- Fluid restriction in critically ill
Indiscriminate intravenous fluid administration is extremely common, and nephrologists’ advice on fluid restriction often lands on deaf ears. Fluid management often becomes the battlefield involving intensivists, surgeons, and nephrologists. ‘Patient appears cool’ (when actually its the freezing air conditioner), ‘Skin turgor is poor’ (80-year-old lady, with dry and wrinkled skin for years, won’t glow up to pose for fairness cream ad), ‘BP isn’t picking up, give a bolus’ and so on! So many excuses! Most intriguing of all was this: I once asked a surgical fellow the reason for adding 1.5 liters overnight to the already massive positive fluid balance of a patient with pancreatitis, and he replied “my boss feels ‘cool’ about pushing in fluid”!
The harm of fluid overload has been clearly and consistently documented in children, post-operative surgical, and critically ill patients especially those on respiratory support for ARDS, leading to the default strategy of restricted fluid administration in many ICUs. While the beneficial effects of fluid restriction on lung function, and other surrogates like ICU stay were shown in previous studies, its effect on mortality is not clear.
The CLASSIC trial was set out to fill this evidence gap-1554 patients with septic shock (across 31 ICUs in 8 countries) were randomized; 770 were in the restrictive-fluid group and 784 in the standard-fluid group. 9.6 vs 11.1 L fluid was administered in the first week in restrictive and liberal arms respectively. At 90 days, death occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% CI −4.7 to 4.9; P=0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, −1.7 percentage points; 99% CI, −7.7 to 4.3). At 90 days of follow-up, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups.
What do the results mean? Do they support liberal fluid administration? What do we take away to the bedside? Given the harm of volume overload and multiple trials showing no benefit of early aggressive fluid therapy (ARISE, ProMISe, ProCESS) restricted fluid administration is increasingly becoming a default strategy of fluid therapy. For instance, fluid administered in the first week following randomization has steadily declined over time: 17.6 vs 20.8 L in the 2006 FACTT trial, 12.4 L vs 13.6 L in the 2016 CLASSIC feasibility trial, and 9.6 vs 11.1 L in the 2022 CLASSIC final trial, in restrictive vs liberal arms, respectively. This ‘era effect’ is also evident from a study involving a national database of over 25000 patients with sepsis and septic shock, where fluid administered on day 1 was much lesser than that advocated by guidelines. Five-day cumulative positive fluid balance in the liberal fluid arm of THE 2006 FACTT trial (6.9L) is two times higher than in the 2022 CLASSIC trial!
Before you accept CLASSIC as the defeat of restrictive fluid strategy, wait. First, the results of the CLASSIC trial should be interpreted on this important background: change in the standard of care, which might have protected the control arm of the trial from the harm of fluid excess. Second, fluid administration is only one of the many interventions that can affect 90-day mortality in critically ill patients. The effect of these co-interventions is not clear from the published results. The CLASSIC trial thus no way refutes the harm of fluid excess (as claimed in the discussion section by authors) but rather reassures us that the restrictive fluid approach is feasible and safe. Another pitfall in most fluid trials is the assumption that all patients will be similarly affected (benefited or harmed) by a fluid administration strategy. “Fluid administration—->increased cardiac output—->increased O2 delivery——->increased O2 consumption” -this series of assumptions is the basis of fluid therapy. Many of these assumptions are not true in critically ill patients, for example, fluid bolus will increase cardiac output in only half of these patients. So this ‘one size fits all approach does not differentiate patients who are most likely to be fluid responsive from those who will be harmed by fluids. Therefore, future trials should assess the better metrics of fluid response (like increased cardiac output, or O2 delivery) to guide the fluid therapy. Let’s not forget that, in the setting of AKI, water is one of the most important uremic toxins, and restrictive fluid strategy becomes even more important.
2. Steroid treatment for IgA nephropathy
In many Asian countries, IgA nephropathy is the most common GN and an important cause of preventable ESRD burden and death. The need for prediction tools and appropriate therapies is more pressing here than anywhere else. The role of steroids in this condition is debated and their use is fraught with the risk of serious side effects as highlighted by the STOP IgA trial, and the initial report of the TESTING trial; immunosuppressed individuals with IgA nephropathy had an excess risk of infections, related hospitalizations, and death.
After getting halted by DSMB (due to the harm of immunosuppression), TESTING was resumed after 4 months, with modification of protocol: the dose of steroids was reduced to half the initial dose and TMP-SMX (cotrimoxazole) prophylaxis was added for infection prevention. 503 participants with proteinuria > 1 g/d, and eGFR of 20 to 120 mL/min/1.73 m2 were randomized (257 received methylprednisolone (MPS) and 246 received placebo, including 262 based on the original full-dose protocol and 241 based on the reduced-dose protocol). In combined results over a mean of 4.2 years of follow-up, the primary outcome-composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease occurred in 74 (28.8%) vs 106 (43.1%) participants in the MPS vs Placebo (HR 0.53 [95% CI, 0.39-0.72]; P < .001).
TESTING is now the largest of the RCTs evaluating the role of the steroids in IgAN, and investigators should be applauded for pursuing the trial for over four years even after initial disappointing results. While TESTING takes steroids out of the ‘black box’, results pose several questions about the optimum utilization of steroids in this disease. Seemingly contrasting results of STOP IGA (showing little or no benefit of steroids and possible harm) may not be entirely explained by the racial/ethnic differences as proposed by the authors. A run-in phase, wherein non-immunosuppressive measures were intensified, was an important feature of the STOP IGA trial, and at the end of this phase, almost half of the participants which were initially thought to be candidates for immunosuppression (for proteinuria), achieved a significant decrease in proteinuria. The wider use of SGLT2 inhibitors may also further expand the scope of non-immunosuppressive treatment in this disease. Another puzzling characteristic of TESTING participants was a lower prevalence of hypertension (about 50%) as compared to the Indian GRACE IGANI (over 80%) cohort and STOP IGA participants (over 90% on RASi at enrollment and average requirement of 2-3 drugs for BP control). With relatively preserved renal function at enrollment, the TESTING control arm reported a higher rate of GFR decline (>5 ml per min/ year) than previously reported. TESTING participants were much younger than STOP IGA (~35yrs vs 43yrs), and excess risk of infections, hospitalizations, and death in these young patients is concerning when they may have excellent outcomes after dialysis/transplant. Unfortunately, many of these patients in developing countries still lack access to RRT and one of the reasons for starting immunosuppressives may be a desperate attempt to avoid dialysis at any cost, which can sometimes be a patient’s life.
TESTING has paved new hope for steroid use, however, it also leaves hard questions for future studies about the risk-benefit; hopefully, targeted-release form of the glucocorticoid-budesonide and other steroid-sparing strategies, histological predictors of response may help us better define the place of immunosuppression in IgA nephropathy.
3. The race for better eGFR equations continues
If a poor common man tries telling you the truth, you silence him by telling him how ordinary and therefore unreliable he is. Then in search of the truth, we assemble a committee of multiple judges and assume their verdict as the best approximation of the truth. After having advocated, this ‘best substitute for truth’ for decades, we wake up on one fine morning, telling the world that we have been ‘not so correct’, and now the time has come to put another ‘good-looking guy’ in the assembly of judges to have a relook at the elusive truth.
Sounding like a Netflix courtroom drama, it’s the story of eGFR; where the director has decided to put another twist with the addition of smarter-looking guy ’Cystatin C’ to the existing CKD EPI equation. Retrospective individual patient data of 62 000 US adults ( 20 773 Black and 41 238 non- Black) enrolled in 8 well-characterized US cohort studies among the general population and among individuals with CKD were analyzed. Based on these data, the performance characteristics of 4 versions of the CKD-EPI equation were evaluated: (1) the original serum creatinine only– based CKD-EPI equation with the Black race coefficient intact (termed 2009 eGFRcr[ASR -Age,Sex, Race]); (2) a revised race-free serum creatinine only–based CKD-EPI equation (termed 2021 eGFRcr[AS]); (3) a previously developed race-free cystatin C only–based CKD-EPI equation (termed 2012 eGFRcys[AS]); and (4) the newly proposed race-free equation incorporating both serum creatinine and cystatin C (termed 2021 eGFRcr-cys[AS]). As expected, equation 4 showed a significantly higher prevalence of decreased kidney function in blacks at all levels of kidney function. So this equation allows one to eliminate race from the equation, a drive to eliminate racism from medical discourse.
NHANES survey showed higher serum creatinine values in blacks—->without much thought, you jumped on to conclude that it’s due to different body composition——-> introduced ‘race factor’ in the eGFR equation to make GFR less different than non-blacks ——>got alarmed by worse kidney outcomes in blacks—–> took part in ‘race needs to be eliminated from scientific discourse’ campaign——>no more race factor in eGFR—–>oops! blacks have lower eGFR than whites—–>Add on cystatin C.
IMHO, if you know serum creatinine well, with proteinuria and blood pressure it is enough for day-to-day clinical assessment of renal function, and apart from avoiding lawsuits (for example; you may be sued if gadolinium is given to a patient with eGFR 29ml/min and not if 31 ml/min), eGFR serves little purpose in routine clinical care. When checked yesterday, with twelve nephrology colleagues, none could recall using the eGFR calculator in the last week. Attempts to improve serum creatinine measurements are likely to impact the diagnosis and care of kidney disease much more than newer eGFR equations, more so in populations where none of the existing eGFR equations are formally validated.
After several decades of its use, efforts to improve the accuracy (decreasing analytic variations) of serum creatinine estimation are showing the desired results, with more and more labs reporting results traceable to IDMS international standards. Cystatin C will also need to be standardized before its widely used for eGFR equations and has its own limitations (check this Oct 2021 post for more on this). The new equation is likely to receive a grand welcome in KDIGO guidelines, which already have a 2C recommendation for cystatin c use.
Can experts now tell us “what was the contribution of the ’race factor’ in traditional eGFR equation to the late detection and overall poor CKD outcomes in blacks?”
4. Tebipenem of drug-resistant complicated urinary tract infection
The pace of developing antibiotic resistance far exceeds that of the discovery and clinical evaluations of the newer antibiotics. Global rise in MDR pathogens is a concern no lesser than melting glaciers and ecological collapse. It is commonplace to see a patient with pyelonephritis walking into the clinic (with little or no antibiotic exposure in past) with a scary antibiogram, showing none of the oral options valid, and not uncommonly ESBL producing gram-negative bug. Outpatient intravenous treatment has become a new norm now, which can be challenging due to the cost and resource constraints. This study is a much-needed addition to our antibiotic armamentarium, for the treatment of MDR uropathogens. In this phase 3, international, double-blind, non-inferiority, double-dummy trial, Tebipenem pivoxil hydrobromide (an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including ESBL –producing and fluoroquinolone-resistant strains) was evaluated in 1372 hospitalized adult with complicated pyelonephritis. Overall response (58.8 vs 61.6%), clinical cure (93.1 vs 93.6%), and adverse events-most were mild- (25.7 vs 25.6%) were comparable between tebipenem and ertapenem. Welcome, Tebipenem.
Features common to ecologic collapse and antibiotic resistance are a lack of seriousness amongst clinicians, a lack of appropriate action (judicious and appropriate use), and a lot of plans at the bench with little action at the bedside. Nephrologists can play a definite role-pursuing surgery and physician colleagues to stop treating asymptomatic bacteriuria, avoiding treatment of CRBSI without cultures (this is an unfortunate culture in many dialysis units), and de-escalating to one (gram-positive or negative cover) as soon as possible while treating CRBSI or PD peritonitis.
5. Apixaban vs warfarin for treatment of VTE in patients on dialysis
It is challenging to use warfarin effectively in patients on dialysis. There are several challenges like drug interactions, time in therapeutic range, and inherent risk of bleeding in patients with CKD to name a few.
Direct oral anticoagulants (DOACs) are being increasingly used for thromboprophylaxis in patients with CKD. But there is no data about the safety and efficacy of NOACs/ DOACs in the treatment of VTE in patients on dialysis.
Wetmore et al conducted a retrospective cohort study using the United States Renal Data System data from 2013 to 2018. The study included dialysis patients who received a new prescription for apixaban or warfarin following a venous thromboembolism diagnosis. The outcomes were recurrent venous thromboembolism, major bleeding, and death. Of 12,206 individuals, 3130 were in the apixaban group. Apixaban, compared with warfarin, was associated with lower risks of both recurrent venous thromboembolism (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.77) and major bleeding (HR, 0.78; 95% CI, 0.62 to 0.98) in the intention-to-treat analysis over 6 months of follow-up. However, there was no difference between apixaban and warfarin in terms of risk of all-cause death (HR, 1.04; 95% CI, 0.94 to 1.16).
The majority of the cohort had DVT without pulmonary embolism.
There are several limitations. The article doesn’t mention the dose of apixaban used. While 2.5mg twice a day is approved in patients on dialysis, the RENAL AF trial, which is yet to be published, has used a dose of 5mg twice a day. It is unclear if the dose could affect the efficacy and/or safety outcomes. In the group that received warfarin, there is no information about INR or time in the therapeutic range. The study may have missed bleeding episodes managed in the emergency department.
Conducting an RCT comparing warfarin to DOACs will be a Herculean task. Till then we will have to make use of these data in shared decision-making.
1,3, 4 written by Tukaram Jamale and peer reviewed by Vaibhav Keskar, Manjunath Kulkarni and Divya Bajpai
2 written by Manjunath Kulkarni and peer reviewed by Tukaram Jamale, Vaibhav Keskar and Divya Bajpai
5 written by Vaibhav Keskar and Peer reviewed by Tukaram Jamale, Manjunath Kulkarni and Divya Bajpai
