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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2002  |  Volume : 13  |  Issue : 2  |  Page : 155-162
Diabetic Nephropathy in Childhood and Adolescence


Department of Pediatrics, King Hussein Medical Center, Amman, Jordan

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How to cite this article:
Hasan MA. Diabetic Nephropathy in Childhood and Adolescence. Saudi J Kidney Dis Transpl 2002;13:155-62

How to cite this URL:
Hasan MA. Diabetic Nephropathy in Childhood and Adolescence. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2022 Aug 7];13:155-62. Available from: https://www.sjkdt.org/text.asp?2002/13/2/155/33128

   Introduction Top


Diabetic complications are tragic for patients and their families and are great burden to the health economy of any country. We know that the basis for future diabetic complications may commence in childhood. The goal of treatment in children with type 1 diabetes mellitus is to acheive adequate glycemic control in order to allow for proper growth and development.

The cumulative risk of developing diabetic nephropathy (DN) in type 1 diabetes is 30­40%, peaking after approximately 18 years of insulin dependent diabetes mellitus (IDDM). [1]

Diabetic nephropathy is defined by persistent albuminuria (albumin excretion rate {AER} > 300 mg/day; Albustix-positive), declining glomerular filtration rate {GFR} and rising blood pressure. [2]

Regular screening for microalbuminuria (MA) is not usually employed before five years from the time of diagnosis but could be justified earlier in those with poor glycemic control. [3] Two case-reports of pre­pubertal poorly controlled diabetic patients with rapid onset of overt DN in less than five years of diabetes were published. [3],[4] Identification of incipient diabetic nephro­pathy gives the treating team the chance of starting the diabetic patient on measures that prevent farther deterioration of kidney function. Recent estimates suggest that more than 100,000 inhabitants in the Middle East suffer from type I diabetes and that about 6000 subjects in this region develop the disease each year. [5]

The prevalence of diabetes mellitus in USA school children has demonstrated rates of 1.9/1000 and a linear increase with age. Accordingly, type 1 DM is the most common metabolic disorder of childhood. [6] The incidence of type I diabetes in Jordanian children aged 0-14 years is among the lowest in the region (2.8/100,000 in 1992) but is increasing. [7]

In the Diabetes Control and Complications study in adolescents with IDDM, [8] MA was used as an important intermediary end point to evaluate progression of renal disease. It was clear that this progression could be impeded significantly in more than half of the patients by intensive insulin treatment. Therefore, MA is an important effect parameter for optimizing the general care of diabetes.

DN is rarely seen during childhood, but current evidence suggests that this dreadful complication originates in the early years of the disease when the patients are under the management and control of the pediatrician. There is every reason to believe that appropriate intervention during this stage may have a significant impact on its eventual prevention. Kussman et al, [9] in a retrospective analysis of patients with type 1 DM from the Joslin Clinic, found that the mean duration of life after the onset of proteinuria was only 4.8 years, with the longest survival was 13.3 yeas. Green, [5] estimated that for pediatric patients with clinically overt nephropathy, the life expectancy was reduced; it may be less than seven years in the Middle East region.

Studies on the natural history of DN are largely limited to retrospective data in adult patients. The original work of defining MA as a predictive test of later onset of overt DN in at least 80% of cases was conducted in adults some 18 years ago. [10]

We aim in this report to firstly define the MA and the natural history of DN in childhood and adolescence and secondly to discuss the recent published research and issues regarding prevention and treatment of DN and their applicability to diabetic children and adolescents.


   Natural history of diabetic nephropathy Top


The earliest clinical evidence of nephropathy is the appearance of MA, which represents a low-level, but abnormal, albuminuria (> 30 mg/day or > 20 mcg/min.) that can be detected by a radioimmunoassay method described by Keen et al in 1963. [11] It has been reported that MA provides a specific parameter for early detection of incipient renal involvement in type 1 and, less specificaly, in type 2 DM. [1]

Once persistent proteinuria (diagnosed by three or more successive urinalysis at least three months apart that show 30 mg/day or more of protein) appears, progression to renal failure (RF) almost always follows. The median time between the appearance of persistent proteinuria and RF was signi­ficantly shorter for patients whose diabetes was diagnosed after puberty than those who were younger at onset (8 versus 14 years, respectively). Moreover, the risk of proteinuria declined after the age of 35 regardless of the duration of diabetes. [13] Forsblim et al concluded in their study that the predictive value of MA was different in IDDM of over 15 years' duration and such patients should be excluded from trials aiming at preventing progression of DN. [14]

When overt nephropathy develops, in the absence of specific interventions, the GFR gradually falls over a period of several years at a rate that is highly variable from individual to individual (range 2-20 ml/min/ year, mean of 1.2 ml/min/year). End-stage renal disease (ESRD) develops in 50% of type I diabetic individuals with overt DN within 10 years and in > 75% by 20 years. [15],[16]

Detailed morphometric studies have demon­strated increments in various dimensions of the kidneys of diabetic patients and animals. Micropuncture studies have elucidated the pattern of heightened glomerular-capillary pressures and flows that drive the hyper­filtration. The glomerular capillary retards the filtration of circulating negatively charged macromolecules such as albumin by a variety of fixed negative charges within its wall. Diminution of the wall charges reduces the repulsive electrostatic interactions with the negatively charged plasma proteins and promotes the proteinuria of DN. [17] The kidney of a diabetic patient is characterized by thickening of the basement membrane, though this does not correlate with the risk of progression to renal failure. The very first morphological lesion is the reduction of the number of podocytes. [18] A typical biopsy in a patient with advanced DN and declining kidney function contains hyalinized, obliterated glomeruli and open glomeruli with marked mesangial expansion. [19] One proposed explanation [20] of the prog­ressive renal injury in patients with type 1 DM is that the glomerular capillary pressure enlarges the radius of the pores in the glomerular membrane by a mechanism that is mediated at, least in part, by angiotensin II. This enlargement impairs the size-selective function of the membrane so that the protein content of the glomerular filtrate increases, which in turn increases the endo­cytosis of protein by tubular epithelial cells, ultimately resulting in a nephritogenic effect.

The incidence of incipient and overt nephro­pathy in an adolescent diabetic cohort of 135 patients with more than five years old IDDM, was 17% and 3.7%, respectively. [21] In another study, the prevalence of MA in the IDDM patients was approximately 20% in a large clinic. [22]

Screening for DN

The cost of screening must be weighed against the potential benefit of a treatment strategy. A computer simulation cohort of 8,000 patients were analyzed for the cost­benefit of screening for and antihypertensive treatment of early renal disease indicated by MA in patients with type 1 DM. The analysis showed that screening and inter­vention programs were likely to have life saving effects and lead to considerable economic savings. [23] Messent et al [24] in a 23­ year follow-up study found that MA was a powerful predictor of clinically overt diabetic renal disease as well as cardio­vascular mortality. The estimates of the economic burden of diabetes suggested that 4-8% of all UK healthcare expenditure was spent on people who had co-existing diabetes and one third of the total expenditure on diabetes went to those with age between zero-24 years. [25]

Recommendations for screening, monitoring and treatment of MA have recently been set in the St. Vincent Declaration Action Program. [26] All patients with IDDM who are over 12 years old and who have had the disease for at least 5 years, should have their urine tested for albumin excretion at least once a year until 70 years.

Urine Sampling

The utility of this screening approach should take into account the clinical condition of a specific individual. It should be recognized that heavy exercise, urinary tract infection, acute febrile illnesses and heart failure may transiently increase urinary albumin excretion and thus, screening should be postponed in these situations. [27],[28]

Similarly, drugs that may alter urinary protein excretion rate, such as nonsteroidal anti-inflammatory agents or angiotensin­converting enzyme (ACE) inhibitors, should be avoided during screening. [29],[30] It is acknowledged that a timed urinary albumin excretion rate, either a 24-hour or overnight (8 to 12 hour) collection is clearly the most sensitive assay. However, precisely timed urine collections are impractical and incon­venient for many patients, especially children; therefore, it has been reported [31],[32] that compared with the overnight urine collection, the four-hour collection had greater sensitivity, while affording similar specificity and positive predictive value.

The urinary albumin/creatinine ratio (A/C) from a morning urine sample following initial voiding would seem adequate for the detection and monitoring of MA in patients with IDDM. A urinary A/C ratio of > 30 mg/g and < 300 mg/g has been identified as a range that places patients at increased risk for diabetic nephropathy and its comp­lications. If a normal ratio, i.e. < 30 mg/g, is obtained, then the ratio need only be repeated yearly. However, if the urinary A/C ratio is elevated (> 30 mg/g), this abnormality needs to be confirmed. At least two A/C ratios in the range of 30 to 300 mg/g are necessary to indicate the presence of incipient DN, [Table - 1]. [33],[34] At present, routine use of dip­sticks as a method of screening is not recom­mended. These techniques only determine albumin concentration in the urine, and as such, are not as sensitive for the detection of those patients who are at increased risk. Schmit et al [12] have reported that there are few renal diseases as predictable in evolution as DN. A definite renal lesion is seen in all type 1 DM patients who have elevated albumin excretion rates i.e. in the MA range or higher. In contrast, the renal morphology is less uniform in MA type 2 DM patients. [35] A modified scheme proposed by Mongensen [36] is shown in [Table - 2].


   Stages of Nephropathy Top


DN is subdivided into pre-clinical and clinical phases. Stages 1, 2 and 3 would be considered pre-clinical or "silent" whereas stages 4 and 5 are those commonly referred to as "clinical DN".

Stage 1

GFR is elevated on an average by 20-40% above that of age-matched normal controls in both adults and children with type 1 DM, resulting in glomerular enlargement. [37]

Stage 2

Stage 2 is an extension of stage 1 and has glomerular histopathological changes as basal membrane thickness and mesangial expansion begin to be detected within the first two years after the onset of IDDM. This is usually a clinically silent stage with normal albumin excretion rate despite the structural changes. [38] Most patients remain in stage 2, however, 30-40% progress to subsequent stages. [39] The explanation for this variable progression remains obscure and may relate to factors such as the degree of metabolic control and the development of hypertension. Theochari et al [40] observed that children with diabetes had higher 24­hour, daytime, and nighttime values of systolic, diastolic and mean arterial pressure compared with their siblings. Furthermore, blood pressure was slightly higher in­patients with MA than in patients with normal urine albumin values.

Stage 3

Patients in this stage have MA detected. Blood pressure is often elevated, especially after exercise. Patients who have albumin excretion rates (AER) of greater than 30 µg/min are 24 times more likely to develop clinical DN than those with less than 30 µg/min. [10] Accelerated progression of renal disease is seen in patients with elevated blood pressure. [41]

Stage 4

Patients at this stage have overt DN. By definition, the patients usually have persistent clinical proteinuria (AER > 250 µg/min, Albustix-positive urine, or > 360 mg/24hr), hypertension and a decrease in GFR. Once persistent proteinuria is present, the average time until the development of ESRD or death is form 3.3 to 4.8 years. [42]

Stage 5

This is a stage of advanced renal failure. In contrast with the non-diabetic patients, diabetics with ESRD usually have other systemic degenerative manifestations in addition to their renal disease.

Management of patient with micro­albuminuria and diabetic nephropathy

MA can be reduced by treatment. The clinical approach to patients with MA must be global and should tackle the associated risk factors, which include the metabolic and hemodynamic disturbances.

Improving blood glucose control

The Diabetes Control and Complications Trial (DCCT) has shown definitively that intensive diabetes therapy can significantly reduce the risk of development of MA and overt DN in people with diabetes. [43] Once overt nephropathy has developed, the degree of metabolic control may lose its signi­ficance, with other mechanisms having taken over (e.g. hypertension). [13] An exception to this belief was reported by Nyberg et al[44] who found a good correlation between the metabolic control (HbA1c) and the decline of the glomerular filtration rate in 18 IDDM patients with clinical DN.

The new approach to insulin adminis­tration [45] known as "Hepatic Activation" or more descriptively "Chronic Intermittent Intra­venous Insulin Therapy" (CIIIT) corrects the main drawbacks of the traditional sub­cutaneous insulin administration such as the lack of pulsatility and the relative hypo­insulinemia of the hepatocytes. Eugen et al [46] found that CIIIT added to the traditional insulin administration caused a significant delay of progression of DN as well as a significant improvement of glycemic control.

Hypertension control

In patients with type1 diabetes, hyper­tension usually results from the underlying DN and typically appears when patients develop MA. Hypertension in both types of diabetes is associated with expanded plasma volume, increased peripheral vascular resis­tance, and low renin activity. Most hyper­tensive diabetics without renal disease have normal plasma renin activities, while diabetics with proteinuria of two grams per day have significantly reduced plasma renin activity and aldosterone concentration, characte­rizing a "low-renin hypertension". [47],[48] Initial management should include lifestyle modi­fications, such as, reduction of salt, exercise and weight loss in those who are obese.

Antihypertensive therapy in diabetics should be considered if blood pressure is above 130/85 mm Hg with the aim to reduce levels below 125/75 mm Hg, especially for those with MA or DN. [49] Because of the high proportion of patients who progress from MA to overt DN and subsequently to ESRD, use of ACE inhibitors is recom­mended for all type 1 patients with MA, even if normotensive. Both systolic and diastolic hypertension markedly accelerate the progression of DN. Indeed, diabetic patients with persistent MA are at increased risk for all-cause mortality, especially from cardiovascular disease. [50] Although, ACE inhibitors may be antiproteinuric, many type 1 diabetic subjects will still have inadequately controlled blood pressure. This lack of strict blood pressure control may be a major factor in the continued rate of decline in renal function in the captropril treated group, albeit at slower rate, in the Collaborative study. [51] Additional agents may need to be considered including the use of diuretics and calcium channel blockers. [52] The effect of ACE inhibitors appears to be a class effect, so choice of agents may depend on cost and compliance.

Modification of dietary protein intake

There is some role of dietary protein intake in the prevention of DN. There is evidence that low protein diet can reduce glomerular pressure, preserve kidney function and structure, lead to a reduction in albuminuria and GFR in diabetic subjects with MA and glomerular hyperfiltration, and substantially slow the progression of diabetic renal disease in patients with DN. [53] Protein intake below 0.6 g/kg/d may be associated with protein malnutrition and the aim of a diet should be to reduce protein intake to a non-harmful yet achievable level by the majority of patients (i.e. 1-1.3 g/Kg/d). [54]

When GFR begins to decline substantially, referral to a physician experienced in the care of such patients is indicated.


   Summary Top


Annul screening for MA in patients who are at risk will allow the identification of patients with nephropathy at a point very early in its course. Improving glycemic control, antihypertensive treatment and the use of ACE inhibitors may slow the rate of progression of diabetic nephropathy. In addition, other treatment modalities such as protein restriction may have benefits in selected patients.

 
   References Top

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Correspondence Address:
Mjalli Ahmad Hasan
Consultant Pediatrician & Endocrinology, King Hussein Medical Center, P.O. Box 6080, Zarka
Jordan
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