مقاربة مريض الكلية السكرية د. منى دكر اختصاصية بأمراض الغدد الصم و السكري

— Diabetic nephropathy occurs in type 1 (formerly called insulin-dependent or juvenile onset) and type 2 (formerly called non-insulin-dependent or adult onset) diabetes mellitus, and in other secondary forms of diabetes mellitus, for example after pancreatitis or pancreatectomy, in which duration of diabetes is long-enough and level of glycemia high enough to result in complications. INTRODUCTION

CLINICAL FEATURES

The major clinical manifestations of diabetic nephropathy are albuminuria, less often hematuria, and, in many patients, progressive chronic kidney disease,

Albuminuria — Functional characteristics include hyperfiltration in very early disease (primarily in type 1 diabetes

microalbuminuria, called high albuminuria in the new nomenclature (defined as urinary albumin excretion between 30 and 300 mg/day or between 30 and 300 mg/g creatinine on a random urine sample),

macroalbuminuria, called very high albuminuria in the new nomenclature (defined as urinary albumin excretion above 300 mg/day or above 300 mg/g creatinine on a random urine sample).

EPIDEMIOLOGY

Diabetic nephropathy –T1DM T1D ~ 20-30% will have moderate albuminuria after mean duration diabetes 15 years Prior to intensive combined control incidence of overt nephropathy higher 25-45%, and progression from this to ESRD Lower rates due to intensive treatment of HbA1c and BP. In DCCT <2% of intensively treated developed renal insufficiency Stanton Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127; Nathan Arch Intern Med 2009;169: 1307

Diabetic nephropathy T2DM T2D similar renal risk - time to proteinuria from diabetes onset and time to ESRD from proteinuria onset similar for T1 and T2 UKPDS: 5100 patients, 10yrs after diagnosis-25% albuminuria; 5% severe albuminuria; 0.8% Cr>175 or needing RRT Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127; Adler Kidney Int 2003; 63(1):225

Type 1 diabetes The overall incidence of end-stage renal disease (ESRD) was also substantial, with reported rates of 4 to 17 percent at 20 years from time of initial diagnosis and approximately 16 percent at 30 years

Type 1 diabetes In comparison to these findings, subsequent studies have found that the renal prognosis of type 1 diabetes, including the rate of progression to ESRD, has dramatically improved over the last several decades

Type 1 diabetes In addition to the importance of glycemic control, more aggressive blood pressure reduction and the use of angiotensin converting enzyme inhibitors have been shown to reduce the rate of progression of, though not prevent, diabetic nephropathy.

Type 1 diabetes Those patients who have no proteinuria after 20 to 25 years have a risk of developing overt renal disease of only about 1 percent per year

Type 2 diabetes the prevalence of progressive renal disease has generally been lower in type 2 diabetes than in type 1 disease [ 21 ]. However, this observation may be a function of the usually later-onset disease and shorter-duration "exposure" in type 2 than type 1 diabetes, and may not apply to all groups with type 2 diabetes21

Type 2 diabetes Data suggest that the renal risk is currently equivalent in the two types of diabetes.

Type 2 diabetes With respect to the development and progression of nephropathy among almost 5100 type 2 diabetic patients enrolled in UKPDS, the following results were reported [ 26 ]: 26

Type 2 diabetes At ten years following diagnosis, the prevalence of microalbuminuria, macroalbuminuria, and either an elevated plasma creatinine concentration (defined as ≥175 µmol/L [2.0 mg/dL]) or requirement for renal replacement therapy was 25, 5, and 0.8 percent, respectively.

Type 2 diabetes The yearly rate of progression from diagnosis to microalbuminuria, from microalbuminuria to macroalbuminuria, and from macroalbuminuria to an elevated plasma creatinine concentration or renal replacement therapy was 2.0, 2.8, and 2.3 percent.

Type 2 diabetes Based upon a statistical model, an estimation of the median time spent in each stage without progression to another nephropathy stage was 19, 11, and 10 years for those with no nephropathy, microalbuminuria, and macroalbuminuria, respectively. Among those with an elevated plasma creatinine concentration (≥2.0 mg/dL [175 µmol/L]), renal replacement therapy was required after a median period of only 2.5 years

This rate of progression is higher than seen in other studies probably because of two factors: appropriate therapy (eg, angiotensin inhibition and rigorous blood pressure control) was not taken into account; and most of the patients had more advanced renal insufficiency as defined by serum creatinine concentration ≥2.0 mg/dL [175 µmol/L].

Type 2 diabetes As with type 1 diabetes, some patients with microalbuminuria due to type 2 diabetes, particularly those with good glycemic control, experience regression of microalbuminuria [ 27 ]. 27

PATHOLOGY

— Pathologic abnormalities are noted in patients with long-standing diabetes mellitus before the onset of microalbuminuria. There are three major histologic changes in the glomeruli in diabetic nephropathy: mesangial expansion; glomerular basement membrane thickening; and glomerular sclerosis

The last abnormality, which may have a nodular appearance (the Kimmelstiel-Wilson lesion), is often associated with hyaline deposits in the glomerular arterioles (reflecting the insinuation of plasma proteins such as fibrin, albumin, immunoglobulins, and complement into the vascular wall)

Renal Pathology Society classification — A classification of type 1 and type 2 diabetic nephropathy was developed by the research committee of the Renal Pathology Society [ 30 ]. Four classes of glomerular lesions were defined:30

Class I: Isolated glomerular basement membrane thickening. Basement membranes are greater than 430 nm in males older than age 9 and 395 nm in females. There is no evidence of mesangial expansion, increased mesangial matrix, or global glomerulosclerosis involving >50 percent of glomeruli.

Class II: Mild (class IIa) or severe (class IIb) mesangial expansion. A lesion is considered severe if areas of expansion larger than the mean area of a capillary lumen are present in >25 percent of the total mesangium.

Class III: At least one Kimmelstiel-Wilson lesion (nodular intercapillary glomerulosclerosis) is observed on biopsy and there is <50 percent global glomerulosclerosis.

Class IV: Advanced diabetic sclerosis. There is >50 percent global glomerulosclerosis that attributable to diabetic nephropathy.

The severities of interstitial and vascular lesions were also assigned scores:

A score of 0 was assigned if the interstitium had no areas of interstitial fibrosis and tubular atrophy (IFTA); scores of 1, 2 or 3 were assigned if areas of IFTA 50 percent, respectively.

A score of 0 was assigned if no T lymphocytes or macrophage infiltrate was present. Scores of 1 or 2 were assigned if infiltrate was limited to the area surrounding atrophic tubules, or if infiltrate was not limited, respectively.

Scores of 0, 1 or 2 were assigned if no arteriolar hyalinosis, one arteriole, or more than one arteriole with hyalinosis was present.

PATHOGENESIS

— There appear to be different pathogenetic processes leading to the pathologic mechanisms in diabetic nephropathy. Glomerulosclerosis, for example, may result from intraglomerular hypertension induced by renal vasodilatation, or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli

PATHOGENESIS Glycation of tissue proteins also may contribute to the development of diabetic nephropathy and other microvascular complications. In chronic hyperglycemia, some of the excess glucose combines with free amino acids on circulating or tissue proteins. This nonenzymatic process initially forms reversible early glycation products and later irreversible advanced glycation end products (AGEs)

PATHOGENESIS Circulating AGE levels are increased in diabetics, particularly those with renal insufficiency, since AGEs are normally excreted in the urine [ 43 ]. The net effect is tissue accumulation of AGEs, in part by crosslinking with collagen, which can contribute to the associated renal and microvascular complications43

Functional changes* Natural History of NIDDM Proteinuria End-stage renal disease Clinical type 2 diabetes Structural changes † Rising blood pressure Rising serum creatinine levels Cardiovascular death Microalbuminuria Onset of diabetes Years * Kidney size , GFR  † GBM thickening , mesangial expansion 

RISK FACTORS

Risk Factors Non-modifiable - Genetic predisposition - Ethnicity - Age Modifiable - HbA1c - BP - lipids - Weight, diet, smoking, other factors

Genetic susceptibility — Genetic susceptibility may be an important determinant of both the incidence and severity of diabetic nephropathy [ 29,45,84 ]. The likelihood of developing diabetic nephropathy is markedly increased in patients with a diabetic sibling or parent who has diabetic nephropathy; these observations have been made in both type 1 and type 2 diabetes29,45,84

Age — The impact of age at onset of diabetes on the risk of developing nephropathy and end- stage renal disease is unclear. As an example, among patients with type 2 diabetes, increasing age, along with increasing duration of diabetes, has been associated with an increased risk for developing albuminuria in Australia

Age In contrast, in a population-based study of 1856 Pima Indians with type 2 diabetes, patients who developed diabetes prior to age 20 had a higher risk of progressing to end- stage renal disease (25 versus 5 per 1000 patient years at risk) [ 98 ].98

Blood pressure — Prospective studies have noted an association between the subsequent development of diabetic nephropathy and higher systemic pressures.

Glomerular filtration rate — Approximately one-half of patients with type 1 diabetes of less than five years duration have an elevated glomerular filtration rate (GFR) that is 25 to 50 percent above normal.

Glomerular filtration rate In one prospective study, for example, patients with type 1 diabetes and a GFR above 125 mL/min had a risk of developing microalbuminuria within 8 years of approximately 50 percent versus only 5 percent in patients with a lower GFR that was similar to that seen in nondiabetics [ 100 ].100

Glomerular filtration rate The glomerular hyperfiltration in type 1 diabetics is typically associated with glomerular hypertrophy and increased renal size [ 101 ]. The association between these hemodynamic and structural changes and the development of diabetic nephropathy may be related both to intraglomerular hypertension (which drives the hyperfiltration) and to glomerular hypertrophy (which also increases wall stress). Therapy aimed at reversing these changes101

Glomerular filtration rate The findings in type 2 diabetes are somewhat different. Up to 45 percent of affected patients initially have a GFR that is more than 2 standard deviations above age-matched nondiabetic and obese controls [ 102,103 ]. However, the degree of hyperfiltration (averaging 117 to 133 mL/min) is less than that seen in type 1 diabetics. Type 2 diabetics are also older and more likely to have arteriosclerotic vascular disease, which will limit increases in both glomerular filtration and glomerular size [ 104 ].102,

Glomerular filtration rate The potential importance of intraglomerular hypertension in the pathogenesis of diabetic nephropathy may explain why systemic hypertension is an important risk factor for the development of diabetic nephropathy [ 105 ]. 105

Glycemic control — Diabetic nephropathy is more likely to develop in patients with worse glycemic control (higher HbA1c levels).

Race — The incidence and severity of diabetic nephropathy are increased in blacks (3- to 6- fold compared to Caucasians), Mexican- Americans, and Pima Indians with type 2 diabetes

Obesity — A high body mass index (BMI) has been associated with an increased risk of chronic kidney disease among patients with diabetes [ 83, ]. In addition, diet and weight loss may reduce proteinuria and improve kidney function among patients with diabetes [ 116,117 ]. However, the contribution of obesity (or weight loss) to the risk of nephropathy (independent of diabetes and glycemic control) has not been convincingly demonstrated in these studies. 83, ,117

Smoking — Smoking is associated with a variety of adverse effects in patients with diabetes. This includes evidence of increases in albuminuria and the risk of end-stage renal disease and of decreased survival once dialysis is begun.

Oral contraceptives — An initial report suggested a link between oral contraceptive use and the risk of diabetic nephropathy [ 118 ].118

RELATION BETWEEN DIABETIC NEPHROPATHY AND RETINOPATHY

— Patients with nephropathy and type 1 diabetes almost always have other signs of diabetic microvascular disease, such as retinopathy and neuropathy [ 9,11 ]. The retinopathy is easy to detect clinically, and typically precedes the onset of overt nephropathy in these patients. The converse is not true.9,11

Thus, type 2 diabetics with marked proteinuria and retinopathy most likely have diabetic nephropathy, while those without retinopathy have a high frequency of non-diabetic glomerular disease [ 123 ].123

Data from the third National Health and Nutrition Examination Survey suggest that 30 percent of type 2 diabetics with renal insufficiency have non-diabetic renal disease,

NONDIABETIC RENAL DISEASE The major clinical clues suggesting the presence of nondiabetic glomerular disease are :

The onset of proteinuria less than five years from the documented onset of type 1 diabetes, since the latent period for overt diabetic nephropathy is usually at least 10 to 15 years [ 9,11 ]. The latent period is probably similar in patients with type 2 diabetes, but the time of onset is often difficult to ascertain.9,11

The acute onset of renal disease. Diabetic nephropathy is a slowly progressive disorder characterized by increases in protein excretion and the serum creatinine concentration over a period of years.

The presence of an active urine sediment containing red cells (particularly acanthocytes) and cellular casts. However, hematuria and red cell casts can also be seen with diabetic nephropathy alone [ 6-8 ].6-8

In type 1 diabetes, the absence of diabetic retinopathy or neuropathy. In contrast, lack of retinopathy in type 2 diabetes does not preclude diabetic nephropathy, which was absent in 12 of 27 patients with biopsy confirmed diabetic nephropathy in one study [ 121 ]. 121

Signs and/or symptoms of another systemic disease [ 127 ].127

Significant reduction in the glomerular filtration rate (>30 percent) within two to three months of the administration of ACE inhibitors or angiotensin II receptor blockers [ 127 ]. 127

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