This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium–glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in ...states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium–hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.
Whether fluid overload is associated with vascular stiffness parameters in hemodialysis (HD) patients has not been fully elucidated. We hypothesized that interdialytic fluid accumulation increases ...vascular stiffness parameters, which improves with intradialytic ultrafiltration.
Fluid overload and vascular stiffness parameters were assessed in 39 HD patients (20 with and 19 without fluid overload) and compared to 26 healthy controls. Fluid status was assessed 15 minutes before the mid-week HD session by bio-impedance spectroscopy. Following this, ambulatory pulse wave velocity (PWV) and augmentation index (AIx) were measured for 24 hours before another mid-week HD session and then for 5 hours starting 30 minutes before and ending 30 minutes after the session.
HD patients had significant fluid overload compared to healthy controls (2.0±2.4 vs. -0.2±0.6 L; P<0.001) and baseline PWV was higher (10.3±1.7 vs. 8.8±1.4 m/s; P<0.001). There was no significant difference between PWV and AIx in fluid overloaded and non-fluid overloaded HD patients prior to, or during the HD session. AIx of non-fluid overloaded HD patients improved after the HD session (P = 0.04). Average 24-hour AIx was higher in fluid overloaded HD patients (P<0.001).
Inter- and intradialytic changes in fluid volume were only weakly related to vascular stiffness parameters in HD patients. Although there was a modest reduction in AIx in non-fluid overloaded HD patients after the dialysis session, fluid removal did not improve vascular stiffness parameters during the HD session. We speculate that the effect of fluid overload correction on vascular stiffness parameters requires long-term adjustments in the vasculature.
Rationale:
We hope to increase awareness that hypokalemic paralysis may be the first presentation of Sjögren syndrome, for which potassium-sparing diuretics can be an effective adjunct to potassium ...replenishment.
Presenting concerns:
A 73-year-old female presented to a peripheral hospital with quadriparesis and a critically low serum potassium of 1.6 mmol/L with U waves on the electrocardiogram (ECG). The initial arterial blood gas showed a pH of 7.19, bicarbonate of 13 mEq/L, and a CO2 of 35 mm Hg. Over the next 6 days, she was administered a total of 450 mEq of potassium supplements. Despite this, her potassium never increased above 2.9 mmol/L and was thus transferred to the University Hospital for further management. On arrival, her vital signs were within normal limits. Her only other symptoms were fatigue and ocular dryness. Physical exam showed slightly weakened quadriceps muscles bilaterally, graded 4/5. Examination was otherwise unremarkable. Admission investigations included a potassium of 2.8 mmol/L, chloride 118 mmol/L, sodium 136 mmol/L, and eGFR 48 mL/min/1.73 m2. Renin aldosterone ratio was normal.
Diagnoses:
Distal renal tubular acidosis (RTA) was diagnosed based on a normal anion gap metabolic acidosis, positive urine anion gap, and elevated urine potassium to creatinine ratio. Investigation of underlying causes revealed a positive Antinuclear antibody (ANA), elevated rheumatoid factor, and high anti-Ro/SSA titre which directed us toward a unifying diagnosis of Sjögren syndrome. A renal biopsy was undertaken as an outpatient and demonstrated severe interstitial nephritis with acute and chronic components, parenchymal scarring, atrophy, and small vessel arteriosclerosis.
Interventions:
In the acute setting, the patient was treated with bicarbonate and amiloride in addition to potassium supplementation.
Outcomes:
The patient’s hypokalemic paralysis and metabolic acidosis were corrected.
Lessons Learned:
Severe hypokalemic paralysis in distal RTA associated with Sjögren syndrome can be successfully treated with amiloride in addition to potassium supplementation. We also review the literature on the aberrancies seen in H+ATPase, Band 3, Pendrin, and carbonic anhydrase that may underlie the pathogenesis of distal RTA in Sjögren syndrome.
Acutely increased renal venous pressure (RVP) impairs renal function, but the long-term impact is unknown. We investigated whether chronic RVP elevation impairs baseline renal function and prevents ...exacerbation of renal dysfunction and cardiovascular instability upon further RVP increase. RVP elevation (20–25 mmHg) or sham operation (sham) was performed in rats. After 1 wk ( n = 17) or 3 wk ( n = 22), blood pressure, RVP, renal blood flow (RBF), renal vascular conductance (RVC), and glomerular filtration rate (GFR) were measured at baseline and during superimposed RVP increase. Chronic RVP elevation induced extensive renal venous collateral formation. RVP fell to 6 ± 1 mmHg at 1 wk and 3 ± 1 mmHg at 3 wk. Baseline blood pressure and heart rate were unaltered compared with sham. RBF, RVC, and GFR were reduced at 1 wk but normalized by 3 wk. Upon further RVP increase, the drop in mean arterial pressure was attenuated at 3 wk compared with 1 wk ( P < 0.05), whereas heart rate fell comparably across all groups; the mean arterial pressure-heart rate relationship was disrupted at 1 and 3 wk. RBF fell to a similar degree as sham at 1 wk (−2.3 ± 0.7 vs. −3.9 ± 1.2 mL/min, P = 0.066); however, at 3 wk, this was attenuated compared with sham (−1.5 ± 0.5 vs. −4.2 ± 0.7 mL/min, P < 0.05). The drop in RVC and GFR was attenuated at 1 and 3 wk ( P < 0.05). Thus, chronic RVP elevation induced by partial renal vein ligation elicits extensive renal venous collateral formation, and although baseline renal function is impaired, chronic RVP elevation in this manner induces protective adaptations in kidneys of healthy rats, which attenuates the hemodynamic response to further RVP increase.
Background and Objective:
Bioimpedance technologies are increasingly used to determine fluid status in patients with chronic kidney disease and those with end-stage kidney disease on dialysis. We ...aimed to determine whether this technology improves clinical outcomes as compared with usual care.
Methods:
We performed a systematic review and meta-analysis of trials, comparing fluid management guided by bioimpedance technologies to standard of care in patients with chronic kidney disease. Our primary outcome was all-cause mortality. Secondary outcomes included blood pressure control, all-cause hospitalization, major adverse cardiovascular events, and change in left ventricular mass index.
Results:
Our search identified 819 citations of which 12 randomized controlled trials were included (2420 patients). No studies of non-dialysis-dependent chronic kidney disease patients met inclusion criteria. Mean age was 55 years and mean follow-up was 1 year. There was a statistically significant difference in all-cause mortality between both arms studied (risk ratio RR 0.64, 95% confidence interval CI: 0.44, 0.99). Better blood pressure control was observed in the bioimpedance arm of the included articles, weighted mean differences (WMD) −3.13 mm Hg (95% CI: −5.73, −0.53 mm Hg) for systolic blood pressure and WMD −2.50 mm Hg (95% CI: −4.36, −0.64 mm Hg) for diastolic blood pressure. No difference was observed concerning the other outcomes.
Conclusions:
Among patients on maintenance dialysis, bioimpedance-guided volume management showed decreased all-cause mortality and blood pressure but no significant difference in all-cause hospitalization, major adverse cardiac event, or change in left ventricular mass index. This may be due to a younger population sample than previous articles. Moreover, our study identified a knowledge gap by highlighting the lack of studies evaluating this technology in non-dialysis-dependent chronic kidney disease patients.
Indigenous people represent approximately 5% of the world's population. However, they often have a disproportionately higher burden of cardiovascular disease (CVD) risk and chronic kidney disease ...(CKD) than their equivalent general population. Several non-pharmacological interventions (e.g., educational) have been used to reduce CVD and kidney disease risk factors in Indigenous groups. The aim of this paper is to describe the protocol for a scoping review that will assess the impact of non-pharmacological interventions carried out in Indigenous and remote dwelling populations to reduce CVD risk factors and CKD.
This scoping review will be guided by the methodological framework for conducting scoping studies developed by Arksey and O'Malley. Both empirical (Medline, Embase, Cochrane Library, CINAHL, ISI Web of Science and PsycINFO) and grey literature references will be assessed if they focused on interventions targeted at reducing CVD or CKD among Indigenous groups. Two reviewers will independently screen references in consecutive stages of title/abstract screening and then full-text screening. Impact of interventions used will be assessed using the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework. A descriptive overview, tabular summaries, and content analysis will be carried out on the extracted data.
This review will collect and analyse evidence on the impact of interventions of research carried out to reduce CVD and CKD among Indigenous populations. Such evidence will be disseminated using traditional approaches that includes open-access peer-reviewed publication, scientific presentations, and a report. Also, we will disseminate our findings to the government and Indigenous leaders. Ethical approval will not be required for this scoping review as the data used will be extracted from already published studies with publicly accessible data.
Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular ...filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min,
p
<0.05) and GFR (−0.77±0.18ml/min,
p
<0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (−22.4±4.1 vs. −9.9±2.3mmHg,
p
<0.05), whereas the decrease in heart rate (HR) was less (−5±6bpm vs. −23±4bpm,
p
<0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (−0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction.
Increased renal venous pressure (RVP) is common in combined heart and kidney failure. We previously showed that acute RVP elevation depresses renal blood flow (RBF), glomerular filtration rate (GFR), ...and induces renal vasoconstriction in the absence of changes in blood pressure in healthy rats. We used our established rodent model of chronic combined heart and kidney failure (H/KF) to test whether RVP elevation would impair cardiovascular stability, renal perfusion and exacerbate renal dysfunction.
Male rats were subjected to 5/6 nephrectomy (SN
or Sham) and 6% high salt diet followed 7 weeks later by ligation of the left anterior descending coronary artery (CL or Sham). Experimental groups: CL + SN
(
= 12), Sham CL + SN
(
= 9), CL+ Sham SN
(
= 6), and Sham Control (
= 6). Six weeks later, anesthetized rats were subjected to an acute experiment whereupon mean arterial pressure (MAP), heart rate (HR), RVP, RBF, and GFR were measured at baseline and during elevation of RVP to 20-25 mmHg for 120 min.
Baseline MAP, HR, RBF, and renal vascular conductance (RVC) were comparable among groups. Baseline GFR was significantly depressed in CL + SN
and Sham CL + SN
groups compared to Sham Control and CL + Sham SN
groups. Upon RVP increase, MAP and HR fell in all groups. Increased RVP exacerbated the reduction in RBF in CL + SN
(-6.4 ± 0.9 ml/min) compared to Sham Control (-3.7 ± 0.9 ml/min,
< 0.05) with intermediate responses in Sham CL + SN
(-6.8 ± 1.3 ml/min) and CL + Sham SN
(-5.1 ± 0.4 ml/min) groups. RVP increase virtually eliminated GFR in CL + SN
(-99 ± 1%), Sham CL + SN
(-95 ± 5%), and CL + Sham SN
(-100%) groups compared to Sham Control (-84 ± 15% from baseline;
< 0.05). Renal vascular conductance dropped significantly upon RVP increase in rats with HF (CL + SN
: -0.035 ± 0.011; CL + Sham SN
: -0.050 ± 0.005 ml/min·mmHg
,
< 0.05) but not Sham CL + SN
(-0.001 ± 0.019 ml/min·mmHg
) or Control (-0.033 ± mL/min·mmHg
).
Chronic combined heart and kidney failure primarily impairs renal hemodynamic stability in response to elevated RVP compared to healthy rats.
The combination of chronic kidney disease (CKD) and heart failure (HF) is associated with an adverse prognosis. Although clinical studies hint at a specific bidirectional interaction between HF and ...CKD, insight into the pathogenesis of cardiorenal syndrome (CRS) remains limited. We review available evidence on cardiorenal interactions from animal models of CKD and HF and discuss several studies that employed a "double-hit" model to research organ cross talk between the heart and kidneys. Regarding cardiac changes in CKD models, parameters of cardiac remodeling are equivocal and cardiac systolic function generally remains preserved. Structural changes include hypertrophy, fibrosis, and microvasculopathy. In models of HF, data on renal pathology are mostly limited to functional hemodynamic changes. Most double-hit models were unable to show that combined renal and cardiac injury induces additive damage to both organs, perhaps because of the short study duration or absence of organ failure. Because of this lack of "dual-failure" models, we have developed two rat models of combined CKD and HF in which renal dysfunction induced by a subtotal nephrectomy preceded cardiac dysfunction. Cardiac dysfunction was induced either functionally by nitric oxide depletion or structurally by myocardial infarction. In both models, we found that cardiac remodeling and failure were worse in CKD rats compared with controls undergoing the same cardiac insult. Variables of renal damage, like glomerulosclerosis and proteinuria, were also further worsened by combined cardiorenal injury. These studies show that target organ cross talk does occur in CRS. These models may be useful for interventional studies in rats.
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