingly being used.

Staging: The KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease classifies CKD in stages based on GFR and albuminuria as follows:

• The categories of GFR range from G1 (normal or high; GFR ≥90 mL/min per 1.73 m²) to G5 (kidney failure; GFR <15 mL/min per 1.73 m²).

• Category G3 is further split into G3a and G3b, with the long-term prognosis for G3b being worse than that of G3a.

• Within each GFR category, albuminuria can be categorized as A1 (normal to mildly increased; <30 mg/g), A2 (moderately increased; 30-300 mg/g), or A3 (severely increased; >300 mg/g), in order of worsening prognosis.

The following table lists the major causes of severe CKD:

(Source: Stage IV Chronic Kidney Disease. N Engl J Med 2010.)

Management

Interventions to slow the progression of CKD to end-stage kidney disease (ESKD):

• Treatment of hypertension: Blood pressure should be lowered if ≥140/90 mm Hg and treated to a target <130/80 mm Hg (<140/80 in the elderly) in patients with CKD (according to the 2020 ACC/AHA hypertension guideline). These new recommendations suggest using risk estimation to determine BP treatment threshold and goal. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are considered first-line agents. eGFR, microalbuminuria and blood electrolyte levels should be monitored.

• Reduction and slowing progression of CKD: ACE inhibitors or ARBs are effective in reducing proteinuria and slowing down the progression of CKD, especially in diabetic kidney disease. Recent data suggest that nonsteroidal mineralocorticoid receptor antagonists and antidiabetic agents (e.g., SGLT2 inhibitors, GLP1 receptor agonists) slow progression in CKD, the latter specifically in patients with diabetes.

• Glycemic control: Use oral agents or insulin. Ideally the hemoglobin A1c should be <7%.

Other management issues in CKD and ESKD:

• Cardiovascular disease is the leading cause of death in patients with CKD. The following table offers suggestions for the management of cardiovascular risk factors in patients with CKD:

  

  Holistic approach to chronic kidney disease (CKD) treatment and risk modification. *Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker should be first-line therapy for blood pressure (BP) control when albuminuria is present; otherwise dihydropyridine calcium channel blocker (CCB) or diuretic can also be considered. All 3 classes are often needed to attain BP targets. Icons presented indicate the following benefits: blood pressure cuff ¼ blood pressure-lowering; glucometer ¼ glucose-lowering; heart ¼ heart protection; kidney ¼ kidney protection; scale ¼ weight management. ASCVD, atherosclerotic cardiovascular disease; CKD-MBD, chronic kidney disease-mineral and bone disorder; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HTN, hypertension; KDIGO, Kidney Disease: Improving Global Outcomes; MRA, mineralocorticoid receptor antagonist; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; RAS, renin-angiotensin system; SBP, systolic blood pressure; SGLT2i, sodium-glucose cotransporter-2 inhibitor. Modified from Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022;102:S1-S127.23 Copyright ª 2022, KDIGO: Kidney Disease Improving Global Outcomes. Published by Elsevier Inc. on behalf of the International Society of Nephrology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

• Mineral and bone disorders: The kidneys play a critical role in phosphate excretion and vitamin D activation. Hyperphosphatemia, hypocalcemia, and hyperparathyroidism frequently develop in patients with advanced CKD. When limitation of dietary phosphate is recommended, it is often accompanied by initiation of a phosphate binder. Once phosphate level is reduced, reduction of parathyroid hormone (PTH) levels can be achieved by vitamin D, vitamin D analogs, and/or calcimimetics.

• Anemia: A workup for etiology of anemia is necessary. Anemia is often related to inadequate erythropoiesis or gastrointestinal losses. Additionally, iron absorption is decreased in patients with CKD. Anemia should be managed initially with iron supplementation (in the case of iron-deficiency anemia), followed by erythropoiesis-stimulating agents (ESAs).

  • The decision to start an ESA (e.g., epoetin alfa or darbopoetin alfa) is complex.

    • Several predialysis studies (Correction of Hemoglobin Outcomes in Renal Insufficiency [CHOIR] and the Trial to Reduce Cardiovascular Events With Aranesp Therapy [TREAT]) have shown no significant cardiovascular or quality-of-life benefit with using ESAs to target hemoglobin levels above 11-11.5 g/dL.

    • In patients on hemodialysis, initiation of an ESA is generally recommended when hemoglobin levels are between 9 and 10 g/dL (targeting conservative ranges not >11.5 g/dL, given the association with adverse cardiovascular outcomes).

    • Iron stores must be normal and remain so for ESAs to work.

    • ESAs should rarely be used in patients with history of stroke or malignancy (particularly head and neck cancers).

  • Hypoxia-inducible factor prolyl hydroxylase Inhibitors (e.g., roxadustat [not FDA-approved] and vadadustat [FDA-approved]) increase hemoglobin and are a new class of agents for the treatment of anemia in CKD.

• Acidemia: In advanced stages of CKD, the kidneys lose the ability both to excrete organic acids and generate ammonia. KDIGO suggests initiating oral bicarbonate supplementation when serum bicarbonate is <18 mmol/l to improve metabolic and nutritional parameters and even potentially delay CKD progression.

• Volume overload: With the decrease in nephron mass in advancing CKD, the kidneys start to lose the ability to excrete excess volume. Patients often suffer from volume overload, manifesting primarily as hypertension and peripheral edema. Escalating doses of loop and thiazide diuretics in addition to sodium and fluid restriction are often required.

• Diabetes and diabetic nephropathy: Diabetic nephropathy refers to kidney disease due to diabetes with histopathological injury shown by renal biopsy. Diabetic kidney disease is a diagnosis of CKD presumed to be caused by diabetes (presence of albuminuria, decreased eGFR, or both)

  • For initial screening of diabetic kidney disease, a spot urine collection for proteinuria is recommended instead of a 24-hour urine collection.

  • In patients with CKD and type 2 diabetes, finerenone (a nonsteroidal, selective mineralocorticoid receptor antagonist) was associated with lower risks of CKD progression and cardiovascular events as compared with placebo.

  • Among patients with CKD (regardless of the presence or absence of diabetes), the risk of decline in eGFR, ESKD, or death from renal or cardiovascular causes was significantly lower with dapagliflozin (SGLT-2 inhibitor) than with placebo.

  • In patients with chronic kidney disease and diabetes, sotagliflozin (SGLT-2 inhibitor) resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, but was associated with adverse effects such as diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis.

• Advanced CKD and likely progression to ESKD:

  • Elective choice of dialysis mode or conservative therapy: A discussion about future dialysis should occur before RRT is needed. Patients should have discussions with their physician about the various dialysis options — hemodialysis or peritoneal dialysis — and the ways these options are performed. For some patients, conservative (nondialysis) therapy is an option.

  • Consideration of transplantation and timing and referral for evaluation for kidney transplantation: CKD patients with an estimated GFR ≤20 mL/min are eligible to be on the waitlist for deceased donor kidney transplantation. Patients with advancing disease should discuss living related or unrelated transplantation.

  • Vascular access surgery: Planning for vascular access surgery should start when a patient reaches stage 4 CKD. This often involves the creation of an arteriovenous fistula (AVF). Preservation of venous circulation of the upper extremities is crucial and is achieved by avoiding phlebotomy and venous accessing of the nondominant upper extremity. Peripherally inserted central catheters (PICC lines) can cause scarring and stenosis of the subclavian venous system and should be avoided whenever possible.