Microalbuminuria—A Biomarker of Renal Microvascular Disease

Abstract

Microalbuminuria (amount greater than 30–300 mg/day) reflects an abnormal glomerular capillary permeability to protein. It is usually dependent upon three mechanisms. First, loss of negatively charged surface of the glomerular capillary wall secondary to circulating toxic substances injury—namely, oxidative stress and proinflammatory cytokines—allows the albumin with negatively charged surface to freely escape into the urine. Second, intraglomerular hypertension and hemodynamic maladjustment secondary to glomerular endothelial dysfunction increases filtration pressure and enhances sized selective proteinuria leakage. Third, podocyte injury leads to a vicious cycle of hemodynamic maladjustment and endothelial and podocyte injuries. All three of these mechanisms induce glomerular endothelial injury and microalbuminuria, which reflects renal microvascular disease.

Keywords:

• microalbuminuria
• renal microvascular disease
• hemodynamics
• podocyte
• FE Mg

Microalbuminuria is highly prevalent in several disease states. A recent worldwide survey showed that in 40% of the patients with diabetes and without known kidney disease, the levels of urinary albumin were in the microalbuminuria range.[1–3] The transition from normo- to microalbuminuria is frequent despite adequate treatment: 2 to 2.5% per year.[4],[5] The prevalence of microalbuminuria in patients with hypertension is less consistent in large population or cohort studies, varying from 8 to 23%.[6–9] Recently, microalbuminuria has also been described as a cardiovascular risk factor.[10],[11] A 10-year follow up study of middle-aged normotensive and hypertensive men without diabetes concluded that urinary albumin excretion appeared to be a strong predictor of cardiovascular disease in normotensive men,[12] and a significant increase in ischemic heart disease was found after a 10-year follow-up in men and women with microalbuminuria compared with those without microalbuminuria in the Copenhagen City Heart Study.[13]

Although microalbuminuria has been accepted as a predicted indicator of renal disease, as well as cardiovascular disease, it is evident that microalbuminuria is unable to detect early stages of diabetic nephropathy or early chronic kidney disease in a non-diabetic population. In diabetes mellitus, microalbuminuria is observed in a rather late stage of diabetic nephropathy, when a significant nephronal damage has already been established.[14–17] Within this context, it is noted that a reduction in creatinine clearance or elevated level of fractional excretion of magnesium (FE Mg) has already been demonstrated in early stage of diabetes mellitus associated with normoalbuminuria.[18–20] In addition, structural alterations of glomerular as well as tubular compartments are observed in normoalbuminuric diabetes mellitus.[14],[16]

FE Mg is a tubular function that reflects the ability of tubular cell to reabsorb the glomerular filtrate of magnesium and retain the intracellular second-most abundant cation, magnesium. In essence, a normal value of FE Mg reflects an intact tubulointerstitial structure, whereas an elevated value of FE Mg implies of tubulointerstitial disease. By multiple regression analysis, FE Mg correlates directly with the magnitude of tubulointerstitial fibrosis.[21] In diabetes mellitus, elevated level of FE Mg is noted in normoalbuminuric type 2 diabetes, by which it indicates that FE Mg is a more sensitive marker than microalbuminuria in detecting early diabetic nephropathy.[19],[22] For other non-diabetic chronic kidney diseases, FE Mg is also shown to detect early chronic kidney disease associated with tubulointerstitial fibrosis, and is a useful screening marker to differentiate the mild form of renal disease associated with intact tubulointerstitial structure from the severe renal disease associated with tubulointerstitial fibrosis.[21],[23–26]

In accordance with the preceding information, microalbuminuria does not appear to be a useful marker for screening early chronic kidney disease associated with nephronal damage, but rather be a marker that reflects renal microvascular disease. In general, three mechanisms are responsible for the mechanism of microalbuminuria: glomerular endothelial dysfunction, intraglomerular hypertension and hemodynamic maladjustment, and podocyte injury.

GLOMERULAR ENDOTHELIAL DYSFUNCTION

A normal glomerular endothelial cell (1) releases an adequate amount of vasodilators, namely prostacyclin and nitric oxide. These vasodilators normally dilate the renal microcirculation to allow adequate blood perfusion to the nephronal structure. Normally, there is approximately 600 mL/min/1.73m² of renal plasma flow, of which it allows 120 mL/min/1.73m² to filtrate as glomerular filtration rate. The remaining blood passes through the efferent arteriole to become peritubular capillary flow, which supplies the tubulointerstitium. (2) produces negatively charged surface to maintain anticoagulant property.[26],[27] Such a surface would not only prevent the circulating clotting factors from clotting, but also prevent plasma albumin to leak out of the circulation. In diseased kidney, circulating toxins, such as oxidative stress, and proinflammation cytokines, such as the imbalance between enhanced proinflammatory cytokines (tumor necrosis factor alpha, transforming growth factor beta) and defective anti-inflammatory cytokine (interleukin-10), induce glomerular endothelial cell injury and dysfunction. A dysfunctioning glomerular endothelium releases less negative charge for the endothelium. A less negatively charged surface increases the glomerular capillary permeability to albumin and induces microalbuminuria as well as macroalbuminuria.

INTRAGLOMERULAR HYPERTENSION AND HEMODYNAMIC MALADJUSTMENT

A dysfunctioning glomerular endothelium releases more vasoconstrictors, namely angiotensin II and endothelin, and fewer vasodilators. Such a provasoconstrictive state observed in a variety of chronic kidney diseases induces a preferential constriction at the efferent arteriole, so called the hemodynamic maladjustment.[28–30]

The preferential constriction at the efferent arteriole in conjunction with the reduced glomerular surface area for filtration, secondary to the enhanced release of local vasoconstrictors angiotensin II and endothelin, induces intraglomerular hydrostatic pressure elevation. Increased intraglomerular hydrostatic pressure enhances filtration pressure across the glomerular basement membrane barrier, by which it increases glomerular capillary permeability to albumin, a characteristic phenomenon of sized-selective proteinuria. This hemodynamic induction of proteinuria can be ameliorated by correcting the hemodynamic maladjustment with vasodilators, namely, angiotensin-converting enzyme inhibitor and angiotensin receptor blocker. It is noted that a mild form of hemodynamic maladjustment observed in early chronic kidney disease, such as normoalbuminuric type 2 diabetic nephropathy and early IgM nephropathy, can be corrected by a single vasodilator. However, a severe form of hemodynamic maladjustment, such as that observed in micro- and macro-albuminuric type 2 diabetic nephropathy, and a severe form of chronic kidney diseases, such as nephrosis associated with focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis associated with tubulointerstitial fibrosis, and impaired renal function, usually requires multidrug vasodilators.[22],[24],[26],[27],[29],[31]

PODOCYTE INJURY

Podocytes and glomerular endothelial cells are postulated to play important roles in the progression and potential regression of glomerulosclerosis and tubulointerstitial fibrosis.[32] Podocytes normally contain slit diaphragm structures that assist in preventing protein leakage out into the urinary space. In addition, podocytes secrete vascular endothelial growth factor as well as angiopoietins, which are essential to the proliferation and growth of glomerular endothelial cells.[33] Podocyte injury is associated with the glomerular capillary dilation secondary to the intraglomerular hypertension. Capillary dilation detaches podocyte from the glomerular capillary basement membrane.[34],[35] Podocyte loss decreases the production of vascular endothelial growth factor.[36],[37] Depleted vascular growth factor induces further injury to the glomerular endothelium. Further injury to the glomerular endothelium aggravates a greater degree of hemodynamic maladjustment, and eventually a greater magnitude of injury to podocyte, in a vicious cycle manner.

Such a vicious cycle of injury would induce not only a sustained, intraglomerular hypertension with a persistent proteinuria, but also a progressive reduction in peritubular capillary flow and eventually chronic ischemic injury to the tubulointerstitium. Chronic ischemic injury secondary to glomerular endothelial dysfunction has recently been substantiated to be the crucial determinant of tubulointerstitial fibrosis.[38] Therefore, the increase in magnitude of microalbuminuria would reflect the progression of renal microvascular disease in type 2 diabetic nephropathy, which usually coincides with the progression of renal disease severity.

SUPPRESSION OF PROTEINURIA CORRELATES WITH A REGRESSION OF RENAL MICROVASCULAR DYSFUNCTION

The amelioration of proteinuria associated with idiopathic nephrotic syndrome such as mesangial proliferation or minimal change disease can be accomplished by steroid or immunosuppressive therapy. The mechanism of such therapeutic response of proteinuria remains unsettled, although suppression of glomerular capillary membrane permeability and restoration of negatively charged surface have been stipulated. In case of chronic kidney disease with significant hemodynamic maladjustment, amelioration of certain magnitude of proteinuria can be achieved by the correction of hemodynamic maladjustment with multidrug vasodilators. Such a therapeutic response has been demonstrated in chronic kidney diseases such as nephrosis associated with focal segmental glomerulosclerosis, type 2 diabetic nephropathy, and other chronic kidney diseases.[27–29],[31] In the case of nephrosis associated with focal segmental glomerulosclerosis, the remaining and persistent proteinuria following multidrug vasodilators can be totally suppressed by herbal therapy with Ganoderma lucidum, by which it demonstrates that the suppression of proteinuria coincides with the correction of the immunocirculatory imbalance.[27]

The preceding information renders support to the conceptual view of microalbuminuria reflecting renal microvascular disease, which is a crucial determinant inducing renal disease progression. An appropriate suppression of proteinuria—in particular, the correction of the hemodynamic maladjustment with multidrug vasodilators—would also improve the hemodynamic perfusion to the tubulointerstitial structure and effectively restore renal function. Hence, given FE Mg to screen early nephronal damage in chronic kidney disease and microalbuminuria as a marker of renal microvascular disease, it would assist in the early recognition of underlining renal microvascular disease in CKD patients; therefore, the implementation of early and appropriate therapeutic strategy for preventing renal microvascular disease progression would effectively restore the renal function.[39–42]

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

ACKNOWLEDGMENT

This study is supported by Thailand Research Fund and Thailand Research Council Fund.