Nephropathy and Retinopathy in Type 2 Diabetic Patients Living at Moderately High Altitude and Sea Level

Abstract

Background: High-altitude-induced hypoxia results in various diseases, such as chronic mountain sickness and high altitude retinal edema, and may affect severity and incidence of some cardiovascular diseases. In order to evaluate the effects of moderately high altitude on diabetic nephropathy and retinopathy, a cross-sectional study was planned. Material Method: Long-term type II diabetic residents of sea level (n = 75, 38 male, 37 female, mean age 51.9 ± 10.5 in Trabzon and Zonguldak cities) and moderately high altitude (h = 1,727 m, n = 73, 28 male, 45 female, mean age 48.3 ± 12.1, Van city) were compared. Results: No difference was observed in terms of age, gender, diabetes duration, body mass index, smoking, systolic, diastolic, and mean arterial blood pressure values, serum glucose levels, cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, hemoglobin, HbA1C, hypertension control, or blood pressure medications and retinopathy incidence. Mean 24 h protein excretion (210.0 ± 139.9, 127.8 ± 112.1 mg; P = 0.00), proteinuria prevalence (57.5% versus 33.3%, p = 0.003), and serum creatinine levels (1.04 ± 0.22 versus 0.84 ± 0.21, p = 0.00) were significantly higher in the highlanders, glomerular filtration rate (GFR) was significantly lower in sea level (SL) patients (90.9 ± 26.5 versus 83 ± 21.1, p = 0.05). Conclusion: Tendency to diabetic nephropathy as indicated by higher proteinuria and creatinine levels is increased among type 2 diabetic patients living at moderately high altitude. Prospective studies are needed to confirm these findings.

• Diabetes mellitus
• High altitude
• Proteinuria
• Retinopathy
• Diabetic nephropathy

Introduction

Diabetes is prevalent worldwide, and its incidence is increasing. Nephropathy is the diabetes-specific complication associated with the greatest mortality. Retinopathy due to diabetes is the leading cause of blindness in the world.[1] Chronic exposure to high altitude (HA) (definedas > 1500 m) causes a compensatory erythropoietin-induced increase in red blood cell mass, secondary to hypoxia. Some patients exhibit a variety of symptoms and signs, such as headache, dizziness, lethargy, insomnia, cyanosis, plethora, and paresthesias. These variable symptoms have been called chronic mountain sickness (CMS or Monge's disease).[2] Other than CMS, there are reports about the effects of HA on severity and incidence of some cardiovascular diseases. Tahan et al. reported that in HA residents (2,000 m), thrombotic stroke frequency was increased.[3] Hypertension prevalence was also increased in HA residents.[4&5] Another study showed that hypertensive patients at HA have less symptoms compared to the patients at low altitude with comparable blood pressure levels, but have significantly higher morbidity and mortality rates.[6]

It is unknown whether chronic complications of diabetes change among moderately HA residents. We aimed to determine the nephropathy and retinopathy incidences in residents of HA and SL, so a cross-sectional study was planned.

Patients and Method

A total of 148 NIDDM patients admitted to endocrinology outpatient clinics of Yuzuncu Yil University, Van (altitude 1,727 m), Karaelmas University, Zonguldak (sea level), and Karadeniz Technical University, Trabzon (sea level) were evaluated between January 2000 and January 2002 in terms of age, gender, BMI, smoking, duration of diabetes, blood pressure control, and angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blockers (ARB) usage, 24 h urinary protein excretion, serum creatinine, cholesterol, hemoglobin, and HbA1c were determined. Urinary protein and creatinine excretion was measured by spectrophotometricmethod. Patients with overt proteinuria (i.e., > 500 mg/24 h), recent residents (residency of less than 5 years), and frequent visitors (living outside more than 2 months in a year) were excluded from the study. Proteinuria was defined as > 150 mg/24 h. Eye examinations were done by local specialists. SL (Trabzon and Zonguldak patients, n = 75, 37 female, 38 male, mean age 51.8 ± 10.5 range 30–75) and moderate altitude patients (Van, n = 73, 45 female, 28 male, mean age 48.3 ± 12.1 range 29–82) were compared by the above characteristics by using chi-square analysis, Pearson correlation, and t tests.

Results

Results are shown in Table 1. No statistical difference was found between sea level and moderately HA groups in terms of age (p = 0.06), gender (p = 0.13), duration of diabetes (p = 0.42), body mass index (p = 0.49), systolic (p = 0.10), diastolic (p = 0.06) and mean arterial blood pressure values (p = 0.06), serum glucose levels (p = 0.16), cholesterol (p = 0.90), HDL-cholesterol (p = 0.53), LDL-cholesterol (p = 0.15), serum creatinine (p = 0.00), GFR values (p = 0.05), HbA1c levels (p = 0.50), hemoglobin (p = 0.07), smoking (p = 0.82), blood pressure control (p = 0.52), ACE inhibitory or ARB treatment (p = 0.16), and retinopathy prevalence (26/40; 34.7% versus 23/45; 31.5%), respectively. The mean 24 h protein rate for HA (210.0 ± 139.9) diabetics was significantly higher than the SL (127.8 ± 112.1 mg; p = 0.00) (Figure 1). Proteinuria prevalence was significantly higher in the HA group (33.3% versus 57.5%, p = 0.00). The mean serum creatinine level was significantly lower (1.04 ± 0.22 versus 0.84 ± 0.21, p = 0.00) and GFR was significantly higher (91 ± 26 versus 83 ± 22, p = 0.05) for SL patients. When patients were classified as ACE/ARB users and nonusers, there is no difference in terms of urinary albumin excretion rate for both SL (117.6 ± 135 versus 132.1 ± 106.5, p = 0.66) and HA (235.1 ± 149.8 versus 208.3 ± 136, p = 0.47) groups. There is no significant correlation between proteinuria and mean blood pressure, HbA1c, and GFR in both study groups (Table 2).

Table 1. Some Characteristics of Type 2 Diabetic Patients Living at Sea Level and High Altitude (1,727 m).

	Sea level	High altitude	p
Mean age	51.9 ± 10.5	48.3 ± 12.1	0.06
Female/male	37/38	45/28	0.13
Duration of DM (years)	7.6 ± 5.7	6.9 ± 3.8	0.42
BMI	28.8 ± 5.7	29.5 ± 4.7	0.49
Smoking (%)	27.3	29.9	0.82
Glucose	189 ± 77	205 ± 67	0.16
HbA1C (%)	9 ± 2.8	8.8 ± 1.9	0.50
Creatinine	0.8 ± 0.2	1 ± 0.2	0.00
GFR	91 ± 26	83 ± 22	0.05
Cholesterol (mg/dL)	210 ± 47	209 ± 55	0.90
HDL	43 ± 10	42 ± 11	0.53
LDL	136 ± 35	126 ± 40	0.15
Hemoglobin (g/dL)	13.2 ± 2.4	14.1 ± 1.6	0.07
Blood pressure control	39.2%	33.8%	0.52
Systolic BP	137 ± 24	130 ± 23	0.10
Diastolic BP	85 ± 14	80 ± 13	0.06
Mean arterial BP	102 ± 17	97 ± 15	0.06
ACE or ARB usage (%)	20.3	30.4	0.16
Retinopathy	26/40, 34.7%	23/45, 31.5%	0.51
24 h protein excretion	127.8 ± 112.1	210.0 ± 139.9	0.00
Proteinuria (≥ 150 mg/24 h)	25/75, 33.3%	42/73, 57.5%	0.00

Table 2. There Is No Correlation Between GFR, Mean Arterial Pressure, HbA1c, and Proteinuria (Pearson Correlation Test).

	SL		HA
	r	p	r	p
Proteinuria–mean blood pressure	0.08	0.49	0.02	0.88
Proteinuria–HbA1C	0.05	0.67	0.06	0.63
Proteinuria–GFR	0.01	0.94	− 0.13	0.30

Figure 1. 24 h protein excretion for sea level and high altitude residents of NIDDM patients.

Discussion

Hypoxia arising from HA represents a hazard to humans because it reduces energy production and affects organ functions. Chronic exposure to hypoxia also results in polycythemia and thus reduction of the plasma fraction. Polycythemia due to primary and secondary erythrocytosis is invariably associated with hypervolemia. Many features of CMS are similar to those of patients living at SL, with chronic hypoxia secondary to chronic lung disease or congenital cyanotic heart disease. These patients are known to develop hyperuricemia as well as glomerulomegaly and proteinuria. Hypervolemia may represent an important determinant of the structural alteration of the vascular system, including the kidney.[7] Metabolic and biochemical adaptations were compared in streptozotocin-diabetic and nondiabetic control rats exposed for 24 h to a cold environment (4°C) or hypobaric hypoxia (simulated altitude = 12,000 ft). The greater reactivity of the sympathetic nervous system in diabetics suggests a mechanism by which stress leads to increased risk of metabolic complications in diabetes mellitus.[8] On the other hand, Lee et al. demonstrated that short-term HA hiking activity can produce beneficial effects of glycemic control.[9] Dominguez Coello et al. reported that HDL-cholesterol levels are linearly and significantly increased when living at HA.[10] Moore et al. reported that extreme altitude mountaineering is associated with significant risks, such as hypoglycemia, ketoacidosis, and retinal hemorrhage, with the additional difficulties in assessing glycemic control due to meter inaccuracy at high altitude.[11] In our study, the HA group was living in relatively lower altitude for a long period of time. We found no differences in terms of glucose regulation and HDL levels between the two study groups. In AMAS study, a significant decrease in insulin resistance accompanied by an increase in HDL-cholesterol after 3 weeks at moderate altitude was observed.[12] Another dimension of the issue is genetic adaptation to HA. Differences in oxygen transport-related traits between Tibetan, Andean, and European populations have been interpreted as having demonstrated the existence of genetic influences on HA adaptation.[13] These different facts should be taken into account when comparing cardiovascular risk in populations living at different altitudes.

Hansen et al. concluded that acute altitude hypoxia increases urinary albumin excretion despite unchanged tubular function and independent of effects of isradipine on filtration fraction.[14] This finding was supported bytwo other studies, and rapid ascent (> 4,350 m) was shown to increase urinary albumin excretion.[15&16] But in an early study, Pines reported that proteinuria due to HA (5,890 m) was reduced after 12 days of climbing.[17] Jefferson et al. described an association of hyperuricemia, proteinuria, and hypertension with HA polycythemia. In this study, in residents of HA without polycythemia, proteinuria and uric acid level elevations were not present.[18] In our study, urinary 24 h protein excretion and prevalence of proteinuria were significantly higher in the HA, which suggests higher diabetic nephropathy risk in these patients. Parallel to this finding, the serum creatinine level was significantly higher and GFR was significantly lower in the HA group, possibly representing more advanced renal damage in patients who lived in HA.

High-altitude retinopathy is related to hypoxia and is manifested by cotton-wool exudates, tortuosity, and dilation of retinal veins and scotomata. It commonly occurs at altitudes over 5,000 m (16,000 ft), is usually asymptomatic, and usually resolves after 1–2 weeks, even if the patient remains at altitude.[19] But there is no other study about the effect of long-term, moderately HA residency on retinopathy in DM patients. In this study, we could not find any change in retinopathy prevalence between SL and moderately HA patients.

Conclusion

This cross-sectional study suggested an increased tendency for the development of diabetic nephropathy among highlanders. This finding should be confirmed with larger and prospective studies, and if so confirmed, more aggressive preventive approaches are needed for diabetic patients living at moderately HA.