Peripheral neuropathic and renal complications in patients with diabetes mellitus 2

Introduction

Diabetes mellitus (DM) is a highly prevalent chronic disease worldwide. By the year 2045, a prevalence of 10.9% (700 million people)¹ is expected, and early diagnosis is key to preventing chronic microvascular and macrovascular complications, including neuropathy, retinopathy and nephropathy.^1,2

Diabetic peripheral neuropathies are classified as somatic and autonomic.³ Among the former, bilateral sensory polyneuropathies, paresthesias, numbness and tingling as well as decreased tactile, vibrational and thermal sensitivity, discrimination between two points, achilles and patellar hyporeflexia are more frequent; whereas mononeuropathies and muscular amyotrophy may be accompanied by cachexia and muscle pain especially of the muscles of the pelvis and thighs.^2,3 Autonomic neuropathies include a variety of symptoms such as postural hypotension, gastrointestinal and genitourinary changes.²

Diabetic neuropathy (DN) is the most frequent complication of DM. It can be subclinical, diffuse clinical and focal syndromes.^4,5 The first case is detected by alterations in tactile and thermal sensitivity, abnormal test for vibration in the absence of symptomatology. Diffuse clinical neuropathy encompasses distal sensorimotor and autonomic syndromes, the most frequent being diffuse symmetric polyneuropathy (DSP), with distribution in hands and feet, present in more than 90% of DM2 cases.^4,6 Among the focal syndromes, mononeuritis predominates, frequent in older adults.⁴

Worldwide, the prevalence of DN is reported to be between 8 and 51%. In 10% of cases, it is diagnosed at the onset of DM2, and in 90% during the evolution of DM2.⁴ It increases when there are high levels of glycemia, alcohol consumption and smoking, as well as with prolonged illness.⁶ Older adults with poor metabolic control are at greater risk of foot ulcers (25%) and amputation associated with diabetic peripheral neuropathy.⁷

Among the risk factors for DN are smoking, alcohol abuse, metabolic syndrome, genetic aspects, advanced age, and among the risk factors for painful DN are poor glycemic control, female sex, obesity, renal function problems and the severity of neuropathy.⁸

Good glycemic control must be accompanied by strict control of blood pressure to prevent and delay the onset of DN, since hypertension has been described as the main modifiable risk factor for distal symmetric polyneuropathy.⁹ Dyslipidemia may affect neuronal function and contribute to DN because, associated with hyperglycemia, they produce reactive oxygen species and initial chronic inflammation of the axon or Schwuann cell and subsequently affect the entire neuronal tree.⁸

The DN usually manifests in the hands and lower extremities⁸ by producing changes in peripheral nerve and skin tissue irrigation, which results in fiber ischemia and hypoxia in sensory neurons^1,3 and carries the risk of foot ulcers and amputations⁴ because it affects the sensory, motor and autonomic nerve fibers of the peripheral nervous system.^1,3

There are several tests for screening for DN, including the Michigan test, one of the most widely used in outpatient clinics and considered the standard. It has a specificity of 95-100% and sensitivity of 57-93%. It is reproducible and easy to apply in primary care.^10,11 It includes a self-administered questionnaire with questions that evaluate the patient’s perception of lower limb symptoms and the physical examination to identify pulses, anhidrosis, calluses, skin lesions, bony deformities and prominences, infections; as well as the Achilles reflex, the vibration perception test and the Semmes-Weinstein monofilament test.¹²

The prevalence of chronic kidney disease (CKD) has increased worldwide, especially among people with DM2,^13,14 and can vary from 8 to 11% in the United States, Canada, Europe and Japan.¹⁴ In Peru, it was estimated that by the year 2021, 13.07% of Peruvians presented CKD, G1 to G4, and 0.10% of the population was on dialysis.¹⁵

CKD is identified by proteinuria or structural damage evidenced by imaging or biopsy with three to more months’ duration.¹⁶ It may or may not be accompanied by decreased glomerular filtration rate (GFR) < 60 mL/min/1.73 m².^13,14,17 Proteinuria levels are directly related to renal health prognosis and mortality and are therefore considered a marker of systemic damage.¹⁸ It has been described that up to 40% of patients with DM2 may have CKD.¹³ and has an impact on morbidity and mortality, especially cardiovascular morbidity and mortality.^13,14

Diabetic CKD is a microvascular complication that affects about 35% of patients with DM2 and usually progresses to advanced stages. It presents as two phenotypes: albuminuria and altered GFR.¹⁹ When the altered glomerular filtration rate is accompanied by microalbuminuria, it can increase mortality up to ten times, with a high health and social cost.²⁰

Patients with CKD have higher rates of diabetic peripheral neuropathy and peripheral artery disease as documented in 520 patients hospitalized for DM2 followed for 4 years in whom CKD is associated with diabetic foot ulcers (DFU). This relationship was significant only in patients with albuminuric CKD.²¹

According to a cross-sectional study, microalbuminuria is strongly and independently associated with DFU.²² Since insensitivity of the foot predicts subsequent deterioration of renal function, subjects with GFRe < 60 ml/min/1.73m² and/or albuminuria > 30 mg/24H are more prone to diabetic foot ulcer (DFU).²³

Neuropathy affects almost 50% of the diabetic population^7,24 while DM2 nephropathy affects approximately 25% of this population. The duration of DM2, together with glycemic control, blood pressure and lipids, are common risk factors for the development of these complications.²⁴ In Peru, in the first quarter of 2021, DM2 complications were identified with a predominance of polyneuropathy (29.5%), followed by nephropathy (14.4%), retinopathy (9%) and diabetic foot (12.8%).²⁵

We consider it important to identify both PN and CKD in patients with DM2 treated in primary care in order to have updated local clinical-epidemiological information that will allow us to adapt treatment protocols. For this reason, the aim of this research was to identify peripheral neuropathic and renal complications in patients with DM2 in a primary care center and the specific objectives were: to analyse the clinical features of peripheral neuropathy and the clinical and laboratory features of chronic kidney disease in patients with diabetes mellitus 2; to analyse the modifiable and non-modifiable risk factors associated with peripheral neuropathy and chronic kidney.

Methods

Results

Table 1, shows clinical manifestations of neuropathy by age group and gender. Among the signs of DN, anhidrosis and infections predominated in patients of both sexes and different age groups, especially among those over 80 years of age. Anhidrosis was more frequent in the female sex, while infections were more frequent in the male sex. More than 66% of participants had more than two signs of diabetic neuropathy. As for symptoms, burning, prickling and leg pain when walking predominated. These had a greater occurrence in women over 80 years of age.

With the bivariate analysis, Table 2 shows that the majority of patients with neuropathy are between 60 and 79 years of age (45.1%), female (41.3%), and present hypertension (51.2%). The average age was 66.71 ± 11.19 years, average time of illness was 12.83 ± 8.73 years, average Hb1Ac was 7.67% ± 1.69, glucose was 153.93 ± 66.17 and hemoglobin was 12.98 ± 1.39. For the variables analyzed, the Chi-square statistical tests indicated no association and the Man Whitney U test indicated no significant differences in relation to neuropathy. Therefore, in this case, multivariate analysis was no longer performed.

Table 3 shows that most patients are in G I and G II, are female, and have hypertension. The highest average age was found in G IIIB and G IV with 71.08 ± 10.52 years. Likewise, the average time of disease was higher in G IIIB and G IV, with 15.41 ± 8.87years, the higher average HbA1c was 8.14% ± 2.07 located in G I and GII. In G I and G II, we found an average higher glucose of 171.66 ± 87.28; average higher hemoglobin of 13.13 ± 1.42. For qualitative variables, the Chi-square statistical test indicates only a relationship among age group, sex and stages. In the quantitative analysis, the Krustall Wallis test indicates that there are significant differences among patient stages according to age, time of disease and HbA1c.

Table 4 shows the ordinal regression after analysis of the requirements. The dependent variable was the stages of chronic kidney disease. The variables included in the model were the age group in the categories of less than 60 and 60 to 79 years and the absence of hypertension as protective factors. Male sex is also included as a risk factor. The age groups younger than 79 years and the absence of hypertension are considered protective factors since their coefficients are negative and their ORs are less than 1, interpreted as meaning that patients of these ages who do not have hypertension are less likely to increase the stage of chronic kidney disease. Male sex, however, is considered a risk factor for progression of CKD.

Discussion

Diabetic neuropathy (DN) is a common complication in patients with diabetes. It is often overlooked, underdiagnosed and undertreated⁵ due to its wide spectrum of presentations and variable intensity of symptoms, ranging from a mild or asymptomatic clinical picture to a debilitating neuropathy.⁵ The prevalence of DN is highly variable and is a function of age, disease duration, metabolic control and lifestyle.⁷

The variability in the clinical picture of DN is related to the changes that chronic hyperglycemia produces in the nerve fiber. Decreased glutathione depletion and regeneration, with consequent oxidative stress and triggering of proinflammatory reactions and fibrosis,^4,7 have been reported to be responsible. Autooxidation of glucose and its metabolites would be other factors associated with nerve fiber damage, changes that are intensified in poorly controlled diabetics.⁴ It has also been described that DN generates axon damage with variable demyelination,⁵ microvascular insufficiency at the level of peripheral nervous tissue and skin, with fiber ischemia and secondarily hypoxia mainly in sensory neurons.⁴

Thus, DN manifests as decreased tactile and thermal sensitivity, paresthesias, hypoalgesia, among other symptoms.¹ The earliest changes of peripheral ND occur at the level of unmyelinated C-fibers, resulting in pain, allodynia and hyperesthesias. Late changes include segmental axonal demyelination, axonal degeneration of myelinated fibers; resulting in progressive loss of distal sensation in the affected nerve.⁷

In the present study, burning, prickling and leg pain when walking predominated, with greater occurrence in women over 80 years of age. Regarding these sensory symptoms, a study conducted in Mexico reported similar data, finding dysesthesia, pain, burning and sensation of electric shock at the level of the toes.⁴ On physical examination, anhidrosis and fungal infections of the skin and nails predominated in patients of both sexes and especially among those over 80 years of age. Mycoses are the most frequent group of skin infections in patients with DM, especially of nails and feet, generally caused by dermatophytes or Candida species. Anhidrosis or hypohidrosis is also frequent in this type of patient³⁶ and is due to the sudomotor dysfunction characteristic of DM.^36,37

It has been observed that patients with diabetes, whose age is over 64 years, had twice the risk of developing onychomycosis. It also occurs when repeated microtrauma to the nails, longer exposure to pathogenic fungi, weakened immune system, increased work activity and venous insufficiency occur. Likewise, it has been observed that patients with diabetes who have amputations and structural deformities are more likely to develop onychomycosis.³⁸

Almost two thirds of the participants presented more than two signs using the MNSI 28 and were therefore diagnosed as DN. The detection of DN by screening in the diabetic population is important to identify the risk of foot ulceration and prevent amputations, so periodic foot examinations, pain treatment and control of glycemia and glycosylated hemoglobin are recommended.⁷ The present study used the MNSI, an instrument considered standard for detecting DN in outpatients in primary care. Its specificity is 95-100% and its sensitivity 57-93%.^4,28

Among the most important factors associated with neuropathy, age,^8,11 obesity, arterial hypertension,^11,39 smoking^8,11 poor glycemic control,^11,39,40 duration of diabetes >10 years^11,36,37 hypoinsulinemia, and dyslipidemia were mentioned.¹¹ Other factors associated with DN (p<0.05) were female sex, age >60 years, glycemic imbalance (HbA1c > 8%).^39,40 and risk factors for painful DN include poor glycemic control, female sex, obesity, renal function problems and severity of neuropathy.⁸

In the present study, the majority of patients with DN are between 60 and 79 years of age, are female and among the comorbidities, arterial hypertension predominates. The average duration of DM is 12.83 ± 8.73 years, and there is not a good metabolic control reflected in elevated Hb1Ac and glycemia values. However, no statistical significance was found based on Chi-square and Man Whitney U tests.

Regarding the duration of diabetes, an investigation in Ethiopia showed that the duration of DM was an important variable that was negatively associated with DN in patients with newly diagnosed DM2. In addition, more than half of the DN occurred within 6 years after the diagnosis of diabetes mellitus. These findings could indicate that most diabetic patients were diagnosed with DM in late stages and were at risk of developing DN in early stages.⁴¹

On the other hand, it has been shown that the risk of DN increases with age. This could be attributed to the convergence of three fundamental pathological mechanisms: inflammation, oxidative stress and mitochondrial dysfunction, all of which are related to the aging process. The inflammatory response leads to the activation of intracellular pathways such as nuclear factor kappa B (NF-κB), activator protein-1 (AP-1) and mitogen-activated kinases (MAPKs) that play a crucial role in neuronal damage. Likewise, oxidative stress generated by chronic hyperglycemia is mediated by several altered metabolic pathways including the polyol and hexosamine pathways, activation of protein kinase C, formation of advanced glycosylation end products and dysfunctional glycolysis. On the other hand, mitochondrial dysfunction is responsible for the production of most reactive oxygen and nitrosative species, whose toxic actions lead to lipid peroxidation, structural modifications of proteins and damage to nucleic acids. These processes culminate in axonal degeneration and segmental demyelination, characteristic of DN.⁴²

It has been described that strict control of blood pressure is the main modifiable risk factor for distal symmetric polyneuropathy and should accompany glycemic control.⁹ and that dyslipidemia associated with hyperglycemia affect neuronal function by producing reactive oxygen species and initial chronic inflammation of the axon or Schwuann cell and subsequent alteration of the entire neuronal tree.⁸ Hence the importance of maintaining stable lipid and blood pressure values. Some observational studies suggest that treatment of dyslipidemia could prevent neuropathy (HR: 0.52 [95% CI: 0.27, 0.98] with use of fibrates, HR: 0.65 [95% CI: 0.46, 0.93] with use of statins, p ≤ 0.042.³⁷

Multifactorial intervention in lifestyle, physical activity and body weight represent the basis for the treatment of diabetic distal symmetric polyneuropathy, so it is important to identify risk factors or comorbidities associated with DN in the early stages of the disease.³⁷

In the bivariate analysis, no association was found between DN and obesity, dyslipidemia, anemia, and hyperthyroidism. However, another study did report an elevated BMI 40 and obesity as risk factors.³⁹ Furthermore, another study reported that hyperglycemia and dyslipidemia may affect peripheral nerve function in distinct but overlapping ways. While hyperglycemia causes damage, preferentially to large myelinated nerve fibers, which is reflected in motor nerve conduction velocity, dyslipidemia and obesity preferentially affect small nerve fibers and the damage is evident by the density of intraepidermal nerve fibers. These risk factors may be particularly important in sensory axon loss of all sizes, which is the primary pathology underlying the patient’s symptoms and disability.^38,43 These risk factors may be particularly important in sensory axon loss of all sizes, which is the primary pathology underlying the patient’s symptoms and disability.^38,43

The other complication analyzed in this study is chronic kidney disease. It has been described that the patients with CKD present higher rates of diabetic peripheral neuropathy and peripheral arteriopathy, especially in cases of albuminuric CKD,^17,21 and microalbuminuria has been associated with a higher prevalence of diabetic foot ulcer.²² It has been described that the underlying mechanism of both neuropathy and nephropathy is the microvascular involvement that nearly 35% of patients with DM2 present.^19,24

In the present study, most patients were in stages GI and GII, were female, and had hypertension. The older the patient and the longer the duration of DM2, the higher the frequency of stages GIII B and G IV. These findings are consistent with previous studies that have found a directly proportional relationship between these variables and advanced stage^40,44 or progression of CKD.²⁰ Regarding sex, some studies report that there is no difference by sex in the association with CKD. However, the risk of progression and terminal CKD is higher among women than among men with diabetes.⁴⁵

The highest levels of HbA1c and glycemia were observed among patients in stages GI and GII. Likewise, a relationship was found among age group, sex, and CKD stages. According to the Krustall Wallis test, there were significant differences among CKD stages and age, time of duration of DM2, and glycemia and HbA1c values.

Glycemic control is beneficial both in reducing the risk of peripheral neuropathy³⁷ and in preventing progression of CKD. An observational study of 32 patients followed over 24 years demonstrated impairment of sensory motor peripheral nerve function and onset of clinical neuropathy in 64% of members of the group with HbA1c ≥ 7.0%) As opposed to patients with HbA1c <7%.⁴⁶

It has been described that, in patients with CKD, the severity of diabetic peripheral neuropathy (DPN) correlates directly with the duration of the disease, the degree of glycemic control and the degree of uremia. DPN in patients with CKD G4- G5 is presented as a distal symmetrical polyneuropathy with greater involvement of the lower limbs than the upper limbs. The most frequent clinical features of uremic neuropathy are involvement of thick fibers, with paresthesias, altered or absent deep tendon reflexes, altered vibratory sensation, distal foot muscle atrophy, and weakness.^39,47

Likewise, it has been reported that, in patients with diabetes, the development of cardiac autonomic neuropathy and DPN depends on complex interactions between the degree of hyperglycemia, the duration of the disease, age-related neuronal wasting, and systolic and diastolic blood pressures. The diabetic population with stages 4-5 CKD presents an extremely high risk of lower limb amputation.⁴⁷

In the ordinal regression, the dependent variable was the stages of chronic kidney disease. It was found that the age group in its categories of less than 60 and 60 to 79 years and the absence of hypertension are protective factors; male sex is a risk factor for CKD. This last variable has been described in several studies associated with CKD⁴⁸ as well as uncontrolled arterial hypertension and age over 65 years.^44,48

We believe that the results of this research justify a prospective study of the cohort analyzed, as well as the comparison of these results with controlled diabetic population, lifestyles and medications received for the treatment of DM, DN and CKD. The key areas that justify research to prevent the development or progression of DN and CKD in patients with DM are early screening, periodic follow-up, metabolic and blood pressure control, as well as control of dyslipidemia and obesity. In addition, education on risk factors for DN and CKD, healthy eating, physical activity, and adherence to treatment.

We consider that the results of the study can be generalised to the Peruvian population with similar characteristics.

Conclusion

Diabetic neuropathy produces changes in the somatic and autonomic peripheral nervous system, requiring intervention in the initial phase of the disease through lifestyle changes, detection of modifiable factors such as dyslipidemia, arterial hypertension and obesity, and timely treatment to achieve and maintain glycemic control. Diagnosis and treatment of fungal infections, anhidrosis and other clinical examination findings, as well as DN symptoms, are also required.

DN is more frequent in patients between 60 and 79 years of age, female, with arterial hypertension, with hyperglycemia (elevated Hb1Ac and glycemia values) and with a disease duration (DM) of 12.83 ± 8.73 years.

Stages G1 and G2, female sex, and hypertension predominated in patients with CKD. The older the patient and the longer the time with DM, the higher the CKD stage. A relationship was found between age group, sex and CKD stages. Age <79 years and the absence of hypertension are protective factors that prevent the progression of CKD, whereas male sex is considered a risk factor.

Ethical considerations and consent

The protocol that gave rise to this article was presented to the Research and Ethics Committee of the Gerencia de la Red Asistencial La Libertad - EsSALUD (Management of the La Libertad - EsSALUD Health Care Network) before carrying out the research. This committee issued the certificate N° 68 on May 20, 2024, authorizing the execution of the research.

The project was also reviewed and approved by the Ethics Committee of the School of Medicine - UCV (Expert opinion 317-CEI-EPM-UCV-2024 of May 30, 2024).

The Ethics Committee of the Faculty of Medicine - César Vallejo University and the EsSalud Research Committee (with institutional review committee functions) gave authorisation to conduct the research. Due to the research design (retrospective), informed consent was not required.

The ethical principles of the Declaration of Helsinki were applied with respect to the confidentiality and veracity of the data collected during the course of the study, which are faithfully presented. Personal identity data and patient privacy were protected. Authorship contributions and transparency in conflicts of interest were reported.³⁵