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.
1 Nitrofurantoin beats fosfomycin in the treatment of uncomplicated cystitis
“Among women with uncomplicated UTI, a 5-day course of nitrofurantoin compared with single-dose fosfomycin resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion” concluded the authors of this multinational, open-label RCT that randomised patients to oral nitrofurantoin,100mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). Both of these agents are approved the first choice therapy for this indication, however, uncertainties exist regarding the clinical efficacy of single-dose fosfomycin and this study furthers these concerns.
I have never used nitrofurantoin three times a day and I am not sure how much of this difference is related to the dosing advantage to nitrofurantoin (given TDS for 7 days vs single dose of fosfomycin). There is also another reason to prefer nitrofurantoin here; we may be able to reserve fosfomycin for MDR Enterococcus/MRSA where its parenteral use may be needed.
2 Dialysis in elderly: Medicare vs VA
Does it matter who is your predialysis CKD health care provider? Well, yes, if you are an elder with advanced CKD, according to this retrospective cohort study of >11000 patients above the age of 67 years. Patients with incident kidney failure (eGFR <15ml/min) were more likely to be started on dialysis if predialysis care provider was Medicare: 82% vs 53%. RR 1.53 (1.48-1.57). This difference was more pronounced among patients aged 80 years or older and patients with dementia or metastatic cancer, and less pronounced among patients with paralysis (P < .05 for interaction). Mortality was higher among Medicare patients (53% vs 44%).
Making a decision about dialysis or no dialysis in this population is a tough task and we need to face this uncertainty by using shared decision making. Although not an RCT, these results raise an important question about the interaction of incentive structure and utilization of dialysis in this population where homeostenosis can tip the balance towards harm. Possible harms of dialysis initiation in this population have been previously documented as is the differential use of aggressive therapies when patients seek care in the ‘fees for profit’ healthcare systems vs state-sponsored systems.
As editorial accompanying has put it “Given the many unknown factors, the decision on when it is best to initiate dialysis should evoke humility. The goal should be to encourage thoughtful, joint decision making by nephrologists and their patients.”
3 Measuring blood pressure better
One of the most inaccurate measurements that we make daily in our practice may be the clinic blood pressure and until today, the majority of the decisions regarding diagnosis and treatment of BP are largely based on this value. While it’s intuitive to assume that out of office measurements will perform better, there is limited data on the use of ABPM on clinical outcomes. This Spanish ABPM registry data in NEJM adds significantly to the much-needed evidence base for wider application of ABPM.
In a registry-based, multicenter, national cohort that included 63,910 adults (3808 total and 1295 CV deaths occurred over 4.7 yrs of follow up), they evaluated prognostic significance of four different BP phenotypes: 1) sustained HTN (elevated clinic and elevated 24-hour ambulatory BP), 2) “white-coat” HTN (elevated clinic and normal 24-hour ambulatory BP), 3) masked HTN (normal clinic and elevated 24-hour ambulatory BP), and 4) normotension (normal clinic and normal 24-hour ambulatory BP).
Masked HTN posed the highest risk of death: HR 2.83; 95% CI, 2.12 to 3.79, followed by sustained HTN (HR 1.80; 95% CI, 1.41 to 2.31) and white-coat HTN (HR, 1.79; 95% CI, 1.38 to 2.32). Wider use of ABPM is already advocated by NICE and Canadian BP guidelines, other should follow. I have just started realizing the deceptiveness of clinic BP after I started using HBPM and ABPM more often in my practice.
4 Precision in the maintenance dosing of rituximab in vasculitis
Rituximab is non-inferior for induction of remission in ANCA-associated vasculitis (AAV) and may be superior to azathioprine for maintenance of remission. In MAINRITSAN trial, it was used in a fixed schedule, irrespective of CD19+ B cell count, which expected to reflect the biologic activity of rituximab. Can we individualize rituximab dosing during maintenance treatment?
In an open-label, pragmatic, multicentre RCT, (MAINRITSAN 2) 162 adults with new or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who achieved complete remission (BVAS score 0) with cyclophosphamide, rituximab or methotrexate, were randomized to receive rituximab either in fixed-schedule (control group) or individually-tailored fashion within 1 month after completing induction treatment, if they had received cyclophosphamide or methotrexate, or 4–6 months after the last rituximab infusion, if it had been used to obtain remission.
Tailored-infusion-arm patients always received 500 mg of rituximab at randomization; then ANCA and CD19+ B lymphocytes were assessed every 3 months. Another 500 mg were infused when ANCA status differed from the previous control (ie, reappearance after being negative, indirect immunofluorescence- determined ≥2-dilution–titre increase and/or at least doubled ELISA PR3 or MPO arbitrary units) or CD19+ B cell counts exceeded 0/mm3. The last rituximab infusion could be given at month 18. The control group received 500 mg rituximab infusion on days 0 and 14 post-randomization and at months 6, 12, 18 after the first infusion.
The primary endpoint, the number of relapses at month 28, was not different in the two groups- 14 vs 8 (p=0.22). Notably, relapses did occur in the absence of circulating B cells or when ANCA were negative, questioning the relevance of their monitoring. However, the tailored-infusion group received fewer rituximab infusions [medians (IQR) of 3 (2–4) vs 5 (5–5) administrations]. The safety profile of both the strategies was similar.
Although ANCA evolution and/or circulating CD19+ B cells were not reliable predictors of AAV relapses, combining them achieved fewer infusions in the tailored-infusion arm without significantly more relapses. This is precision medicine indeed!
5 DASH Diets with Mortality in Adults on Hemodialysis: The DIET-HD Study
In the DIET-HD study, the association of DASH and Mediterranean diets and mortality was assessed in 9757 adults on hemodialysis. Dietary intake was ascertained using a standardized questionnaire. Scores were calculated based on this data. Higher scores indicated food intake more consistent with these diets.
During a median follow-up of 2.7 years (18,666 person-years), there were 2087 deaths (26%), of which 829 (40%) were attributable to cardiovascular causes. The distributions of the Mediterranean and DASH diet scores among patients who died from cardiovascular causes were similar to those of patients who survived until the end of the follow-up.
DASH diet in general population is associated with 10%–30% lower risk of cardiovascular disease and mortality. This is not the first time that promising interventions to prevent CVD have failed in dialysis patients (remember statin, ICD, anticoagulation etc). This is not surprising given the major role of non-traditional risk factors here. In addition, any intervention at this point in time may be too late to have a meaningful effect.
The entire analysis was based on self-reported intake of foods. The scales might have underestimated the effect of salt intake, and maybe phosphate intake, in the calculation. And probably we don’t know enough about nutrition in patients on dialysis! Until the time they don’t cross limits of potassium intake during weekends and are not going for low protein fad diets, I prefer to let them enjoy their food preferences.
6 Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure
With increasing use of sacubitril/valsartan (Angiotensin receptor-Neprilysin Inhibitor)in heart failure here, cardio-renal friendship seems to be growing. I am increasingly called for acute kidney injury in a patient with congestive heart failure who is on this combo. I often imagine that this drug should be a part of the sick-day-medication list and I end up holding it temporarily until creatinine returns to the baseline.
Do you monitor albuminuria of patients getting treatment for heart failure if they have baseline albumin excretion of about 8 mg/day? You may do that in an RCT of heart failure though.
Over the study duration, the decrease in eGFR was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m2/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m2/year] vs. -2.04 ml/min/1.73 m2/year [95% CI: -2.21 to -1.88 ml/min/1.73 m2/year]; p < 0.001). In participants in whom The urinary albumin/creatinine ratio (UACR) was available (1872 of the 8399 patients), there was a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001).
That means sacubitril/ valsartan leads to increase in albuminuria and still preserves eGFR better. These were not the prespecified analyses and results are based on surrogates. Heart failure treatment is not the setting and time to bother about albuminuria and bumps in creatinine anyways.
7. Water intake and CKD progression
Increasing water intake is widely viewed to have health benefits especially so for patients with CKD. This is, in fact, one of the common reasons for asymptomatic mild hyponatremia in my practice. While this notion is supported by observational studies, controlled trials are lacking.
In this multicentre, Canadian RCT of 631 patients with CKD (mean eGFR 43ml), authors randomized patients to receive “coaching to increase water intake” or to maintain the usual water intake. At the end of one year, there was no significant improvement in the primary outcome of rate of eGFR decline:−2.2 mL/min in the hydration group and −1.9 mL/min in the control group (adjusted between-group difference, −0.3 mL/min/1.73 m2 [95% CI, −1.8 to 1.2; P = .74]). Efficacy of the coaching was assessed by self-reported water intake(which however was less than intended in the intervention group), and plasma coeptin level (a degradation product of AVP which is supposed to be negatively correlated to water intake).
Interestingly, 24 hr urinary creatinine excretion was significantly improved in patients in intervention arm: authors hypothesize this to be due to an effect of increased urine flow rate on tubular creatinine secretion. Short follow up, a small difference in water intake between the groups (~800ml), reliance on eGFR, and small sample size (underpowered to detect smaller benefits in eGFR decline) are important limitations to note. No drop in the serum sodium was noted in the intervention group.
Larger trials with longer follow up duration and better measurements of kidney function are needed (I have this line ready to be put after review of most RCTs in CKD progression!) before we label this simple intervention as ineffective. Until then, everyone can continue to listen to that poorly defined area in the hypothalamus called as thirst center.