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Saudi J Kidney Dis Transpl 2012;23(5):1109-1114 2012 Saudi Center for Organ Transplantation

Saudi Journal of Kidney Diseases and Transplantation

Renal Data from Asia Africa

A Retrospective Review of Diabetic Nephropathy Patients During Referral to the Sub-Urban Nephrology Clinic
Rena Menon1, Fariz Safhan Mohd Noor2, Che Rosle Draman3, Mohd Ramli Seman2, Azril Shahreez Abdul Ghani2
1

Hospital Sultan Ahmad Shah, 2Hospital Tengku Ampuan Afzaan, 3International Islamic University Malaysia, Pahang, Malaysia

ABSTRACT. Diabetic nephropathy (DN) has become the most common cause of end-stage renal failure. Early referral and specific nephrology treatment could delay the disease progression and should reduce the treatment cost, mortality and morbidity rate in these patients. This is a single-center, retrospective review of all DN patients referred to the nephrology clinic in Hospital Sultan Ahmad Shah, Temerloh, from 2000 to 2009, to study and define the clinical characteristics of DN patients at the time of the referral to the nephrology clinic. A total of 75 patient case records were reviewed. Forty-three (57.3%) of them were males, with a median age of 64.3 8.5 years at the time of referral. Only 14.7% of them had blood pressure lower than 125/75 mmHg. Co-morbid and disease-related complications were also commonly diagnosed and 28.4% (n = 21) had ischemic heart disease, 23% (n = 17) had diabetic retinopathy and 20.3% (n = 15) had diabetic neuropathy. The mean serum creatinine at the time of referral was 339.8 2.3 mol/L, gylcated hemoglobin A 1c (HbA1C) was 8.1 2.0 %, serum fasting glucose was 9.6 4.7 mmol/L, serum cholesterol was 5.4 1.2 mmol/L and hemoglobin level was 10.6 2.9 g/dL. Although female patients were less frequently seen in the early stages of chronic kidney disease (CKD), they comprised at least 72.7% of CKD stage 5 (male:female; 6:16, P <0.05). Twenty-nine percent (n=22) of them were referred at CKD stage 5, 48% (n=36) were at CKD stage 4, 17.3% (n=13) were at CKD stage 3, 4% (n=3) were at CKD stage 2 and 1.3% (n=1) was at CKD stage 1. Advanced CKD patients were frequently prescribed with more antihypertensives. CKD stage 5 patients were prescribed with two-and-half types of antihypertensive as compared to two types of anti-hypertensive in CKD stage 2 and stage 3. Furthermore, ACE-inhibitors (ACE-I) were less frequently prescribed to them. Only 22.7% (n=5) of CKD stage 5 patients received ACEI and 30% (n=11) in CKD stage 4 patients as compared to 53.4% (n=7) in CKD patients stage 3. This review shows that DN patients were referred late to the nephrologists and the overall disease management was suboptimal. Antihypertensive requirement was also increased and ACEIs were less frequently prescribed in the advanced diabetic nephropathy patients.

Correspondence to: Dr. Che Rosle Bin Draman, Department of Internal Medicine, Kulliyyah of Medicine, International Islamic University Malaysia, P.O. Box 141, Jalan Hospital 25700, Kuantan, Malaysia E-mail: cherosle@gmail.com

Introduction Diabetes mellitus is highly prevalent in Malaysia. According to the Malaysian National Health Morbidity Survey III (NHMS III, 2006), it has increased from 7% to 11.6%.1 The high prevalence rate was due to various socio-economic, dietary and personal factors. Diabetic kidney disease is also the most common cause

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Menon R, Mohd Noor FS, Draman CR, Seman MR, Abdul Ghani AS 75 43:32 64.3 8.5 (range: 4280) 11 (14.7%) 21 (28.4%) 17 (23%) 15 (20.3%) 24 (32%) 5.4 1.2 10.6 2.9 339.8 2.1 9.6 4.7 8.1 2.0

Table 1. Demographic parameters of the study patients. Total Number Sex (M:F) Age (years) Blood pressure <125/75 mmHg Co-morbidities Ischemic heart disease Retinopathy Neuropathy Gout Cholesterol (mmol/L) Hemoglobin (g/L) Creatinine (mcmol/L) Fasting blood sugar (mmo/L) HBA1C (%)

of end-stage renal failure (ESRF) in our population. Our local data revealed that diabetic nephropathy (DN) was the underlying cause in 4550% of dialysis patients.2 In addition to nephropathy, these patients were also frequently diagnosed with diabetic retinopathy and neuropathy. Despite many trials that have shown the clinical benefit of intensified diabetic control, its management remains sub-optimum.3,4 Adequate glucose control prevents diabetic complications and retards its progression. Various medications are currently available for its renoprotective effect, yet their use is still limited. Apart from that, DN patients has high risk for rapid renal function deterioration and various cardio-vascular diseases. Hence, their optimal management approach should include optimal care of co-morbid diseases, such as hypertension and hypercholesterolemia, which will lead to a reduction in cardiovascular event rate. Despite well-controlled glucose level, a large number of them will develop advanced chronic kidney disease (CKD), and unless they are treated early, many will either succumb to cardiovascular disease or require regular dialysis. Unfortunately, most of the diabetic patients are still referred late to nephrologists. This single-center, retrospective review of DN patients referred to the nephrology clinic in one of the sub-urban, public hospitals was aimed to study and define the clinical characteristics of the patients during their referral. Overall management of the co-morbid diseases

was also reviewed. Materials and Methods This is a single-center, retrospective review of all DN patients who were referred to the Nephrology Clinic, Hospital Sultan Ahmad Shah, Temerloh, from 2000 to 2009. The demographic, clinical and laboratory data were extracted from patient clinical notes. Their comorbid and other diabetes-related conditions were also recorded. Blood pressure less than 130/80 mmHg during the visit was considered optimal. The optimal blood glucose and cholesterol levels were defined according to the local guidelines. Their glomerular filtration rate was then estimated according to the CockroftGault formula. The stage of CKD of each patient was then classified according to the NKFKDOQI classification system. Antihypertensive prescriptions, especially with ACE-inhibitor, were identified for each patient. All the data were recorded and analyzed using SPSS ver. 17.0. Continuous variables were analyzed using the Student T test or MannWhitney U test, and categorical variables were analyzed. with the chi-square test. P-values less than 0.05 were considered significant. Results A total of 75 patients were reviewed (Table 1). Forty-three of them were males and 32 were females. Their mean age was 64.3 8.5 years,

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Diabetic nephropathy patients in the sub-urban nephrology clinic

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Figure 1. Distribution of the study patients according to their CKD stages.

and ranged from 42 to 80 years. Only a few patients (14.7%) had blood pressure less than 125/75 mmHg. Co-morbid illnesses and diseaserelated complications were frequently found during the referral, and 32% (n = 24) had hyperuricemia, 28.4% (n = 21) had ischemic heart disease, 23% (n = 17) had diabetic retinopathy and 20.3% (n = 15) had diabetic neuropathy. At the time of the visit, serum creatinine was 339.8 2.3 mol/L and glycated hemoglobin (HbA1c) was 8.3 2.0%, with fasting blood glucose of 9.6 4.7 mmol/L. Their hemoglobin was 10.6 2.9 g/dL and the total cholesterol was 5.5 1.3 mmol/L.

As noted in Figure 1, at the time of referral, 1.3% (n = 1) had CKD stage 1, 4% (n = 3) had CKD stage 2, 17.3% (n = 13) had CKD stage 3, 48% (n = 36) had CKD stage 4 and 29.3% (n = 22) had CKD stage 5. Among those with CKD stage 3 and stage 4 (n = 49), males outnumbered females with a 2:1 ratio. In contrast, 72.7% of the CKD stage 5 patients (n = 22) were females (Figure 2, P <0.05). Regardless of their CKD stage, the HbA1c and fasting blood sugar levels were not significantly different. CKD stage 1 to stage 3 patients had HbA1c and FBS of 7.8% and 9.8 mmol/L and CKD stage 4 and stage 5 patients had HbA1c and FBS of 7.8% and 9.7 mmol/L

Figure 2. Distribution of study patients according to their CKD stages and gender. Total patients = 75

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Menon R, Mohd Noor FS, Draman CR, Seman MR, Abdul Ghani AS

Figure 3. The use of antihypertensive medications in the study patients (mean).

(P = NS), respectively. More antihypertensives were prescribed to those patients with advanced CKD. The CKD stage 2 and stage 3 patients required at least two anti-hypertensive drugs as compared with two or more in CKD patients of stage 5 (Figure 3). They were also infrequently prescribed with angiotensin-converting enzyme inhibitors (ACEi). Only 22.7% (n = 5) of CKD stage 5 patients received ACEi and 30% CKD stage 4 patients received ACEi (n = 11) as compared with 53.4% patients (n = 7) in CKD stage 3(Figure 4).

Discussion DN patients comprised at least one-third of all patients attending the nephrology clinics. However, it has become the most common cause of ESRF among dialysis-dependent patients in Malaysia. Many guidelines are available, yet DN patients were frequently referred late.5-7 Recently updated local guidelines indicated that DN patients with serum creatinine at least 200 mol/L should be referred to the nephrologist. Yet, our patients were seen in the clinic with creatinine of 339.8 mol/L, far

Figure 4. The use of angiotensin-converting inhibitors in the study patients according to the CKD stages.

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beyond the stated level. In fact, 77.3% of them had CKD stage 4 and stage 5. Various reasons for the late referral were identified and include lack of awareness on the disease progression, some stayed far away from the hospital and the wide hospital catchment area worsened the situation. Late referral to the nephrology clinic is common. The NECOSAD study group also found that at least one-third of their patients, both diabetic and non-diabetic, were referred late.8 The European countries, USA, Australia and South America had estimated its frequency in their patients since 1996, and at least 30% were late referrals and it was associated with higher mortality, morbidity and treatment cost.9 Despite the diagnosis of diabetes mellitus, our patients were still inadequately managed. Their HbA1c level was 8.1%, while the Malaysia guideline regarded 6.5% as the optimal level. Further analysis revealed that diabetic control in our patients was not significantly different between the CKD stages. Overall nutritional state, dietary intake and their clinical status were among the important reasons underlying the finding. Presently, many clinical trials are available to demonstrate the benefit of strict glucose control and stabilization or even reversal of DN.10,11 A post hoc analysis of RENAAL study patients also clearly demonstrated that an intensified treatment protocol prevents diabetic kidney disease progression. In the study, those patients who had an intensive and well-structured care experienced slower disease progression rate regardless of their treatment group. Further extrapolation of the study findings estimated that these patients might delay their dialysis by 16.5100.8 months after recruitment.12 Apart from that, our patients co-morbid illnesses were under-treated, especially their blood pressure and serum lipid levels, which were far beyond the acceptable target. Numerous evidences are currently available to demonstrate that DN patients were at the highest risk for any cardiovascular event. Hence, their blood pressure, glucose and lipid levels should

be aggressively treated. The STENO 2 group had demonstrated that a well-controlled blood pressure, HbA1c, cholesterol, triglyceride and frequent use of ACEi and aspirin reduced the risk for cardiovascular disease by 53%, DN by 61%, retinopathy by 58% and autonomic neuropathy by 63%.13 Not only that, a preliminary report from SHARP trial group concluded that lipid treatment in ESRF patients was associated with better outcomes. Unfortunately, only 14.7% of our newly referred patients achieved optimal blood pressure control, and their cholesterol level was also beyond the target. As noted in this study, advanced CKD patients required more antihypertensives compared with their counterparts. The CKD stage 5 patients required at least two and half (2.5) types of antihypertensives, whereas CKD stage 2 and stage 3 patients required two (2). Treatment with ACEi was also limited due to the concern of hyperkalemia and worsening serum creatinine, especially in advanced diabetic kidney disease patients. These concerns are sometimes true, but are probably over-emphasized. To our surprise, these patients had an adequate hemoglobin level during the referral. Their mean hemoglobin was at least 10 g/dL, and many studies in both dialysis-dependent and non- dialysis dependent patients showed that normalization of the hemoglobin was not required. In fact, normalization of hemoglobin level could increase the risks for cardiovascular events.14,15 This review was adversely affected by some limitations. Limited number of patients and retrospective review of clinical data may be predisposed to selection bias, and some of the data were unavailable for detailed review. The patients were not truly representative of the general population as some of the early referrals were not recorded properly and even discharged early. However, this study demonstrated that our diabetic patients were referred late. Not only that, their co-morbid diseases were not optimally managed and ACEi were less frequently prescribed due to some clinical concerns. Therefore, we strongly recommend that the doctors should establish early contact with the nephro-

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Menon R, Mohd Noor FS, Draman CR, Seman MR, Abdul Ghani AS 8. de Jager DJ, Voormolen N, Krediet RT, Dekker FW, Boeschoten EW, Grootendorst DC. Association between time of referral and survival in the first year of dialysis in diabetics and the elderly. Nephrol Dial Transplant 2011;26:6528. Ben S, Pieter E, Yves V. Late referral of patients with chronic kidney disease: No time to waste. Mayo Clin Proc 2006;81:1487-94. Hans-Henrik P, Hendrik L, Jens B, Ramon G, Steen A, Peter A. For the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group (IRMA-2): The Effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8. Edmund JL, Lawrence GH, William RC, et al. For the Collaborative Study Group (IDNT): Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60. Keane WF, Zhang Z, Lyle PA, et al. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: The RENAAL Study. Clin J Am Soc Nephrol 2006;1:761-7. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: 383-93. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:208598. Tilman BD, Francesco L, Naomi C, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-84.

logist and timely refer them. Their co-morbid illnesses should be aggressively treated and use of ACEi and other RAAS blockade drugs should be the standard practice, and frequent review of these patients for any adverse event is mandatory. References

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10. 1. Letchuman GR, Wan Nazaimoon WM, Wan Mohamad WB, et al. Prevalence of Diabetes in the Malaysian National Health Morbidity Survey III, 2006. Med J Malaysia 2010;65: 173-9. Lim YN, Lim TO. 16th Report of The Malaysian Dialysis and Transplant Registry 2008. National Renal Registry, April 2009. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. The Diabetic Control and Complications Trial Research Group: The effect of intensive treatment of diabetic on the development and progression of long term complications in insulindependent diabetes mellitus. N Engl J Med 1993;329:977-86. Malaysian Ministry of Health Guidelines: Management of Type 2 diabetes mellitus (4th ed). 2009. ADA Clinical Practice Recommendations: Standards of Medical Care in Diabetes. Diabetes Care 2009;33(Supplement 1):S1-2. Oussama MN Khatib. Guidelines for the prevention, management and care of diabetes mellitus (EMRO Technical Publication). WHO, Regional Office for the Easter Mediterranean. October 1, 2006.

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