GFR is used to define CKD, guide routine care, evaluate and manage expected complications of CKD, assess CKD progression, determine drug dosing, and assess prognosis.
GFR may be estimated as the clearance rate of a solute that is 100% filtered.
Clearance of any solute “X” equals [Ux]V/[Px], where [Ux] and [Px] represent the concentrations of solute “X” in the urine and plasma, respectively, and V represents the urine volume per unit time.
Traditionally, creatinine (Cr) has been used as the “solute” of choice in estimating GFR because the kidney freely filters Cr.
Limitations of using Cr as a marker of GFR:
Cr level may reflect muscle mass and dietary intake, independent of glomerular filtration.
Cr levels are typically in the low normal range for elderly patients or patients with malnutrition, limb amputation(s), or cirrhosis (reduced hepatic Cr synthesis, volume overload/dilutional). Cr levels may be in the high normal range despite having normal GFR in muscular young individuals.
Cr is also secreted by renal tubules, which leads to overestimation of GFR.
The ideal solute for calculation of GFR should be:
A solute that is both filtered by the glomerulus and secreted by the tubules (e.g., Cr) will overestimate the GFR because there will be more solute in the urine than if the solute comes from filtration alone. Additionally, tubular Cr secretion is upregulated in advanced CKD, which can further overestimate GFR in this patient population.
A solute that is both filtered by the glomerulus and reabsorbed by the tubules (e.g., urea) will underestimate the GFR because less solute will be seen in the urine than if the solute comes from filtration alone.
For reasons above, GFR estimates from 24-hour urine collections in advanced CKD are typically calculated as the average of creatinine clearance (CrCl) and urea clearance.
Alternatively, drugs that inhibit tubular secretion of Cr may be used during the 24-hour urine collection for a more accurate assessment of GFR. Traditionally, cimetidine may be used for this purpose. Of interest, other drugs that may inhibit proximal tubular secretion of Cr include dronedarone, trimethoprim, probenecid, pyrimethamine, salicylates, dolutegravir, cobicistat, ranolazine, and tyrosine kinase inhibitors, including imatinib.
CrCl and urea clearance require a 24-hour urine collection and can be cumbersome.
Use of exogenous filtration markers (in lieu of serum creatinine [SCr]): inulin, iothalamate, iohexol, ethylenediaminetetraacetic acid, and diethylenetriaminepentaacetic acid: These markers are chelated to radioisotopes for easy detection with nuclear scanning. In clinical settings where determination of exact kidney function is necessary (i.e., evaluation of potential kidney donor’s kidney function), GFR as measured by inulin or iothalamate may be obtained.
Female: same as formula for male above × 0.85 (empirical correction factor for presumed lower muscle mass in females)
Note that CG formula is in mL/min. To normalize to 1.73 m2 body surface area (BSA), multiply CrCl above by the ratio (1.73/patient’s BSA).
Limitations of CG formula:
Derived from patients with CKD
MDRD equations were derived based on urinary clearance of 125I-iothalamate.
MDRD-4 variables (age, gender, race [African American vs. non-African American], calibrated standardized SCr). SCr should be measured by specific assay traceable to the international standard reference materials and minimal bias compared to isotope dilution mass spectrometry (IDMS) reference methodology.
MDRD-6 variables (age, gender, race [African American vs. non-African American], calibrated standardized SCr, albumin, blood urea nitrogen [BUN])
Limitations of MDRD equations:
Underestimate GFR in patients with GFR >60 mL/min/1.73 m2, which over-reports the incidence of CKD. Many laboratories report eGFR greater than 60 as “>60 mL/min/1.73 m2” rather than an actual calculated value due to inaccurate estimates in patients with higher GFR range.
Not validated in geriatric patients, children, and pregnant women
Not validated in nonsteady states such as acute kidney injury (AKI)
Not derived for races other than “white” or “African American”
Both MDRD-4 and CG overestimate true GFR in sick hospitalized patients.
Derived from large database of research studies’ participants with diverse characteristics, including those with and without CKD, diabetes mellitus (DM), and known organ transplantation
Dependent variables are similar to those used in MDRD-4 and include age, gender, white or black race, SCr
Derived based on either SCr-alone CKD-EPI(creat) or cystatin C (cys)-alone CKD-EPI(cys) or both SCr and cystatin C CKD-EPI(creat-cys)
Compared to CKD-EPI(creat), CKD-EPI(cys) is not more accurate in estimating measured GFR, but is more accurate in estimating GFR in patients with low body mass index (BMI) and more accurate for risk predictions.
Compared to either CKD-EPI(creat) or CKD-EPI(cys) alone, combined CKD-EPI(creat-cys) is more accurate for estimating GFR.
Better accuracy for eGFR >60 mL/min/1.73 m2
Better accuracy for risk predictions
Applicable across more diverse population
Advantages of MDRD over CKD-EPI: MDRD performs better and provides better accuracy in estimating GFR in severely obese individuals.
The use of cystatin C in lieu of SCr:
Cystatin C is a cationic low-molecular weight (LMW) cysteine proteinase inhibitor that is produced at a constant rate by all nucleated cells. It is 99% filtered by glomeruli and metabolized by proximal tubular cells.
Serum cystatin C level reflects GFR well.
Both males and females: ages 20 to 50 years: 0.70 to 1.21 mg/L; age >50: 0.84 to 1.55 mg/L
Young healthy individuals: 0.53 to 0.95 mg/L
Advantages of using serum cystatin C compared to SCr:
Cystatin C may more accurately estimate GFR than SCr in patients with reduced muscle mass (e.g., liver disease, neuromuscular disease).
Cystatin C has been reported to be a better predictor of deaths from cardiovascular causes and CKD complications.
Whereas cystatin C correlates linearly with cardiovascular risk (e.g., heart failure), SCr correlates in a J-curve relationship.
Limitations of using cystatin C:
There is evidence of tubular secretion of cystatin C and extrarenal elimination (15% to 20%); thus, GFR may be overestimated.
Cystatin C production and metabolism may be altered by various clinical conditions. Higher cystatin C levels may be seen in patients with older age, male gender, white race, obesity, DM, inflammatory state, and lower serum albumin level. Other factors that may alter cystatin C levels are thyroid disease, malignancy, and steroids.
Cystatin C measurement is expensive and not widely available.
Standardization of cystatin C measurement is still lacking.
Unless combined with SCr, eGFR formulas with cystatin C alone are not more accurate in estimating GFR or predicting end-stage kidney disease (ESKD).
Equation derived based on three principles:
The average GFR for healthy populations (children, adolescents, and young adults) is 107.3 mL/min/1.73 m2 after kidney function matures (around 2 years of age) until the age of 40 years.
The age decline in GFR begins at ˜40 years.
The FAS equation has been reported to be valid even in patients with eGFR > 60 mL/min.
Less accurate in nonsteady state
Clinical laboratories should measure SCr using a specific assay with calibration traceable to the international standard reference materials and minimal bias compared to IDMS reference methodology.
Racial-ethnic and regional modifications to CKD-EPI Cr equations are required.
Additional testing (e.g., cystatin C) or clearance measurement is suggested for confirmation when SCr-based eGFR is less accurate (e.g., patients with low muscle mass).
In adults with eGFR(Cr) of 45 to 59 mL/min/1.73 m2 who have no other markers of kidney damage and confirmation is required, cystatin C measurement is suggested. If eGFR(cys) or eGFR(Cr-cys) is also <60 mL/min/1.73 m2, the diagnosis of CKD is confirmed.
Categorization of eGFR:
Total proteinuria comprises LMW proteins, albumin, immunoglobulins (Igs), and Tamm-Horsfall proteins, among many others.
Normal degree of proteinuria is generally <150 to 200 mg/d (or <0.2 g/g Cr) but may be up to 250 to 300 mg/d (or <0.3 g/g Cr) in normal pregnancy.
LMW proteins are easily filtered but are also easily reabsorbed by proximal tubules daily. Proximal tubular injury leads to the loss of LMW proteins.
Proteinuria associated with tubular injury is referred to as “tubular proteinuria.”
Tubular proteinuria is typically <1 to 2 g/d (or <1 to 2 g/g Cr) and comprises predominantly LMW protein, not albumin.
Proteinuria associated with glomerular injury (i.e., glomerular diseases) varies in range depending on the type of injury (nephrotic vs. nephritic glomerular disease).
Glomerular proteinuria predominantly comprises of albumin.
Albuminuria is a marker of glomerular basement membrane (GBM) injury. Hence, albuminuria is used as a marker of early diabetic nephropathy.
The degree of albuminuria may be used as a marker of extent of GBM defect. The degree of albuminuria may be classified as:
The high production and glomerular filtration of LMW paraproteins (e.g., light chains with multiple myeloma) overwhelms the proximal tubular reabsorptive
capacity and leads to proteinuria. This form of proteinuria is called “overflow proteinuria.”
Overflow proteinuria may be >1 g/d depending on the amount of light chains produced and filtered. Albuminuria may be present if there is concurrent GBM injury due to paraprotein or associated amyloid depositions.
Routine urinalysis (RUA) dipstick detects predominantly albuminuria based on its ability to change pH.
RUA does not detect tubular proteins or light-chain Igs well.
The degree of proteinuria based on RUA must be correlated with hydration status.
24-hour urine proteinuria detects all types of proteins but is cumbersome to collect. Interpretation of proteinuria from a 24-hour collection requires confirmation of collection adequacy. An adequate collection should contain approximately 15 to 20 mg/kg/d for an “average” female and 20 to 25 mg/kg/d for an “average” male.
Urine protein-to-creatinine ratio (uPCR) detects all types of proteins and reduces variations due to hydration status. It may be expressed as µg/mg Cr, mg/g Cr, g/g Cr, or mg/mmol Cr. For newly diagnosed CKD, obtain either uPCR or 24-hour urine collection for proteinuria. The latter may be collected for better accuracy.
Proteinuria comprised of <25% albuminuria may suggest either the presence of LMW proteins due to tubular injury and/or overflow proteinuria from monoclonal gammopathy.
Significant proteinuria mismatch (i.e., high degree of proteinuria from either uPCR or 24-hour urine collection in association with minimal proteinuria from RUA) suggests the presence of free light chains (Bence Jones protein).
Proteinuria selectivity refers to the ratio of clearance of immunoglobulins such as IgG (molecular weight of 160 kDa) to those of smaller proteins such as albumin (66.5 kDa) or transferrin (88 kDa). A value of <0.1 suggests highly selective proteinuria, which presumably reflects a lower degree of injury to the glomerular filtration barrier, hence lower disease progression risk, or, in the case of minimal change disease, better responsiveness to glucocorticoid compared to values >0.2.
Microalbumin dipstick detects albuminuria, a marker of GBM defect.
Having kidney damage ≥3 months, as defined by structural or functional abnormalities of the kidney, with or without a decrease in GFR, manifest by either pathologic abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests, or having
GFR <60 mL/min/1.73 m2 for ≥3 months with or without underlying kidney damage (e.g., hepatorenal or cardiorenal syndrome)
Overall lifetime risks for CKD stages 3a, 3b, and 4 and ESKD in the United States have been reported to be 59.1%, 33.6%, 11.5%, and 3.6%, respectively.
Women have higher CKD risk but lower ESKD risk compared to men.
Lifetime risks of CKD stages 4 and 5 and ESKD were higher in blacks and developed 10 to 15 years earlier than in whites.
While the prevalence of CKD stages 1 to 4 remain relatively stable over the years, the prevalence for ESKD (stage 5) has increased at a much greater rate. The difference in the prevalence increase is referred to as the “CKD and ESKD paradox.”
Theories for CKD and ESKD paradox:
Improved survival of CKD patients from cardiovascular events over the years
More rapid loss of kidney function over the years. This theory is less likely due to more aggressive blood pressure (BP) control and more use of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB).
Early renal replacement therapy (RRT) initiation
Kidney Disease: Improving Global Outcomes (KDIGO) 2012: In predicting risk for outcome of CKD, identify the (1) cause of CKD, (2) GFR category, (3) albuminuria category, and (4) other risk factors and comorbid conditions.
Proteinuria comprising of nonspecific proinflammatory proteins can lead to direct tubular injury and/or complement activation with resultant tubulointerstitial inflammation.
Exposure of tubular epithelial cells to a high-protein concentration can increase the synthesis of endothelin 1 (ET-1), a potent vasoconstrictor and a stimulator of renal cell proliferation and extracellular matrix, and transforming growth factor (TGF)-β synthesis. TGF-β is known to increase collagen and fibronectin production, both of which play a key role in tissue fibrosis.
Higher degree of albuminuria is associated with an increased risk of ESKD.
Increases plasma protein filtration via both hemodynamic effect and direct podocyte effect, the latter via stimulation of AT1R
Increases oxidative stress-associated injury, synthesis of cytokines, chemokines, TGF-β, connective tissue growth factor, chemotactic and cell adhesion molecules, all leading to increased plasma mesangial cell proliferation, extracellular matrix synthesis, and macrophage activation and infiltration
Increases aldosterone synthesis. Aldosterone increases plasminogen activator-inhibiting factor I (PAI-I). Plasminogen activator normally induces proteolysis. Plasminogen activator inhibitor PAI-I reduces mesangiolysis and fibrinolysis, thus favoring mesangial expansion and fibrosis.
The presence of ≥1 high-risk APOL1 variants (G1/G1, G2/G2, or G1/G2) confers resistance to Trypanosoma brucei rhodesiense infection and improved survival in endemic areas.
African Americans (with or without diabetes) with two APOL1 risk alleles develop more rapid CKD progression and increased risk of ESKD.
Nonetheless, it should be noted that less than 40% of adults with two APOL1 risk alleles develop kidney disease. This observation suggests the interacting role of environmental factors with APOL1 variants to result in CKD.
Fetal, but not maternal, APOL1 high-risk alleles have been shown to be associated with a 1.84-fold increased odd of preeclampsia.
Presence of risk factors for cardiovascular disease: metabolic syndrome, elevated homocysteine, dyslipidemia, inflammatory prothrombotic and/or oxidative stress markers
Illicit drug use (findings from the Chronic Renal Insufficiency Cohort Study)
The persistent use of cocaine, heroin, or methamphetamine was associated with increased risk for CKD progression and mortality among adults with CKD.
The use of marijuana was not associated with CKD progression.
Tobacco smoking was not associated with CKD progression but with all-cause mortality.
Environmental exposures: Lead and air pollution have been shown to be associated with increased incident CKD.
High BMI: Obesity is thought to be associated with ESKD risk when accompanied by metabolic syndrome, diabetes, or HTN.
Use of proton-pump inhibitors (PPIs)
Observational studies have reported the association of PPI long-term use and incident CKD.
Cause-effect relationship is not known but theorized to be related to associated hypomagnesemia. Unrecognized PPI-induced tubulointerstitial nephritis may also contribute.
Water volume: High intake has not been shown to be renoprotective.
Sodium: High-sodium intake may increase CKD progression risk via exacerbation of existing HTN in salt-sensitive individuals and endothelial damage via oxidative stress and upregulation of TGF-β.
Coffee intake of ≥2 cups daily may be associated with a lower risk of ESKD in men (without polycystic kidney disease [PKD]).
Sodas: Sugar-sweetened drinks and diet sodas may be associated with increased CKD risk.
Hyperuricemia, apolipoprotein E (APOE) genetic variation, increased pulse pressure >10 mm Hg, hypomagnesemia
Accumulation of lipids in tissues such as that seen with nonalcoholic fatty liver disease is thought to induce worse outcomes via the release of inflammatory, profibrotic, coagulant, oxidative mediators.
Fluid overload has been suggested to be a more important factor than DM for rapid progression and initiation of RRT in CKD stages 4 and 5.
Tangri calculator (http://ckdpcrisk.org/lowgfrevents/) has been shown to accurately predict 2- and 5-year kidney failure risks as well as nonfatal cardiovascular events and death risk for adults with eGFR <60 mL/min/1.73 m2. Calculated risk is based on patient’s age, gender, race (black on white), eGFR, systolic blood pressure (SBP), history of cardiovascular disease, DM, urine albumin-to-creatinine ratio (UACR), and smoking history.
RAAS inhibition reduces intraglomerular pressure, hyperfiltration, and proteinuria
Inhibits aldosterone-induced increase in PAI-I, the major inhibitor of fibrinolysis and proteolysis, thus reduction in extracellular proteins/collagen accumulation
Reduces TGF-β production
Increases hepatocyte growth factor, a factor with antifibrotic potential
Reduces albuminuria. Albuminuria has been shown to stimulate inflammatory response, vasoactive peptide production/release (endothelin), and fibrotic processes.
MRAs such as spironolactone or eplerenone mimic the molecular structure of the natural MR ligands.
Either MRA above can decrease proteinuria (albuminuria) and BP when added to RAAS inhibition in patients with either diabetic or nondiabetic CKD.
Adverse effects of current MRAs: hyperkalemia and metabolic acidosis for both agents; sex hormone-related side effects may also be problematic with spironolactone.
Combined ACEI and MRA may reduce proteinuria more than combination of ACEI and ARB. Hyperkalemia, however, has been shown to be worse with the former combination.
Finerenone represents a nonsteroidal compound designed to induce a conformational change to the MR complex to reduce its stability and nuclear translocation. Finerenone causes less hyperkalemia compared to traditional MRAs. Ongoing trials to test the efficacy and safety of finerenone in patients with diabetic kidney disease (DKD) include FIDELIO-DKD and FIGARO-DKD.
2017 Hypertension Clinical Practice Guidelines (American College of Cardiology/American Heart Association): Goal BP for everyone is <130/80 mm Hg except older fragile individuals with multiple comorbidities.
For patients with glomerular disease and proteinuria, treat systolic blood pressure to goal <120 mm Hg as safely tolerated.
Note that BP goals tend to change over the years by different professional organizations. Readers are suggested to check with most current guidelines.
Use an ACEI or ARB in diabetic adults with CKD and urine albumin excretion (UAE) ≥30 mg/24 h (or equivalent).
MDRD study involving patients with nondiabetic proteinuric renal disease: Strict BP control to target 125/75 mm Hg in patients with proteinuria > 1 g/d reduced GFR decline more than target 140/90 mm Hg. However, 48% of lower target BP group received ACEI compared with 28% in higher BP group.
African American Study of Kidney Disease and Hypertension (AASK) trial: Strict BP control to MAP 92 mm Hg (equivalent to 125/75 mm Hg) did not result in reduced GFR decline compared to higher MAP group of 102 to 107 mm Hg (equivalent to 135/85 to 140/90 mm Hg), unless significant proteinuria was present.
Ramipril Efficacy in Nephropathy 2 (REIN-2) trial involving patients with chronic, nondiabetic, proteinuric nephropathies: Addition of other agents to baseline ramipril to achieve tight BP control <130/80 mm Hg did not confer additional benefits in terms of reduction in proteinuria or GFR rate of decline.
Keeping BP > 128/85 mm Hg may be advisable due to concerns for possible “J-curve” phenomenon of worse cardiovascular outcomes.
J-curve phenomenon observed (Farnett et al.): Literature review of 13 studies noted that lower diastolic BP (DBP) control was associated with worse cardiac events, but not with stroke. The beneficial DBP was thought to be 85 mm Hg.
J-curve not observed:
Hypertension Optimal Treatment (HOT) trial: Patients assigned to DBP goal <80 mm Hg had fewer cardiovascular outcomes compared with other BP groups. No J-curve effect was noted.
Appropriate Blood Pressure Control in Diabetes (ABCD) trial: no difference in cardiovascular outcome or benefit with BP target of 132/75 mm Hg versus 138/85 mm Hg
REIN study (ramipril): Baseline proteinuria correlated significantly with GFR decline.
KDOQI guideline: Target hemoglobin (Hb) A1C ˜7% if safely tolerated to prevent or delay progression of microvascular complications of diabetes including DKD. Tighter control is not indicated.
ADVANCE, ACCORD, VADT: Glycemic control reduced albuminuria, but no change in GFR.
DCCT, EDIC, UKPDS: Glycemic control reduced both albuminuria and GFR decline.
Intensive glycemic control led to increased hypoglycemic episodes.
Sodium glucose transporter-2 inhibitors (SGLT-2is):
Empagliflozin and canagliflozin have been shown to reduce the risk of macroalbuminuria, doubling of SCr, ESKD, and renal death.
Dapagliflozin has been shown to reduce the risk of having >40% decrease in eGFR to <60 mL/min/1.73 m2, ESKD, and renal death.
Mechanisms for the renoprotective effect of SGLT-2i include:
Reduction of glomerular hyperfiltration (via proximal tubular sodium wasting and tubuloglomerular feedback with afferent vasoconstriction to reduce GFR)
Reduction of renal hypoxia
BP-lowering effect via sodium wasting
Glucagon-like peptide-1 (GLP1) analog:
Liraglutide has been shown to reduce new onset of persistent macroalbuminuria, change in UACR, doubling of SCr, ESKD, and renal death.
Semaglutide has been shown to reduce macroalbuminuria, doubling of SCr, ESKD, and renal death.
Mechanism for the renoprotective effect of GLP1:
Reduction of glomerular hyperfiltration (via proximal tubular sodium wasting and tubuloglomerular feedback with afferent vasoconstriction to reduce GFR)
However, this presumed beneficial effect may be counteracted by the direct nitric oxide (NO)-dependent vasodilatory effect of GLP1 on afferent arterioles.
Other beneficial effects of GLP1: weight loss 0.8 to 1.4 kg, improvement in fasting and postprandial lipid profiles, modulation of tissue inflammation or fibrosis
Dipeptidyl peptidase-4 (DPP4) inhibitors:
Saxagliptin and sitagliptin minimally reduced albuminuria.
Sitagliptin and linagliptin did not show any clinically significant beneficial renal effects.
Metabolic acidosis usually occurs at eGFR <30 mL/min/1.73 m2.
Adverse associated clinical effects:
Increased oxidation of branched chain amino acids (valine, leucine, isoleucine)
Increased protein degradation, catabolic rate, muscle breakdown
Decreased albumin synthesis
Impaired vitamin D synthesis, bone metabolism, increased bone lysis
Accelerated CKD progression
Upregulation of ammonia, endothelin, and aldosterone production to promote tubular acid excretion
Increased all-cause mortality
KDIGO 2012: provide oral bicarbonate supplement to keep serum HCO3– ≥22 mmol/L
Of note, HCO3– > 24 mmol/L may be associated with higher rate of heart failure, independent of alkali supplementation. Mechanism is unclear but thought to be unrelated to volume.
See SGLT-2i, GLP1, DPP4 inhibitors above
Methylxanthine derivative that acts as a phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, antifibrotic properties
Open-label, prospective, randomized trial designed to determine whether the addition of PTF to RAAS blockade slows CKD progression in DM2 and CKD stages 3 and 4
PTF (1,200 mg/d) (n = 82) versus control (n = 87) × 2 years. All received similar doses of RAAS inhibitors.
eGFR had decreased by 2.1 ± 0.4 mL/min/1.73 m2 in PTF versus 6.5 ± 0.4 mL/min/1.73 m2 in control (p < 0.001). Albuminuria was +5.7% in control versus -14.9% in PTF (p = 0.001).
Data on the renoprotective effects of statins have been mixed:
Studies revealing improvement in GFR:
ASCOT trial: 10,305 subjects with HTN and >3 cardiovascular risk factors: Atorvastatin significantly improved eGFR compared to placebo.
Effect of Statins on Renal Function in Chronic Kidney Disease Patient: Hu et al. (2018): The renoprotective effect of statins was significant in patients with CKD stages 3b to 5 (odd ratio [OR] 0.68, 95% confidence interval [CI] 0.48 to 0.95), but not statistically significant in those with CKD stages 1 to 3a (OR 0.97, 95% CI 0.68 to 1.38). The renoprotective effect of statins was significant in patients with proteinuria ≥1,000 mg/d (OR 0.63, 95% CI 0.43 to 0.92), but not in those with proteinuria <1,000 mg/d (OR 1.02, 95% CI 0.74 to 1.41).
Studies not revealing improvement in GFR:
Combination of simvastatin and ezetimibe conferred a 17% cardiovascular risk reduction in patients with CKD.
Renoprotective effect not proven.
PLANET trial: Atorvastatin versus rosuvastatin in patients with diabetic and nondiabetic CKD:
Atorvastatin improved proteinuria, not eGFR.
Rosuvastatin was associated with a fall in eGFR.
Fluvastatin RCT: No improvement in proteinuria.
There is currently no guideline regarding the use of statins for the sole purpose of renoprotection.
KDIGO general lipid guidelines (2013):
Initial assessment of lipid status with a lipid profile is recommended for adults with CKD, but follow-up measurements are not required for the majority of patients.
In adults with dialysis-dependent CKD, it is suggested that initiation of statins or statin/ezetimibe combination not be done.
In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, continuation of these agents is suggested.
In adults ≥50 years old with eGFR < 60 mL/min/1.73 m2 (GFR categories G3a to G5), but not treated with chronic dialysis, treatment with a statin or statin/ezetimibe combination is recommended (regardless of lipid profile).
In adults ≥50 years old with CKD and eGFR ≥60 mL/min/1.73 m2 (GFR categories G1 to G2), treatment with a statin is recommended.
In adults aged 18 to 49 years with CKD, treatment with a statin is suggested for those with one or more of the following: known coronary artery disease (CAD), DM, prior ischemic stroke, or estimated 10-year incidence of coronary death or nonfatal MI >10%.
In adult with kidney transplant recipients, treatment with a statin is suggested.
Efficacy and Safety of Evolocumab (proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in CKD in the FOURIER trial revealed benefits extending to patients with CKD stages G2, G3a, and 3b.
Low-density lipoprotein cholesterol (LDL-C) lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups.
Presumed pathogenesis involved in kidney injury with elevated UA levels:
RAAS activation, oxidative stress, mitochondrial dysfunction, epithelial-mesenchymal transition, endothelial dysfunction, vascular smooth muscle proliferation
Clinical complications attributed to hyperuricemia: arteriosclerosis, glomerular HTN, glomerulosclerosis, interstitial disease, AKI, metabolic syndrome, nonalcoholic fatty liver disease, HTN, DM
Clinical trials involving UA-lowering therapy:
Meta-analysis 2018 (Liu et al.): 12 RCTs, total n = 832: UA lowering was associated with reduced risk of worsening kidney function, ESKD, or death.
Japanese HTN Evaluation with ARB Losartan Therapy (J-HEALTH) study: n = 7,629 HTN patients: Change in serum UA inversely correlated with change in eGFR. Lower serum UA levels are associated with lower cardiovascular events. (Losartan has a uricosuric effect that can lower serum UA levels.)
Vascular Function and Uric Acid-Lowering in stage 3 CKD, 2017 RCT, Jalal et al., involving 80 adults with CKD stage 3 and asymptomatic hyperuricemia (≥7 mg/dL in men and ≥6 mg/dL in women), treated with allopurinol versus placebo: There were no significant between-group differences in BP or serum markers of inflammation and oxidative stress.
Large high-quality RCTs are still needed.
“There is INSUFFICIENT EVIDENCE to support or refute the use of UA-lowering agents in CKD and either symptomatic or asymptomatic hyperuricemia in order to delay progression of CKD.”
Treatment of hyperuricemia is “not benign.”
Stevens-Johnson syndrome may occur with allopurinol therapy.
Both allopurinol and febuxostat (xanthine oxidase inhibitors) can increase urinary xanthine levels, which can be nephrotoxic.
See Table 4.1. Note that there are concerns for strict sodium dietary restriction due to possible associated activation of RAAS and SNS, higher risks for CKD progression and odds of death. Two to 3 g daily sodium intake may be a more prudent approach. Lower sodium intake in patients with proteinuria >1 g/d may be associated with increased AKI events and excessive stimulation of RAAS.
Oral agent that can inhibit various cytokines, including TGF-β, tumor necrosis factor-α, platelet-derived growth factor, and epithelial growth factor
Proved effective in reducing injury in cyclosporine and tacrolimus nephrotoxicity, anti-GBM glomerulonephritis, doxorubicin toxicity in experimental models
Clinical trials proving renoprotective effects of pirfenidone are still lacking.
ET-1 mediates secretion of proinflammatory cytokines, growth factors, TGF-β.
Type A receptor (ETAR) mediates vasoconstriction, sodium retention, podocyte dysfunction.
Type B receptor (ETBR) mediates vasodilatation, sodium excretion.
Clinical study involving avosentan (nonselective ET-1 inhibitor) was terminated early due to excess congestive heart failure (CHF) complications (ASCEND trial).
Clinical studies on ETAR-selective antagonism with atrasentan:
Phase 2 trial (RADAR trial): Atrasentan reduced albuminuria.
Phase 3 trial (SONAR) was stopped prematurely due to a lower-than-expected number of renal events.
Table 4.1 Nutrition guidelines for patients with chronic kidney disease
Increased troponin level is associated with a two- to fourfold increased risk of all-cause mortality and major cardiovascular events.
Brain natriuretic peptide (BNP):
BNP is a less reliable marker of volume overload in CKD patients. Interpret with caution in patients with eGFR <60 mL/min/1.73 m2.
However, BNP levels provide a good index for left ventricular mass and dysfunction.
D-Dimer level can be elevated in CKD. A higher cutoff value may be needed in patients with advanced CKD to rule out pulmonary embolism.
Acute-phase reactants associated with cardiovascular risk that may be elevated in CKD: fibrinogen, ceruloplasmin
Structural changes with aging:
Reduction in kidney mass: 250 to 270 g kidney mass in 40 to 50 years old becomes 180 to 200 g by the age of 70 to 90.
Cortical thinning with relative medullary sparing (likely due to increased glomerulosclerosis)
Histologic changes with aging:
Focal global glomerulosclerosis, thickening of GBM, mesangial expansion, ischemic changes with segmental adhesion to Bowman capsule
Tubular atrophy with cystic formation, interstitial fibrosis
Arteriolar intimal fibrosis—may be associated with thinning of media; hyaline arteriosclerosis seen in smaller vessels
Functional changes with aging:
GFR reduction of 0.8 mL/min/1.73 m2/y after age 40 may be observed.
Albuminuria in 30% among patients ≥70 years old
Reduced concentrating and diluting capacities, which explains the propensity for increased nocturia and hyponatremia, respectively, in the elderly
Normal renal reserve
Total Na+ retention 950 mmol = 22 g
Total water retention 6 to 8 L
Plasma volume increases by 30% to 45% (up to 1.25 L) by the second trimester.
Lower serum osmolality: 270 to 275 mOsm/kg versus nonpregnancy range of 280 to 290 mOsm/kg
Lower S[Na+]: 132 to 135 versus nonpregnancy range of 138 to 142 mmol/L
Kidney length increases by 1 cm.
Renal plasma flow and GFR increase by 50% by the second trimester.
Glomerular hyperfiltration causes the midterm SCr to be as low as 0.4 to 0.6 mg/dL. A SCr ≥1.0 mg/dL is most likely abnormal.
Hemodynamic changes made by the kidneys during pregnancy are essential for normal fetal growth and development. Reduced renal function can adversely affect fetal outcomes.
Hyperdynamic changes and glomerular hyperfiltration in pregnancy accelerate progression of CKD.
Increased loss of water-soluble vitamins, hence the need for prenatal vitamins.
Increased proteinuria up to 300 mg/d or uPCR up to 0.3 g/g Cr is normal (predominantly tubular [nonalbumin, LMW] proteinuria).
Glucosuria is considered physiologic for later stages of pregnancy, which may be due to reduced tubular reabsorption or hyperfiltration overflow. However, early glucosuria requires testing for glucose intolerance or undiagnosed DM.
Reduced vascular resistance:
Systemic arterial vasodilation mediated by NO and relaxin
Relative resistance to vasoconstrictors such as angiotensin II
Increased cardiac output, increased thirst
Decreased systemic BP: