With ever increasing number of scientific publications, we, clinicians, struggle to make sense of the research. Only a fraction of published research will ever actually help change the way our patients ‘feel-function-survive’. We are trying to think aloud on the published evidence, and no way claim to be the final word which probably doesn’t exist in science.
1 Early Postoperative Acetaminophen Exposure and AKI in Children after Cardiac Surgery
In a primary cohort of 666 children and a validation cohort comprising of 333 children who underwent cardiac surgery with cardiopulmonary bypass, the incidence of AKI was higher among those with no acetaminophen exposure than among those with acetaminophen exposure, according to the result of this retrospective observational study. This is thought to be due to reduced oxidation of free hemoglobin by preventing the oxidation of iron from Fe3+ to Fe4+ by acetaminophen. Exposure to this agent was protective against postoperative AKI (odds ratio, 0.86 [95%CI, 0.82-0.90] per each additional 10mg/kg). About 50% of the children in the primary cohort had AKI (defined as an increase by ≥0.3mg/dL from baseline or at least 1.5-fold more than the baseline).
Apart from not getting exposed to acetaminophen, controls had a lot of other reasons to develop AKI (younger age, lower weight, longer duration on CPB, higher nephrotoxin exposure to mention a few). Given all the limitations of the retrospective study, this finding is hypothesis generating at best. A similar but smaller study in patients with sepsis failed to show such a protective effect.
2 Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women
Most uncomplicated UTIs are self-limiting, but they are almost always treated with antibiotics. In a randomized, controlled, double-blind non-inferiority trial, Vik et al randomized 383 non-pregnant women presenting with symptoms of uncomplicated UTI to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. By day 4, 38.7% of the patients in the ibuprofen group ‘felt cured’ versus 73.6% in the pivmecillinam group. After 4 weeks’ follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group. The number needed to harm here was 26!
More than half of the patients initially treated with ibuprofen got well without taking antibiotics. Who are these patients? If we could identify these less severe cases who don’t progress to pyelonephritis, we may avoid antibiotic exposure to these people. Until then, it is prudent to continue prescribing antibiotics for uncomplicated UTIs.
3 Oral Antibiotic Exposure and Kidney Stone Disease
Disruption of the gut and urinary microbiota is associated with nephrolithiasis. Effect of antibiotics on the microbiome is well established. To examine if antibiotic exposure is associated with nephrolithiasis, Tasian et al conducted a population-based, nested case-control study with 25,981 patients with nephrolithiasis and 259,797 controls observed for a median of 5.4 years. Sulfas, cephalosporins, fluoroquinolones, nitrofurantoin/ methenamine, and broad-spectrum penicillins were associated with an increased odds of nephrolithiasis diagnosis 3–12 months after antibiotic prescription. The highest magnitude of risk was estimated for exposure to these antibiotics at younger ages and for antibiotic exposure 3–6months before diagnosis (compared to more distant antibiotic use).
Oral antibiotics often prescribed for various indications, may be contributing to the increasing prevalence and earlier age at onset of nephrolithiasis.
Change in the overall diversity of the gut microbiome, selection of multidrug-resistant bacteria in the urinary microbiome that promotes the stone formation and direct antibiotic crystallization in the kidney could underly these findings. However, it is very difficult to ignore a major confounding factor here- UTIs. Both the antibiotics as well and stones are associated with UTIs. Although the sensitivity analysis excluding the previous UTIs showed similar findings, I think it will be very difficult to remove this confounding factor. (For example, nitrofurantoin prescriptions must have been given for UTI). But these findings are hypothesis-generating and a more detailed analysis, particularly in children, should be able to clarify these doubts.
4 The Drug-Intoxication Epidemic and Solid-Organ Transplantation
The opioid crisis has led to a dramatic increase in the number of drug overdose deaths in the United States, with an increase in the number of donors who died from drug overdose.
In a study published in NEJM from the United States, Mehta et al noted a large increase in the proportion of organ donors who died from drug intoxication — from 59 (1.2%) in the year 2000 to 1029 (13.7%) in the year 2016. This shift accounted for much of the increase in organ transplantation activity. In contrast, in Europe, there was no significant change over time in the frequency of drug intoxication as the cause of donor death (≤1% in any year). The survival among recipients of allografts from donors who died from drug intoxication was similar to survival among recipients from donors who died from other causes.
If the much of the increase in the donor pool was because of deaths from drug intoxication, there is an urgent need to explore other ways to expand the donor pool.
Reliance on drug overdose-related donors is unique to the US solid organ transplantation system and is untenable. Alternative sources of organ recovery and expansion of donor pool much needed, as efforts to curb the drug overdose epidemic take root. @BWHResearch
To me, this observation also highlights the need for a national transplant registry, which is not present in many countries including India. If we don’t have the data, we will not realize our problems, leave aside solving them.
5 A Novel Method for Rapid Bedside Measurement of GFR
‘One accurate measurement is infinitely superior to thousand expert opinions’ -Grace Brewster Murray Hopper.
During my daughter’s summer vacation, I learned many amazing games she and her friends innovate. I must share one of them with the nephrologists. They would arbitrarily divide the entire sky into 4 parts and 4 teams will start counting the number of stars in their quarter share of the space. The team that gets to count the highest number wins. They have no doubt in their mind that the number estimated is the right one. When I said, it’s not a true number, they replied ‘we are well aware of the fact and this is just a game. So please shut up.’
Now, doesn’t that sound similar to estimating GFR by various equations and assume that it reflects the true kidney function? Forget about clinical practice, even research trials continue to rely on eGFR and even manage to get FDA approvals for the studied drug.
This interesting phase 2b study in JASN is a step ahead towards having mGFR (measured GFR) in practice. Authors developed a novel marker, VFI (Visible Fluorescence Injectate) which after administration can be easily measured in the plasma (rapid readout unlike iohexol where time-consuming HPLC or mass spectroscopy is needed). mGFR by VFI showed almost perfect correlation with the gold standard – mGFR by iohexol (coefficient correlation value of 0.996). This performed similarly well in patients with normal and abnormal kidney function (CKD 3 and 4).
This is exciting, promising and much needed ‘precision’ in the measurement of kidney function that can be potentially put into clinical practice. I am waiting to read more about this.
6 Burosumab Therapy in Children with X-Linked Hypophosphatemia
Before it is stopped after correct diagnosis, repeated massive doses of vitamin D have already calcified kidneys of many patients with X-Linked Hypophosphatemia (XLH). Diagnosis and treatment of this disease are one of those ‘ah!’ moments in medicine, when a crippled child starts ambulating and growing after phosphate replacement. Whether you use traditional Joulies solution or newer phosphate preparation, GI intolerance is a major limiting factor and also a common reason for noncompliance. Also, hyperparathyroidism resulting from phosphate administration can worsen the bone disease and needs active vitamin D to control, which in turn further worsen hypercalciuria and nephrocalcinosis. Vicious cycle of disease—>therapy—> disease—->therapy.
Burosumab -a monoclonal antibody that targets FGF-23- precisely acts at the site of the defect in this disease and has shown promising results in this open-label, phase 2 trial, of 52 children with XLH. Burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets (assessed by Thacher rickets severity total score). Given the similar pathogenesis, this may also work for other hypophosphatemic diseases like autosomal recessive hypophosphatemic rickets and tumor-induced osteomalacia. If the cost of this agent permits, this is a great news for patients with these rare disorders.
7 Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery
In this pragmatic trial of 3000 patients undergoing major abdominal surgery, restrictive versus liberal fluid administration in the first 24 hrs didn’t result in significant difference in the primary endpoint of disability-free survival at 1 year (you can debate about the impact of fluid therapy in first 24 hours on an outcome at 1 year). However restrictive fluid group suffered more episodes of AKI (8.6% vs 5%) and needed renal replacement therapy (RRT) more often (0.9% vs 0.3%) which were secondary endpoints.
I can only hope that this doesn’t encourage our surgery colleagues to pump in fluids indiscriminately. AKI and RRT need were secondary outcomes and can’t be considered definitive as very few patients developed severe AKI. While we are not sure whether blood urea or creatinine by themselves kill patients with AKI, evidence suggests that water can. Note the number of events for benefit and harm of these two approaches: 13 vs 4 (P=0.04) for RRT need (NNT=166) and 20 vs 32 (P=0.1) for pulmonary edema (NNH=125) in restrictive vs liberal strategy respectively. Case for statistical versus clinical significance!
sBE is reported in all the ABGs, however many don’t routinely use this value for assessment of acid-base disturbances. For those like me who hate mathematics, BE is a much easier method for interpretation of ABG, with two important caveats: first, you interpret it along with anion gap, second, your blood gas devices should standardize the standard base excess equation and use only the standard base excess calculation recommended by the National Committee for Clinical Laboratory Standards. Interesting recap of the history of acid-base assessment starting from Copenhagen polio epidemic, through transatlantic debate to the current standard of care is a nice read.
Another ‘don’t miss’ review is on APLA syndrome. Renal involvement in this disease can come rarely as AKI due to catastrophic APLA, or a chronic vaso-occlusive disease. 30% of the SLE patient will have these antibodies. Recap of latest definitions, clinical syndromes, laboratory test interpretation and management is worth your time.