Residual Renal Function (RRF) refers to the filtration, reabsorption and endocrine functions of the preserved nephron after renal tissue damage. RRF plays an important role in solute clearance, electrolyte fluid balance, calcium and phosphorus control, inflammation and anemia. In this review, the importance of RRF, the influencing factors of RRF, how to calculate and evaluate RRF effectively and the protective measures of RRF are summarized, aiming at drawing attention to the protection of RRF and providing theoretical basis for clinical treatment and decision-making.
Hemodialysis; Importance; Influencing Factors; Protection; Residual Renal Function
Chronic Kidney Disease (CKD) has been recognized as a major global public health problem, and the global prevalence of CKD is estimated to be about 13.4% (11.7-15.1%) [1]. The latest epidemiologic survey shows that the prevalence of CKD in the Chinese adult population is 8.2% [2]. When CKD progresses to the stage of end-stage renal disease (ESRD), patients need to Take Renal Replacement Therapy (RRT), which includes Hemodialysis (HD), Peritoneal Dialysis (PD), and kidney transplantation. In the United States, HD accounts for 93% to 98% of first-time renal replacement therapy modalities for ESRD patients over 65 years old, PD accounts for 2% to 5%, and kidney transplantation is <2% [3]. Long-term Maintenance Hemodialysis (MHD) results in a progressive loss of Residual Renal Function (RRF) in ESRD patients. RRF is commonly overlooked in HD patients compared to peritoneal dialysis. Growing evidence shows that higher levels of RRF in HD patients are associated with better outcomes, such as improved quality of survival, solute clearance, nutrition, anemia, and phosphate control [4]. This review summarizes the research progress on RRF, aiming to draw attention to the protection of RRF and provide a theoretical basis for clinical treatment and decision-making.
RRF is the filtration, reabsorption, and endocrine function of surviving renal units after damage to renal tissue. There is no uniform definition of RRF, which varies from study to study. A study by Singhal MK et al [5] defined loss of RRF as urine output <100 ml/d or creatinine clearance <1.0 mL/min. And in another study [6], it was defined as urine output <200 ml/d. RRF helps to achieve adequate solute clearance and is closely related to the health and survival of CKD patients. In addition, RRF maintains fluid balance and regulates electrolyte balance, reducing inflammation, anemia, and renal bone disease.
Importance of RRF
When ESRD patients undergoing HD, a substantial RRF is present. Whereas, with the increase of dialysis vintage, RRF gradually decrease due to different cause. However, it can still be maintained at a low level, and once RRF is completely lost, dialysis efficacy is greatly reduced and the risk of death increases [7,8]. An analysis of the Netherlands cooperative study on the adequacy of dialysis (NECOSAD), which followed 740 HD patients, showed that per 1/week higher renal urea Kt/V the risk of mortality was reduced by 56% over a median follow-up of 1.7 years [9]. Importantly, RRF, even when maintained at low levels, reduces mortality in HD patients [10]. Thus, the presence of residual renal clearance is an important predictor of survival in HD patients.
RRF and clearance of solutes
HD provides interstitial solute clearance, whereas natural renal function is continuous, which may explain the benefit of RRF in patients with ESRD.RRF not only enhances clearance of small molecule solutes, but also plays an important role in the clearance of intermediate molecules and protein-bound uremic toxins, which are difficult to remove by HD. In a study involving 297 patients, beta-2 micro globulin (B2M) was used as a representative intermediate molecule and it was found that RRF was associated with better clearance of B2M [11].
RRF and fluid balance
RRF plays an important role in the maintenance of fluid balance in dialysis patients, and the degree of removal of sodium and water is an important determinant of survival in dialysis patients [12]. RRF may be affected by changes in intravascular volume, and the occurrence of acute hypotension and volume depletion is responsible for a more rapid decline in RRF in HD patients [13-14].
RRF and inflammation
A microinflammatory state exists in 35% to 65% of patients on hemodialysis [15], which are associated with platelet contact activation and complement cascade activation. Blood flow through the extracorporeal circuit leads to the release of a range of pro-inflammatory cytokines. In addition, decreased RRF is also an important factor causing a microinflammatory status [16]. In the CHOICE study, The levels of C-reactive protein and interleukin-6 were lower in patients with urine output (UO) >250 ml per day [17,18].
RRF and nutritional status
RRF has a significant impact on the overall nutritional status of dialysis patients, which can be assessed by subjective overall assessment, grip strength or lean body mass [12]. The degree of RRF also affects micronutrient intake, including water- and fat-soluble vitamins and minerals [19]. In a retrospective study, RRF was shown to be associated with better nutritional status [20]. The involvement of native kidneys in protein metabolism may underlie the observation that patients on chronic HD who have RRF have better nutritional status [17].
RRF and renal anemia
During the course of CKD, since the remnant nephrons are able to produce some amount of Erythropoietin (EPO), so RRF contributes to ameliorate renal anemia by improving the efficacy of EPO therapy and reducing EPO dosage. The CHOICE study showed that EPO requirements were reduced in hemodialysis patients with baseline urine output more than 250ml per day, and this was particularly notable in patients with preserved urinary output in one year after incident hemodialysis [18].
RRF, calcium and phosphorus metabolism
Abnormal calcium and phosphorus metabolism is a common complication in MHD patients [21], which contributes largely to vascular and valvular calcification. Vascular calcification leads to a higher risk of death among HD patients [22], whereas heart valve calcification predicts overall mortality and cardiovascular disease mortality in patients undergoing peritoneal dialysis [23]. The results of a Latin American study in MHD patients [24,25] showed that too high or too low blood phosphorus and calcium concentrations increased all-cause mortality in HD patients. Some studies have confirmed a significant contribution of RRF to phosphate homeostasis, furthermore, the upregulation of FGF-23 may be a compensatory response that promotes phosphate excretion in MHD patients with RRF [26].
RRF and cardiovascular disease
It is well known that cardiovascular disease is the leading cause of death in patients with MHD, and important determinants include accelerated atherosclerosis and Left Ventricular Hypertrophy (LVH). It has been demonstrated [25] that decreased RRF in HD patients is a risk factor for LVH, while the progressive loss of RRF leads to endovascular calcification and triggers adverse cardiovascular events.
Assessment and calculation of RRF
Renal function assessment in CKD patients mainly refers to Glomerular Filtration Rate (GFR) measurement, and there are 2 ways to assess GFR, namely, measured GFR (mGFR), which is assessed by the level of exogenous biomarkers, and estimated GFR (eGFR), which is assessed by the level of endogenous biomarkers. Inulin has long been the gold standard for mGFR, but is not widely used in clinical practice because of the complexity of the method. Radionuclides such as iodophthalate, 99mTc-DTPA, and 51Cr-EDTA have also been used for GFR determination [26,27]. Currently, 99mTc-DTPA renal dynamic imaging is often used clinically to measure GFR, which allows calculation of renal blood flow and assessment of single kidney function. Endogenous filtration markers such as serum creatinine (Scr) and urea nitrogen have been widely used to assess renal function. However, these methods have more or less drawbacks and limitations when assessing RRF in dialysis patients.
In HD patients, there is no practical and validated method to assess RRF, and many factors in dialysis can affect its accuracy. Ideal markers for measuring GFR need to have the hallmark characteristics of constant production, free filtration, no metabolism, and not secreted or reabsorbed by the renal tubules [28]. For HD patients, the addition of inability to be cleared by dialysis is also needed. Therefore, small molecule solutes with high dialysis clearance, such as Scr and urea, would be inappropriate for RRF assessment. The assessment of RRF in dialysis patients is generally done by collecting 24-hour urine to determine their creatinine or urea concentration and calculating it. The KDOQI guidelines recommend the use of the mean value of urea nitrogen clearance and creatinine clearance in HD patients as an indicator for evaluating RRF [29]. In addition to the need to collect all urine from patients in the inter-dialysis period, this method also requires the collection of blood samples at multiple time points due to the huge fluctuations in serum concentrations of urea nitrogen and creatinine caused by dialysis clearance. These make the clinical operation very difficult and make it difficult to be widely used in the clinic. The simplest method to measure RRF is urine volume, which, despite its shortcomings, has been correlated with GFR in studies. Most authors define loss of RRF as a urine volume of <200 mL/d [6], and patients with RRF may undergo urine collection at baseline and every 1 to 3 months (PD for 24 hours and HD for the inter-dialysis period). Moreover, in a separate prospective cohort study, it was showed that higher residual urine volume was significantly associated with a lower risk of death and exhibited a stronger association with mortality than GFR calculated using 24-hour urine collection and eGFR-urea, creatinine, suggesting that determining residual urine volume may be useful and additive to predict prognosis in patients on dialysis compared with the other RRF indices [27].
The difficulty in obtaining reliable urine collection during the inter-dialysis period has prompted the search for new and improved methods. Proteins are gradually becoming a new direction in assessing RRF in dialysis patients due to their high molecular weight and low dialysis clearance. The molecules that have been the subject of more clinical studies include cystatin C (CysC), β2-Microglobulin (B2M) and β-Trace Protein (BTP). Cystatin C is a cysteine protease with a molecular weight of 13.3 kD, produced by all nucleated cells. It is freely filtered in the glomerulus and is almost entirely absorbed and catabolized by the proximal tubule [30]. Cystatin C increases with inflammation, hyperthyroid states, and may be affected by smoking, high doses of steroids, and triglycerides [31]. In contrast to Scr, the most important characteristic of Cystatin C is that it is produced continuously, independent of muscle mass, age, or gender, and is not secreted or absorbed. Because of its unique properties, it has been used as a marker of mild renal damage in most studies [32-34]. Disadvantages of Cystatin C include the higher cost of immunoassays and too much intra-individual variability to detect renal damage early.
B2M is part of the major histocompatibility class I antigens with a molecular weight of 11.8 kD and is present on the cell surface of all nucleated cells [35]. B2M is freely filtered in the glomerulus and then enters the proximal tubule for catabolism and metabolism. With the exception of chronic kidney disease, elevated B2M is associated with inflammatory status, myeloma, age, and male gender [36]. B2M is cleared by high flux HD and hemofiltration [37]. Individual differences in B2M are evident, especially in patients with very weak renal function or no RRF. BTP is a glycoprotein with a molecular mass between 23-29 kD and has been used as a marker of cerebrospinal fluid leakage [38]. It accumulates in renal failure, and serum BTP levels correlate closely with residual urine volume in hemodialysis. BTP cannot be removed by conventional low or high-flux dialysis. Although hemodiafiltration removes some BTP, [39] its levels are not significantly altered during the inter-dialysis period [40]. extra-renal elimination appears to be minimal [41]. Because of these properties, BTP is expected to serve as a marker of RRF in dialysis patients.
In isolation, Cystatin C, B2M, and BTP do not meet the ideal criteria for endogenous markers of the GFR. Therefore, it has been suggested that more accurate prediction equations can be derived by combining the factors [34]. These prediction equations are considered preliminary and require extensive external experiments for validation.
Currently, the KDOQI guidelines identify several risk factors for RRF decline in CKD patients, such as age, race, blood pressure, and proteinuria [42,43]. It is indicated that the higher the ultrafiltration rate in HD patients, the faster the decline in RRF and the lower the survival rate [44]. The risk of RRF loss was reported to be 65% lower in patients treated with peritoneal dialysis than in patients treated with HD, which was attributed to better hemodynamic stability [45]. Obesity and high BMI are important risk factors for RRF decline after the initiation of dialysis treatment [46,47], and despite a more rapid decline in RRF, it is associated with better survival, at least in HD patients [13]. In addition, diabetes mellitus, congestive heart failure [48], and high ferritin levels [49] are important predictors of RRF loss. Some treatment-related factors such as hypotension on dialysis, biologically incompatible dialysis membranes, and frequent dialysis have been associated with rapid loss of RRF.
Drugs to protect RRF
The role of ACEIs and ARBs analogs in slowing CKD progression and reducing proteinuria in non-dialysis CKD patients is well known [50,51]. A meta-analysis by Ding et al [52] showed that the use of ACEIs or ARBs reduced the decline in RRF in patients on peritoneal dialysis. There are fewer studies on ACEIs and ARBs in HD patients. Xydakis et al [53] reported that enalapril was associated with better preservation of RRF in a 1-year study of 42 HD patients.
Opinions on the effect of diuretics on RRF are not yet uniform. Two studies involving patients with PD [54-55] showed that the use of diuretics independently predicted a more rapid decline in RRF. In contrast, in another study [56], results showed that patients treated with diuretics were twice as likely to have retained urine output at 1 year after the start of dialysis treatment. Chen et al [57] is conducting a randomized controlled trial in China to further evaluate the role of furosemide for prevention of intradialytic hypotension and its effect on RRF in HD patients.
Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have been shown to slow the progression of chronic kidney disease [50], and therefore may provide protection against RRF among dialysis patients [58]. Recently, a case series of report indicated that the use of SGLT2i in DKD patients starting iHD on a 1–2 weekly regimen appears to be safe and effective in preserving RRF [59].
The relationship between RRF and blood pressure is complex, both hypotension and hypertension leading to an increased risk of RRF decline in dialysis patients [14]. The KDOQI guidelines currently recommend ACEIs or ARBs as the drug of choice for blood pressure control in patients with severe RRF deficiency [33]. Currently, there is no clear definition of the ideal blood pressure level for dialysis patients, and excessive blood pressure fluctuations as well as prolonged hypotension or hypertension should be avoided.
Incremental dialysis has received increasing attention in recent years. Currently, the impact of incremental dialysis on RRF is unclear, and the results of studies vary. There is no clear signal of an overwhelming risk or benefit of twice-weekly HD compared with three times-weekly HD [32]. KDOQI and EBPG support the use of incremental HD prescriptions, provided that the RRF is monitored regularly to avoid inadequate dialysis.
Repetitive exposure of blood to dialysis membranes during HD gives rise to inflammation that affect RRF adversely. Indeed, compared to HD patients treated with cellulose acetate membrane, those patients with the more biocompatible polysulfone membrane had a slower decline of RRF [47]. Ultrapure dialysate fluid combined with high-flux synthetic membranes is reported to slow the loss of RRF in HD patients [30]. Avoidance of radiographic contrast agents, nonsteroidal anti-inflammatory drugs, and aminoglycosides is an important consideration for RRF in MHD patients. The results of a meta-analysis showed that the use of contrast agents may not lead to a significant reduction in RRF in dialysis patients [28]. However, the long-term effects of radiographic contrast agents on RRF are minimized by using low-permeability contrast agents as much as possible in the clinic and by implementing an appropriate hydration regimen.
Of note, some research data suggest that adopting a low-protein diet (0.6-0.7 g/kg/d) in combination with incremental dialysis on non-dialysis days may be helpful for RRF preservation. The KDOQI guidelines recommend a protein intake of 1.2 g/kg/d for stable MHD patients, but in practice many patients have difficulty achieving the guideline-recommended level. Some studies have suggested that combining a low or very low protein diet with essential amino acids or ketones is beneficial in preserving RRF in dialysis patients while avoiding malnutrition and inflammation [7-8]. During hemodialysis, a routine to high protein diet can still be recommended considering the higher catabolic rate and loss of amino acids.
In conclusion, RRF has been shown to be important for the long-term survival of dialysis patients, mainly in terms of benefiting various aspects such as nutritional status, fluid balance, metabolism, and other aspects. Therefore, increased attention to and protection of RRF in HD patients, regular monitoring of RRF, and targeted preventive measures can lead to better protection of RRF in dialysis patients, resulting in improved quality of life and survival.
Citation: Ji M, Ren L and Dai H (2024) Advances in Residual Renal Function. J Nephrol Renal Ther 10: 096.
Copyright: © 2024 Mengying Ji, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.