Karen A. Griffin

Acute kidney injury: a springboard for progression in chronic kidney disease

Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD.

Pathophysiology of Hypertensive Renal Damage. Implications for Therapy

Unlike the majority of patients with uncomplicated hypertension in whom minimal renal damage develops in the absence of severe blood pressure (BP) elevations, patients with diabetic and nondiabetic chronic kidney disease (CKD) exhibit an increased vulnerability to even moderate BP elevations. Investigations in experimental animal models have revealed that this enhanced susceptibility is a consequence of an impairment of the renal autoregulatory mechanisms that normally attenuate the transmission of elevated systemic pressures to the glomeruli in uncomplicated hypertension. The markedly lower BP threshold for renal damage and the steeper slope of relationship between BP and renal damage in such states necessitates that BP be lowered into the normotensive range to prevent progressive renal damage. When BP is accurately measured using radiotelemetry in animal models, the renal protection provided by renin-angiotensin system (RAS) blockade is proportional to the BP reduction with little evidence of BP-independent protection. A critical evaluation of the clinical data also suggests that the BP-independent renoprotection by RAS blockade has been overemphasized and that achieving lower BP targets is more important than the selection of antihypertensive regimens. However, achievement of such BP goals is difficult in CKD patients without aggressive diuresis, because of their proclivity for salt retention. The effectiveness of RAS blockers in lowering BP in patients who have been adequately treated with diuretics, along with their potassium-sparing and magnesium-sparing effects, provides a more compelling rationale for the use of RAS blockade in the treatment of CKD patients than any putative BP-independent renoprotective superiority.

Adverse renal consequences of obesity

Emerging evidence indicates that obesity, even in the absence of diabetes, contributes significantly to the development and progression of chronic kidney disease (CKD). Glomerular hyperfiltration/hypertrophy in response to the increased metabolic needs of obesity are postulated to lead to the development of glomerulosclerosis (GS) in a manner analogous to that in reduced renal mass states. Nevertheless, the individual risk for developing GS with obesity is very low. It is proposed that glomerular hyperfiltration/hypertrophy are per se not pathogenic in the absence of an enhanced glomerular blood pressure (BP) transmission, and the modest preglomerular vasodilation that is likely present in the large majority of obese individuals is not sufficient to result in such increased BP transmission. However, in the small subset of obese individuals who are also born with a substantially reduced nephron number, there is a greater risk of enhanced glomerular BP transmission due to the substantially greater preglomerular vasodilation. Of perhaps greater clinical importance, similar additive deleterious effects of obesity on BP transmission would be expected in individuals with reduced renal mass, either congenital or acquired, or with concurrent renal disease, leading to accelerated progression. Of note, a low birth weight may be a risk factor for not only reduced nephron numbers at birth, but also for obesity and hypertension, resulting in a clustering of risk factors for progressive GS. Therefore, even though the individual risk for developing obesity GS is low, the cumulative impact of obesity on the public health burden of CKD is likely to be large because of its huge prevalence.

Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys.

Hypertensive mechanisms are postulated to play a major role in the progressive glomerulosclerosis (GS) after renal mass reduction. But, in contrast to converting enzyme inhibitors, BP reduction by calcium channel blockers, has not provided consistent protection. Radiotelemetric BP monitoring for 7 wk was used to compare nifedipine (N) and enalapril (E) in the rat approximately 5/6 renal ablation model. After the first week, rats received N, E, or no treatment (C). The overall averaged systolic BP in C (173 +/- 7 mmHg) was reduced by both E and N (P < 0.001), but E was more effective (113 +/- 2 vs. 134 +/- 3 mmHg, P < 0.01). GS was prevented by E (2 +/- 1 vs. 26 +/- 5% in C) but not by N (25 +/- 6%). GS correlated well with the overall averaged BP in individual animals of all groups, but the slope of the relationship was significantly steeper in N compared with C+E rats (P < 0.02), suggesting greater pressure transmission to the glomeruli and GS for any given BP. Since autoregulatory mechanisms provide the primary protection against pressure transmission, renal autoregulation was examined at 3 wk in additional rats. Autoregulation was impaired in C rats, was not additionally altered by E, but was completely abolished by N. These data demonstrate the importance of autoregulatory mechanisms in the pathogenesis of hypertensive injury and suggest that calcium channel blockers which adversely affect pressure transmission may not provide protection despite significant BP reduction.

Renoprotection by ACE Inhibition or Aldosterone Blockade Is Blood Pressure-Dependent

Abstract—Renin-angiotensin-aldosterone system blockade has been shown to protect against renal damage in salt-supplemented, stroke-prone spontaneously hypertensive rats (SHRsp). Based on intermittent tail-cuff blood pressure (BP) measurements, it has been claimed that such protection is BP-independent and mediated by a blockade of the direct tissue-damaging effects of angiotensin and/or aldosterone. BP radiotelemetry was performed for 8 weeks in ≈10-week-old male SHRsp who received a standard diet and either tap water (n=10) or 1% NaCl to drink. Saline-drinking SHRsp were either left untreated (n=12), received enalapril (50 mg/L) in drinking fluid (n=9), or had subcutaneous implantation of time-release 200-mg pellets of aldactone (n=10). The average systolic BP (mean±SEM) during the final 3 weeks was significantly higher (P <0.05) in untreated saline-drinking (215±6 mm Hg) SHRsp but not aldactone-treated (198±4 mm Hg) or enalapril-treated treated SHRsp (173±1 mm Hg), as compared with tap water–drinking SHRsp (197±3 mm Hg). Histological renal damage scores at 8 weeks paralleled the BP in all groups, with an excellent correlation (r =0.8, P <0.001, n=41). Moreover, a renal damage score of >5 was only observed in SHRsp whose average systolic BP during the final 3 weeks exceeded 200 mm Hg, indicating a threshold relation with BP. These data show that protection by renin-angiotensin-aldosterone system blockade in this model is BP-dependent and mediated by preventing the severe increases in BP seen in untreated salt-supplemented SHRsp and further underscore the limitations of interpretations based on conventional tail-cuff BP measurements.

Protective Importance of the Myogenic Response in the Renal Circulation

Primary essential hypertension is second only to diabetic nephropathy as a etiology for end-stage renal disease.1 In addition, coexistent/superimposed hypertension plays a major role in the progression of most forms of chronic kidney disease (CKD), including diabetic nephropathy.2–5 Nevertheless, the individual risk is very low, with <1% of the hypertensive population developing end-stage renal disease. Such data indicate that there must be mechanisms that normally protect the kidneys from hypertensive injury of a severity sufficient to result in end-stage renal disease. The following Brief Review summarizes the evidence that indicates that the renal autoregulatory response, primarily mediated by the myogenic mechanism, is largely responsible for such protection. Moreover, the differing patterns of renal damage that are observed in clinical and experimental hypertension are best explained when considered in the context of alterations in the renal autoregulatory capacity. Recent data also indicate that hypertensive renal damage correlates most strongly with systolic blood pressure (BP).6–8 Accordingly, the review further emphasizes the kinetic characteristics of the renal myogenic response to oscillating BP signals that render it particularly capable of providing protection against systolic pressures. Most individuals with primary hypertension develop the modest vascular pathology of benign nephrosclerosis.5 The glomeruli are largely spared, and, therefore, proteinuria is not a prominent feature. Because it progresses fairly slowly with limited ischemic nephron loss, renal function is not seriously compromised, except in some genetically susceptible individuals or groups, such as blacks, in whom a more accelerated course may be seen.2–5 Thus, the slope of the relationship between renal damage and BP through most of the hypertensive range is fairly flat in individuals with benign nephrosclerosis.2–4 However, if the hypertension becomes very severe and exceeds a critical threshold, severe acute disruptive injury of malignant nephrosclerosis to the renal arteries and arterioles develops …

Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer.

To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies (a) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and (b) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertension-induced renal injury in the rat.

Progression of Renal Disease: Renoprotective Specificity of Renin-Angiotensin System Blockade

Recent guidelines for management of patients with chronic kidney disease recommend both lower optimal BP targets and agents that block the renin-angiotensin system (RAS) for specific additional BP-independent renoprotection. Although there are other compelling rationales to use RAS blockade in patients with chronic kidney disease, including its antihypertensive effectiveness and ability to counteract the adverse effects of diuretics, a critical review of the available scientific evidence suggests that the specificity of renoprotection that is provided by RAS blockade has been greatly overemphasized. Little evidence of truly BP-independent renoprotection is observed in experimental animal models when ambient BP is assessed adequately by chronic continuous BP radiotelemetry. Although the clinical trial evidence is somewhat stronger, nevertheless, even when interpreted favorably, the absolute magnitude of the BP-independent component of the renoprotection that is observed with RAS blockade is much smaller than what is due to its antihypertensive effects.

Long-term renal consequences of hypertension for normal and diseased kidneys.

Substantial evidence indicates that the adverse effects of hypertension on the kidney depend on the degree to which systemic blood pressure elevations are transmitted to the renal microvasculature. Such blood pressure transmission and consequent susceptibility to hypertensive renal damage is markedly exacerbated in states characterized by preglomerular vasodilation and an impairment of the normally protective renal autoregulatory mechanisms, e.g. diabetes or chronic renal disease. Moreover, this pathophysiology gives rise to the prediction that prevention of hypertension-induced barotrauma will require blood pressure to be reduced well into the normotensive range in such patients, as is being recognized in the currently recommended blood pressure goals. Agents that block the renin-angiotensin system should be preferred as initial therapy as they may provide additional risk reductions and minimize the potassium and magnesium depletion associated with the diuretic use usually necessary to achieve the lower blood pressure targets. The current failure to achieve optimal blood pressure reductions may be contributing not only to the still escalating incidence of end-stage renal disease in diabetic patients, but also to their greatly increased cardiovascular morbidity and mortality.

Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.