Before you read this months post, do have a look at the beautiful infographic of our last month’s post by Omar Taco (@Errantnephron) of Nephrology Social Media Collective (NSMC)
Coming back to this month’s post:
1 Balanced Crystalloids versus Saline in Critically Ill Adults
If you want 9 reasons not to use normal saline, you can find them here. In addition, non-believers have two large RCTs published in NEJM that compared normal saline with balanced solutions.
The SMART trial investigators conducted a pragmatic, single-center, unblinded, cluster randomized, multiple-crossover trial in which the use of balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) was compared with saline for intravenous fluid administration among 15,802 critically ill adults admitted to five ICUs at Vanderbilt University Medical Center between June 1, 2015, and April 30, 2017. The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction defined as an elevation of the creatinine level to ≥200% of baseline.
Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P = 0.04). The number needed to treat, if you calculate that here, would be 90.9. Is this 1.1% difference clinically significant? Or large sample size has made it possible for the difference to be statistically significant? If true, this effect would be important at the population level.
Individual components of the primary endpoint were not different between the groups.
Fewer patients in the balanced-crystalloids group had high plasma chloride or low plasma bicarbonate.
Should we stop using NS after these results? Probably not. Though the study is robust, the results may not be enough to seal the fate of NS. (See a good post about caveats.)
Another lesson here for nephrology research community-pragmatic trials may answer many questions in clinical practice, where traditional randomized controlled trials are difficult, expensive or simply impractical to conduct. They may be easier to conduct. They are highly generalizable. However, Certain methodological issues are already being discussed. There was a concern that consent was not obtained from the patients.
Look at this twitter thread. The scientific community has probably never had an opportunity to interact the way they are doing now on social media. With all its limitations and challenges, social media is proving a useful tool in the learning process.
2 History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease
See the NephJC summary by Michelle Rheault here. Visual abstract created by Michelle Lim (@whatsthegfr)
In a nationwide, population-based, historical cohort study in Israel, investigators reviewed baseline examination records of 1,521,501 adolescents before compulsory military service between 1967 and 1997. Inclusion in the cohort required normal kidney function, no proteinuria, and normal blood pressure irrespective of a history of childhood kidney disease categorized as CAKUT (congenital anomalies of the kidney and urinary tract), pyelonephritis and glomerular disease. The adolescent cohort data was linked to the Israeli ESRD registry and hazards ratios for ESRD associated with childhood kidney disease were estimated. Persons with diabetes mellitus, systemic lupus erythematosus, vasculitis or any rheumatic disease, cancer, hypertension, or evidence of impaired renal function from any cause at the time of pre-conscription assessment were excluded.
Over 30 years of follow up, 2490 (0.2%) persons developed ESRD. Multivariable-adjusted analysis showed a history of any childhood kidney disease was associated with a hazard ratio of 4.19 for adult ESRD with HR of 5.19 for CAKUT, 4.03 for pyelonephritis, and 3.85 for glomerular diseases. A history of childhood kidney disease was associated with an earlier age of onset of ESRD (41.6 years vs 48.6 years).
What is not captured in the dataset is whether there were any risk factors developed between the pre-conscription assessment in adolescence and identification of ESRD in adulthood.
A history of childhood kidney disease, even when renal function was normal in adolescence, was associated with a four-fold risk of ESRD in adulthood. These findings suggest the need for early identification and interventions to prevent the progression of CKD.
Even with several limitations, this study is an important piece of information. Similar to the development of renal insufficiency in living donors or in people with low nephron endowment, patients with past history of kidney disease, even when current GFR is normal and there is no hypertension or proteinuria, could develop ESRD.
To sum up, don’t ever discharge the patients from your clinic if they have a history of childhood kidney disease.
3 Risk of ESRD in Prior Living Kidney Donors
“Doctor, will my mom need dialysis just because she donated me her kidney?”, an anxious 20-year-old man on dialysis asked me. What should I tell this young man?
Various cohort studies have tried to answer this question. Typically, as the follow-up duration increases, the studies find that there is a small increase in the risk of End Stage Renal Disease (ESRD) in renal donors. Quantifying this risk is important. The risk of ESRD after kidney donation does not exceed ESRD risk in the general population; however, it is higher than healthy matched donors.
Wainright et al analyzed the Organ Procurement and Transplantation Network and Centers for Medicare and Medicaid Services data to study ESRD in 123,526 living kidney donors who donated in the US between 1994 and 2016. 218 donors developed ESRD, with a median duration of 11.1 years after kidney donation, giving 20 years overall cumulative post-donation ESRD incidence of 49 per 10,000 donors. Hypertension, glomerulonephritis, and diabetes were the leading causes.
The risk was low but was highly variable. A 20-year-old white female donor had a predicted 20-year ESRD risk of 8 per 10,000, compared to 111 per 10,000 for a 20-year-old black male donor.
Male gender, higher BMI, being African-American, living in a neighborhood with low income, being a first degree relative of the recipient and having a low GFR at donation were associated with a higher risk. Older age at donation for white donors and younger age at donation for black donors conferred a higher risk.
While informing the prospective donors the risks of donation, these real-world figures are important. The pre-transplant clinic visits are always emotionally charged. In the authors’ words- “Relative risks among donors are useful to clinicians, but potential donors must also understand their absolute risk when making the decision to donate. Potential donors should receive the best available information – including limitations of existing research – about their own personal risk of ESRD after donation.”
4 Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis
A group of nephropathologists proposed modifications to the ISN/ RPS classification of lupus nephritis to improve problematic definitions that form the basis of the lupus nephritis classification and thereby increase the interobserver agreement between nephropathologists worldwide.
Apart from clarification of various definitions, the group proposes two important alterations- Elimination of segmental versus global designation in class IV and replacing ambiguous III/IV-A/C with III/IV-modified activity and chronicity score.
Below is the summary of these changes.
| Class | Modification Suggested |
| Class II | Definition for mesangial hypercellularity adjusted: Four or more nuclei fully surrounded by the matrix in the mesangial area not including the hilar region. |
| Class III and IV | The term endocapillary proliferation is replaced by endocapillary hypercellularity |
| The term crescent is used for a lesion consisting of extracapillary hypercellularity, composed of a variable mixture of cells. Fibrin and the fibrous matrix may be present; 10% or more of the circumference of Bowman’s capsule should be involved. | |
| Cellular crescent: more than 75% cells and fibrin and less than 25% fibrous matrix | |
| Fibrous crescent: more than 75% fibrous matrix and less than 25% cells and fibrin. | |
| Fibrocellular crescent: 25%–75% cells and fibrin and the remainder fibrous matrix. | |
| Adhesion: an area of isolated continuity of extracellular matrix material between the tuft and capsule even when the underlying segment does not have overt sclerosis | |
| Fibrinoid necrosis: fibrin associated with glomerular basement membrane disruption and/or lysis of the mesangial matrix; this lesion does not require the presence of karyorrhexis | |
| Elimination of segmental and global subdivisions of class IV | |
| Modification of the NIH lupus nephritis activity and chronicity scoring system to be used instead of the currently used A, C, and A/C parameters | |
| Tubulointerstitial lesions | Indicate whether interstitial inflammation occurs in presence or absence of interstitial fibrosis |
I am curious to see how the efforts to define the disease better improve the way we treat our patients better.
5 Outcomes after ICD implantation in patients with CKD
CVD is the most common cause of death in a 73-year-old man who has poor LV function (due to ischemic and non-ischemic aetiologies), hypertension and other comorbidities. If a nephrologist sees him, he also gets an additional disease called as ‘CKD stage 3a/3b’ that has reached epidemic proportions in some parts of the world. 1556 such individuals who happened to need ICD implantation, were compared with 4321 matched controls with heart failure, and similar CKD in a retrospective cohort study at 4 Kaiser Permanente health care delivery systems. At the end of 3.1 year of follow up, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization.
This research is a significant addition to the evidence which is scarce to guide practice here. Several limitations should be noted: confounding by indication (those with lower EF and severe heart failure are more likely to be selected for ICD), doubtful validity of CKD definition based on eGFR without albuminuria in elderly, lack of information on precise causes of increased hospitalisation (may or may not be related to ICD use), high competing risks of death and predominantly non-ischemic LV dysfunction are significant limiting generalisability of these findings to all CKD population.
I don’t think this data is enough to exclude patients with community-dwelling CKD needing ICD insertion as per current ACC/AHA guidelines 2012, after a shared decision making.
6 Worsening Renal Function (WRF) in Acute Heart Failure Patients Undergoing Aggressive Diuresis
“Stop/decrease diuretics, avoid contrast, hold RASi for now”-after seeing this renal consult, my cardiology colleague finding hard to keep his eyes open after a busy night shift, used to ask,”why don’t briefly summarise it as -cardiologists to go to sleep for now?”
As a nephrology registrar early in my residency, it was a tough task completing all consults in a given 24 hrs duty time. I recall developing a triage mechanism, where some of these consults can be assigned -“attend last”-cardiology was one of them. ‘Cardio-renal’ wasn’t born until then. By the time I used to reach cardiac floors, more than half the patients have already normalized their ‘hypercreatininemia’ and no longer required my help. After we had a uniform and sensitive diagnostic criteria for AKI in 2004, small increases in the serum creatinine levels were found to be associated with adverse outcomes-causality of which is still today is largely hypothetical. However, this led to growing concern among cardiologist using aggressive diuretic therapies for treating heart failure -‘cardiorenal syndrome’ was born. This study in Circulation is a post hoc analysis on 283 of 360 patients participated in ROSE AHF trial may alleviate this anxiety to some extent. Authors noted no difference in kidney tubular injury biomarkers (urinary NAG, NGAL, KIM1) in 60 patients who developed WRF (>20% decline in GFR estimated by cystatin C) when compared to 233 without WRF. Those who actually developed kidney injury i.e. had WRF and increase in injury biomarkers, survived better than those who didn’t-probably indicating that diuresis worked. These provocative findings are not conclusive but hypothesis generating, also, this analysis was underpowered to conclude definitively on survival. However WRF in such settings was not associated with adverse outcomes (here, here, and DOSE trial) in previous reports. Save them from drowning in their secretions, before you start bothering about creatinine or biomarkers.
7 Trimethoprim, UTI, and adverse events
In this large UK cohort study of 1,78, 238 older patients in the general population, treatment with trimethoprim for a urinary tract infection (UTI) was associated with a 72% increase Higher odds of acute kidney injury were seen with TM (OR 1.72, 95% CI 1.31 to 2.24) and to a lesser extent with ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. TM was also associated with a greater than doubling of the odds of hyperkalemia compared with amoxicillin. Findings remained consistent across various subgroups and sensitivity analyses.
Adverse effects of TMP-SMX and ciprofloxacin, when used in combination with RASi or spironolactone, were highlighted previously, however, this is the first time that a large, general practice based evaluation trimethoprim is linked to adverse events. While one can argue about the relevance of serum creatinine elevation alone (that can occur due to inhibition of tubular secretion due to TMP), hyperkalemia is a potentially serious concern. Safety issues with TMP-SMX in patients receiving RASi or spironolactone have been documented previously, however, this study raises suspicion on the role TMP over SMX in mediating these effects. Unlike many other countries, TMP use is common in the UK (as per guidelines)- I see TMP here as a favorite choice of some urologists for chronic prostatitis.
In patients who are 65+, already challenged by homeostenosis, it takes little to tip the balance and TMP can be one of these reasons. If compelled to use, monitor carefully.
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