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The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of blood pressure (BP) in chronic kidney disease (CKD) supersedes the 2004 Kidney Disease Quality Outcomes Initiative document on this topic. The new guideline has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. The recommendations in the guideline acknowledge that no single BP target is optimal for all CKD patients and encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mm Hg systolic and ≤90 mm Hg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mm Hg systolic and ≤80 mm Hg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the renin-angiotensin-aldosterone system is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes. Special considerations relevant to children and those of older age and those who have received a kidney transplant are included. Ongoing controversies in BP management in the context of CKD are highlighted along with key areas for future research.

Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Improving quality of life and survival of CKD patients necessitates a large number of preventive and therapeutic interventions. To resolve these issues several organizations have developed guidelines, which are difficult to compare comprehensively. The Kidney Disease: Improving Global Outcomes website at http://kdigo.org compares five major guidelines. The section ‘compare guidelines’ covers 41 topics distributed over five major subjects: (1) general clinics; (2) hemodialysis (HD); (3) vascular access for HD; (4) peritoneal dialysis; and (5) chemistries. The tables compare guideline recommendations and the evidence levels on which they are based, with direct links to each of the guidelines. These data show that the different guideline groups tend to propose similar targets, but that nuances in the guideline statements, their rationale, and grading of evidence levels present some discrepancies, although most guidelines are based on the same literature. We conclude that there is an urgent need to harmonize existing guidelines, and for a global initiative to avoid the parallel development of conflicting guidelines on the same topics. The tables displayed on the website offer a basis for structuring this process, a procedure which has recently been initiated by a body composed of the five guideline development groups.

Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function. Background There is growing evidence of long-term pathological consequences following renal ischemia. Endothelin (ET) receptor antagonists have proved beneficial in the treatment of ischemic acute renal failure (IARF); however, the long-term outcomes have not been assessed in this disease. Methods Experimental IARF was induced in uninephrectomized female Sprague-Dawley rats ( N = 8) by clamping of the renal pedicle. At 24-hours postischemia, a once-only administration of drug or vehicle was given. One ischemic group received saline only (saline ischemic), and two other ischemic groups received either SB 234551 (ET A receptor antagonist, ET A group) or SB 209670 (ET A and ET B receptor antagonist, ET A /ET B group). A uninephrectomized control group was sham operated to simulate operative conditions without ischemia and was given a once-only saline infusion (sham ischemic). All groups were sacrificed at six-months postischemia. Serum creatinine was assessed daily for one week and then every four weeks. Glomerular filtration rates (GFRs), systolic blood pressure, 24-hour urine collection, and creatinine clearance were performed just prior to sacrifice. Immunohistochemistry for monocytes and macrophages (Mo and Mφ), myofibroblasts (MF, α-SMA), collagen IV, and collagen III was also evaluated. Cell kinetics were studied by immunostaining for proliferating cell nuclear antigen (PCNA) and by TUNEL. Results Urinalysis revealed significant increases in urinary protein and albumin in the ET A /ET B group when compared with all other groups. GFRs and creatinine clearance were also decreased significantly in the ET A /ET B group. Urine albumin, protein, GFR, and creatinine clearance in the ET A group, however, were not different from the sham ischemic and saline ischemic groups. Systolic blood pressure was increased in the saline ischemic group as compared with all other groups. Kidney weights were increased in all ischemic groups, but no differences were observed between the saline ischemic group and ET R antagonist-treated groups. Immunohistochemistry revealed relationships between Mo and Mφ, MF, and tubulointerstitial collagen III, where the saline ischemic and ET A /ET B groups were increased as compared with the sham ischemic and ET A groups. There was no change observed in tubulointerstitial collagen IV accumulation. The largest number of proliferating cells was demonstrated in the ET A /ET B group, whereas apoptotic cells were identified in small amounts in all groups, with the largest number being found in the saline ischemic group. Conclusions Renal ischemia appears to have long-term functional and pathological consequences that can be prevented by treatment with ET A receptor antagonists. Blockade of both ET A and ET B receptors, however, appears to be detrimental to long-term kidney function.

Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis. Background Tissue factor (TF) pathway inhibitor (TFPI), the major endogenous inhibitor of extrinsic coagulation pathway activation, protects renal function in experimental crescentic glomerulonephritis (GN). Its glomerular expression and relationship to TF expression and fibrin deposition in human crescentic GN have not been reported. Methods Glomerular TFPI, TF, and fibrin-related antigen (FRA) expression were correlated in renal biopsies from 11 patients with crescentic GN. Biopsies from 11 patients with thin basement membrane disease and two normal kidneys were used as controls. Results TFPI was undetectable in control glomeruli but was detectable in interstitial microvessels. In crescentic biopsies, TFPI was detected in cellular crescents and was more prominent in fibrous/fibrocellular crescents, indicating a correlation with the chronicity of crescentic lesions. TFPI appeared to be associated with macrophages but not endothelial or epithelial cells. TFPI was generally undetectable in regions of the glomerular tuft with minimal damage. In contrast, TF and FRA were strongly expressed in regions of minimal injury, as well as in more advanced proliferative and necrotizing lesions. Despite prominent TF expression, FRA was less prominent in fibrous/fibrocellular crescents in which TFPI expression was maximal. Conclusions These data suggest that TFPI is strongly expressed in the later stages of crescent formation and is inversely correlated with the presence of FRA in human crescentic GN. This late induction of TFPI may inhibit TF activity and favor reduced fibrin deposition in the chronic stages of crescent formation.

Collagen studies in newborn rat kidneys with incomplete ureteric obstruction. Collagen studies in newborn rats with incomplete ureteric obstruction were performed to describe and quantify changes in collagen deposition resulting from urinary tract obstruction at an early developmental age. Incomplete ureteric obstruction was created in three-day-old rats by placing the left ureter in a tunnel formed by the psoas muscle, and sham-operated controls underwent a laparotomy. The rats were sacrificed at 10, 17, 24 or 31 days. Collagen types I, III, IV, and V were localized by indirect immunofluorescence microscopy, the total collagen content of the kidney was quantitated using hydroxyproline analysis, and collagen types I and III were quantitated using cyanogen bromide (CNBr) peptide analysis. Increased immunofluorescent staining for all of the collagens was found in the diffusely widened medullary interstitium of the obstructed kidney, and more focally in the cortical interstitium. Collagen types I, III and V, but not collagen type IV, were also found in bands in the interstitium at the junction of the cortex with the medulla. Increased staining for collagen type IV was found in thickened and tortuous tubular basement membranes (TBM) of the obstructed kidneys. The total collagen content of the obstructed kidney was significantly increased compared to the amounts in both the contralateral kidneys and in the kidneys from sham-operated controls at 24 and 31 days of age (P < 0.01 in each case, Wilcoxon matched pairs rank sum test and Mann Whitney U-test, respectively). The amount of collagen in the kidneys correlated with the degree of hydronephrosis (Spearman correlation test, r = 0.78, P < 0.02). CNBr peptide analysis demonstrated that over 50% of the collagen in the normal neonatal rat kidney was collagen type I and approximately 25% was collagen type III. In the obstructed kidneys most of the collagen was also collagen type I and collagen type III, although the proportion of total collagen comprised by these collagen types was decreased compared with the controls. The amount of collagen type III in the contralateral kidneys was reduced compared to that in the controls. Thus, the neonatal renal response to obstruction resulted in increased amounts of a range of collagens in the interstitium and TBM, and the extent of this response was partially related to the degree of hydronephrosis.

Ischemic acute renal failure: Long-term histology of cell and matrix changes in the rat. Background The cellular infiltration and matrix accumulation accompanying acute renal ischemia and reperfusion have been frequently noted but poorly defined. The long-term consequences of ischemia may irreversibly damage the kidney. Methods Female Sprague-Dawley rats (200 g) underwent unilateral nephrectomy. After five days, the left renal pedicle was occluded for 45 minutes. Animals were sacrificed at 0, 1, 2, 4, 8, 16, 32, 64, and 180 days postischemia ( N = 6). Immunohistochemistry for monocytes/macrophages (Mo/Mϕ, ED-1), myofibroblasts [α-smooth muscle actin (α-SMA)], collagen III and IV, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antigen (PCNA) and terminal dUTP nick end labeling (TUNEL) were performed. Results Kidney weights of postischemic animals were increased at all time points (postischemic to controls, 1.47 ± 0.21 to 0.94 ± 0.12 g at day 8; 1.49 ± 0.20 to 1.27 ± 0.13 g at day 64; and 1.86 ± 0.1 to 1.24 ± 0.2 g at day 180). Serum creatinine values increased to 0.42 ± 0.10 mmol/L at day 2 but returned to control levels by day 8 (0.05 mmol/L). Glomerular collagen IV was decreased from 2 to 16 days postischemia, which was accompanied by an increase in MMP-2. The fractional area of the interstitium was greatest at day 8 (19.55 ± 0.91% compared with day 0 at 8.08 ± 0.27%), with a second increase observed at day 180 (16.61 ± 0.70%). Interstitial Mo/Mϕ increased postischemia from days 2 through 8 (8.84 ± 2.12 to 133.32 ± 14.04 per 0.91 mm 2 ) and then decreased. Myofibroblasts proliferated locally (PCNA double labeling was demonstrated), and increased numbers were found from days 2 through 16 (maximal at day 8, 26.96 ± 3.04%, compared with day 0, 0.88 ± 0.11%). In the postischemic groups, collagen IV increased to day 8 (20.84 ± 1.30%), but then decreased to below control values at day 64 (2.22 ± 0.15%) before returning to normal by day 180. Interstitial collagen III increased to 8 days (0.45 ± 0.07% to 2.55 ± 0.36%) and then decreased to control levels by day 32, but showed a marked increase to approximately 6% at days 64 and 180. Cellular proliferation (PCNA) was maximal at days 2 and 4 (affecting tubule cells and myofibroblasts but not macrophages). Apoptosis was maximal at day 8 (in both interstitial and tubule cells) in the postischemic groups. Conclusion Marked changes in the accumulation of Mo/Mϕ, MF, and collagen IV were found in this model of ischemic acute renal failure. The reversibility of functional and structural changes is in marked contrast to that found in progressive disease. The increases observed for collagen III at 64 and 180 days postischemia suggest that in the long term, however, further chronic structural changes may be observed.

Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists.BackgroundEndothelin (ET) may be a mediator of injury following ischemia-induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when administered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed.MethodsWe investigated the use of ETR antagonists, PD 156707 (ETA) and SB 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SB 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SB 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/Mφ), α-smooth muscle actin–positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen.ResultsAll ischemic groups of rats initially developed raised serum creatinine levels; however, no significant difference was observed between the groups (Kruskal–Wallis). Creatinines returned to preischemic values in all groups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/Mφ was significantly reduced in groups treated with ETR antagonists (P< 0.001). The presence of myofibroblasts was also significantly reduced in the antagonist-treated groups (P < 0.001). This was also paralleled by reduced quantities of collagen IV in the treated rat groups (P < 0.001). The interstitial area was also significantly greater in the saline group (P < 0.001). The amount of collagen III did not significantly differ between rat groups. Apoptosis was reduced (P < 0.001) by treatment with ETR antagonists, whereas proliferation was enhanced (P < 0.005). All non-ischemic groups showed no variation in any parameter studied at this time point.ConclusionsTreatment of ischemic ARF in the rat with ETR antagonists PD 156707 and SB 209670 attenuated cellular infiltration and matrix accumulation. An advantage of one antagonist over the other could not be determined in this study. The marked discrepancy between function and pathology (former unchanged, latter markedly improved) may be due to the time frame of this experiment, and longer outcome measures need to be assessed.