Residual kidney function in kidney failure

INTRODUCTION — Many patients starting dialysis have significant residual kidney function. According to the United States Renal Data System, only 15 percent of individuals starting dialysis in 2020 had an estimated glomerular filtration rate (eGFR) <5 mL/min/1.73 m² [1].

Preservation of this residual kidney function has been associated with improved outcomes, and nephrologists should try to preserve this residual kidney function as long as possible. However, while residual kidney function is beneficial to patients on dialysis, patients should not be initiated on dialysis earlier to take advantage of more abundant residual kidney function as this has not been associated with improved outcomes.

Even when the eGFR is very low, the urine output is variable, ranging from oliguria to normal levels. Volume expansion (due to sodium retention) and a urea osmotic diuresis (as the daily urea load is excreted by fewer functioning nephrons) play an important role in preserving urine output in the setting of advanced chronic kidney disease (CKD) [2-4].

This topic will review the clinical importance of residual kidney function in patients with kidney failure and factors that may affect residual kidney function in this patient population.

CLINICAL IMPORTANCE OF RESIDUAL KIDNEY FUNCTION — There are two essential components to residual kidney function: clearance of uremic toxins and urinary volume. The loss of residual kidney function in patients with end-stage kidney disease (ESKD) has important clinical manifestations, including adverse effects upon volume control, patient survival, health-related quality of life, and other clinical parameters [5-12].

Clearance of uremic toxins — Although the remaining glomerular filtration rate (GFR) may only be 4 to 5 mL/min in patients initiated on maintenance dialysis, this is sufficient to make a significant contribution to the removal of potential uremic toxins since filtration is continuous, as opposed to the 12 hours per week that the patient is undergoing hemodialysis [13]. In addition, residual kidney function allows for the clearance of larger molecules, such as beta-2 microglobulin, which dialysis filters cannot remove. Thus, this residual function encompasses more than the urea clearance that can be calculated as a contribution to dialysis dose. Even in patients with residual kidney volume less than 1.5 mL/min, patients who were not anuric had significantly lower levels of nonurea solutes such as indoxyl sulfate and asymmetric dimethylarginine than patients on dialysis [14].

Volume control — Urine output is an essential function of the kidney and has a significant effect on the quality of life of patients on hemodialysis. As an example, a residual urinary output of just 1 liter/day will equate to 3 liters over the weekend interval, which is beneficial to the patient. The increased urine output may allow for increased fluid intake by that patient and also necessitate less fluid removal with dialysis. This decreases cramping and the possibility of intradialytic hypotension, which can lead to myocardial stunning, ischemia, and increased mortality [15]. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Outcomes'.)

In peritoneal dialysis, the need to remove less fluid allows for the use of dialysate with a lower glucose concentration, decreasing the caloric intake from peritoneal dialysis and the toxicity of glucose and glucose intermediates to the peritoneal membrane [16]. (See "Peritoneal dialysis solutions", section on 'Low-molecular-weight agents'.)

Survival — Among patients on peritoneal dialysis or hemodialysis, the beneficial effect of continued residual kidney function on survival is clear, as shown in the CANUSA study, a large study of Canadian and United States patients on peritoneal dialysis [17]; the Netherlands Cooperative Study of the Adequacy of Dialysis (NECOSAD), a study of 1800 patients on hemodialysis and peritoneal dialysis; and others [8-11,18,19]. This is discussed separately. (See "Prescribing peritoneal dialysis" and "Prescribing and assessing adequate hemodialysis".)

In patients on dialysis, the magnitude of the association between residual kidney function and improved survival is illustrated by the following:

●In a study of over 600 incident patients on peritoneal dialysis, there was a 36 percent reduction in relative risk of death with increased urine volume; residual GFR was not associated with improved mortality [17].

●In a study including over 700 incident patients on hemodialysis, preservation of urine output of greater than 250 mL/day was associated with a 30 percent reduction in all-cause mortality [8].

Thus, one should adopt measures aimed at preserving residual kidney function among patients on peritoneal dialysis and hemodialysis and improving endogenous fluid removal through increased urine volume. Even if urea clearance is small, the urinary volume is beneficial. (See 'Factors that may affect residual kidney function' below.)

Health-related quality of life and other clinical parameters — Among patients on dialysis, residual kidney function is associated with better quality of life [8,12]. In addition, observational data suggest that residual kidney function may confer the following benefits:

●Less inflammation, as defined by C-reactive protein and interleukin 6 levels [8]

●Increased responsiveness to erythropoietin stimulating agents [8,20]

●Improved nutritional status [21]

●Fewer dietary restrictions [22]

●Decreased chronic kidney disease–associated pruritus [23]

EFFECTS OF DIALYSIS ON RESIDUAL KIDNEY FUNCTION — Both volume expansion and the high urea load per nephron are rapidly reversed by dialysis (of any form), which removes sodium, water, and urea. Thus, it is not surprising that many patients have a marked reduction in, or even cessation of, urine output when dialysis is instituted [2]. This observation has raised the question of whether dialysis itself worsens residual kidney function. This issue is unresolved in acute kidney failure. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)

Peritoneal and hemodialysis may have different effects on residual kidney function, as discussed in the following sections.

Hemodialysis — Evidence suggests that the institution of maintenance hemodialysis alone may accelerate injury to the few nephrons that are still functioning at the onset of dialysis [24], presumably due to ischemic insults (from intradialytic hypotension and/or postdialysis hypovolemia), exposure to nephrotoxic mediators (from dialysis tubing and impurities), and deactivation of remaining nephrons [25,26]. This injury results in a progressive fall in the residual glomerular filtration rate (GFR) [13,27-30].

The characteristics of the hemodialysis procedure may affect the rate of loss of function:

●Biocompatible membranes – Hemodialysis with biocompatible membranes may better preserve residual kidney function compared with bioincompatible membranes [31-33]. (See "Clinical consequences of hemodialysis membrane biocompatibility".)

Most of the studies in this area have suffered from methodologic flaws or small sample sizes. As examples:

•In a multicenter trial that randomly assigned 159 incident patients on hemodialysis to dialysis with high-flux membranes or low-flux bioincompatible membranes, there was no significant difference in the rate of change of kidney function, although the residual kidney function at the start of the study was quite low (approximately 1 mL/min in the bioincompatible membrane group and 0.7 mL/min in the control group) [34].

•In a trial that randomly assigned 20 patients on dialysis to dialysis with either cellulose or polysulfone membranes, there was better preservation of residual kidney function in the polysulfone group at one year [35].

●Dialysate – The possible role of the hemodialysis dialysate was addressed in a trial in which 30 patients initiating hemodialysis were randomly assigned to dialysis using either conventional or ultrapure dialysate [36]. Residual kidney function in the ultrapure group was significantly higher at 24 months (4.3 versus 2.5 mL/min). Markers of inflammation, such as C-reactive protein, were also significantly lower among these patients. (See "Ultrapure dialysis fluid".)

●Frequency of dialysis – More frequent hemodialysis may accelerate the loss of residual kidney function:

•One study evaluated residual kidney function in participants of the Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials [37]. Patients assigned to frequent nocturnal dialysis (six times per week) had significantly lower urine volume and urea clearance at 4 and 12 months compared with conventional nocturnal dialysis (three times per week). There was no significant difference in loss of urine volume or residual kidney function in patients who did frequent versus conventional daily dialysis, although there was likely not enough statistical power to identify a difference.

•In a retrospective review of patients who initiated dialysis in a large dialysis organization in the US, among 351 individuals who started hemodialysis with fewer than three treatments per week, both kidney urea clearance and urine volume declined more slowly over time compared with a matched cohort of 8065 patients who dialyzed three times weekly [38]. The median kidney urea clearance and urine volume were 4.8 mL/min/1.73 m² and 1150 mL in the less frequent dialysis group versus 3.04 mL/min/1.73 m² and 800 mL in the conventional dialysis group. There was no difference in survival between the two groups. However, in a subgroup analysis of patients who had a baseline kidney urea clearance <3 mL/min/1.73 m², those who started twice-weekly hemodialysis experienced higher mortality compared with those in the conventional hemodialysis group.

●Incremental dialysis – Incremental hemodialysis is a method of dosing hemodialysis by which residual kidney function is incorporated into the calculation of hemodialysis dose. Including residual kidney function can lead to the need for less than three hemodialysis treatments per week, shorter treatments, or less intense treatments. (See "Incorporating residual kidney function into the dosing of intermittent hemodialysis".)

Whether incremental dialysis helps to preserve residual kidney function is unclear. In a multicenter feasibility trial that randomly assigned 55 incident patients on hemodialysis with a urea clearance of ≥3 mL/min/1.73 m² to conventional hemodialysis (three times weekly for 3.5 to 4 hours) or incremental hemodialysis (twice weekly, upwardly adjusting hemodialysis dose as residual kidney function was lost) for 12 months, there was no change in the urea clearance slope between the two treatment arms [39]. Larger studies and multisite clinical trials are in progress that will address this question [40].

●Ultrafiltration rate – Higher ultrafiltration rates during hemodialysis are associated with faster declines in residual kidney function. In a study of over 7700 incident patients on conventional, thrice weekly hemodialysis, higher ultrafiltration rates were associated with a greater decline in urine output after one year [41]. Similarly, in another study of over 1500 incident patients on an incremental hemodialysis regimen, higher ultrafiltration rates were associated with faster loss of residual kidney function [42].

Peritoneal dialysis — Certain features of peritoneal dialysis may affect residual kidney function:

●Modality – Although some studies suggest that automated forms of peritoneal dialysis (APD) might be associated with a more rapid decline in residual kidney function [43-45], other studies have found minimal effect of peritoneal dialysis modality on the loss of residual kidney function [46-48]. The effect of peritoneal dialysis modality on the patient's quality of life should be more important in determining modality than possible effects on residual kidney function decline.

●Peritoneal dialysis solutions – Some [49,50], but not all [51-54], studies have suggested that more biocompatible peritoneal dialysis solutions, specifically those with low glucose degradation products and a neutral pH, preserve residual kidney function. In a 2015 meta-analysis of six trials, patients who underwent peritoneal dialysis with these biocompatible solutions had a slower rate of decline of residual kidney function, a higher achieved Kt/V, and a higher urine volume compared with patients who were treated with conventional peritoneal dialysis solutions [55].

Icodextrin solution has also been compared with biocompatible peritoneal dialysis solutions. In one trial, there was no difference in residual kidney function between groups at one year [56]. However, patients using icodextrin had a slower decline in urine volume compared with patients using biocompatible solutions.

●Weight gain – Preventing weight gain may preserve residual kidney function. One study analyzed the effect of weight gain on residual kidney function among 148 patients on peritoneal dialysis [57]. In a multivariate model, patients with a weight increase greater than 2.3 kg had a fourfold increased risk of loss of residual kidney function. Other variables in the model that predicted faster loss of kidney function included diabetes mellitus, proteinuria, elevated C-reactive protein, and elevated systolic blood pressure. Additional studies are needed to confirm these findings.

●Other factors – In another study of patients on peritoneal dialysis (the balANZ trial), better preservation of residual kidney function was associated with male sex, higher baseline residual kidney function, higher systolic blood pressure, biocompatible fluids, lower peritoneal ultrafiltration, and lower dialysate glucose exposure [58].

Other risk factors for developing anuria among patients on peritoneal dialysis include serum bicarbonate <24 mEq/L [59] and development of peritonitis [60].

Hemodialysis versus peritoneal dialysis — For reasons that are incompletely understood, the loss of residual kidney function appears to occur more rapidly with hemodialysis than with peritoneal dialysis [13,27-30]. As examples:

●In a prospective study of 279 patients on hemodialysis and 243 patients on peritoneal dialysis, loss of residual kidney function was greater in patients on hemodialysis than in those on peritoneal dialysis, with patients on peritoneal dialysis on average having a 30 percent higher residual GFR than those on hemodialysis [30].

●In a retrospective study of 811 patients on hemodialysis and 1032 patients on peritoneal dialysis, patients on peritoneal dialysis had a 65 percent lower risk of oliguria (self-reported urine volume <200 mL/day) at one year of follow-up compared with those on hemodialysis [28].

However, it is important to note that many of the studies addressing this issue are older, and, at the time, modern hemodialytic techniques such as volumetric control, ultrapure water, and biocompatible membranes were not in use. Residual kidney function has also been studied extensively in the peritoneal dialysis population, but there have been few studies in the hemodialysis population. It is reasonable to mention to patients who are preparing for dialysis that residual kidney function is likely better preserved using peritoneal dialysis rather than hemodialysis. However, survival with either modality appears to be equivalent, and lifestyle preferences should remain the predominant factor when choosing dialysis modality. (See "Dialysis modality and patient outcome".)

Potential reasons for differences in loss of residual kidney function with hemodialysis include more frequent exposure to ischemic injury from intermittent hypotension and activation of nephrotoxic inflammatory mediators during treatments [30,61,62]. In one study of 522 patients initiating either peritoneal dialysis or hemodialysis, predictors of the rate of decline in residual kidney function at baseline included a higher diastolic blood pressure and increased proteinuria [30]. Over time, decreases in residual kidney function were associated with hypotension with hemodialysis and dehydration episodes with peritoneal dialysis. Relatively higher kidney function was consistently observed with peritoneal dialysis, which increased over time. (See "Intradialytic hypotension in an otherwise stable patient".)

Another possible explanation for the different effect upon residual kidney function is that volume expansion with continuous peritoneal dialysis may help to preserve kidney function [30,61,63]. In one study that examined volume control versus the use of antihypertensive agents for control of hypertension in patients on hemodialysis with a baseline urine production of approximately 1600 mL/day, urine output dropped by only 12 percent during treatment with antihypertensive medications, but, with the use of volume removal, urine output decreased to <200 mL/day in all patients [63]. Blood pressure control improved, and left ventricular mass decreased significantly with volume removal.

As mentioned above, newer hemodialytic techniques may result in a slower rate of decline of residual kidney function. In one study, the loss of residual kidney function was similar in a comparison of 175 patients receiving continuous ambulatory peritoneal dialysis (CAPD) versus 300 patients dialyzed with ultrapure water, bicarbonate buffer, and high-flux polysulphone membranes [62].

FACTORS THAT MAY AFFECT RESIDUAL KIDNEY FUNCTION

Intradialytic hypotension — It is important to avoid hypotension with or after dialysis. Hypotension during dialysis not only causes myocardial, cerebrovascular, and mesenteric ischemia but can also lead to decreased kidney perfusion and loss of kidney function. (See "Intradialytic hypotension in an otherwise stable patient".)

Hypotension may result from attempts to challenge the target weight (ie, reduce the target weight) in an effort to achieve euvolemia in patients who are just starting dialysis. Among patients who start dialysis with reasonable residual kidney function, attempts to aggressively remove fluid may result in low blood pressures that can cause progressive loss of kidney function, even in the absence of symptoms such as cramping or presyncope [64].

When a patient is new to dialysis, if blood pressure is well controlled and there is no edema or heart failure present, aggressive fluid removal should be avoided, and the patient should be "run even" without fluid removal. The physician should be alerted if hypotension develops. However, when a patient is new to dialysis and has persistent hypertension, edema, or heart failure, volume removal should be considered, with an effort to avoid hypotension.

Diuretics — Unless urine output is negligible, diuretics should be continued in patients who initiate dialysis. Loop diuretics increase urine and sodium excretion (though they do not affect residual kidney function) [65] and decrease the need for volume removal with dialysis [7]. In a trial of 61 patients on peritoneal dialysis randomly assigned to either furosemide (250 mg/day) or no furosemide, urine volume at 6 and 12 months was significantly higher in the group receiving the diuretic, although clearance of creatinine and urea had declined at a similar rate in both groups [65].

There are no evidence-based guidelines or safety data for chronic dosing of furosemide in patients on hemodialysis or peritoneal dialysis. In one study, chronic daily administration of 250 to 2000 mg of furosemide resulted in sun-induced bullous dermatosis in 3 of 10 patients without evidence of ototoxicity [66]. While furosemide has been associated with deafness, there are no reported cases of deafness from furosemide in patients with end-stage kidney disease (ESKD) receiving furosemide. In the author's experience, doses of furosemide up to 120 mg orally each day with 5 mg metolazone are in general well tolerated. While these agents confer significant benefit in terms of increased urinary volume, the lack of clinical safety data, benefits, risks, and alternatives should be discussed with the patient. It is important that these agents be stopped when urine output becomes negligible and patients be monitored for hearing loss and skin changes.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers — The preservation of residual kidney function among those undergoing peritoneal dialysis may be enhanced by the administration of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). In a 2014 Cochrane review of six nonblinded trials and 257 patients, the decline in eGFR was modestly smaller at 12 months among patients who were treated with an ACE inhibitor or an ARB [67]. Among patients on hemodialysis, results from small trials of ACE inhibitors or ARBs compared with placebo for preservation of residual kidney function are conflicting [68,69].

Based on these findings, the use of ACE inhibitors or ARBs is recommended to help preserve residual kidney function in those who require antihypertensive medications [70,71].

Nephrotoxic agents

Aminoglycosides — Given that aminoglycosides are nephrotoxic, it is generally believed that aminoglycosides should be used with caution to preserve residual kidney function. (See "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

However, a number of studies have found no effect of aminoglycoside use on the decline of residual kidney function. As an example, residual kidney function was determined at baseline and at follow-up in 70 patients on peritoneal dialysis who received cefazolin and gentamicin for peritonitis, 61 individuals with peritonitis who received vancomycin and ciprofloxacin, and 74 control patients without peritonitis [72]. There was no significant difference in the rate of kidney function decline between groups. The lack of effect of aminoglycosides was also observed in a retrospective analysis of 1412 patients [73]. The change in residual kidney function over time was similar in 1075 patients who received empiric aminoglycosides for peritonitis as compared with 339 who did not.

Another study of 102 patients who received either cefazolin and netilmicin or cefazolin and ceftazidime showed no differences in residual kidney function between groups [74].

Thus, limited data suggest that the risk of loss of residual kidney function from short-term use of aminoglycosides for peritonitis is low.

Iodinated radiocontrast agents — Iodinated radiocontrast agents can cause acute tubular necrosis, possibly leading to the loss of residual kidney function. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)

However, three studies that prospectively evaluated the effect of contrast on residual kidney function found no loss of function:

●In one study, residual kidney function was evaluated at baseline and two weeks after contrast administration in 36 patients on peritoneal dialysis [75]. Thirty-six control patients also underwent determination of residual kidney function two weeks apart. Studies were performed with adequate prehydration and minimal contrast usage (mean urinary volume 104 mL). No differences were found between baseline and follow-up residual kidney function and urine volume in those receiving contrast, and results were not statistically different from controls.

●In a second study of 10 patients on peritoneal dialysis who received nonionic hypo-osmolar contrast media, residual kidney function was measured on days 1 through 7, day 10, and day 30 [76]. There was a mild decline in mean renal clearance on day 6, but clearance subsequently increased back to baseline by day 30.

●One study showed no difference in the rate of loss of residual kidney function at six months in 42 patients who were given approximately 100 mL of iodixanol contrast compared with 45 patients who did not receive contrast [77].

Despite these studies, it may be prudent to avoid high doses of radiocontrast agents in patients on dialysis, if possible.

Decreased sodium intake — Decreasing dietary sodium intake may be beneficial for preserving residual kidney function in patients on peritoneal dialysis. In one study that examined the relationship between dietary salt intake (based on a three-day dietary record) and residual kidney function among 62 patients on peritoneal dialysis, high dietary salt intake (≥8 g/day) was associated with an increased rate of decline of residual kidney function compared with nonhigh dietary salt intake [78].

Other factors — Other factors may affect residual kidney function. These include:

●Cardiac disease [46]

●Elevated baseline uric acid levels [79]

●Repeated episodes of peritonitis [80,81], although this was not confirmed in all studies [72]

●Peripheral vascular disease [81]

●Larger body mass index (BMI) [82]

●Diabetes [82]

●Increasing age [83]

●Higher baseline GFR [83]

●Hypertension [83]

●Proteinuria [83]

●Initiation of dialysis after kidney transplant failure [84]

●Other nephrotoxic agents (eg, nonsteroidal inflammatory drugs [NSAIDs])

MEASUREMENT OF RESIDUAL KIDNEY FUNCTION — Residual kidney function can be estimated by determining the urea clearance from a 24-hour urine collection and from the plasma urea. These calculations are discussed separately:

●Patients on hemodialysis (see "Incorporating residual kidney function into the dosing of intermittent hemodialysis", section on 'Monitoring residual kidney function')

●Patients on peritoneal dialysis (see "Prescribing peritoneal dialysis", section on 'Addition of residual kidney function')

MANAGEMENT OF KIDNEY ALLOGRAFT FAILURE IN PATIENTS STARTING HEMODIALYSIS OR PERITONEAL DIALYSIS — The withdrawal of immunosuppression in patients with kidney transplant failure is a complex management issue since prolonged immunosuppression increases the risk of infection and sepsis posttransplant, but overly rapid withdrawal of immunosuppression can lead to symptomatic acute rejection and rapid worsening of kidney function. This issue is discussed elsewhere. (See "Kidney transplantation in adults: Management of the patient with a failed kidney transplant".)

SUMMARY AND RECOMMENDATIONS

●Clinical importance of residual kidney function – Residual kidney function and urinary output are important and beneficial to patients on dialysis. Increased urinary output allows for more flexibility with fluid intake and less fluid removal with dialysis, resulting in the avoidance of hypotension and cramping during hemodialysis. Importantly, among patients on peritoneal dialysis or hemodialysis, continued residual kidney function is associated with improved survival. We therefore suggest the adoption of measures aimed at preserving residual kidney function among patients on peritoneal dialysis (Grade 2B) and those on hemodialysis (Grade 2C). (See 'Survival' above and "Prescribing peritoneal dialysis" and "Prescribing and assessing adequate hemodialysis".)

●Effects of dialysis – Both volume expansion and the high urea load per nephron are rapidly reversed by dialysis of any form. Thus, many patients have a marked reduction in, or even cessation of, urine output when dialysis is instituted. Residual kidney function may be better maintained in patients on peritoneal dialysis compared with hemodialysis. However, comparison studies may not account for modern techniques in hemodialysis that may result in preservation of kidney function. (See 'Effects of dialysis on residual kidney function' above.)

●Factors that may affect residual kidney function – Measures to preserve residual kidney function include avoiding hypotension during and after dialysis, avoiding nephrotoxins as much as possible, and using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in hypertensive patients.

We also maintain or initiate patients on diuretics to increase urine volume although this does not affect residual kidney function. It is preferable to maintain euvolemia with diuretics rather than increased ultrafiltration. (See 'Factors that may affect residual kidney function' above.)