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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 5  |  Page : 1264-1272
The relationship of electrophysiological parameters of uremic polyneuropathy and uremic toxins in patients with chronic kidney disease


1 Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Sawangi (Meghe), Wardha, Maharashtra, India
2 Department of Neurology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Sawangi (Meghe), Wardha, Maharashtra, India

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Date of Web Publication4-May-2022
 

   Abstract 


We aimed to study the correlation of measurable uremic toxins with electrophysiological parameters of uremic polyneuropathy in chronic kidney disease (CKD) patients. This study was conducted between January 2018 and December 2018, 40 CKD patients on hemodialysis (HD) and 40 controls were included in the present study. Prevalence of peripheral neuropathy in CKD patients was 50% clinically and 65% of patients found to have neuropathy by electrophysiological study. The mean age of patients was 36.9 ± 12 years in which, 26 (65%) were male and 14 (35%) were female. All patients were recently diagnosed CKD on HD since <1 year duration. In the present study 16 (40%) patients had mild-to-moderate neuropathy and 4 (10%) had severe neuropathy according to modified NDS score. The most common pattern of neuropathy was axonal and mixed sensorimotor. On correlation of serum creatinine (Cr) and blood urea nitrogen (BUN) with nerve conduction study parameters, statistically significant association was present but other uremic toxins including serum potassium, calcium, phosphorus, uric acid, and parathyroid hormone did not correlate with neuropathy indices. Peripheral neuropathy is common in CKD patients causing significant morbidity at very early stage and though BUN and Cr are dialyzable toxins, they correlate significantly with neuropathy severity and can be guiding markers for optimization of dialysis therapy.

How to cite this article:
Bakre A, Aradhey P, Acharya S, Kumar S. The relationship of electrophysiological parameters of uremic polyneuropathy and uremic toxins in patients with chronic kidney disease. Saudi J Kidney Dis Transpl 2021;32:1264-72

How to cite this URL:
Bakre A, Aradhey P, Acharya S, Kumar S. The relationship of electrophysiological parameters of uremic polyneuropathy and uremic toxins in patients with chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 25];32:1264-72. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1264/344745



   Introduction Top


The prevalence of chronic kidney disease (CKD) is increasing progressively and it is becoming a public health issue. In developing countries, 15% of population is suffering from CKD and prevalence rises to 40% among people over 65 years old. Approximately 60% of patients suffer from neurological complications (Brouns and De Deyn, 2004), and it affects the nervous system at all levels, central as well as peripheral, leading to weakness, sensory impairment causing prolonged disability and alteration sensorium. The most common manifestation is uremic neuropathy. Various studies have demonstrated that 60%–100% of patients on dialysis experience neuropathic symptoms.[1] Kidney failure leads to derangements in extracellular volume, inorganic ion concentrations, and accumulation of organic waste products which is termed as uremia but these molecules are not identified completely and despite of extensive research, the pathophysiology of uremic neuropathy is yet to be established. There are two main postulated hypotheses. “Middle Molecule Hypothesis” postulates that uremic neuropathy is a consequence of retention of neurotoxic molecules in the middle molecular range (300–12000 Da) which are slowly dialyzable by hemodialysis (HD) membrane.[2],[3] However, there is little evidence that such molecules are actually neurotoxic. Second hypothesis comes from recent nerve excitability studies which had demonstrated that patients with uremic neuropathy had motor and sensory axonal changes before dialysis suggesting that hyperkalemia could be a contributing factor to the development of neuropathy.[4]

Ongoing research on this subject is contradictory. Recent investigation has shown that dialysis uncommonly leads to improvement of uremic neuropathy. Some researchers had suggested that dialysis slow down the progression of neuropathy in most patients. On the other hand, some have suggested that in patients on dialysis there is a gradual worsening of the neuropathy.[1] There is a lack of knowledge about which uremic toxic molecule contributes to development of neuropathy.[5] So the present study was conducted to evaluate correlation of neuro electrophysiological parameters with common uremic toxins.


   Materials and Methods Top


The present study of clinical profile of uremic polyneuropathy in CKD patients and its correlation with uremic toxins from January 2018 to December 2018 Study included total of 40 patients of CKD who were undergoing maintenance HD in a tertiary care multi-specialty hospital of Central India and 40 healthy controls. Those patients who were diagnosed as CKD and put on HD therapy within a year of diagnosis were enrolled in the present study.

Inclusion criteria for cases were patient of CKD on HD secondary to glomerulonephritis, medullary cystic kidney disease, hypertensive nephropathy, and polycystic kidney disease. CKD patients with other comorbidities like diabetes mellitus, alcoholics, hypothyroidism, neurotoxic medication, connective tissue disease, systemic lupus erythematosus, amyloidosis which are known to cause neuropathy independently were excluded from the present study. The control group included normal healthy individuals who gave consent for enrolling in study and renal donor patients who were undergoing evaluation for transplant patients were evaluated clinically by the same observer for their neuropathic symptoms and signs and categorized by modified neuropathy neuropathy disability score. All patients of CKD who were enrolled in study were evaluated for common uremic toxins like creatinine (Cr), blood urea nitrogen (BUN), potassium, uric acid, parathyroid hormone level, and serum calcium. All subjects included in the control group were evaluated for routine biochemical profile to exclude subclinical potential neuropathic causes.

Nerve conduction study

All nerve conduction studies were done on Nicolet Viking machine by the same technician. Following parameters were tested in cases and controls

  1. Motor nerve conduction studies for the median, ulnar, common peroneal, and tibial nerves. The assessed parameters were the distal latency (ms), amplitude of the compound muscle action potential (CMAP mV), (peak to peak), duration of CMAP, nerve conduction velocity (NCV, m/s)
  2. Sensory nerve conduction studies for the ulnar, median, peroneal and sural nerves. The onset latency, peak latency, amplitude of sensory nerve action potential (SNAP, μV) (peak to peak), and NCV were the recorded sensory parameters
  3. F wave study for all nerves examined by motor study.


Ethical issues

There are no ethical issues related to the study as all investigations are routinely indicated in these patients and proper consent will be obtained before enrolling a patient in the study group.


   Statistical Analysis Top


The data collected was evaluated using standard statistical methods using Microsoft Excel software. All values were expressed as mean ± standard deviation. Values were compared using unpaired Student’s t-test. To correlate the uremic toxin and nerve conduction parameters, Pearson’s correlation coefficient was applied. Significant probability value was considered when P <0.05.


   Results Top


The present study included a total of 40 CKD patients, out of which 26 patients (65%) were male and 14 patients (35%) were female. The control group included 18 (45%) male and 22 (55%) female healthy persons. The mean age of case group was 35.9 years and control group was 35.4 years [Figure 1] and [Figure 2]. The present study has total 26 patients of CKD who had neuropathy (65%) and 14 patients of CKD has no neuropathy (35%). Neuropathy was observed more commonly in male patients than female (69.23% of males vs. 57.14% of females). However, this gender difference in the prevalence of neuropathy in CKD patients was not found statistically significant (P = 0.65). Neuropathy was more common in patients of CKD whose age was ≥35 years than patients whose age was ≤35 years (90% vs. 40%, respectively). This age difference in neuropathy prevalence was moderately significant. (P = 0.05). On clinical examination, 37.5% of patients reported positive sensory symptoms and 25% reported negative sensory symptoms. Pinprick and temperature sensation were impaired in 10% and vibration joint position was impaired in 20% cases. Deep tendon reflexes were depressed or absent in 40% of patients. As per the modified neuropathy disability score, 16 (40%) patients had mild-to-moderate neuropathy and four (10%) had severe neuropathy. We found that maximum pathological electrophysiological parameters in CRF patients were observed in peroneal (70%), sural (50%), and tibial nerve (45%). The involvement of median (20%) and ulnar nerve (10%) was minimum as shown in [Table 1]. On nerve conduction study of case group, we found neuropathy in 65% and there was no neuropathy in 35% of patients. Comparison of cases and controls showed significantly low CMAP and motor conduction velocity (MCV) in the cases group [Table 2]. Common uremic toxins were measured in cases. The mean values of these parameters are given in [Table 1].
Figure 1: Gender distribution of cases and control.

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Figure 2: Age distribution of cases and control group.

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Table 1: Mean values of biochemical parameters in study group.

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Table 2: Comparison of electrophysiological parameters of cases and controls.

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Mean value of Cr in our study group was 10.64 ± 6.22 mg/dL. We correlated Cr levels of patients with nerve conduction parameters of median, ulnar, peroneal, tibial, and sural nerve. We found that there was significant correlation between Cr and CMAP of median (r = 0.45, P = 0.046), ulnar (r = 0.47, P = 0.036), peroneal (r = 0.54, P = 0.014), and tibial nerve (r = 0.54, P = 0.013). We also found highly significant correlation of creatinine with SNAP of sural nerve (r = 0.64, P = 0.0024). Also, there was significant correlation with superficial peroneal nerve SNAP (r =0.47, P = 0.036).

Mean value of BUN in patients of CKD in our study group was 89.78 ± 53.13 mg/dL. On correlating BUN levels of patients with their nerve conduction parameters, we found that CMAP of peroneal nerve (r = 0.64, P = 0.0024), tibial nerve (r = 0.74, P = 0.00019), ulnar nerve (r = 0.51, P = 0.021), and median nerve (r = 0.49, P = 0.028) had significant correlation. We also found that there was significant correlation between BUN and SNAP of sural nerve (r = 0.49, P = 0.028) and peroneal nerve (r = 0.54, P = 0.014). There was a significant correlation between MCV of tibial nerve and BUN level (r = 0.46, P = 0.041) [Table 3].
Table 3: Correlation of uremic toxins with nerve conduction parameters.

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In our study group, patients have mean potassium of 4.79 ± 0.88 mEq/L. We correlated serum potassium level with nerve conduction parameters of the patients, but there was no significant correlation between two (P >0.05). Mean serum uric acid level of CKD patients in our study group was 7.76 ± 2.55 mg/dL. There was no correlation between neuropathy parameters and uric acid level (P >0.05). Mean calcium level of CRF patients was 8.7 ± 0.82 mg/dL. We found that there was significant negative correlation between serum calcium and CMAP of peroneal nerve (r = -0.59, P = 0.0061), ulnar nerve (r = -0.69, P = 0.00076). Furthermore, there was significant correlation between calcium and MCV of tibial nerve (r = -0.47, P = 0.036). Other nerve conduction parameters did not correlate with calcium levels. We observed significant correlation between serum phosphorus and CMAP of peroneal nerve (r = 0.44, P = 0.05) and tibial nerve (r = 0.49, P = 0.028). In addition, there was correlation between phosphorus and SCV of sural nerve (r = 0.47, P = 0.037). The mean value of parathyroid hormone level in patients of CRF included in study was 169.12 ± 172.85 pg/mL. We correlated serum PTH levels of CRF patients with nerve conduction parameters, but we do not find any significant correlation between it.


   Discussion Top


The present study included 40 cases and 40 controls of both genders whose mean age was approximately 35 years and they were compared for electrophysiological parameters and it was found that there was a significant impaired motor and sensory parameters in case group. Furthermore, there were asymptomatic subclinical uremic polyneuropathy patients detected with nerve conduction study in case group which included CKD patients who were put on HD therapy within a year of diagnosis. Our findings suggest the early development of polyneuropathy in CKD patients.

Although it is very well proven that peripheral nervous system involvement is very common in uremic patients, pathophysiology of neuropathy in uremic patients remains unresolved mystery. The number of uremic toxins toxins are claimed to be a potential cause but none has proven etiological factor for uremic polyneuropathy. The identification of potential neurotoxic compounds in uremia is based on the correlation between their plasma concentration and the degree of MCV depression.[2],[6] Uremic neuropathy has been attributed to many compounds that increase in uremia such as urea, creatinine, guanidine compounds, myoinositol, parathyroid hormone, and middle molecules.[2],[6] However, the identification of the putative uremic neurotoxin must take into account that an improvement in MCV is consistent only after renal transplantation.

To study the effect of various common measurable uremic toxins on the electrophysiological parameters, we correlated levels of these toxins in our study population with them. We correlated Cr, BUN, potassium, uric acid, calcium, phosphorus, and parathyroid hormone with CMAP, MCV, SNAP, and SCV of different nerves we tested in uremic patients.

We found that there was significant correlation between Cr and nerve conduction parameters of median, ulnar, peroneal, tibial, and sural nerve. Similarly, on correlating BUN levels of patients with their nerve conduction parameters, we found a significant correlation of peroneal, tibial, ulnar, and median nerve parameters. We also found that there was significant correlation between BUN and SNAP of sural and peroneal nerve.

In review article of KDOQI CKD Guidelines in which author included six studies on the topic, states that below a glomerular filtration rate (GFR) of 8–13 or serum Cr above 7–8 mg/dL, 50% or more patients with decreased kidney function had abnormal NCV. Though studies suggest a correlation between impairment of GFR and NCV in patients with CKD, they do not demonstrate a threshold value of GFR at which NCV is lowered. Levels of urea and Cr have been correlated with reduction of NCV and peripheral manifestations of neuropathy.[7]

In a study done by Di Paolo et al there was a direct correlation of MCV and SCV with decreasing renal function although the compromise of SNCV appeared an earlier phenomenon.[8] In a study done by Sultan, they have also reported a positive correlation between blood urea and serum creatinine and severity of neuropathy.[9] In one excitability study by Krishnan et al in which they found that only other potential toxin (other than potassium) which correlated well with predialysis excitability parameters was urea (TEd40–60 ms, r = 0.86, P =0.01; TEd 90–100 ms, r = 0.76, P = 0.05).[10] In another study done by Tatjana et al, they showed a significant correlation between neurophysiological and biochemical parameters such as Cr, BUN, and potassium, dialysis adequacy.[11]

However, in one study by Stanley et al there was no correlation between peripheral nerve function and blood urea or creatinine levels.[12] Hence, he concluded that it is difficult to relate the changes in nerve function to BUN, Cr, or to serum electrolyte levels, particularly since they are rapidly correcting defects and hence appear to be less effective in causing peripheral nerve damage.[13] In another study by Krishnan et al, found that excitability parameters (changes in threshold electrotonus and super-excitability) correlated strongly with pre-dialysis serum K+ as compared to other parameters like Cr, BUN, calcium, b-2M, and PTH.[14] In our study we found that there was significant correlation of BUN and creatinine with electrophysiological parameters, especially with CMAP and SNAP which were the most commonly involved parameters in cases of uremia. Hence, we concluded that creatinine and urea are contributing toxins in pathogennesis of uremic polyneuropathy. Our findings are consistent with observation made by Di Paolo B et al,[8] Sultan et al,[9] Krishnan et al[10] and Tatjana et al.[11] But our observations are not consistent with findings of by E. Stanley et al[12] and Krishnan.[14]

In a review article Bostock et al had postulated that potassium is a strong contributor of uremic neurotoxicity, and that potassium being a driving force for depolarization of nerve and muscle membranes, chronic persistent hyperkalemia leads to damage to nerves by interfering with ionic homeostasis.[4] Tatjana et al also found a significant correlation between potassium and neurophysiological parameters.[11] In another study by Sultan,[9] they also had significant correlation with potassium level.

On correlating serum potassium level with nerve conduction parameters of the patients, there was no significant correlation. Our findings are against the potassium hypothesis of neurotoxicity which was supported by above mentioned studies, but our findings are consistent with observation of Krishnan et al who found that there was no correlation between parameters from standard NCS with symptom severity or serum K+, though there was significant correlation of serum potassium with excitability parameters in his study.[10]

Purines which are commonly retained in CKD includes uric acid, xanthine, and hypoxanthine. The purines accumulation leads to decreased calcitriol production and increased metabolism seen in CKD patients. Calcitriol is involved in various processes such as myelin genesis and axonal maintenance which is impaired due to low calcitriol levels. Uric acid is a small water-soluble compound; commonly measurable uremic purine toxin. Though uric acid is dialyzable molecule like Cr and BUN; its removal from the intracellular compartment is not efficient. Hence, uric acid which accumulates in uremic serum is important uremic toxin.[15] Hence, we correlated serum uric acid level with neurophysiological parameters, but there was no correlation between them. Hence, we concluded that our observation does not support the hypothesis of uric acid as potential uremic toxin.

Uremia causes increased calcium-phosphorus product predisposing to calcium deposition in soft tissues and, hence, a rise in nerve calcium and it is associated with low serum calcium. Low serum calcium leads to secondary hyperparathyroidism seen in CKD patients. Goldstein et al in their animal study showed that excess PTH is a major determinant underlying the increment in nerve calcium in uremia.[16] Therefore, they hypothesized that prolonged exposure of peripheral nerves to excess PTH may result in accumulation of calcium within the nerve and may cause peripheral neuropathy.[17]

Hence, we correlated calcium level of chronic renal failure patients (mean 8.7 ± 0.82 mg/dL) with nerve conduction study parameters and we found that there was significant negative correlation between serum calcium and CMAP of peroneal nerve (r = -0.59, P = 0.006), ulnar nerve (r = -0.69, P = 0.000). Also, there was significant correlation between calcium and MCV of tibial nerve (r = -0.47, P = 0.036). Other nerve conduction parameters did not correlate with calcium levels. Also, we observed significant correlation between serum phosphorus and CMAP of peroneal nerve (r = 0.44, P = 0.05) and tibial nerve (r = 0.49, P = 0.028). Also, there was significant correlation between phosphorus and SCV of sural nerve (r = 0.47, P = 0.037). Our findings give minimal evidence in support of hypothesis that calcium-phosphorus product predispose to calcium deposition in soft tissues and, hence, a rise in nerve calcium which may be responsible for pathogenesis of neuropathy in uremic patients. Avram et al compared motor conduction velocity with simultaneously measured PTH hormone level.[18] They found that degree of impairment of motor conduction velocity was more in patients with the highest levels of PTH hormone than the group with normal or slightly elevated PTH (P <0.01).[19] We also correlated serum PTH levels of CRF patients (mean 169.12 ± 172.85 pg/mL) with nerve conduction parameters but we did not found any significant correlation between them (P >0.05).

Our findings are consistent with results of Krishnan’s study[10] in which they did not find the correlation between parathyroid hormone and neuropathy. Thus, our findings do not support hypothesis of parathyroid as a potential neurotoxin causing peripheral neuropathy.


   Conclusion Top


Although Cr and BUN are small dialyzable molecules, they correlated well with electrophysiological parameters suggesting their contribution to pathogenesis of neuropathy. Hence, optimum dialysis schedule to keep these uremic toxins in control can decrease morbidity associated with neuropathy in end-stage renal disease patients.

Conflict of interest: None declared.



 
   References Top

1.
Ramírez BV, Gómez PA. Uremic neuropathy: A review. Int J Genet Mol Biol 2012;3:155-60.  Back to cited text no. 1
    
2.
Pan Y, Ramachandran TS. Uremic Neuropathy. Available from: http://emedicine.medscape. com/article/1175425-overview#a0199. [Last updated on 2011 Aug 01].  Back to cited text no. 2
    
3.
Vanholder R, Van Laecke S, Glorieux G. The middle-molecule hypothesis 30 years after: Lost and rediscovered in the universe of uremic toxicity? J Nephrol 2008;21:146-60.  Back to cited text no. 3
    
4.
Bostock H, Walters RJ, Andersen KV, Murray NM, Taube D, Kiernan MC. Has potassium been prematurely discarded as a contributing factor to the development of uraemic neuropathy? Nephrol Dial Transplant 2004;19: 1054-7.  Back to cited text no. 4
    
5.
Janda K, Stompór T, Gryz E, et al. Evaluation of polyneuropathy severity in chronic renal failure patients on continuous ambulatory peritoneal dialysis or on maintenance hemodialysis. Przegl Lek 2007;64:423-30.  Back to cited text no. 5
    
6.
Arnold R, Issar T, Krishnan AV, Pussell BA. Neurological complications in chronic kidney disease. JRSM Cardiovasc Dis 2016;5:2048004016677687.  Back to cited text no. 6
    
7.
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification; Guideline 11. Association of Level of GFR with Neuropathy; 2002. Available from: http://www.kidney.org/ professionals/kdoqi/guidelines_ckd/p6_comp_ g11.htm. [Last accessed on December 2019].  Back to cited text no. 7
    
8.
Di Paolo B, Cappelli P, Spisni C, et al. New Electrophsiological Assessment for the early diagnosis of encephalopathy and peripheral neuropathy in chronic uraemia; Int J Tissue React 1982;4:301-7.  Back to cited text no. 8
    
9.
Sultan LI. Evaluation of the clinical and neurophysiologic parameters of peripheral nerve functions in uremic Egyptian patients. Egypt J Neurol Psychiat Neurosurg 2007;44: 473-87.  Back to cited text no. 9
    
10.
Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Kiernan MC. Sensory nerve excitability and neuropathy in end stage kidney disease. J Neurol Neurosurg Psychiatry 2006;77:548-51.  Back to cited text no. 10
    
11.
Tatjana R, Nikolic J, Ivana R, Dragan M. Registration of polyneuropathy in patients on continuous ambulatory peritoneal dialysis (CAPD). Med Youth 2007;58:67-70.  Back to cited text no. 11
    
12.
Stanley E, Brown JC, Pryor JS. Altered peripheral nerve function resulting from hemodialysis. J Neurol Neurosurg Psychiatry 1977;40:30-43.  Back to cited text no. 12
    
13.
Krishnan AV, Kiernan MC. Uremic neuropathy: Clinical features and new pathophysiological insights. Muscle Nerve 2007;35:273-90.  Back to cited text no. 13
    
14.
Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Bostock H, Kiernan MC. Altered motor nerve excitability in end-stage kidney disease. Brain 2005;128:2164-74.  Back to cited text no. 14
    
15.
Glorieux G, Schepers E, Meert N, Vanholder R. Uraemic toxins in chronic kidney disease. Port J Nephrol Hypert 2008;22:287-302.  Back to cited text no. 15
    
16.
Goldstein DA, Chui LA, Massry SG. Effect of parathyroid hormone and Uremia on peripheral nerve calcium and motor nerve conduction velocity. J. Clin Invest 1978;62:88-93.  Back to cited text no. 16
    
17.
Arnold R, Pussell BA, Pianta TJ, et al. Effects of hemodiafiltration and high flux hemodialysis on nerve excitability in end-stage kidney disease. PLoS One 2013;8:e59055.  Back to cited text no. 17
    
18.
Avram MM, Feinfeld DA, Huatuco AH. Search for the uremic toxin. Decreased motor nerve conduction velocity and elevated parathyroid hormone in uremia; N Engl J Med 1978;298:1000-3.  Back to cited text no. 18
    
19.
Said G. Uremic neuropathy. In: Handbook of Clinical Neurology. Vol. 115. Elsevier, Netherlands;2013. p. 607-12.  Back to cited text no. 19
    

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Correspondence Address:
Parag Aradhey
Department of Neurology, Jawaharlal Nehru Medical College, Sawangi Datta Meghe Institute of Medical Sciences (Deemed to be University) Sawangi (Meghe), Wardha, Maharashra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.344745

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