Progression Of Hypertensive Kidney Disease Research Articles

Hypertension in chronic kidney disease: What lies behind the scene

Hypertension is a frequent condition encountered during kidney disease development and a leading cause in its progression. Hallmark factors contributing to hypertension constitute a complexity of events that progress chronic kidney disease (CKD) into end-stage renal disease (ESRD). Multiple crosstalk mechanisms are involved in sustaining the inevitable high blood pressure (BP) state in CKD, and these play an important role in the pathogenesis of increased cardiovascular (CV) events associated with CKD. The present review discusses relevant contributory mechanisms underpinning the promotion of hypertension and their consequent eventuation to renal damage and CV disease. In particular, salt and volume expansion, sympathetic nervous system (SNS) hyperactivity, upregulated renin–angiotensin–aldosterone system (RAAS), oxidative stress, vascular remodeling, endothelial dysfunction, and a range of mediators and signaling molecules which are thought to play a role in this concert of events are emphasized. As the control of high BP via therapeutic interventions can represent the key strategy to not only reduce BP but also the CV burden in kidney disease, evidence for major strategic pathways that can alleviate the progression of hypertensive kidney disease are highlighted. This review provides a particular focus on the impact of RAAS antagonists, renal nerve denervation, baroreflex stimulation, and other modalities affecting BP in the context of CKD, to provide interesting perspectives on the management of hypertensive nephropathy and associated CV comorbidities.

GSTM1 Copy Number and Kidney Disease in People With HIV

GSTM1 Copy Number and Kidney Disease in People With HIV

Modeling the Progression of Hypertensive Kidney Disease in African Americans

Chronic kidney disease (CKD) is associated with the progressive functional loss of nephrons and hypertension (HTN). Several clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, but there are few long‐term clinical studies that determine the impact of CCBs in patients with hypertensive CKD. African Americans (AA) have a faster progression to end stage renal disease as compared to the white population which may be partially explained by factors such as salt‐sensitive blood pressure (BP) and greater prevalence of uncontrolled HTN. Observational studies demonstrate BP to be a strong independent risk factor for CKD progression, yet intense BP lowering in AA does not diminish the renal function decline any more than standard therapy. The African American Study of Kidney Disease and Hypertension (AASK) trial suggests AA with proteinuric CKD may have detrimental responses to CCB as compared to an angiotensin converting enzyme (ACE) inhibitor. Therefore, using a large physiological model, we set out to replicate the AASK trial findings and predict the roles of the renin‐angiotensin system, salt intake, and intensive antihypertensive therapy in a virtual population during CCB therapy. Our current mathematical model, HumMod, is a large physiological simulator that is comprised of key systems that play an integral role in BP control such as neural, endocrine, circulatory, and renal systems. All of the parameters (n=335) that control these systems were randomly varied and resulted in over 3,000 unique models that we define as a virtual population. We calibrated this virtual population to patient level data from the AASK trial (BP and glomerular filtration rate [GFR] before and after 3 years of amlodipine). After matching the virtual population to individual level data, the virtual population (n=140) was associated with statistically similar BP and GFR before and after CCB therapy (Figure) as well as similar increases in glomerular damage. Baseline factors such as elevated single nephron GFR and increased tubuloglomerular feedback were correlated with greater declines in renal function and increased glomerulosclerosis after 3 years of CCB. Interestingly, when looking at the models with severe CKD (<35 mL/min), glomerulosclerosis and angiotensin II significantly increased with CCB despite significant falls in mean BP (‐7 ± 7 mmHg). Adding an ACE inhibitor decreased angiotensin II levels and abrogated the increase in glomerulosclerosis while further decreasing BP (‐12 ± 9 mmHg). Decreasing salt intake in addition to the CCB+ACE inhibitor therapy further benefited systemic and glomerular pressures but significantly decreased overall GFR independent of any glomerular damage. Finally, all antihypertensive therapies were associated with significant decreases in left ventricular mass. These data suggest the current clinical markers of renal function such as eGFR may not fully reflect the actual progression of CKD, especially with intensive antihypertensive treatment. Our simulation also supports that angiotensin system inhibitors are renoprotective and cardioprotective when combined with CCB therapy in African American CKD patients.

Loss of Cingulin‐like 1 in Dahl Salt‐Sensitive Rats Leads to Reduced Renal Injury and Blood Pressure

Hypertension is both a cause and effect of chronic kidney disease (CKD) and impacts a significant proportion of patients, with a worldwide prevalence of 10‐15%. Previous genetic studies involving the Dahl salt‐sensitive (SS) rat, a model of hypertensive CKD, identified multiple genetic loci linked to kidney injury, including a region on chromosome (Chr) 8. Subsequently, an S.SHR(8) congenic (i.e. transfer of kidney injury resistant SHR genome onto the SS background) demonstrated significantly reduced proteinuria and improved renal function compared to SS control. To identify the gene/s responsible, genome sequencing and bioinformatics analysis identified cingulin‐like 1 (Cgnl1) as a putative gene linked to kidney injury on Chr. 8. Cgnl1 is known to localize to adherens and tight cell‐cell junctions, mediating junction assembly via regulating the activity of the small GTPases such as RhoA and Rac1. A SS‐Cgnl1−/− knockout (KO) was developed to test the hypothesis that loss of Cgnl1 will result in a significant attenuation of kidney injury compared to SS (WT). Both on low and high‐salt (LS=0.3% or HS=2.0% NaCl), KO animals (n=6) demonstrated reduced proteinuria compared to WT animals (n=6) for the entirety of the experiment (HS; KO= 28.7 ± 2.9 versus WT= 161.4 ± 33.1 mg/24hr at week 15, p<0.0001). To further validate Cgnl1’s effect on blood pressure and kidney injury, a temporal analysis (6‐12 weeks) using telemetry and additional renal measurements were conducted on WT and KO animals. On HS, KO animals (n=6) demonstrated reduced proteinuria compared to WT (n=6) for the entirety of the experiment (52.1 ± 7.2 versus 395.9 ± 29.8 mg/24hr at week 12, p<0.0001). While HS fed WT animals exhibited a significant increase in BP compared to LS WT (MAP=197.0 ± 5.0 versus 142.8 ± 3.5 mmHg, p<0001), KO remained unchanged (MAP= 127.6 ± 2.7 and 133.9 ± 3.7 mmHg respectively, NS). Kidney pathology measures, including glomerular and tubular injury were all significantly improved (all p<0.05) in KO compared to WT. Nephron number was measured with no significant difference between WT and KO in young animals, but HS fed WT demonstrated a significant loss of nephrons compared to KO. Bulk RNAseq of kidneys from WT and KO identified Cgnl1 as top downregulated gene with altered expression of many known genes linked with Cgnl1 compared to WT, along downregulation of genes associated with renal injury, mainly reflective of physiological differences from week12‐15. To better identify genes involved in onset of injury, single nuclei RNAseq was performed at week 4 (before physiological differences) to evaluate impact of Cgnl1 in distinct cell populations initiating injury. Additional work is also currently being done on HEK293‐ Cgnl1 knockout cell lines for more mechanistic study of Cgnl1 and pathways. In total, the molecular work, along with the physiological characterization of the SS‐Cgnl1−/−, is expected to provide insight into the role of Cgnl1 in the onset and progression of hypertensive kidney disease and identify new therapeutic targets.

Genetic Knockout of Cingulin‐like 1 Reduces Renal Injury and Blood Pressure in Dahl Salt‐Sensitive Rats

Chronic kidney disease (CKD) has been estimated to impact 37 million people, ranking kidney diseases to be the ninth leading cause of death in the United States. Hypertension is very common in patients with CKD, and is a risk factor for the progression of kidney disease. Previous genetic studies involving the Dahl salt-sensitive (SS) rat identified multiple genetic loci linked to kidney injury, including a region on chromosome 8. To confirm the genetic association, an S.SHR(8) congenic was developed to transfer the linked chromosome 8 genomic segment from the SHR (resistant to kidney injury) onto the SS genetic background. The S.SHR(8) demonstrated significantly reduced proteinuria and improved renal function compared to SS control. Based on whole genome sequencing and bioinformatics analysis of the chromosome 8 region, cingulin-like 1 (Cgnl1) was identified as a putative gene linked to kidney injury. Cgnl1 is known to localize to adherens and tight cell-cell junctions, mediating junction assembly via regulating the activity of the small GTPases such as RhoA and Rac1. A knockout animal (SS-Cgnl1−/−) was developed to test the hypothesis that loss of Cgnl1 will result in a significant attenuation of kidney injury compared to SS-WT. A temporal analysis of cardiovascular and renal measurements was conducted on SS-WT and SS-Cgnl1−/− from 6–15 weeks of age under low or high-salt diets (0.3% or 2% NaCl). On low-salt, SS-Cgnl1−/− animals (n=6) demonstrated reduced proteinuria compared to SS-WT animals (n=6) for the entirety of the experiment (21.9 ± 0.6 versus 87.6 ± 9.3 mg/24hr at week 15, p=0.03). Similar results were seen with high-salt (28.7 ± 2.9 versus 161.4 ± 33.1 mg/24hr at week 15, p<0.0001). While high-salt fed SS-WT animals exhibited a significant increase in terminal mean arterial pressure (MAP) compared to low-salt SS-WT (156 ± 5.9 versus 133.9 ± 4.0 mmHg, p=0.0095), MAP for SS-Cgnl1−/− remained unchanged between low and high-salt groups (119.3 ± 3.2 and 124.8 ± 3.8 mmHg respectively, NS). Kidney pathology measures were all significantly improved in SS-Cgnl1−/− compared to SS-WT animals, including glomerular injury and tubulointerstitial injury (all p<0.05). RNA sequencing was performed on kidneys from SS-WT and SS-Cgnl1-/- to investigate molecular changes associated with reduced blood pressure and renal protection. Cgnl1 was identified as top down-regulated gene in the dataset, with many known genes linked with Cgnl1 observed to be differentially expressed compared to SS-WT. We are currently conducting additional studies using telemetry to monitor blood pressure differences over the time course. Additionally, we are working to develop a Cgnl1 knockout cell line using CRISPR/Cas9 gene-editing (HEK293) for more mechanistic study of Cgnl1 and pathways. The molecular work, along with the physiological characterization of the SS-Cgnl1−/−, is expected to provide insight into the role of Cgnl1 in the onset and progression of hypertensive kidney disease and identify new therapeutic targets.

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT1 receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.

Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension.

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis.

Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.

CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis.

Recent studies have shown that angiotensin II (Ang II) plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms are poorly understood. In this study, we investigated the role of CXCR6 in Ang II-induced renal injury and fibrosis. Wild-type and CXCR6-green fluorescent protein (GFP) knockin mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg per minute after unilateral nephrectomy for ≤ 4 weeks. Wild-type and CXCR6-GFP knockin mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that was similar between wild-type and CXCR6-GFP knockin mice. CXCR6-GFP knockin mice were protected from Ang II-induced renal dysfunction, proteinuria, and fibrosis. CXCR6-GFP knockin mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts and produced less extracellular matrix protein in the kidneys after Ang II treatment. Furthermore, CXCR6-GFP knockin mice exhibited fewer F4/80(+) macrophages and CD3(+) T cells and expressed less proinflammatory cytokines in the kidneys after Ang II treatment. Finally, wild-type mice engrafted with CXCR6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts, macrophages, and T cells in the kidney after Ang II treatment when compared with wild-type mice engrafted with CXCR6(+/+) bone marrow cells. Our results indicate that CXCR6 plays a pivotal role in the development of Ang II-induced renal injury and fibrosis through regulation of macrophage and T-cell infiltration and bone marrow-derived fibroblast accumulation.

Critical Role of CXCL16 in Hypertensive Kidney Injury and Fibrosis

Recent evidence indicates that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that chemokine (C-X-C motif) ligand 16 (CXCL16) was induced in renal tubular epithelial cells in response to angiotensin II in a nuclear factor-κB-dependent manner. To determine whether CXCL16 plays a role in angiotensin II-induced renal inflammation and fibrosis, wild-type and CXCL16 knockout mice were infused with angiotensin II at 1500 ng/kg per minute for up to 4 weeks. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from angiotensin II-induced renal dysfunction, proteinuria, and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys of angiotensin II-treated mice, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the kidneys of angiotensin II-treated mice compared with wild-type mice. Finally, CXCL16 deficiency reduced angiotensin II-induced proinflammatory cytokine expressions in the kidneys. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of angiotensin II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation.

Hypertensive nephrosclerosis: not enough of a good thing?

glutathione s -transferases (GSTs) are multifunctional enzymes that are perhaps best known to participate in cell detoxification by catalyzing the conjugation of reduced glutathione to a wide variety of xenobiotics that have electrophilic centers. Production of these adducts promotes cytoprotection

Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis (P = 0.04) and in the time to GFR event, dialysis, or death (P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

CXCL16 REGULATES ANGIOTENSIN II-INDUCED INFLAMMATION AND PROTEINURIA

Hypertension is a major cause of chronic kidney disease. Recent studies have shown that inflammation plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We have found that CXCL16, a recently discovered chemokine, is induced in the kidney in a murine model of angiotensin II (Ang II)-induced hypertension. Therefore, we examined whether CXCL16 regulates inflammatory cell infiltration and renal injury using CXCL16 knockout (CXCL16-KO) mice. Wild-type (WT) and CXCL16-KO mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg/min for up to 4 weeks. To accelerate renal injury, all mice were subjected to unilateral nephrectomy and received 1% NaCl in drinking water. WT and CXCL16-KO mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that is similar between WT and CXCL16-KO mice. Immunohistochemical analysis showed that targeted disruption of CXCL16 inhibits infiltration of F4/80+ macrophages and CD3+ T cells in the kidney of Ang II treated mice compared with WT mice. Real time RT-PCR demonstrated that targeted disruption of CXCL16 reduced gene expression of inflammatory cytokines (IL-1β and TNF-α) in the kidney of Ang II treated mice. Histological analysis revealed that CXCL16 deficiency inhibited Ang II-induced renal injury. Furthermore, targeted deletion of CXCL16 reduced Ang II-induced proteinuria and podocyte loss. In Summary, our results indicate that CXCL16 plays a pivotal role in the development of renal injury and proteinuria through regulation of macrophage and T cell infiltration.

Role of AT1receptor-mediated salt retention in angiotensin II-dependent hypertension

Activation of type 1 angiotensin II (AT(1)) receptors in the kidney promotes blood pressure elevation and target organ damage, but whether renal AT(1) receptors influence the level of hypertension by stimulating sodium retention or by raising systemic vascular resistance has not been established. In the current studies, we used a kidney cross-transplantation strategy to determine whether increased sodium reabsorption by AT(1) receptors in the kidney mediates the chronic hypertensive response to angiotensin II. We found this to be true. In addition, we also identified a second, nontrivial component of blood pressure elevation induced by activation of renal AT(1) receptors that is sodium-independent. As the kidney has the capacity to limit the transmission of elevated systemic blood pressure into the renal microcirculation, prior studies struggled to clearly discriminate the relative contributions of blood pressure elevation vs. activation of AT(1) receptors to hypertensive kidney injury. In our model, we found that rapid surges in blood pressure, which may overcome the kidney's capacity to prevent perturbations in renal hemodynamics, correlate closely with kidney damage in hypertension. Moreover, maximal kidney injury in hypertension may require activation of a pool of nonrenal, systemic AT(1) receptors. These studies provide insight into precise mechanisms through which AT(1) receptor blockade influences the progression of hypertensive kidney disease.

Effect of Blood Presssure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease: Results From the AASK Trial—Correction

Effect of Blood Presssure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease: Results From the AASK Trial—Correction

The Relationship Between Magnitude of Proteinuria Reduction and Risk of End-stage Renal Disease

The magnitude of proteinuria is associated with a graded increase in the risk of progression to end-stage renal disease and cardiovascular events. The objective of this study was to relate baseline and early changes in proteinuria and glomerular filtration rate (GFR) to long-term progression of hypertensive nondiabetic kidney disease. Post hoc analysis of a randomized 3 x 2 factorial trial. A total of 1094 African Americans with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were followed up for a median of 3.8 years. Participants were randomized to a mean arterial pressure goal of 102 to 107 mm Hg (usual) or 92 mm Hg or less (lower) and to initial treatment with a beta-blocker (metoprolol), an angiotensin-converting enzyme inhibitor (ramipril), or a dihydropyridine calcium channel blocker (amlodipine) Baseline proteinuria and GFR predicted the rgate of GFR decline. For each 10-mL/min per 1.73 m(2) lower baseline GFR, an associated mean +/- SE 0.38 +/- 0.08-mL/min per 1.73 m(2) per year greater mean GFR decline occurred, and for each 2-fold higher proteinuria level, a mean +/- SE 0.54 +/- 0.05-mL/min per 1.73 m(2) per year faster GFR decline was observed (P < .001 for both). In multivariate analysis, the effect of baseline proteinuria GFR decline persisted. Initial change in proteinuria from baseline to 6 months predicted subsequent progression, with this relationship extending to participants with baseline urinary protein levels less than 300 mg/d. The change in the level of proteinuria is a predictor of subsequent progression of hypertensive kidney disease at a given GFR. A prospective trial is needed to confirm this observation.

Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from the AASK trial

Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from the AASK trial