INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR
UNIVERSIDADE DO PORTO
MESTRADO INTEGRADO EM MEDICINA
Estimating Residual Kidney Function: Present and Future Challenge
Inês Maria Lucas Crista de Sousa Castro
Endereço de correio eletrónico: [email protected]
Orientadora
Professora Doutora Anabela Soares Rodrigues
Professora Associada Convidada com Agregação ICBAS/UP
Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto
UMIB – Unit for Multidisciplinary Investigation in Biomedicine, Universidade do Porto
Nefrologia, Centro Hospitalar Universitário do Porto – Hospital de Santo António
Estimating Residual Kidney Function: Present and Future Challenge
Dissertação de Mestrado Integrado
Dedicatória
Aos meus pais, pelo apoio incansável
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Agradecimentos
Um agradecimento especial à Drª Anabela Rodrigues pela extraordinária orientação, pelo
interesse e disponibilidade constantes e motivação para a ciência e investigação que me
transmitiu.
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Resumo:
A função renal residual foi recentemente reconhecida como fator preponderante de prognóstico em doentes com doença renal crónica de estadio avançado, não só na diálise peritoneal, mas também na modalidade de hemodiálise. Os avanços dos últimos anos promovem a proteção da função renal residual como um objetivo primordial nos doentes dialíticos e recomendam a utilização de diálise incremental, através da estimativa da função renal residual como um parâmetro de programas de diálise individualizados. A estimativa da taxa de filtração glomerular é apenas uma das dimensões da função renal, negligenciando a função tubular, com diversas limitações na sua avaliação qualitativa e quantitativa. A necessidade de colheita de urina interdialítica para quantificar a função renal residual, através da média da clearance de ureia e creatinina é um processo moroso e que predispõe a erro no paciente dialítico.
Esta dissertação aborda a estimativa da função renal residual sem colheita de urina, através de marcadores como a Cistatina C, Beta-2-Microglobulina e Proteína Beta Trace, assim como o comportamento destas moléculas nas várias modalidades de diálise, os seus fatores modificadores e o seu potencial de uso para estratificação de risco. A análise por bioimpendância de multi-frequência é também descrita como um possível instrumento de estimativa da função renal residual, demonstrando a importante ligação entre a diurese e a volémia.
A revisão foi realizada através da análise de referências selecionadas com base na pesquisa através das palavras chave “Residual Kidney Function, Dialysis; Peritoneal Dialysis; Cystatin C; Beta Trace Protein; Beta 2 Microglobulin” na base de dados PubMed-Medline, entre setembro de 2018 e março de 2019, com consideração para artigos escritos na língua inglesa. Os artigos considerados foram selecionados com base na sua atualidade e relevância de publicação na última década. Na primeira seleção foram considerados 116 artigos, com posterior exclusão de 35, por apenas abordarem a função renal em doentes não dialíticos ou mesmo sem doença renal, sem consideração para a função residual.
Conclui-se que a quantificação da função renal residual com base nas fórmulas standard de quantificação da taxa de filtração glomerular é insuficiente e limitada, ignorando a dimensão biológica da função renal. São necessárias ferramentas inovadoras e mais abrangentes de avaliação da função glomerular e tubulo-intersticial, pelo que as novas equações abordadas nesta dissertação devem ser validades em cohorts de maior escala, com a esperança de serem implementados como uma prática clínica inovadora.
PALAVRAS CHAVE: Função Renal Residual, Diálise, Diálise Peritoneal, Cistatina C, Proteína Beta
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Abstract:
Residual kidney function has recently been recognized as a major prognosis factor in patients with end-stage renal disease under peritoneal dialysis, as well as under hemodialysis. Advances in later years promoted residual kidney function protection as an adequacy target and the advocacy of incremental dialysis, utilizing residual kidney function assessment as a parameter of individualized dialysis schedules. Glomerular filtration rate measurement is only a dimension of kidney function neglecting the share of tubular function, with several dialytic limitations. The need for interdialytic urine collections to quantify residual kidney function, by the mean of urea and creatinine clearances, is cumbersome and prone to errors in dialysis patients.
This review will approach residual kidney function estimation without urine collection, mainly with biomarkers such as Cystatin C, Beta-2-Microglobulin and Beta-Trace-Protein as well as the behavior of these molecules on various dialysis modalities, their non-renal determinants and its potential use for risk stratification. Multi-frequency bioimpedance analysis is also described as a promising approach to estimate residual kidney function, being an opportunity to highlight the relevant link between volume balance and diuresis.
This review was based on the analysis of the research published through the key words: “Residual Kidney Function, Dialysis; Peritoneal Dialysis; Cystatin C; Beta Trace Protein; Beta 2 Microglobulin” on the database Pub-Med/Medline, between September 2018 and March 2019, with consideration for articles written on the English language. The articles selected were chosen based on their actuality and impact of publication, especially on the last 10 years. 116 articles were firstly selected, with latter exclusion of 35, since they only approached assessment of kidney function on non-dialytic CKD patients or healthy patients.
We conclude that standard glomerular filtration rate estimation formulas are not sufficiently accurate for residual kidney function assessment. There is a need for innovative tools that consider glomerular and interstitial function to be implement in clinical practice, therefore the new equations already developed and approached in this thesis should be validated in larger cohorts.
KEY WORDS: Residual Kidney Function, Dialysis; Peritoneal Dialysis; Cystatin C; Beta Trace Protein; Beta 2 Microglobulin
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Lista de Abreviaturas/Abbreviation Index
B2M – Beta-2-Microglobulin BIA – Bioimpedance analysis BTP – Beta Trace Protein
CAPD - Continuous Ambulatory Peritoneal Dialysis CCPD - Continuous Cycling Peritoneal Dialysis CKD – Chronic Kidney Disease
CKD – EPI - Chronic Kidney Disease Epidemiology Collaboration CSF - Cerebral Spinal Fluid
CVD – Cardiovascular Disease CysC – Cystatin C
eGFR – Estimated Glomerular Filtration Rate ESRD – End Stage Renal Disease
GFR – Glomerular Filtration Rate HD – Hemodialysis
HDF – Hemodiafiltration
KDOQI - Kidney Disease Outcome Quality Initiative MDRD - Modification of Diet in Renal Disease PD – Peritoneal Dialysis
PhA – Phase Angle
mGFR – Measured Glomerular Filtration Rate R - Resistance
rGFR – Residual Glomerular Filtration Rate RKF – Residual Kidney Function
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Index
Resumo: ...ii
Abstract: ... iii
Lista de Abreviaturas/Abbreviation Index ... iv
Lista de Tabelas/Table Index: ... vi
Lista de Figuras/Figure Index: ... vii
Introduction: ... 1
Residual Kidney Function is more than glomerular filtration rate: ... 1
Residual Kidney Function Assessment: ... 2
Novel Filtration Markers on the evaluation of Residual Kidney Function: ... 4
❖ Cystatin C ... 4
❖ Beta-Trace Protein ... 5
❖ Beta-2-Microglobulin:... 6
❖ Non-GFR determinants: ... 6
❖ Risk Stratification ... 7
New equations to estimate Residual Kidney Function in dialysis: ... 7
Conclusion: ... 10
Conflict of interest: ... 10
Appendix: ... 11
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Lista de Tabelas/Table Index:
Table I - Elimination of Middle Molecules by dialysis modalities………12 Table II - Non-Glomerular Filtration Rate (GFR) determinants and risk association of middle molecules……….13 Table III - Equations for estimation of residual Glomerular Filtration Rate………14
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Lista de Figuras/Figure Index:
Figure 1 - Articles published in PubMed when searching “Residual Kidney Function Assessment” – 1980-2018……….11
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Introduction:
Chronic Kidney Disease (CKD) is a public health problem, that affects 11-13% of the world’s adult population1 and has a close association with progression to end-stage renal disease, cardiovascular
disease and increased risk of death.2-4 In spite of some advances, there are still limitations on the
assessment of kidney function, especially in the latter stages of CKD. Residual kidney function (RKF) in patients with end stage renal disease (ESRD) is associated with better survival in both hemodialysis and peritoneal dialysis5-8, with many clinical advantages including easier volume
control, less inflammation, better nutrition, improved phosphate levels and endocrine function.9
Preservation of RKF is recommended as a parameter of adequate dialysis, with individualized schedules of treatment. In the last decades there has been a growing interest on finding a Gold Standard for RKF estimation (Figure 1), particularly in patients undergoing dialysis, after the recognition of its biologic relevance and to the increased use of its obligatory evaluation to prescribe incremental dialysis schedules. This review considers the assessment of kidney function during this transition period and showcase the latest advances on this clinically relevant subject.
Residual Kidney Function is more than glomerular filtration rate:
Urine output is variable throughout the ESRD spectrum, ranging from normal levels to anuria; it is determined not only by glomerular filtration rate (GFR) alone, but also by the rate of tubular reabsorption. This RKF has an importance that is disproportionately high relative to its measured value in uremic solute removal. The removal of slowly diffusing intracellular uremic compounds is dialysis treatment time dependent, however glomerular filtration is continuous (as opposed to the 10-15h/week for intermittent dialysis) and RKF can more effectively clear these compounds.7,10
Measured RKF also underestimates the removal of toxins that can be cleared by tubular secretion (p-cresol sulfate, indoxyl sulfate). Glomerular permeability to large molecules (such as Beta-2-Microglobulin) is also greater than that of dialysis membranes; such toxins are not effectively removed by dialysis11,12 but are removed by RKF13,14. There has been major interest on
middle-molecules clearance, which is not achieved by standard low-flux hemodialysis and is dependent of RKF. RKF has been better studied for peritoneal dialysis (PD) than hemodialysis (HD) and is routinely included for dialysis dosage10, however, its value has shown to be important for HD as well.15 RKF
is strongly associated with improved survival in both modalities: each 1 ml/min/1,73 m2 higher creatinine clearance is associated with 12-44% lower risk of death.7,13 Another major advantage of
RKF is in fluid and electrolyte balance. It allows a lower rate of fluid removal by dialysis which translates to lower risk of interdialytic hypotension and thus less myocardial stunning, ischemia and mortality.16 There has been a growing interest on incremental dialysis, which depends on the
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presence and continuous evaluation of residual native kidney function. It is widely accepted that RKF declines more slowly in PD than in HD. However, recent evidence suggests that the decline in RKF with twice weekly incremental dialysis results in a decline comparable to that of PD. 17
Furthermore, long frequent hemodialysis15 as well as low flux hemodialysis18 correlate with
accelerated loss of residual kidney function and consequently higher mortality. Given this it has been recommended by the Kidney Disease Outcome Quality Initiative (KDOQI) Clinical Practice Guideline for Hemodialysis Adequacy (level 1C) to inform patients about the risk of loss of residual kidney function on long standing hemodialysis and to decrease number and duration of dialysis when RKF is still present.15
The role of tubulointerstitial changes in the progression of kidney disease and the trajectory of RKF also after dialysis initiation, must be taken into account.19
The clinical relevance of RKF in both peritoneal and hemodialysis, independently of specific schedules in each of the modalities, calls for a revised and integrated concept of adequacy: this should include the dimensions of renal protection, kidney function estimation, renal tubular secretion of uremic toxins, volume balance and sodium removal, as well as acknowledging the serious limitation of Kt/V urea as an estimate of uremic solutes removal.
Residual Kidney Function Assessment:
GFR is generally accepted as the best overall measurement of kidney function.20 Its assessment is
crucial for clinical practice, approach to kidney disease, drug dosing and also for the management of prognosis21. However, CKD is not merely a filtration disorder, but a complex disease, based on
kidney structural changes and which can affect endocrine and metabolic functions, as well as reabsorption and secretion. This applies generally to all stages of kidney disease, however the limitations of GFR in assessing kidney function should be especially considered in ESRD.
GFR is preferably estimated with the clearance of exogenous filtration markers that are eliminated by the kidney through filtration only. In clinical practice, urea and creatinine clearances are measured with urine collection prone to serious limitations 18, 22, 23. GFR estimations can be made
without urine collection21, with equations based on measurement of creatinine, and other variables
such as age, sex and ethnicity.22,23 Non-GFR determinants however can affect the plasma
concentration of creatinine, due to physiological processes that also affect its value, such as its generation by muscle and other kidney functions as tubular reabsorption or secretion and extrarenal elimination24.
The assessment of residual kidney function in hemodialysis is recommended by the European Best Practice Guidelines and is made by the mean urinary clearance of urea and/or creatinine from an interdialytic urine collection corrected to body surface area. Since urea and creatinine levels vary
3 over this period, this mean level should account for the post-HD concentration immediately after dialysis and the pre-HD immediately before the next cycle (Evidence Level C)25. KDOQI Guidelines
for Hemodialysis Adequacy state that in patients with significant residual kidney function (residual urea clearance >2mL/min/1.73m2) , the dose of hemodialysis may be reduced if this value is measured periodically to avoid inadequate dialysis (Recommendation Level Not Graded)15 Residual
function has been considered for many years.10 In peritoneal dialysis, current guidelines suggest
that it should be measured at least every 6 months, ideally every 2-4 months, from urea in dialysate and urine. In these patients, urea clearance is usually measured and incorporated into the Kt/V urea with the total renal and dialytic clearances used to determine dialysis dose. However, since urea is absorbed by the renal tubules, it underestimates GFR by about 40%, which therefore underestimates its contribution to uremic solute removal. This underestimate has often been considered favorably as it provides a margin of safety given that abrupt declines in RKF may occur and go unrecognized. To get a true estimate of GFR in peritoneal dialysis there is the same recommendation for the use of the mean of urea and creatinine clearance, which more closely reflects actual GFR.
In clinical practice, for estimation of GFR in other stages of CKD, mainly two equations are mainly used: The Modification of Diet in Renal Disease (MDRD) Study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). MDRD equation has been widely used in clinical practice since 200026,27, however CKD-EPI GFR estimating equation is considered to have superior
accuracy.21,23 Both account for creatinine, sex, race and age. The main issue with residual kidney
function assessment in patients undergoing dialysis is that the MDRD Study equation and the CKD-EPI equations cannot estimate GFR in pre dialysis, as creatinine is lowered by treatment.28, 29
Therefore, interdialytic urine collections are needed to calculate the mean of urea and creatinine clearances.
Urine collections are typically collected over the full (approximately 44h) interdialytic period and are prone to errors leading to over or underestimation of RKF.28 There are several limitations to this
process: if a patient is treated with intermittent dialysis there will be considerable variation of urine production throughout the week, assuming a 3x/week schedule. There are also issues as to when to evaluate urea levels (given its post dialysis rebound) and the less than ideal relationship between more accurate investigative measures of GFR and those obtained by averaging urea and creatinine clearances. This cumbersome and problematic process for patients and physicians limits RKF assessment.
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Novel Filtration Markers on the evaluation of Residual Kidney Function:
Creatinine is not an ideal endogenous filtration marker of GFR 29 since it is secreted variably by thetubules30 and in ESRD also undergoes elimination by the GI tract.31 Investigation has risen on the
search for new filtration markers that improve the estimated GFR, especially in ESRD, decreasing the impact of non-GFR determinants. 32
New equations can be useful for CKD patients but also for other special cases which are not covered by the present creatinine based GFR estimating formulas, such as non-white, non-African American, despite ethnic correction.33,34 During the past decade, alternative markers for GFR, such as Cystatin
C (CysC), B2 Microglobulin (B2M), Beta-Trace Protein (BTP) and others have emerged.32,35-39 These
new markers are not physiologically inert like serum creatinine but are enzymatic components of important biological pathways. Other advantage is their function as early urinary markers of tubular dysfunction, presumably accounting for the tubulointerstitial share of RKF in later stage of CKD. Cystatin C and B2 Microglobulin are freely filtered, reabsorbed and metabolized by proximal tubular cells and therefore absent from the urine of patients without tubular dysfunction.29
❖ Cystatin C
Cystatin C is an 120 amino acid nonglycosylated protein (13.3kDa), expressed in all nucleated cells, with multiple biologic functions: modulation of the immune system, antibacterial and antiviral activity and response to brain injury.40 One of the advantages of this marker for estimating kidney
function is that after being freely filtered in the glomerulus it is then absorbed in the kidney tubules, where it is fully degraded locally, with no active tubular secretion or significant extrarenal elimination.41 Recent studies have shown that Cystatin C is strongly associated with risk of
cardiovascular disease35,36,42, but may also be a better predictor of non-cardiovascular disease, such
as pulmonary, cancer and infection.43
There are several factors that may be non-GFR determinants of Cystatin C such as inflammation (C-reactive protein), obesity, thyroid dysfunction, use of corticosteroid, current smoking and male sex.41,44-49 and therefore, reduce its accuracy on these patients. These associations may reflect
higher metabolic rate in men vs women and in smokers vs non smokers, which may also contribute to stronger association of low estimated GFR by Cystatin (eGFRCys) with cardiovascular disease and mortality.35,48 However, some studies have contradictory results and don’t show clear association
between Cystatin C and inflammation or sex 28,50. A major advantage of cystatin over creatinine
level is that its value is independent of muscle mass and nutritional status, therefore it is more accurate in a greater range of body types, including pediatric patients and elders.41 Cystatin C
5 Similarly to other middle-molecules it is not removed by low-flux dialysis, but is removed by high-flux and hemodiafiltration11. Its levels during hemodiafiltration are inversely correlated with
diuresis51 and its’ values undergo a rebound in the post dialytic period, remaining stable in the
interdialytic period. However, the use of Cystatin C in dialytic patients is limited since non-renal clearance predominates over renal clearance and has significant interindividual variation.52
Regarding peritoneal dialysis, its removal is highly dependent of RKF with very low peritoneal clearance . 53,54 However Clearance of Cystatin C was reported to be higher during Continuous
Ambulatory Peritoneal Dialysis (CAPD) when compared to Continuous Cycling Peritoneal Dialysis (CCPD), but still the proportion of peritoneal clearance was only around 3-20% of total Cys C clearance .55
The most recent guidelines recommend the use of Cystatin C formulas for confirmation of GFR, in adults with eGFRcr of 45-59 ml/min/1.73m2 without markers of kidney damage.21,56 However, even
with the association of creatinine and cystatin C, the accuracy of eGFR vs measured GFR (mGFR) and its use for clinical decision making, especially for ESRD remain elusive32,57,58, making the
evaluation of novel filtration markers a growing area of research.
RKF should preferably be evaluated with combined glomerular and tubular function assessment since at such an advanced stage of CKD, interstitial lesions play a role in both excretion and endocrine kidney abilities.
❖ Beta-Trace Protein
Beta trace protein (BTP) is an 168 amino acid glycoprotein with varying molecular weight between 23 and 29 kDa, also known as lipocalin type prostaglandin D synthase.37,59 BTP promotes the
conversion of prostaglandin H2 to prostaglandin D237,60 and can be found in a number of organs
including the brain, retina, testes, heart and kidney.61 The major sources of circulating BTP are on
the central nervous system and it is 1 of 2 proteins found in human cerebral spinal fluid (CSF) and not in blood.29 Its serum level can be used to estimate GFR in non-dialysis patients, with rising values
associated with declining kidney function.62 BTP, however, has greater within-person variability
than other markers.63 BTP levels have stronger association than creatinine to CKD progression and
mortality in adults with hypertensive kidney disease and non-diabetic kidney disease and also to all-cause and CDV mortality in adults on hemodialysis 35,38,61,64,65, likely related to its involvement in
prostaglandin biosynthesis29. Unlike Cystatin C and B2M, BTP does not undergo significant tubular
reabsorption in healthy tubules, however its levels also rise in CKD, even though it is always present in urine. One explanation could be because of increased local production due to physiologic stress, independent of changes in GFR or tubular function.29 BTP is not removed by high or low flux dialysis
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remain in a steady state, however there is not much information about its clearance by this modality.66 Non-GFR determinants of BTP include: age (with weaker association than creatinine),
sex, race, urine protein and weight.28,37,48 BTP might also be affected by corticosteroids, therefore
its use might not be appropriate in patients receiving this treatment28. BTP has low correlation to
creatinine after adjustment to mGFR, therefore it might be useful as an addition to creatinine based GFR estimation equations in CKD.48 It could be considered for estimation of residual kidney function
particularly in hemodialysis and peritoneal dialysis patients, given the stability throughout the dialytic and interdialytic period.66
❖ Beta-2-Microglobulin:
Beta 2 microglobulin (B2M) is an 100 amino acid protein, 12-16 kDa protein and is a component of the class I major histocompability molecules present on all nucleated cells.67 The serum
concentration of both B2M and BTP are generally more strongly associated than creatinine with mortality, end stage renal disease and cardiovascular disease in both general population and CKD studies.35,38,39,61 Non-GFR determinants of B2M include urine protein and smoking, as well as age,
sex and race in a lesser extent than creatinine.32,48. There is high correlation between B2M and
cystatin C, suggesting that B2M may replace Cystatin C if not available.48 B2M levels increase with
progressive kidney failure, inflammation and malignancy and correlate with residual kidney function in both hemodialysis and peritoneal dialysis, being RKF the most significant determinant of B2M levels in HD patients17,28,61. Its clearance in low-flux dialysis is lower than high-flux with mean
pre-dialysis B2M in low-flux HD 6 mg/L higher.18 There was also correlation of long term high flux
dialysis (>3,7 years) and hemodiafiltration with lower levels of B2M over time which translates to lower mortality17,68. In a study by Cheung et al, regarding the results of the HEMO study it was found
that patients with B2M values of 42.5-50 mg/L had 60% higher risk of death than those with <27,5 mg/L.18 Regarding peritoneal dialysis, B2M has a similar behavior to Cystatin C, since they have
similar molecular weights, which difficult the diffusive and convective transport across the pores of the peritoneal membrane. Both rely heavily on RKF for excretion and have lower clearance than creatinine and urea.54,69 There appears to be a relationship between duration of dialysis and
clearance of middle molecules, depending mainly on the total dwell hours of PD and not on the number of exchanges of peritoneal dialysate, with higher removal achieved by CAPD.69-71
(Table 1)
❖ Non-GFR determinants:
Some current studies have tried to estimate GFR with BTP, B2M and Cystatin C, aiming to overcome Creatinine’s non-GFR determinants.32,72,73 As already discussed, BTP, B2M and cystatin C are less
7 influenced by age, sex and race than creatinine. BTP and B2M do not vary across different body mass indexes or diabetes, however in spite of these qualities, they do not improve GFR estimation beyond creatinine and Cystatin C equations.32 Cystatin C, B2M and BTP are also affected by
non-GFR determinants that should be considered when developing new equations.48 One advantage of
the BTP-B2M GFR estimating equations is that they do not require age, sex or race and therefore can be used to access eGFR without the use of demographics, especially race.32 Since BTP increases
with the use of steroids, B2M with malignancy and both potentially with inflammation, failure to account for these non-GFR determinants can limit the use of both markers in estimating GFR.
❖ Risk Stratification
BTP, B2M and the association of all four markers (BTP, B2M, Creatinine and Cystatin C) are independently associated with risk of ESRD and all-cause mortality; B2M and the 4-marker composite were also associated with risk of cardiovascular events, evidencing greater association than with estimated GFR(creatinine) alone, therefore another possible relevant use for these markers
is risk stratification.36,74 Notably, these associations were independent of mGFR, indicating that
non-GFR determinants also contribute to outcome in CKD.36 These and other uses of BTP-B2M
equations should, nevertheless, be weighed against their additional high cost and availability. (Table 2)
New equations to estimate Residual Kidney Function in dialysis:
Serum concentrations of the markers previously approached are correlated with measured GFR and their low or inexistent removal by dialysis turns them to be good markers for RKF, being a possible solution for its assessment without 24h urine collection28,29,75 Use of Cystatin C for estimation of
residual kidney function has been studied, with equations proposed by Hoek et al in 2007 and Yang et al in 2011.76,77. Hoek et al compares his new formula based on Cystatin C with the MDRD equation
and residual glomerular filtration rate (rGFR) estimated by the mean clearance of creatinine and urea corrected by body surface area and tested it on both HD and PD patients. At the time of the article CKD-EPI equation was not yet developed and the results were promising for Cystatin C, resulting in better accuracy and precision than the MDRD formula.76 In 2011, Yang et al produce a
new Cyst C based equation and compare it to the Hoek et al’ equation, MDRD and rGFR estimated by urea/creatinine in PD patients and state that Cyst based equations have superior sensitivity and specificity for identifying significant RKF (>2mL/min/1.732) and 30-50% higher accuracy than the
8
Hoek formula.77 More recently both equations were externally validated and compared to the
CKD-EPI equation: it was concluded that Cystatin-C derived equations outperform CKD-CKD-EPI, as well as MDRD, when estimating rGFR, although, still overestimate its value.57,58
We believe that, in spite of such overestimation, serial measurements in patients under dialysis could be used to monitor RKF trajectory and adjust dialysis schedule, while avoiding the cumbersome urine collection.
The clinical relevance of this translates in updated investigations. In the later years, there have been other attempts at producing equations that accurately estimate RKF. Vilar et al68 studied Cystatin C
and B2M on high-flux dialysis and hemodiafiltration (HDF) patients. This equation could be used to identify patients with significant RFK, with a specificity of 90% and a sensitivity of 65%. In this case, B2M levels <19,15 mg/L could identify RKF >= 2mL/min/1.732 the cut-off defined by KDIGO
guidelines.56
On the same track , BTP and B2M are promising candidates as predictors of RKF.61 BTP is a promising
marker for RKF estimations, without necessity for timed urine collection, in peritoneal dialysis and hemodialysis11,64,66, however its levels are not as accurate in patients receiving hemodiafiltration.66
Different studies show different results for these two molecules. It has been shown that inclusion of both BTP and B2M into regression equations, can better estimate RKF than either alone.61 Shafi
et al published various equations based on serum Cystatin C, BTP and B2M as well as urea and creatinine, and compared it to CKD-EPI creatinine equation.These equations reflect higher accuracy for detection of rGFR.28 This study has demonstrated that these low molecular weight proteins can
have better performance than those including metabolites such as creatinine and urea and also have high diagnostic accuracy for identifying patients with CLurea>=2ml/min and therefore can be used in place of timed urine collections.28 In hemodialysis patients, BTP shows increased association
with mortality risk.64,65 Wong et al suggest that serum levels of BTP and B2M may not be accurate
enough to replace the standard estimation of GFR using creatinine and urea clearance, nevertheless in their cohort of n=40 HD patients, combined BTP/B2M equation correctly identified 95% of patients with residual urea clearance >2 ml/min/1.73 m2, which could potentially suggest its use for KDIGO incremental dialysis algorithm.
The advantages of these new equations are that clearance of urea can be estimated without urine collection, based on serum values, and then used to adjust dialysis dose. BTP equations are not influenced by diet and dialysis schedules but there is still a need for research to determine whether dialysis dose can be safely modified with estimating equations instead of timed-urine collections.28
Based on this information, serum BTP equations may be the most reliable for assessing residual kidney function in dialysis patients. However, BTP assays are not readily available, contrary to B2M and cystatin C.28
9 Shafi et al propose the use of their Urea + Creatinine equation, which considers dialysis determinants, as a screening tool to estimate RKF in patients with self-reported urine output >=250 mL (1 cup/day) and further use of low molecular weight proteins, mainly BTP, for more reliable estimation and clinical decision making. This equation might be better than CKD-EPI because it was optimized to reflect nonrenal (dyalitic) clearance. Precision and accuracy were better using BTP + B2M than Urea + Creatinine equations, especially in patients treated with hemodialysis. However, the equations overestimated the change in clearance over time and therefore there is still a need for improvement for individual patient use. The use of these biomarkers is still inaccessible for clinical practice, but it is time to invest in them and find an useful formula to evaluate RKF.28
In 2018, Beberashvili et al, have tried a different approach to the assessment of RKF. As already discussed, RKF is variable throughout the interdialytic period, mainly due to changes in hydration status. This hydration status is also variable during the hemodialysis sessions but also over the years of treatment, with increasing interdialytic water-weight gain, related to loss of kidney function. Patients with good RKF will have less variation in hydration status.7 Changes in body-fluid
compartments could be assessed with multi-frequency bioimpedance analysis (BIA) and therefore it was hypothesized that measuring body-fluid immediately before and after dialysis, could be a good procedure to estimate RKF. With BIA, Beberashvili et al accessed BMI, body surface area, body cell mass, lean body mass and extracellular water to total body water ratio. Values of resistance (R) at 5 and 100 Hz – inversely related to tissue water content, reactance (Xc) at 5 and 50 Hz – proportional to the cell membranes, phase angle (PhA) at 5 and 50 Hz – indicator of membrane integrity and water distribution between intra and extra-cellular spaces – were obtained and an equation was proposed (see Table 3), then applied to a validation group and compared to rGFR estimated by mean urea and creatinine clearance corrected by body surface area. This process was repeated 2 weeks later. The new equation showed high diagnostic accuracy (85% of sensitivity and 89% of specificity) to estimate RKF at a cut-of>2 mL/min/1.73 m2 and reproducibility over time. This study also tried to answer if the residual urinary volume could correlate with residual kidney function assessed by BIA, in response to a recent study that concluded that residual urine volume has a stronger association with mortality than rGFR.78 It was proposed that 200ml/day could
correspond to rGFR (Urea/Creatinine) of 2 mL/min/1.73 m2 with a sensitivity of 94% and specificity
of 72%. Nevertheless, since for estimation of rGFR with the mean of urea and creatinine clearance, urinary volume is taken into account, this relation could be misleading. There is room for investigation of the relationship between residual urinary volume and residual kidney function. This method was validated in a small cohort and should be evaluated in wider populations with various co-morbidities.79 Other biomarkers, radionuclide methods and formulas for RKF evaluation were
10 (Table 3)
Conclusion:
Assessing residual kidney function is of major importance since it combines glomerular filtration rate but also tubular role in fluid and sodium removal and active tubular secretion of uremic toxins. RKF loss has impact on patient survival both in peritoneal and hemodialysis patients. This evidence calls for revised and integrated concepts of adequacy that should include renal protection and estimation of function in both modalities of dialysis. Its evaluation is also critical for incremental dialysis implementation and has been recommended by the most recent guidelines. The mean creatinine and urea clearance with interdialytic urine collections is the standard for RFK assessment, however this can be impractical. Creatinine and urea are affected by dialysis and general equations for estimation of GFR on other stages of kidney disease do not apply to ESRD. Clinicians should move from the GFR approach and account for tubular biomarkers of kidney function. New equations identify correctly patients with >2 mL/min/1.73 m2 which could be an advantage for
incremental dialysis. Besides cardiovascular disease, prognostic information beyond RKF measurement with such biomarkers may add on patient risk stratification. Nevertheless, middle molecules utilized on these equations are expensive and of difficult use for clinical practice. Body-fluid assessment with BIA is an opportunity to highlight the link between Body-fluid balance and residual urinary volume and could be a new way to approach the issue, but still requires validation on larger populations. A task force should be put on RKF, which could improve dialytic patients’ survival. This is an area of investigation that still has many factors to develop, however, using accessible markers that don’t require special collaboration from patients, excessive biological samples or that are easily available in the clinical practice, should be the future on the evaluation of chronic kidney disease.
Conflict of interest:
11
Appendix:
FIGURE 1 – Articles published in PubMed when searching “Residual Kidney Function Assessment” – 1980-2018 0 5 10 15 20 25 30 35 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020
12
TABLE I - Elimination of Middle Molecules by dialysis modalities. HDF – Hemodiafilitration: HD – Hemodialysis; PD – Peritoneal Dialysis.
HDF High-flux HD Low-flux HD PD
Cystatin C
Removed11 Removed11 Not removed11 Low clearance,
Mostly Dependent of RKF53,54,81 B2M Increased clearance. Large post-dialysis rebound68 Large pos-dialysis rebound68 Mean pre-dialysis B2M is 6 mg/L higher than
high-flux18
Low clearance, Mostly dependent of RKF54,69,70
BTP
Only partially removed by
HDF11,64,66
13
Marker Non-GFR determinants Prognosis
Cystatin C Inflammation, obesity, thyroid dysfunction, use of corticosteroid, current smoking44-49
Associated with risk of CVD, pulmonary disease, cancer and infection35,43
B2M
Urine protein, smoking, age, sex and race (in a lesser extent than creatinine),
malignancy and inflammation32,48
Stronger association than creatinine to mortality, ESRD and CVD35,39
BTP
Age, sex, race ((in a lesser extent than creatinine), urine protein, weight,
corticosteroids, inflammation37,48
Stronger association than creatinine to mortality, ESRD and CVD35,65
14
TABLE III - Equations for estimation of residual Glomerular Filtration Rate
Equations for estimation of residual Glomerular Filtration Rate
Author/Year Equations Modality Modeling
group Validation group Hoek/200776 𝑟𝐺𝐹𝑅 = −0,70 + 22 ( 1 𝐶𝑦𝑠𝐶) HD and CAPD 215 HD + 95 PD 107 HD +48 PD Yang/201177 𝑟𝐺𝐹𝑅 (𝐶𝑦𝑠𝐶) = 𝑠𝑖𝑛ℎ (𝑙𝑛(6,736 − 0,566 𝐶𝑦𝑠𝐶)2) CAPD 120 40 Vilar/201568 𝑟𝐺𝐹𝑅 (𝐵2𝑀) = 160,3 × 1 𝐵2𝑀− 4,2 High-flux dialysis and hemodiafil tration 111 HD + 230 HDF 50 Shafi/201628 𝑟𝐺𝐹𝑅 (𝐶𝑦𝑠𝐶) = 123 × 𝐶𝑦𝑠𝑡 𝐶−2,468 𝑟𝐺𝐹𝑅 (𝐵𝑇𝑃 𝐵2𝑀) = 673 × 𝐵𝑇𝑃−1,406 × 𝐵2𝑀−1,096( × 1,670 𝑖𝑓 𝑚𝑎𝑙𝑒) HD and PD 44 NECOSAD 587 HD, 239 PD Wong/201661 𝑟𝐺𝐹𝑅 (𝐵𝑇𝑃 𝐵2𝑀) =9,097 𝐵𝑇𝑃 + 37,568 𝐵2𝑀 + 0,402 × 𝑒𝑡ℎ𝑛𝑖𝑐𝑖𝑡𝑦 𝑓𝑎𝑐𝑡𝑜𝑟 − 2,049 High-flux dialysis and hemodiafil tration 158 HDF + 33 HD 32 HDF + 8 HD Beberashvili/2018 79 𝑟𝐺𝐹𝑅 (𝐵𝐼𝐴) = 1.074 × (𝑃ℎ𝐴50𝑝𝑜𝑠𝑡 − 𝑃ℎ𝐴100𝑝𝑜𝑠𝑡) + 0.037 × (𝑅5𝑝𝑟𝑒 − 𝑅100𝑝𝑟𝑒) − 0.592 × [(𝑋𝑐50𝑝𝑟𝑒 − 𝑋𝑐5𝑝𝑟𝑒) /(𝑋𝑐50𝑝𝑜𝑠𝑡 − 𝑋𝑐5𝑝𝑜𝑠𝑡)] + 4.059 × 𝐻2 + 0.040 × 𝑎𝑔𝑒 − 0.871 × 𝐶𝑟𝑒 − 7.589 HD 66 22
15
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