Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.

Abstract

The human end-stage kidney and its experimental analogue, the remnant kidney in the rat, exhibit widespread tubulointerstitial disease. We investigated whether the pathogenesis of such tubulo-interstitial injury is dependent upon adaptive changes in tubular function and, in particular, in ammonia production when renal mass is reduced. Dietary acid load was reduced in 143nephrectomized rats by dietary supplementation with sodium bicarbonate (NaHCO3), while control rats, paired for serum creatinine after 14 nephrectomy, were supplemented with equimolar sodium chloride. After 4-6 wk, NaHCO3-supplemented rats demonstrated less impairment of tubular function as measured by urinary excretory rates for total protein and low molecular weight protein and higher transport maximum for para-aminohippurate per unit glomerular filtration rate, less histologic evidence of tubulo-interstitial damage, less deposition of complement components C3 and C5b-9, and a lower renal vein total ammonia concentration. Such differences in tubular function could not be accounted for simply on the basis of systemic alkalinization, and differences in tubular injury could not be ascribed to differences in glomerular function. Because nitrogen nucleophiles such as ammonia react with C3 to form a convertase for the alternative complement pathway, and because increased tissue levels of ammonia are associated with increased tubulo-interstitial injury, we propose that augmented intrarenal levels of ammonia are injurious because of activation of the alternative complement pathway. Chemotactic and cytolytic complement components are thereby generated, leading to tubulo-interstitial inflammation. Thus, alkali supplementation reduces chronic tubulo-interstitial disease in the remnant kidney of the rat, and we propose that this results, at least in part, from reduction in cortical ammonia and its interaction with the alternative complement pathway.

Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease

“…Several other studies demonstrated a significant association of serum K + <4.0 mEq/L and mortality, but the index of inflammation and follow up on CKD progression were not evaluated in sufficient detail [41][42][43] . Collectively, consistent with prior studies in animal CKD models [44] and known information of hypokalemia being a stimulator for ammonium genesis, angiotensin II, inflammatory mediators, and oxidative stress [28,45] , even mild degrees of hypokalemia, 3.5-4.0 mEq/L (which may be considered "normal") in patients with CKD can induce inflammation and poor clinical outcomes.…”

“…NH 4 + is generated in the proximal tubules and secreted into the lumen via [21,28,29] and potentially promoting ongoing kidney damage. Indeed, metabolic acidosis in CKD is associated with more rapid CKD progression [30,31] and increased mortality [32] .…”

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

“…Crry is heavily expressed within the glomerular mesangium of mice, as well as at the basolateral surface of the renal tubules (26), both of which are areas of C3 deposition in ischemic ARF. At baseline there is C3 deposition around the renal tubules indicating that there is a low level activation in the interstitium despite these inhibitors (25). In rats, treatment with an Ab to Crry led to renal injury marked by tubulointerstitial damage and cast formation, demonstrating the necessity of complement inhibition to prevent spontaneous tubular injury (27).…”

“…4). This has been attributed to complement activation by ammonia, which can modify C3 to form a C3 convertase and activate complement (25). C3 was present along Bowman's capsule and in small quantities within the glomerular mesangium.…”

Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes

“…Taken together, if complement activation is truly etiologic in renal IRI, this must be occurring through the alternative pathway. The site of activation could be on the apical surface of tubules [because this site lacks complement regulators (2)] or on the basolateral surface [a site that is clearly susceptible to spontaneous complement activation (17) as is illustrated by the finding of C3 deposits in this location in normal animals (22)]. …”