Hemodialysis Induced Hypoglycemia in Chronic Kidney Disease Patients

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1 ORIGINAL ARTICLE Jan 01 / Vol / Issue 1 Hemodialysis Induced Hypoglycemia in Chronic Kidney Disease Patients 1 Rajesh Khyalappa, Shrikant Devdikar 1 Professor,Post Graduate ; Dept. of Medicine D.Y Patil University's,D Y Patil Medical College, Kolhapur. Abstract A prospective and comparative study was conducted on hundred subjects selected from the patients coming to the dialysis unit, eligible & willing for the study, divided in to two groups of diabetic & non-diabetic (fifty each). Quantitative data like BSL and DSL values were calculated and analyzed along with the Qualitative data like symptoms on hypoglycemia and compared interchangeably with both groups at specific intervals of time. 46/100 subjects showed hypoglycemia (7 diabetics, 19 non-diabetics), out of which, 1/46 (11 diabetics, 1 non-diabetic) had symptomatic hypoglycemia, whereas, 34/46 (16 diabetics, 18 non-diabetics) had asymptomatic or occult. Subsequently, the dialysate sugars also showed a statistically significant rise, in both the groups, as the blood sugar levels went down. All this concluding, quantitatively, that the fall in BSL values in diabetics & non-diabetics, was statistically significant in the first half of dialysis i.e. 90mins from the start of dialysis (z = 3.58, p< 0.05 for 30mins & z = 4.9, p<0.05 for 90mins in diabetics & z = 5.6, p< 0.05 for 30mins & z = 6.14, p<0.05 for 90mins in non-diabetics), whereas even if the fall was n't significant statistically in the latter half of dialysis i.e. after 90mins & in post dialysis samples (z = 0.96, p>0.05 in diabetics & z = 1.03, p>0.05 in non-diabetics), it indicated a rise in the BSL, suggestive of recovery from hypoglycemia in diabetic subjects. Quantitatively, the difference in distribution of diabetes & non-diabetes according to the presence or absence of symptoms was statistically significant (x = 5.55, p<0.05), probably suggesting that patients undergoing dialysis should be given mid-dialysis snack to avoid hypoglycemia and it's complications, insulin doses should be adjusted as per dialysis scheduled days & possibility of glucose containing dialysate solution should be explored. Keywords: Hemodialysis, hypoglycemia, chronic kidney disease, diabetic renal disease. INTRODUCTION The kidney plays an important role in glucose homeoeostasis, in addition to metabolising 30-40% of insulin, it provides up to 45% of endogenous glucose through gluconeogenesis during a prolonged fast. In chronic kidney disease (CKD), the kidney cannot metabolise insulin or generate glucose, thereby 1, increasing the risk of hypoglycemia. In this scenario, the risk of hypoglycemia gets highest on dialysis days, 3 than on non-dialysis days, as glucose is lost through 4,6 dialysis. This in turn signifies that CKDs landing into hypoglycemia is an early occult marker of multi system failure. Hence, early screening and appropriate therapeutic interventions can prevent morbiditymortality of this vast engulfing giant. *Author Correspondence: Dr Rajesh Khyalappa, Professor of Medicine, Dr DY Patil Hospital and Research Institute, Kadamwadi, Kolhapur , Maharashtra * khyalappa@gmail.com The present study was designed to assess the effect of hemodialysis (HD) on plasma & dialytic glucose. Blood and dialysate fluid were sampled at regular intervals. We conducted a prospective comparative study that included one hundred patients who were undergoing maintenance HD. The frequency of symptomatic hypoglycemic episodes were recorded, by analyzing the intra-dialytic glycemic patterns of the diabetic CKD patients, we compared them with that of a nondiabetic CKD pattern. Fall in plasma glucose may not have been considered to be clinically relevant in daily practice because despite the patients were hypoglycemic, they did not show symptoms of 4,5 hypoglycemia, may be because of blunting of counter regulatory hormones in CKD which act to guard hypoglycemia or the brain glucose uptake continued to be same despite the body suffered from 7 hypoglycemia. Various studies across the world using similar parameters, have collected a good amount of data, but RGUHS J Med Sciences, January 01 / Vol / Issue 1 5

2 taking into consideration the nourishment, cultural & socio-economic status of the Indian CKDs, that data is more, to form any helpful guideline to the Indian CKD family. Hence, new guidelines can be formed looking at the Indian scenario of CKD with respect to their food intake on dialysis & non-dialysis days & insulin doses on dialysis days as per individual patient s needs. This study was conducted to analyse the occurrence of hypoglycemia in patients of chronic kidney disease on maintenance hemodialysis; with simple, cheap, noninvasive tests of BSL & DSL in patients coming regularly to Dialysis Unit; also aiming to study & compare the occurrence of hypoglycemia on hemodialysis between DM & NDM subjects. Review of Literature CKD The Global Impact: Data from United States suggests that for every patient with ESRD there are more than 00 patients with overt CKD in stage 3 and 4 and almost 5000 patients with covert renal 8 disease (stage 1 and ). But, none of the studies of this sort have taken place here in India to conclude regarding covert CKD stages. The National Health and Nutrition Examination Survey (NHANES III) in a population based survey in USA estimated that 11% of 9 the adult population may have some stage of CKD. The HOORN study showed that renal impairment was directly associated with cardiovascular mortality in 10 the general population. The Indian CKD patient: It is estimated that 1,00,000 new patients of stage 5 CKD enter renal 11. replacement programs annually in India In an initial 1, survey conducted by Mani et al in the rural population of Chennai from South India, the evidence of CKD short of renal failure was 0.7%. In a population based study from Bhopal in Central India, 13 Modi et al have reported the average crude and age adjusted incidence rates of stage 5 CKD as 151 and 3 per million populations. In a community based 14 study by Agarwal et al, from Delhi in Northern India the prevalence of earlier stages of CKD was reported 10 to be 785 per million populations. Glomerular filtration rate (GFR) in southern Indian population are consistent with the general belief that the normal 19 ranges of GFR may be lower in Indian subjects. In an Indian study, ESRD incidence was estimated for four consecutive calendar years (00 005) among 5,7,09 subjects residing in 36 of the 56 wards of the city of Bhopal. The mean age was 47 years, and 58% were males. Diabetic nephropathy was the commonest (44%) cause of ESRD. This study provided the first population-based ESRD incidence data from India and revealed it to be higher than previously estimated. Diabetic nephropathy was the leading cause of stage 5 15 CKD. The Indian CKD patient will thus pose a need for an upcoming National program for prevention, control & detection of covert CKD under the Government of India, leading to an urgent need to provide nationwide improvement of facilities for RRT. Hypoglycemia on hemodialysis is very frequently observed but less attended complication occurring in every center. There are various complex mechanisms, such that the kidneys help to metabolise 30-40% endogenous insulin and help in gluconeogenesis, both of which act to guard against hypoglycemia. As features like gluconeogenesis and insulin metabolism lag behind in CKD patients, the possibilities of hypoglycemia increases. On the other hand, as the brain uptake of glucose even in a hypoglycemic state remains the same hence unawareness of hypoglycemia takes place (occult hypoglycemia), leading to neuroglycopenic symptoms, further deteriorating the neurological state, subjecting him into uremia. Diabetic Nephropathy in an Indian context is one of the leading causes of chronic renal failure in India. It has been reported that among 4837 patients with chronic renal failure seen over a period of 10 years, the prevalence of diabetic nephropathy was 30.3% followed by chronic interstitial nephritis (3.0%) and chronic glomerulonephritis (17.7%). MODY refers to a type of non-insulin dependent diabetes in which the patients develop diabetes at <5 years of age and have clinical characteristics similar to type diabetes. The prevalence of MODY in a cohort of 4560 patients was found to be 4.8% in South India 17. RGUHS J Med Sciences, January 01 / Vol / Issue 1 6

3 A comparison of sibling pairs showed strong familial clustering of diabetic nephropathy in patients with type diabetes in South India. Two groups of diabetic siblings of type diabetic patients matched for age, body mass index and duration of diabetes mellitus were studied. In one group, siblings of probands with diabetic nephropathy were included. The other group c o m p r i s e d s i b l i n g s o f p r o b a n d s w i t h normoalbuminuria. It was found that proteinuria was present in 50% and microalbuminuria in 6.7% of the siblings of probands with diabetic nephropathy. In contrast, the prevalence of proteinuria and microalbuminuria among siblings of probands with 16 normoalbuminuria was 0% and 3.3% respectively. Hypoglycemia A review Hypoglycemia is most convincingly documented by the Whipple's triad Symptoms consistent with hypoglycemia, a low plasma glucose concentration measured with a precise method (not a glucose monitor) & relief of the symptoms after the plasma glucose level is raised. The lower limit of the fasting plasma glucose concentration is normally approximately 70 mg/dl (3.9 mmol/l), but substantially lower venous glucose levels occur normally, late after a meal. Glucose levels less than 55 mg/dl (3.0 mmol/l) with symptoms that are relieved promptly after the glucose level is raised document hypoglycemia. Hypoglycemia in Renal failure patients Among hospitalized patients, serious illnesses such as renal, hepatic, or cardiac failure, sepsis, and inanition are second only to drugs as causes of hypoglycemia. Although the kidneys are a source of glucose production, hypoglycemia in patients with renal failure is also caused by the reduced clearance of insulin and reduced mobilization of gluconeogenic precursors in renal failure. Sepsis is a relatively common cause of hypoglycemia. Increased glucose utilization is induced by cytokine production in macrophage-rich tissues such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace. Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia. Hypoglycemia is the most frequent complication of diabetes, affecting 10% to 5% of diabetic patients at least once a year and accounting for 3% to 4% of deaths in those treated with insulin therapy. In this scenario, hypoglycemia affects 67% of diabetic 18 patients - with renal failure. Diabetic renal disease is a common complication and is the most prevalent cause of end stage renal disease, as the kidney plays an important role in glucose 6 homeoeostasis. Its occurrence is often a marker of multisystem failure and has an ominous prognostic implication. When no obvious cause can be demonstrated, the hypoglycemia is referred to as spontaneous. Spontaneous uremic hypoglycemia has been attributed to deficiency of precursors of gluconeogenesis, that is, alanine, deficient gluconeogenesis, impaired glycogenolysis, diminished renal gluconeogenesis and impaired renal insulin degradation and clearance, poor nutrition, and, in a f e w c a s e s, d e f i c i e n c y i n a n i m m e d i ate counterregulatory hormone such as catecholamine and glucagon. However, the mechanism(s) seems to differ from one patient to the other. Also, hypoglycemia exhibits changes in mental or neurologic status. Glucose values are significantly lower on dialysis days than on nondialysis days despite similar energy intake. The risk of asymptomatic hypoglycemia is highest within 4 h of dialysis. Glucose is lost in dialytic fluid leaving the dialyser in significantly lower amounts when using glucose-added solution than glucose-free solution. Aim: Study of hemodialysis induced hypoglycemia in CKD. Objectives: To evaluate occurrence of hypoglycemia in diabetic and non-diabetic CKD patients on hemodialysis, by monitoring their glucose levels in blood & dialysate at fixed intervals. Material This is a prospective and comparative study involving hundred CKD patients regularly coming for maintenance HD at Dialysis Unit. Data collection was completed by April 011 in a period of 4 months. Informed consent in Marathi (local language) was taken from all the individuals participating in the study. RGUHS J Med Sciences, January 01 / Vol / Issue 1 7

4 Criteria for subject selection: Inclusion: Age 18 years, Sex Both, Ability to read and understand and give informed consent, CKD Stage V. Exclusion: Antibiotics-dependent infection during 8 weeks preceding enrollment, Concomitant Liver Disease. Methodology & Study plan A prospective & comparative study was conducted hundred subjects selected from the patients coming to the dialysis unit, eligible & willing for the study, divided in two groups of diabetic and non-diabetic (fifty each). The blood sugar levels and dialysate levels at start of dialysis, following consecutively at 30mins, 90mins and post dialysis were analyzed in both groups. The frequency of symptomatic and asymptomatic hypoglycemic episodes was recorded in both the groups. Comparison was done between diabetic and non-diabetic blood sugars as well as dialysate fluids at each interval consecutively. This was done by non-invasive methods. Patient's BSL taken from the outlet just immediate (red arterial line) after the patient's body access for dialysis, avoiding recurrent & uncomfortable pricks to the patient. Dialysate glucose was analyzed at similar intervals, in a laboratory setting with GOD-POD method (light photometric method). Statistical Analysis: The standard error of difference between two means (Z test/relative deviate) was used for Quantitative data. x (chi-square) test was used for testing the significance of difference between proportions. Statistical significance was set at P < Yate's correction was applied in distribution of subjects according to their symptoms, as x test couldn't be applied directly because expected value was <5. RESULTS There was significant rise in the dialysate sugar levels & a fall in the blood sugar levels in both the groups as dialysis progressed. Diabetic subjects were seen to be more prone for development of hypoglycemia (58.69%), whereas, non-diabetic subjects had a lesser tendency (41.30%), also showing more neuroglycopenic symptoms towards hypoglycemia (40.74%) than the non-diabetics (05.3%). Though symptomatic hypoglycemia was seen more frequently in diabetic patients (91.66%) compared to nondiabetics (08.33%), occult hypoglycemia was more in non-diabetics (5.94%) along with lesser recovery from hypoglycemia (30.76%) with comparison to diabetics (47.05%) who also showed a better recovery from hypoglycemia (69.3%). The fall in BSL values in diabetics & non-diabetics, was statistically significant in the first half of dialysis i.e. 90mins from the start of dialysis (z = 3.58, p< 0.05 for 30mins & z = 4.9, p<0.05 for 90mins in diabetics & z = 5.6, p< 0.05 for 30mins & z = 6.14, p<0.05 for 90mins in nondiabetics), whereas even if the fall wasn't significant statistically in the latter half of dialysis i.e. after 90mins & in post dialysis samples (z = 0.96, p>0.05 in diabetics & z = 1.03, p>0.05 in non-diabetics), it indicated a rise in the BSL, suggestive of recovery from hypoglycemia in diabetic subjects. The rise in Mean DSL values compared in diabetics & non-diabetics were statistically highly significant throughout the dialysis session i.e. sample values at 30, 90 & post-dialysis (z = 13.76, z = 14.93, z = respectively, with p < in all). Of the 7 diabetic subjects, 11 (40.7%) reported symptoms while the remaining 16 (59.3%) did not have any symptoms. Among the non-diabetics, only 1 (5.3%) subject had symptoms while the remaining majority i.e. 18 (94.7%) did not report any symptoms (x = 5.55, p <0.05). This difference in the distribution of diabetes & nondiabetes according to the presence or absence of symptoms was statistically significant (x = 5.55, p<0.05). Chart 1 Sex distribution RGUHS J Med Sciences, January 01 / Vol / Issue 1 8

Chart Age Sex distribution Chart 3 Age & Diabetic Non-diabetic distribution We observed 3 types of trends by analyzing the blood sugar levels at

Recovered hypoglycemics: Show a steep fall in the BSL initially, following a plateau later, finally followed by a rise (8.

Non-hypoglycemics: Show a fluctuation in BSL at various times (mostly depending on the baseline levels), but never go below the hypoglycemic

Distribution according to sex & diabetic non-diabetics [x test cannot be applied directly because expected value is <5, hence Yate's correction

7%) reported symptoms while the remaining 16 (59.3%) did not have any symptoms. Among the non-diabetics, only 1 (5.

5 Chart Age Sex distribution Chart 3 Age & Diabetic Non-diabetic distribution We observed 3 types of trends by analyzing the blood sugar levels at fixed intervals of time i.e. pre-dialysis (I), 30mins (II), 90mins (III) & post-dialysis (IV). Recovered hypoglycemics: Show a steep fall in the BSL initially, following a plateau later, finally followed by a rise (8.6%) Non-recovered hypoglycemics: Show a gradual fall in the BSL throughout, not followed by any rise (71.73%). Non-hypoglycemics: Show a fluctuation in BSL at various times (mostly depending on the baseline levels), but never go below the hypoglycemic cutoff, and may even show a rise in final samples (54%) Chart 6 Distribution of patients according to symptoms Chart 4 Total hypoglycemic Distribution according to sex & diabetic non-diabetics [x test cannot be applied directly because expected value is <5, hence Yate's correction has been applied] Chart 5 General Glycemic trends on hemodialysis x = 5.55, p < 0.05 Of the 7 diabetic subjects, 11 (40.7%) reported symptoms while the remaining 16 (59.3%) did not have any symptoms. Among the non-diabetics, only 1 (5.3%) subject had symptoms while the remaining majority i.e. 18 (94.7%) did not report any symptoms (x = 5.55, p <0.05). This difference in the distribution of diabetes & nondiabetes according to the presence or absence of symptoms was statistically significant (x = 5.55, p<0.05). RGUHS J Med Sciences, January 01 / Vol / Issue 1 9

Chart 7 Hypoglycemia among recovered & non-recovered x = 0.8, p>0.05 Of the 7 diabetic patients, 9 (33.3%) recovered while remaining 18 (16.7%) patients didn't recover.

Apparently, recovery rate was better in diabetics as compared to non-diabetics, however this difference in the recovery among the two groups was not statistically significant Chart 8: Comparison of

05 The mean BSL 3 & BSL 4 (at 90mins & post-dialysis) of DM patients was 89.95 mg% with a SD of 49.96 mg%, while that of the NDM group was 79.9 mg% with a SD of 7.3 mg%.

Chart 9 Comparison of DSL levels Diabetics v/s Non-diabetics Mean DSL values were highly significantly higher in comparison with both the groups.

6 Chart 7 Hypoglycemia among recovered & non-recovered x = 0.8, p>0.05 Of the 7 diabetic patients, 9 (33.3%) recovered while remaining 18 (16.7%) patients didn't recover. Among the non-diabetics, only 4 (%) out of 19 recovered while remaining 15 didn't. Apparently, recovery rate was better in diabetics as compared to non-diabetics, however this difference in the recovery among the two groups was not statistically significant Chart 8: Comparison of BSL levels: Diabetics v/s Non-diabetics values of DM group were higher than the NDM group, This difference was however not significant statistically. z = 1.3, p>0.05 & z = 1.75, p>0.05 The mean BSL 3 & BSL 4 (at 90mins & post-dialysis) of DM patients was mg% with a SD of mg%, while that of the NDM group was 79.9 mg% with a SD of 7.3 mg%. Although, apparently the mean BSL3 & 4 among the DM group was higher than the NDM counterpart, this difference failed to reach the critical level of statistically significance. Chart 9 Comparison of DSL levels Diabetics v/s Non-diabetics Mean DSL values were highly significantly higher in comparison with both the groups. DSL 1 DSL DSL 3 DSL 4 DM NDM DM NDM DM NDM DM NDM Mean DSL SD (BSL I pre-dialysis, BSL at 30mins, BSL 3 at 90mins & BSL 4 post-dialysis) z =.1, p<0.05 The mean BSL 1 (pre dialysis) of diabetic (DM) patients was mg% with a standard deviation (SD) of mg%, while that of the non-diabetic group (NDM) was mg% with a SD of mg%. This difference in the baseline (pre dialysis) BSL levels between two groups was statistically significant. z = 1.64, p>0.05 Although, apparently the mean BSL (at 30mins) Chart 10 Comparison of Intra-dialytic glucose fluctuations a. Diabetic subjects b. Non-diabetic subjects RGUHS J Med Sciences, January 01 / Vol / Issue 1 10

Chart 9 Comparison of DSL levels Diabetics v/s Non-diabetics CONCLUSION Hypoglycemia on hemodialysis was seen both in diabetic & non-diabetic CKD patients.

7 Chart 9 Comparison of DSL levels Diabetics v/s Non-diabetics CONCLUSION Hypoglycemia on hemodialysis was seen both in diabetic & non-diabetic CKD patients. Diabetic CKD subjects were more prone for hypoglycemia with neuroglcopenic symptoms 3. Occult hypoglycemia was seen in both groups, but non-diabetics showed more occult hypoglycemia & lesser chances of recovery. Probable suggestions of the study: 1. Patients undergoing dialysis should be given mid-dialysis snack to avoid hypoglycemia & its complications. Insulin doses should be adjusted as per dialysis scheduled days 3. Possibility of glucose containing dialysate solution should be explored. REFERENCES 1. Haviv YS, Sharkia M, Safadi R Hypoglicemia in patients with renal failure. Ren Fail000;: Arem R Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am 1989;18: Loipl J, Schmekal B, Biesenbach G. Long-term impact of chronic hemodialysis on glycemic control and serum lipids in insulin-treated type -diabetic patients. Ren Fail 005; 7: Jackson MA, Holland MR, Nicholas J, et al. Occult hypoglycemia caused by hemodialysis. Clin Nephrol 1999;51: Akmal M. Hemodialysis in diabetic patients. Am J Kidney Dis001;38:S195-S Takahashi A, Kubota T, Shibahara N, et al. The mechanism of hypoglycemia caused by hemodialysis. Clin Nephrol 004;6: Patrick J. Boyle, M.D., Scott F. Kempers, B.A., Annem. O'Connor, B.S.N., Roger J. Nagy, B.S. Brain glucose uptake and unawareness of hypoglycemia in patients with insulindependent diabetes mellitus N Engl J Med 1995;333: Udayakumar N. Chronic kidney disease in India: From a resident physician's perspective. Postgrad Med J 006; 8: Coresh J, Ashor BC. Prevalence of chronic kidney disease and decreased kidney function in adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 003; 41: Narula AS. Chronic Kidney Disease: The Looming Threat. MJAFI 008; 64 : Kher V. End stage renal disease in developing countries. Kidney Int 00;6: Mani KM. Prevention of chronic renal failure at the community level. Kidney Int 003; 63: Modi GK, Jha V. The incidence of end-stage renal disease in India: A population-based study. J Internat Soc Nephrol 006;70; Agarwal SK, Dash SC, Mohammad I, Sreebhuasn R, Singh R, Pandy RM. Prevalence of chronic renal failure in adults in Delhi, India. Nephrology Dial Transplantation 005; 0: Modi GK, Jha V, The incidence of end-stage renal disease in India: A population-based study ESRD incidence in India Kidney International 70, Viswanathan V.Type diabetes and diabetic nephropathy in India magnitude of the problem Nephrol. Dial. Transplant. 1999: 14 (1): Mohan V, Ramachandran A, Snehalatha C et al. High prevalence of Maturity onset Diabetes of the young (MODY) among Indians. Diabetes Care 1985; 8: Sherwin RS. Diabetes mellitus. In: Goldman L, Bennett JC, eds. Cecil textbook of medicine. 1st ed. Philadelphia, PA: Saunders, 000: Shyam C, Sreenivas V, Dakshinamurty KV. Chronic kidney disease Indian J Med Res 007:16, 485 RGUHS J Med Sciences, January 01 / Vol / Issue 1 11

Glucose-added dialysis fluid prevents asymptomatic hypoglycaemia in regular haemodialysis

Nephrol Dial Transplant (2007) 22: 1184 1189 doi:10.1093/ndt/gfl710 Advance Access publication 1 February 2007 Original Article Glucose-added dialysis fluid prevents asymptomatic hypoglycaemia in regular