The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m for 3 or more months. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time [1].

In 2002, K/DOQI published its classification of the stages of chronic kidney disease, as follows:

• Stage1: Kidney damage with normal or increased GFR (>90mL/min/1.73 m) 

• Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

• Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)

• Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m ́)

• Stage 5: Kidney failure (GFR<15 mL/min/1.73 m2 or dialysis)

In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities on imaging studies, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease [6].

The K/DOQI definition and classification of chronic kidney disease allow better communication among physicians and facilitate intervention at the different stages [1-5].

Patients with chronic kidney disease stages 1-3 are generally asymptomatic; clinically manifestations typically appear in stages 4-5 (see Clinical). Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with chronic kidney disease. These may delay, or possibly halt, progression [6-7].

Uremia is considered as one of the secondary acquired causes of autonomic neuropathy, the cause remains unknown, although either accumulated toxins or lack of neurotrophic factors may be responsible [7-9].

Autonomic nervous system links many different parts of the central nervous system (CNS) to each other and makes reflex responses possible to different stimuli. It links the brain to the pituitary and peripherally located endocrine organs through the hypothalamus. It also connects higher brain centers to the cholinergic, nor adrenergic and serotonergic pathways and with other brain stem centers to regulate internal homeostasis [7,11,17].

Autonomic nervous system function impairment in patient with CRF has been documented in many studies using different simple tests to assess the degree of autonomic damage even when it's a symptomatic [12-14]. Uremia is considered as one of the secondary acquired causes of autonomic neuropathy, the cause remains unknown, although either accumulated toxins or lack of neurotrophic factors may be responsible [7-9].

Uremic neuropathy, generally, present with both sympathetic and parasympathetic presentation. The most common symptoms are orthostatic intolerance which represents the most disabling and often the first recognized one. However, other symptoms can occur such as diarrhea especially nocturnal type and sweating abnormalities, [15-16].

Post sepal sweating. Genitourinary symptoms include urinary incontinence, impotence and ejaculatory dysfunction among males [2].

The Aim of the Study

• To verify the presence of autonomic dysfunction among CRF patients in Mosul province

• To verify the autonomic dysfunction among CRF patients in Mosul province with different modalities of management, i.e. chronic hemodialysis, intermittent peritoneal dialysis and conservative management

• To study the pattern of involvement of autonomic nervous system in those patients

Patients and Methods

100 patients from nephrology division at Ibinsenna teaching hospital in Mosul with CRF as determined by their GFR were studied for evaluation of their autonomic nervous system function [15]. Males were 54 patients (59.2%) and females were 46 patients (40.8%). Their ages between 20-50 years the mean was (40+11). Three groups of patients were studied:

• Hemodialysis group: Fifty patients were included in this group (29 males and 21 females) their ages 26-47 with mean of 37+3 and were maintained on hemodialysis program for a period from six months to two years with regular three sessions a week

• Intermittent peritoneal dialysis (IPD) group: This group included 25 patients (17 males and 8 females) they had age range 42-50 years with mean 44.1+1. Patients were maintained on IPD for periods of two weeks to one year

• Conservative management group: 25 patients were included in this group (15 and 10 females) age range 30-50 year with mean 45.2+1.6. Patients were maintained on conservative measures especially protein restriction and one alpha calcidol and calcium for periods range from two months to two years. The above uremic groups were compared to a control group which consisted of 50 age matched healthy individuals (26 males and 24 females) their age range of 25-50 years and mean was 40+12

Exclusion Criteria Were Patients With

• Diabetes mellitus

• Sever hypertension or receiving hypotensive medications

• Cardiac insufficiency

• Cardiac rhythm disturbances

• Amyloidosis

• Mean corpuscular volume >100 fl

• Family history of autonomic neuropathy

• Chemotherapeutic medications and alcohol

• Autonomic disorders with brain involvement

• Autonomic disorders with spinal cord involvement

• Reflex Sympathetic Dystrophy and Causalgia

• Coeliac disease

• History of Diphtheria

• History of connective tissue disease

• Malignancy

Assessment of Parasympathetic Function: HR response to Valsalva maneuver

The Valsalva maneuver consist of four phases:

• Phases 1 (Straining starts): HR decreased due to increased BP

• Phases 2 (Continued straining): BP drops initially because of decreased cardiac output secondary to decreased venous return. Stimulation of baroreceptors, Reflex compensation via sympathetic stimulation so HR increased

• Phase 3 (Release of straining): BP decreases because (essentially reverse of phase 1)HR increased further HR may unchanged because the phase is very brief

• Phase 4 (Continued relief): BP overshoots above the baseline initially because of vasoconstriction baroreceptor inhibited ,reflex vagal stimulation so HR decreased

The individual were asked to blow a tube connected to a mercury sphygmomanometer and maintained the pressure of 40 mm Hg for 15 seconds while the HR was recorded continuously on an ECG paper(normal persons show reflex tachycardia during this maneuver). After 15 seconds the pressure was abruptly released and the ECG recorded for 30 seconds (normal persons show reflex bradycardia after this maneuver).The Valsalva ratio is Minimum heart rate (longest R-R interval) in phase 4 divided by the maximum heart rate (longest R-R interval) in phase 2bradycardia. The ratio reflecting cardio vagal function was calculated by taking longest R-R interval divided by shortest R-R interval during the test as follow. 

Valsalva ratio= the longest R-R interval/ the shortest R-R interval - Valsalva ratio is normally greater than 1.5, impaired autonomic function:<1.5.

HR Response to Deep Breath

The subject sits and asked to take a deep breath evenly at a rate of six breaths per minute with five seconds allocated for each of inspiration and expiration. The shortest R-R interval during inspiration and the longest R-R interval during expiration were measured in a minute then divided by mean of each six respiratory cycle to give the instantaneous HR. The difference between the two HR was taken as a result which is normally >1.5 as shown in Table 1 [5,17-18].

Detection of Sympathetic Dysfunction

Orthostatic Blood Pressure Changes: The B.P was measured using a standard sphygmo- manometer; the diastolic B.P was measured by recording the fifth phase (disappearance of the sound). The B.P was taken while the individual was lying down and two minutes after standing, too. The difference in systolic B.P was taken as the measure of orthostatic B.P change normally<10 mm Hg as determined in Table 1.

Sustained Hand Grip Test

Maximum voluntary contraction was measured first byusing   an   inflated  cuff   of  a sphygmomanometer  as a hand grip dynamiter and the hand grip were then maintained steadily at 30% of the maximum voluntary contraction for as long as possible up to maximum of five minutes. During sustained hand grip, B.P was measured with a sphygmo- manometer on the non-exercising arm with observations.

Made three times of one minute intervals during sustained hand grip and a fourth just before releasing the grip [2-3,10,17]. The response to sustained hand grip was measured as the difference in diastolic B.P between the mean of the rest and three readings and just before releasing the gripas demonstrated in Table 1 [2-3,10,17].

Normally diastolic B.P rise 16 mm Hg in order to minimize the hemodialysis effect on B.P patients were chosen who have been on hemodialysis program for six months or more, in order to alleviate the early hypotensive effect of hemodialysis. Moreover, patients with ultrafiltration had been excluded and the test was done just before the hemodialysis session [2-3,12].

The results of our tests are classified into normal and abnormal Table 1. Mean resting H.R in patients and controls are illustrated in Table 2, the control group had significantly lower resting H.R in contrast to the three uremic groups (chronic hemodialysis group, intermittent peritoneal dialysis (IPD) group and conservative management group) p<0.012. Mean resting B.P in all uremic groups and controls are shown in Table 2. The control groups had significantly lower resting systolic B.P compared to case groups (hemodialysis group, intermittent peritoneal dialysis (IPD) group, and conservative management group) p<0.01.

Regarding the parasympathetic tests 46% of patients on hemodialysis, 48% of patients on intermittent Regarding the parasympathetic tests 46% of patients on hemodialysis, 48% of patients on intermittent peritoneal dialysis (IPD) group and 52% of conservative management group had an impairment of parasympathetic function (Table 3).

Table 1: Normal Value of Autonomic Function Test

The test	Normal	Abnormal
Teast reflecting parasympathetic functions	>1.5	<1.5
A-Valsalva ratio
B-HR response to deep breathing	bet/minute	bet/minute
Test reflecting sympathetic functions	mmHg	mmHg
A-Postural fall in B.P (systolic B.P decrement)
B-Sustained hand grip (diastolic increment)	mmHg	mmHg

Table 2: Clinical Characters of the Cases and the Control Groups

*p **

Table 3: The Frequency of Parasympathetic Impairment in the Study Population

Table 4: The Frequency of Sympathetic Impairment in the Study Population

Table 5: Comparison of Prevalence of Autonomic Neuropathy between the Patients Group and the Control Group

*p0.05 **p0.05

Table 6: Comparison between Sympathetic and Parasympathetic Impairment in Relation to the Method of Management of Uremic Group

*p0.01

Table 7: Comparison of Patients Group and the Control Group with Positive Autonomic Test with the Frequency of Autonomic Symptoms

21% of patients on hemodialysis had positive sympathetic tests (orthostatic hypotension and hand grip tests), 24% of patients on intermittent peritoneal dialysis (IPD) group and 36% of conservatively managed group had sympathetic dysfunction (Table 4).

There were no significant statistical results on comparison among uremic group (hemodialysis group, intermittent peritoneal dialysis (IPD) group and conservative management group) regarding parasympathetic involvement p>0.05 whereas significant were observed when comparing the case groups to control group for parasympathetic impairment (Table 5).

Clearly, significant differences hadn't been observed among case group (hemodialysis group, intermittent peritoneal dialysis (IPD) group and conservative management group), in testing the sympathetic function, while significant difference was noted on comparing autonomic tests (sympathetic and parasympathetic) in both conservative and control group p<0.001 (Table 6).

In addition, significant discrepancy was seen with parasympathetic involvement more obvious than sympathetic involvement when sympathetic and parasympathetic dysfunction were studied in the same group with in the cases i.e.(hemodialysis group, intermittent peritoneal dialysis group, and conservative management group) (Table 6).

No statistical difference had been found between patients with positive autonomic neuropathy and those with negative tests in relation to the age and hemoglobin level (p>0.05).

The frequency of symptoms suggestive of autonomic neuropathy in patients and control group showing that postural dizziness and impotence are the most prevalent s symptoms among case groups and males of the cases consequently (Table 7).

Autonomic neuropathies are a collection of syndromes and diseases affecting the autonomic neurons, either parasympathetic or sympathetic, or both. Most often, they occur in conjunction with a somatic neuropathy, but they can also occur in isolation. Because of lacking of diagnostic test and criteria a reasonably sensitive and specific criterion, we used cardiovascular autonomic reflex tests to provide objective diagnosis of the autonomic nervous system function impairment in uremic patients. This study suggest the damage to the cardiovascular autonomic reflex is wide spread in patients with chronic renal failure which reflects generalized autonomic damage throughout the body [4-7]. The cause of uremic neuropathy remains unknown, although either accumulated toxins or lack of a neurotrophic factor may be responsible because renal transplantation reverses autonomic dysfunction while dialysis does not [7]. Autonomic nervous system is very complicated network; cardiovascular autonomic reflex tests measure the overall cardiovascular autonomic reflex but don't localize lesions to afferent, efferent or central part of reflex arch. Hemodialysis group is the largest sector of the case group; many previous studies in Iraq didn’tinclude them because the hemodialysis effect on B.P [16,19-20] Autonomic nervous system function test are classified into sympathetic and parasympathetic depending on Changes on B.P and H.R or both. This approach had been proved very useful clinically. [17,20] The sympathetic function test included the B.P response to the standing and sustained hand grip. In this study, all case groups had resting systolic and diastolic B.P higher than control group Table 2. This can be due to several factors contributing to hypertension in uremic patients including:

• Local reduction of nitric oxide level within glomeruli causing intraglomerular hypertension

• Defects of other mechanism for hypertension in uremic patients [11,14]

• The results of both sympathetic function tests conclude that abnormalities of sympathetic system in CRF patients are present and this study in agreement with other studies [20]

The parasympathetic function test included the H.R response to the Valsalva maneuver and H.R variation to deep breathing. All case groups were found to have resting H.R higher than control group. Similar finding are also described by other studies. [12-13, 8] This reflects the natural history of cardiovascular autonomic neuropathy in which an early parasympathetic dysfunction may elevate the resting H.R. Results of the H.R provide good evidence for the presence autonomic dysfunction involving the parasympathetic regulation of the heart in uremic patients treated conservatively, with IPD and those on hemodialysis as all have similar degree of parasympathetic dysfunction. Other studies concluded to same results. [12,8,20] Solder et al showed that marked reduction of the R-R interval is a sign of vagal reflex arc dysfunction in uremic patients. In this study, on comparing the sympathetic and parasympathetic dysfunctions, both were present in our patients with evidence of involvement of parasympathetic function to a greater extent than sympathetic functions Table 6 [20]. Similar results were obtained by other studies this explained by the fact that parasympathetic nerves are more liable to metabolic derangement than the sympathetic nerves which may improve by dialysis [12-13,8,20]. Age was not significantly affecting this study because the selected groups are young to middle age spectrum, moreover other studies didn't find statistical significance of the age factor in different groups of patients [19]. Despite the evidence of autonomic damage symptoms suggesting autonomic dysfunction are infrequent apart from impotence in males in case groups which need further evaluation and analysis to exclude other causes related to the disease itself, depression, for example. Although, some of the vague symptoms attributed to uremia may be due to autonomic damage, many other studies focused on symptomatic autonomic neuropathy [5,8,12,20].

The results in this study showed that CRF patients in Mosul province have autonomic neuropathy proved by cardiovascular autonomic reflexes dysfunction. This study concluded that vagal abnormalities were more evident than peripheral sympathetic involvement in uremic patients whether had been managed conservatively, with I.P.D or were on hemodialysis program.

Recommendations

Further studies are needed to coin reasonably sensitive and specific criteria for diagnosing autonomic nervous system impairment beside a reliable severity score of the disease. Other simple tests need to be included in future projects, squatting test to assess the baroreceptor functions, for example. Inclusion of renal transplant patients in the future studies, will clarify the impact of transplantation on over all autonomic function.

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