Understanding Development of Malnutrition in Hemodialysis Patients: A Narrative Review

Table 3:

We appreciate and agree with this comment. The type of membrane used with dialysis technique does make a difference as the combination of dialyzer membrane with greater seiving coefficient with HDF technique has been shown to introduce greater albumin losses as indicated by Krieter et al. (2010). As previously mentioned in Lines 163-166, the combination use of highly permeable membrane (MCO or HCO) with HF or HDF technique is not encouraged.

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“dialysis adequacy [103,104] through maintaining the pre-dialysis serum bicarbonate levels between 24-26 mmol/L [107 “. The threshold for pre-dialysis bicarbonate is set too high and should not exceed 24 mmol/L. The risk is to reach a symptomatic alkalosis level at the end of the dialysis session that ensues vomiting and hypotension. 

Madhukar M Nephrol Dial Transplant 2016; 31: 1220-1224,

Bommer JLF, Am J Kidney Dis 2004; 44: 661-671;

Tentori FKA Am J Kidney Dis 2013; 62: 738-746,

Wu DSC, Clin J Am Soc Nephrol 2006; 1: 70-78;

Vashisha T Clin J Am Soc Nephrol 2013; 8:254-264;

The threshold of 24-26 mmol/L as stated in the manuscript refers to the current opinion of NKF-KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update. The literature you have cited is based from 2016 and earlier providing the pre-dialysis serum bicarbonate at more than 22 mmol/L, which was proposed by the earlier KDOQI Guideline (2000). We prefer to use the current opinion by the NKF-KDOQI Guidelines. In the text, we have amended the sentence to:

Section 3.8: Efficacy of Metabolic Acidosis Correction, Line 308-309:

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“In one study, patients with serum bicarbonate levels ≤22 mmol/L rather than serum bicarbonate levels >22 mmol/L had lower serum albumin levels (p=0.046)”.

Usually the higher is the protein intake, the lower is the serum bicarbonate because as in non-dialysis patients, the protein intake increases the acid load.  Therefore the acidosis in dialysis patients is often associated with a better nutritional status. After adjustment for the nutritional status, acidosis is often associated with an increased risk of mortality as bicarbonate > 24 mmol/L. Correction of the metabolic acidosis by increasing the bicarbonate concentration of the dialysate seems not adequate and is also associated with an increased mortality risk.

We conquer with the reviewer’s comment and given the pausity of studies in this area, there is a grey area in terms of the ideal bicarbonate level. In acknowledgement, we have added a qualifying statement in the text as follows (Lines 338-342):

In one study, patients with serum bicarbonate levels ≤22 mmol/L rather than serum bicarbonate levels >22 mmol/L had lower serum albumin levels (p=0.046) [135]. In these patients, high serum bicarbonate levels negatively correlated with nPCR (r=-0.492, p=0.045) but positively with serum albumin (r=0.432, p=0.019). Acidosis-led catabolism triggers breakdown of the endogenous proteins, which influence higher nPCR levels. In different malnourished HD populations, a serum bicarbonate level of >23 [136,137] or >27 mmol/L [128,137] have been associated with greater mortality risk. As malnutrition is a confounding factor for serum bicarbonate level, there is no an ideal serum bicarbonate level that fits for all dialysis patients [138].

138. Misra, M. Pro: Higher serum bicarbonate in dialysis patients is protective.          Nephrol Dial Transplant. 2016, 31:1220-1224.

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“Contrarily, serum bicarbonate levels >27 mmol/L promote mortality risk in malnourished HD  patients

We take note of this comment and the associated literature and have amended our text as follows (Lines 338-340):

In different malnourished HD populations, a serum bicarbonate level of >23 [136,137] or >27 mmol/L [128,137] have been associated with greater mortality risk.

136. Wu, D.Y.; Shinaberger, C.S.; Regidor, D.L.; McAllister, C.J.; Kopple, J.D.; Kalantar-Zadeh, K. Association between serum bicarbonate and death in hemodialysis patients: is it better to be acidotic or alkalotic? Clin J Am Soc Nephrol. 2006,1(1),70–

137. Bommer, J.; Locatelli, F.; Satayathum, S.; Keen, M.L.; Goodkin, D.A.; Saito, A.; Akiba, T.; Port, F.K.; Young, E.W. Association of Predialysis Serum Bicarbonate Levels With Risk of Mortality and Hospitalization in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004,44(4):661-71.

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We have taken note of this comment and amended Line 462 to:

Reference 48: “Florens, N.; Julliard, L. Large Middle Molecule and Albumin Removal: Why Should We Not R Vanholder, R.; Pletinck, A.; Schepers, E.; Glorieux, G. Biochemical and Clinical Impact of Organic Uremic Retention  Solutes: A Comprehensive Update. Toxins. 2018, 10(1), 33. 

It seems that you mixed two different references: Toxins (Basel). 2018 Jan; 10(1): 33. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update Raymond Vanholder,* Anneleen Pletinck, Eva Schepers, and Griet Glorieux

We take note of this comment and have amended the reference [57] correctly to:

Florens, N.; Juillard, L. Large Middle Molecule and Albumin Removal: Why Should We Not Rest on Our Laurels?Contrib Nephrol. 2017, 191,178-187.

We take note of this comment and have amended the reference [116] to:

We have amended “total renal clearance" in Line 247 to "total clearance”.

The following comment was added to Section 2. Development of Malnutrition at the Time of HD Initiation and Indicators of Poor Nutritional Status (Lines 97-107):

Earlier opinion on dialysis initiation did consider poor nutritional status as a factor to initiate dialysis. However, this was not based on markers of malnutrition but rather signs and symptoms of malnutrition such as anorexia, nausea and fatigue [24]. Van de Luijtgaarden et al. (2012) reported 53% of nephrologists agreeing to initiate dialysis in patients with poor nutritional status [25]. However, a review on dialysis initiation observed the lack of data on benefits of early dialysis initiation in patients with low serum albumin level or in improving nutritional status [26]. The Canadian Society of Nephrology Guidelines (2014) [27] ceased to recommend dialysis initiation based on decline in nutritional status as indicated by serum albumin, lean body mass or Subjective Global Assessment), whereas the Caring for Australians with Renal Impairement Guidelines [28] do recommend dialysis with GFR <10 mL/ min per 1.73 m² to reduce uremic symptoms or signs of malnutrition.

24. Ledebo, I.; Kessler, M.; van Biesen, W.; Wanner, C.; Wiecek, A.; Prichard, S.; Argilés, A.; Ritz. E.Initiation of dialysis: Opinions from an international survey: Report on the dialysis opinion symposium at the ERA-EDTA Congress, 18 September 2000, Nice. Nephrol Dial Transplant. 2001, 16(6), 1132–1138.
25. van de Luijtgaarden, M.W.; Noordzij, M.; Tomson, C.; Couchoud, C.; Cancarini, G.; Ansell, D.; Bos, W.J.; Dekker, F.W.; Gorriz, J.L.; Iatrou, C.; Garneata, L.; Wanner, C.; Cala, S.; Stojceva-Taneva, O.; Finne, P.; Stel, V.S.; van Biesen, W.; Jager, K.J. Factors Influencing the Decision to Start Renal Replacement Therapy: Results of a Survey Among European Nephrologists. Am J Kidney Dis. 2012, 60(6), 940-948.
26. Rosansky, S.J.; Cancarini, G.; Clark, W.F.; Eggers, P.; Germaine, M.; Glassock, R.; Goldfarb, D.S.; Harris, D.; Hwang, S.J.; Imperial, E.B.; Johansen, K.L.; Kalantar-Zadeh, K.; Moist, L.M.; Rayner, B.; Steiner, R.; Zuo, L. Dialysis Initiation: What’s the Rush? Semin Dial. 2013, 26(6), 650–657.
27. Nesrallah, G.E.; Mustafa, R.A.; Clark, W.F.; Bass, A.; Barnieh, L.; Hemmelgarn, B.R.; Klarenbach, S.; Quinn, R.R.; Hiremath, S.; Ravani, P.; Sood, M.M.; Moist, L.M. Canadian Society of Nephrology 2014 clinical practice guideline for timing the initiation of chronic dialysis. CMAJ. 2014, 186(2) 112-117.
28. Kelly, J.; Stanley, M.; Harris, D. Caring for Australians with Renal Impairment (CARI). The CARI guidelines. Acceptance into dialysis guidelines. Nephrology (Carlton). 2005,10(4), S46-60.

The following paragraphs have been added to detail the interplay of malnutrition with oxidative stress (Section 3.3 Dialysis-induced Inflammation: Lines 211-225)

Another impact of the HD treatment is the activation of polymorphonuclear white blood cells, which trigger production of ROS and other pro-oxidants [91]. Indeed, increased indices of oxidative damage along with decreased indices of antioxidant defense have been observed in HD patients post-dialysis [92]. Low antioxidant levels in HD patients may also occur from limited vegetable and fruit intakes to prevent hyperkalemia [93]. Resultant low intakes of vitamin A, C, E, and selenium would affect antioxidant defence mechanisms [93.94]. Additionally, involuntary removal of vitamins also occurs with every HD session as mentioned in Section 3.1.

However, Silva et al. (2019) found no different in markers of oxidative stress and antioxidant defences in malnourished HD patients identified using Global Objective Assessment compared to mild or well-nourished patients [95]. In contrast, accumulation of advanced glycation end products, a biomarker of oxidative stress measured using skin auto fluorescence was significantly associated with markers of malnutrition in HD patients such as lower serum albumin, lower handgrip strength and lower protein intake [96]. HD patients with protein-energy wasting were 5.2 times more likely to experience oxidative stress as demonstrated by high protein carbonyl levels (95% CI: 24.0-1.1,p=0.039) [97].

91. Liakopoulos, V.; Roumeliotis, S.; Zarogiannis, S.; Eleftheriadis, T.; Mertens, P.R.Oxidative stress in hemodialysis: Causative mechanisms, clinical implications, and possible therapeutic interventions. Semin Dial. 2019, 32(1),58-71.
92. Navarro-García, J.A.; Rodríguez-Sánchez, E.; Aceves-Ripoll, J.; Abarca-Zabalía, J.; Susmozas-Sánchez, A.; González Lafuente, L.; Bada-Bosch, T.; Hernández, E.; Mérida-Herrero, E.; Praga, M.; Ruilope, L.M.; Ruiz-Hurtado, G. Oxidative Status before and after Renal Replacement Therapy: Differences between Conventional High Flux Hemodialysis and on-Line Hemodiafiltration. Nutrients. 2019, 11(11), 2809.
93. Fatonah, S.; Sulchan, M.; Sofro, M. A. U. Macronutrients, micronutrients intake and inflammation in hemodialysis patients. Potravinarstvo Slovak Journal of Food Sciences, 2019,13(1), 891-897.
94. Barroso, C.F.; Pires, L.V.; Santos, L.B.; Henriques, G.S.; Pessoa, P.P.; de Araújo, G.N.; de Araújo, C.O.D.; Oliveira, C.M.C.; Maia, C.S.C. Selenium Nutritional Status and Glutathione Peroxidase Activity and Its Relationship with Hemodialysis Time in Individuals Living in a Brazilian Region with Selenium-Rich Soil. Biol Trace Elem Res doi: 10.1007/s12011-020-02388-1
95. Silva, R.E.; Simões-E-Silva, A.C.; Miranda, A.S.; Justino, P.B.I.; Brigagão, M.R.P.L.; Moraes, G.O.I.; Gonçalves, R.V.; Novaes, R.D. Potential Role of Nutrient Intake and Malnutrition as Predictors of Uremic Oxidative Toxicity in Patients with End-Stage Renal Disease. Oxid Med Cell Longev. 2019, doi: 10.1155/2019/7463412.
96. Viramontes Hörner, D.; Selby, N.M.; Taal, M.W. The Association of Nutritional Factors and Skin Autofluorescence in Persons Receiving Hemodialysis. J Ren Nutr. 2019, 29(2),149-155.

We do not wish to discuss MIA syndrome in this review as:

MIA syndrome only occurs with the association between inflammation, malnutrition and atherosclerosis. Our review focuses on the development of malnutrition and the categorization of contributing causes into iatrogenic and non-iatrogenic factors. This classification is overarching to include inflammation [Section 3.3 Dialysis-induced inflammation] is the iatrogenic contributive factor of malnutrition but cannot include atherosclerosis. For this reason, our review area has been explained in Lines 57-61.

We have added the following paragraphs to Section 3.3 Dialysis-Induced Inflammation, Lines 180-190:

Whether dialysis access directly contributes to malnutrition has not been shown. Arteriovenous fistula (AVF) failure were not influenced by markers of poor nutritional status except for high cholesterol (p=0.034) and low nPCR levels (p=0.029) [77]. HD patients with catheter access compared to fistula and graft had significantly higher MIS scores and lower serum albumin levels [78].

In fact, AVF have 52% greater survival rate compared to those on central venous catheter (CVC) irrespective of nutritonal status although malnutrition was found to lower survival rate by 2% [79]. Instead, catheter rather graft and fistula access appears to be a significant predictor of greater inflammatory response and associated with the highest all cause-mortality rate [78] mediated by infection [20].

Therefore, the route of dialysis access is rather associated with inflammation and mortality risk [78], whereby presence of malnutrition may influence the survival rate [79].

77. Gagliardi, G.M.; Rossi, S.; Condino, F.; Mancuso, D.; Greco, F.; Tenuta, R.; Savino, O.; Bonofiglio, R.; Domma, F.; Latorre, G. Malnutrition, infection and arteriovenous fistula failure: Is there a link?J Vasc Access 2011, 12 (1), 57-62.
78. Dukkipati, R.; Molnar, M.Z.; Park, J.; Jing, J.; Kovesdy, C.P.; Kajani, R.; Kalantar-Zadeh, K. Association of Vascular Access Type with Inflammatory Marker Levels in Maintenance Hemodialysis Patients. Semin Dial. 2014, 27(4), 415–423.
79. Zavacka, M.; Zelko, A.; Madarasova Geckova, A.; Majernikova, M.; Pobehova, J.; Zavacky P. Vascular access as a survival factor for the haemodialysis population: a retrospective study. Int Angiol. 2020, doi: 10.23736/S0392-9590.20.04401-6

We have added this paragraph to Introduction, Lines 63-70:

Comorbidities such as heart failure (left ventricular failure) and CKD-mineral bone disorder have a bidirectional association with nutritional status [13,14]. The related mechanisms includes malabsorption due to gut edema, poor appetite due to cytokine production, difficulty in oral intake and food preparation arising from fatigue and breathing difficulty [15]. However, malnutrition is acknowledged to be a kidney-specific risk factor for heart failure in CKD patients [14], and with HD patients there is lack of association between malnutrition assessment and echocardiographic findings [16] or CVD risk [17].

13. Bonilla-Palomas, J.L.; Gámez-López, A.L.; Anguita-Sánchez, M.P.; Castillo-Domínguez, J.C.; García-Fuertes, D.; Crespin-Crespin, M.; López-Granados, A.; Suárez de Lezo, J. Impact of malnutrition on long-term mortality in hospitalized patients with heart failure. Rev Esp Cardiol. 2011, 64(9):752-758.
14. Tuegel, C.; Bansal N. Heart failure in patients with kidney disease. Heart. 2017 103(23):1848-1853.
15. Grossniklaus, D.A.; O’Brien, M.C.; Clark, P.C.; Dunbar, S.B. Nutrient intake in

heart failure patients. J Cardiovasc Nurs. 2008, 23(4), 357-363.

16. Naini, A.E.; Karbalaie, A.; Abedini, M.; Askari, G.; Moeinzadeh, F. Comparison of malnutrition in hemodialysis and peritoneal dialysis patients and its relationship with echocardiographic findings. J Res Med Sci. 2016 21,78. doi: 10.4103/1735-1995.189695.
17. Spatola, L.; Finazzi, S.; Calvetta, A.; Reggiani, F.; Morenghi, E.; Santostasi, S.; Angelini, C.; Badalamenti, S.; Mugnai, G. Subjective Global Assessment-Dialysis Malnutrition Score and cardiovascular risk in hemodialysis patients: an observational cohort study. J Nephrol. 2018, 31(5):757-765.