Acute Oxalate Nephropathy

Acute oxalate nephropathy is a rare but well described cause of acute kidney injury (AKI) leading to acute tubular necrosis due to the deposition of calcium oxalate crystals within the tubules.
Acute oxalate nephropathy can occur in both primary and secondary hyperoxaluria.

• Primary hyperoxaluria is a group of autosomal recessively inherited enzymatic deficiencies that lead to the increased urinary excretion of oxalate. 
• Secondary hyperoxaluria can occur due to increased dietary oxalate intake, increased absorption of oxalate from the bowel (also known as enteric hyperoxaluria), and increased production of oxalate. 

This mechanism of enteric hyperoxaluria is manifested in several ways, including with orlistat therapy, Roux-en-Y gastric bypass surgery, celiac disease, and Crohn's disease. Increased production of oxalate is mainly due to increased levels of oxalate precursors, more commonly glyoxylate, which is associated with ethylene glycol ingestion, and less commonly ascorbic acid. Oxalate nephropathy has also been seen in association with large quantities of iced tea consumption and most recently with "green smoothy cleanse".

Let's review a typical clinical scenario.

A young patient with history of alcoholic abuse who arrived to the emergency department with seizures, AKI (creatinine of 35 mg/dL, normal baseline), high anion gap metabolic acidosis, high osmolal gap (20 mOsm/l), oliguria, neurological signs and who strongly denied any drugs-of-abuse or suicidal toxic ingestion. The toxicological serum and urine examination did not show any evidence of toxic substances. No alcohol was noted on breath. The measurement of ethylene glycol serum level was not available. No family history of diabetes or any kidney diseases. Because of accompanying seizures, the patient was admitted to the ICU and treated with CRRT. Radiographic imaging demonstrated posterior reversible encephalopathy syndrome (PRES). A kidney biopsy was performed and showed the presence of several calcium oxalate monohydrate crystals mainly within tubular lumens consistent with acute oxalate nephropathy (Figure above). Eventually, the patient confirmed ingestion of small quantities of car antifreeze solution.

Ethylene glycol is a common component of automotive radiator antifreeze solution and is sometimes used as a substitute for ethanol. It can be ingested voluntarily, accidentally, or consumed in a suicidal or homicidal attempt. Ethylene glycol ingestion can lead to AKI from tubular deposition of oxalate crystals and can also cause neurological damage and death.

The diagnosis of ethylene glycol intoxication is based on a history of ingestion, clinical examination, high anion gap metabolic acidosis, high osmolal gap, and a measured serum level of ethylene glycol. However, it is often times difficult to ascertain an exact time frame of ingestion or have 100% certainty of consumption. Often times ethylene glycol levels are unknown as well. In this case kidney biopsy is essential in making the correct diagnosis. Therefore, a high index of suspicion for this disorder should be maintained in the presence of unexplained metabolic acidosis, hyperosmolality, unexplained AKI, and neurologic dysfunction.

Francesca Cianciotta
Nephrology Resident
University of Bari
Italy

Jaundice and Renal Failure

In patients with combined renal and liver dysfunction it is important to differentiate between renal impairment that is secondary to liver disease i.e. hepatorenal syndrome, and conditions where an insult directly affects both the liver and kidney.  

I recently saw a 20-something year old student who was a regular kayaker in local rivers.  He had a 5 day history of myalgia, fever and headache with no vomiting or diarrhoea.  He took paracetamol (acetaminophen) and ibuprofen within recommended limits for his symptoms.  In the 24 hours prior to his admission he developed jaundice and noticed decreased urinary output. On arrival to hospital he was jaundiced but examination was otherwise unremarkable.  There were no signs of chronic liver disease and the liver was not palpable.  He was hemodynamically stable.  Blood tests showed a raised (conjugated) bilirubin at 453umol/L (25 mg/dL), ALT within normal limits and mildly elevated ALP at 162U/L.  He had an acute kidney injury with creatinine 427umol/L (4.83 mg/dL), potassium 3.4mmol/L.  He was anemic and thrombocytopenic with a neutrophilia, and blood film showed toxic granulation, with no red cell fragments.  An ultrasound of his liver was unremarkable and his kidneys were at the upper limit of normal size with no hydronephrosis. For 36 hours he was anuric despite fluid resuscitation, and required a short period of CRRT.  After this time he began passing urine and his creatinine spontaneously fell, although bilirubin remained elevated.  He was treated empirically with ceftriaxone and doxycycline for leptospirosis, and six days later urine PCR and serum IgM came back positive for leptospirosis.  

Photo from ACG Case Reports Journal

Leptosporosis is a zoonosis usually transmitted to humans through rodent urine in water.  The majority of cases cause a self-limiting febrile illness, but in its severe form - Weil’s syndrome – patients can develop jaundice, renal failure, pulmonary haemorrhage and aseptic meningitis.  Renal impairment in leptospirosis can be secondary to a number of different mechanisms including sepsis/critical illness, a direct nephrotoxic effect to the renal tubule by the leptospira toxin, tubulointerstitial nephritis, rhabdomyolysis and hyperbilirubinemia.  Patients often maintain good urine output despite renal injury, and tubular dysfunction means most patients are hypo- or normokalemic even if oliguric.  Another characteristic finding is enlarged kidneys with normal parenchymal echogenicity on ultrasound.  

Included in our initial differential was that his renal impairment was secondary to hyperbilirubinemia.  Bilirubin causes renal impairment again through a range of mechanisms including direct toxicity to the nephron, bile acid casts causing tubular obstruction, and hypoperfusion from vasodilation.  Renal biopsy can show pigmented bile casts within the tubules and tubular hypertrophy (see image).  Electron microscopy can show bile acid accumulation within lysosomes and dilated mitochondrial cristae.  In those with normal baseline renal function and short-lived hyperbilirubinemia changes are often mild and reversible, but irreversible damage can occur in those with underlying renal impairment.  

Early clues for leptospirosis in this case include hypokalemia despite being oligoanuric, enlarged kidneys on ultrasound and of course his social history.  


Post by Ailish Nimmo

Cidofovir nephrotoxicity and Probenecid

I recently saw an interesting case. A woman was being treated with cidofovir for adenovirus which was presumed to be responsible for an acute cardiomyopathy. Concurrent with cidofovir, she was also receiving probenecid for renoprotection, which I was not familiar with.

Cidofovir is a nucleotide analogue used primarily to treat CMV retinitis in patients with AIDS. However, cidofovir is also used to treat a number of DNA viruses including adenovirus. The main toxicity of cidofovir is nephrotoxicity, which can manifest as AKI, proteinuria, or a Fanconi-type syndrome with proximal tubular dysfunction. Nephrotoxicity can be reduced by co-administration with iv fluids and probenecid (the dosing regimen for the latter is 2g po 3 hours prior to the dose, then 1 g po 2 hours and 8 hours after.

How does probenecid reduce cidofovir nephrotoxicity? Over 80% of cidofovir is excreted unchanged in the urine in 24 hours. Most of this occurs via glomerular filtration, but cidofovir is also actively taken up from blood by the kidneys via the "organic anion transporter" located on the basolateral side of renal proximal tubular cells, and is then more slowly secreted into the tubular lumen. Renal clearance of cidofovir therefore exceeds the corresponding GFR.

The relatively slow secretion of cidofovir into the tubular lumen, in comparison to uptake from the blood, results in a long intracellular half-life of the drug in the proximal tubular cells which appears to underlie the nephrotoxicity. Probenecid, by inhibiting the organic anion transporter, prevents tubular uptake and protects the kidneys. This was demonstrated nicely in a pilot study in HIV patients. Interestingly, and somewhat paradoxically, this means that probenecid reduces nephrotoxicity while also DECREASING the renal clearance of the drug and thus INCREASING serum cidofovir concentrations as much as two-fold.

Probenecid is a banned drug for athletes for a related reason - because it blocks entry of certain drugs into the urine, it has been used as a masking agent for other banned performance-enhancing drugs including steroids. 

Posted by David Leaf

Renal Grand Rounds - A Chilling Case of Hyperkalemia

A 62 year old man with ischemic cardiomyopathy (EF 35%) and CKD (baseline Cr ~3 mg/dl) had a witnessed out-of-hospital cardiac arrest.  EMS arrived within 3 minutes.  He received CPR and was shocked out of ventricular fibrillation (VF).  He was intubated and therapeutic hypothermia was initiated in the field. He was admitted to the CCU, where therapeutic hypothermia was continued for 24 hours.  He received aggressive KCl repletion for hypokalemia (see graph below) and supraventricular arrhythmias.  On the second hospital day the patient was rewarmed, developed severe DIC (INR 10), worsening shock requiring 3 pressors, and renal was consulted for hyperkalemia and oliguric AKI on CKD.

Clinical pearls: Hypokalemia is a frequent complication of hypothermia for two major reasons: 

1) cold diuresis, which is believed to result from peripheral vasoconstriction, increased venous return, and increased ANP; 

2) catecholamine-induced shift of KCl into cells.  

Interestingly, the latter seems to depend on the type of protocol used to induce hypothermia.  Core cooling increases norephinephrine but not epinephrine, and therefore does not cause a shift of K into cells.  In contrast, external cooling (which was used in this case, with the application of cooling pads) increases epinephrine disproportionately to norepinephrine.  The B₂ agonist actions of epinephrine cause a shift of K into cells.  It is therefore critically important to avoid KCl repletion during rewarming due to the risk of rebound hyperkalemia, particularly in oliguric patients such as this one who are unable to deal with the excess potassium load once it moves back out of the cells during rewarming.

Posted by David Leaf

BWH Path Conference - AIN... or is it

Nephrology was consulted by the general medicine service for AKI in an elderly man with endocarditis. He had MSSA bacteremia for which he was being treated with oxacillin and rifampin. There was no report of rash or recent fever. He had no aminoglycoside, IV contrast, or NSAID exposure, and no severe hypotension. His creatinine had risen from 1.1 on admission to 1.8 mg/dl. Urinalysis showed 3+ blood, 2+ protein, and trace leukocytes. Urine sediment showed 5-10 WBC, WBC casts and dysmorphic RBCs. He had no RBC casts, and no granular casts. He had a peripheral eosinophilia (2%). Urine eosinophils were negative. Serologies and complement levels were normal. Oxacillin was discontinued under the presumptive diagnosis of AIN secondary to beta-lactam antibiotics. Despite this intervention, his creatinine continued to rise and a renal biopsy was obtained. The biopsy results are shown below:

Two glomeruli with diffuse hypercellularity of the tuft. There is minimal interstitial inflammation

The infiltrating cells in the glomerular capillaries are predominantly mononuclear cells with isolated neutriphils.

Scattered deposits of IgG are noted along the peripheral capillary walls and in the mesangium.

EM shows large and confluent subendothelial electron dense deposits.

Diagnosis: Diffuse proliferative glomerulonephritis, most likely post-infectioius and related to the patient's sepsis.

This case appeared to be a relatively straight-forward case of AIN based on the exposure to a common culprit medication, the presence of eosinophilia and urinary white cell casts and the time course following admission. The presence of dysmorphic red cells was atypical although this is observer-dependent and there were no red cell cats which, while specific, are not very sensitive for the diagnosis of an acute GN. Traditional treatment comprising withdrawal of the offending medication and potential exposure to steroids may have been detrminetal in his case leading to inadequate treatment of his MSSA bacteremia.

The classic constellation of clinical signs in AIN is present in a minority of cases. For example, rash is present in ~15%, fever in 27%, eosinophilia in 23% and the triad in only ~10% of patients. White blood cell casts are sensitive but are a non-specific marker of intra-renal inflammation and are associated with a wide differential diagnosis. Urinary eosinophils are neither sensitive or specific and should not be used to make the diagnosis of AIN.

This case highlights the difficulty in making a clinical diagnosis of acute interstitial nephritis and the importance of a renal biopsy to confirm the clinical suspicion.

Posted by Katherine Garlo

Renal Functional Reserve: Time for a Kidney stress test in clinical practice?

GFR varies under normal physiological conditions and during illnesses. A popular example is a low GFR in vegetarians and a higher GFR in consumers of large quantities of animal protein, even when they have a similar normal renal mass. It is not clear what the maximum GFR can be, but it can be approached with an acute animal protein load. One to two hours after an animal protein load, individuals with healthy kidneys will show a significant rise in their GFR independent of their baseline GFR. The difference between baseline and maximal (i.e. stress or peak) GFR is called the Renal Functional Reserve (RFR).

The maximum capacity of a functioning renal mass is not reflected by the baseline GFR of a given individual. Bellomo et al used an example of 4 different patients to explain this concept. Patients A (animal protein consumer) and B (vegetarian) have the same renal mass but different baseline GFRs owing to different basal protein in-takes levels. Patient A has a GFR of 120 ml/min that can be stimulated to 170 ml/min. Patient B has a baseline GFR of 65 ml/min that also can be stimulated to 170 ml/min. Therefore, the RFR in these two patients is different because they are using their GFR capacity at a different level. Patient C had a unilateral nephrectomy. His baseline GFR corresponds to his maximal GFR under unrestricted dietary conditions. If a moderate protein restriction is applied to his diet, his baseline GFR may decrease and some degree of RFR become evident. Patient D, who is a vegetarian who underwent unilateral nephrectomy, will have a lower baseline compared to patient C but a higher RFR. Therefore, in general, restoring some RFR requires a severe protein restriction, and hence baseline GFR does not always correspond to the extent of functioning renal mass unless we place it in the context of maximal capacity. Bellomo et al concluded the section about GFR by using a very interesting, possibly true, statement:

“In this regard GFR is not unlike a resting ECG for the kidney. When it is grossly abnormal, renal function is impaired, but when it is normal, a stress test is required.”

The GFR rises considerably during pregnancy. This physiological rise is multifactorial and is mainly attributed to increase in cardiac output and renal blood flow. It becomes apparent from the 1st month and peaks at 40% – 50% above baseline levels by the 4th or 5th month of pregnancy. This increase in GFR is referred to as renal hyperfiltration. The RFR is consumed as a part of adaptation to this physiological demand that occur during pregnancy. This was demonstrated by Ronco et al. They assessed GFR changes in pregnant women, with normal kidneys, before and after protein load. After acute protein load, all women had a significant increase in GFR. This rise was more in the first than in the last trimester. This finding explains, at least partially, renal hyperfiltration in pregnancy.

RFR allow for an increase in GFR during stressful conditions to ensure maintenance of adequate kidney function. When RFR is lost or fully utilized and the kidney insult continues, changes in baseline GFR and serum creatinine occur. After an AKI episode, creatinine and GFR may return to normal, displaying an apparent complete recovery of the kidney. Unfortunately, this recovery might be at the expense of reduction or loss of the RFR. In my opinion, without performing a kidney stress test to assess the RFR post-AKI, it will remain unclear whether the recovery from AKI was complete or was it just a biochemical recovery (reflected by creatinine level) at the expense of RFR utilization. Conceptually, recovering baseline GFR and creatinine level post-AKI without recovering the RFR should be labelled as new-onset CKD because it actually reflects an irreversible loss of nephrons/RFR. I have no evidence to support this, but I would hypothesize that these patients who lose their RFR post-AKI are the ones who were shown to progress to CKD in previous studies.

I think the following are potential benefits for using a kidney stress test/ checking RFR:

1. Assessment of recovery post-AKI: It will help to detect patients who are likely to progress to CKD.
2. Assessment of living kidney donors prior to donation: It is likely that a low RFR might increase the long-term risk of CKD during the post-donation period.
3. To assess the risk of AKI in patients undergoing contrast studies and high-risk surgeries.

Of course robust studies are needed to assess the diagnostic and the prognostic utility of RFR and kidney stress test in the clinical setting.


Post by Mohammed Kaballo

False-positive AKI and the perfectly imperfect biomarker

A small absolute change in serum creatinine level, 0.3 mg/dl, is used by Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines to define the presence of Acute Kidney Injury (AKI). The base of this definition was formed by several studies findings of strong association between adverse outcomes and minor changes in serum creatinine level. Subsequently, evidence emerged suggesting that this may not be true to the same extent in people with pre-existing CKD, because variations in serum creatinine concentration are common in these individuals.

As with all other laboratory tests, serum creatinine measurements are affected by within- and between-sample coefficients of variation, intra-individual variation and biologic variation. Biological variation may result from variations in diet, muscle mass and breakdown, tubular secretion, variability in volume homeostasis and from medications uses. The variation in measured serum creatinine level could be as high as 9%. Because only a small increase in serum creatinine is needed to meet AKI criteria, random variation in creatinine level may be a significant contributor to AKI diagnosis in the absence of a true reduction in GFR. This is called a false-positive AKI. It has been shown that high variation in serum creatinine in the period, of days, preceding the development of AKI was not associated with the anticipated inpatient mortality or dialysis. This observation supports the existence of false-positive AKI.

Lin et al demonstrated, using the KDIGO definition, an 8% overall false-positive rate for AKI diagnosis. This rate was much higher, 31%, for the subgroup of CKD patients with serum creatinine ≥1.5 mg/dl. Therefore, an absolute change in serum creatinine of 0.3 mg/dl may represent a relative inconsequential change in GFR in CKD patients rather than a superimposed acute injury.

In my opinion, false-positive AKI could largely explain why most randomized trials for early intervention in AKI have been unsuccessful in improving outcomes. AKI is misclassified under frameworks that do not reflect true GFR reduction. Consequently, patients with false-positive AKI are included in AKI studies and dilute observed effect sizes. This potentially leads to false-conclusions that certain interventions are ineffective and do not improve outcomes. The underlying severe disease is quite likely the actual mediator of adverse outcomes seen in AKI. Therefore, small changes in serum creatinine may be nothing more than a reflection of the severity of the underlying disease process. This point remains a topic of hot debate. Moreover, AKI definition using small increments in serum creatinine level has not been validated among patients with CKD.

It is obvious now that serum creatinine is an imperfect AKI biomarker; especially that it is being used on the basis of a relative change in value of a continuous variable instead of the crossing of a particular threshold. The ideal biomarker would accurately detect true reduction in GFR, be detectable early in the course of renal dysfunction to allow for timely intervention, and predict outcomes. It is likely that current AKI criteria will eventually be modified at least in part by sensitive and specific biomarkers of kidney injury. The use of such biomarkers will help in the development of a new paradigm for classifying AKI that is not only dependent upon serum creatinine. Meanwhile, the awareness about false-positive AKI should be highlighted and the limitations of serum creatinine, as an AKI biomarker, should be re-emphasized.

Authored by Mohammed A. Kaballo, Nephrology Fellow, Ireland

Remote ischemic preconditioning (RIPC)— Preparing your kidneys for surgery.

Prevention of perioperative AKI, mostly from ATN by ischemic insult, has been a major challenge in nephrology. Recent study (Zarbock et al. JAMA) showed a simple, non-invasive method—remote ischemic preconditioning (RIPC), could be a promising strategy.

This multicenter, double-blind study in Germany randomized 240 patients undergoing on-pump cardiac surgery, who had high risk for AKI (based on Cleveland Clinic Foundation score). Exclusion criteria included eGFR below 30 ml/min or transplant recipient. Intervention consisted of: 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mmHg (or 50 mmHg higher than the systolic pressure) to one upper arm, followed by 5-minute reperfusion with the cuff deflated.

Primary endpoint was the incidence of AKI within 72-hour post-op (KDIGO criteria). They found significantly fewer patients in RIPC group developed AKI (37.5% vs 52.5%; p=0.02; RR, 71% 95% CI, 54-95%). Use of renal replacement therapy was also lower (5.8% vs 15.8%; p=0.01). Of note, the authors examined urine biomarkers: tissue inhibitor of metaloproteinases 2 (TIMP-2) x insulin-like growth factor-binding protein 7 (IGFBP7), as well as urine neutrophil gelatinase-associated lipocalin (NGAL) and high-mobility group box (HMGB). TIMP-2 and IGFBP were measured by Nephrocheck® (see previous blog entry for details). Biproduct of TIMP2 x IGFBP7 and HMGB increased right after RIPC, suggestive of cell cycle arrest as an epithelial defensive mechanism against ischemic insult, however, in 4-24 hours post-op, TIMP2 x IGFBP7 and NGAL were lower in RIPC group compared to control (schematic figure above from eSupplement), indicating less kidney damage.

 RIPC has been studied in kidney transplant field as well. The REPAIR trial recruited 406 live donor-recipient pairs and looked into 12-month post-transplant eGFR with or without early or late RIPC for both donors and recipients. The result was not significant, but as Zarbock et al. pointed out in their article, it could be due to differences in study protocols, confounding comorbidities, or surgical technique. Further studies to explain the mechanism of protection is warranted and it might be no exaggeration to say that RIPC would be a standard pre-op protocol for cardiac surgery in the near future. Are your kidneys ready for surgery?

Naoka Murakami

Update from Hepatology: AKI and HRS in patients with cirrhosis

In the recent edition of Hepatology, the International Club of Ascites (ICA) have published their revised recommendations on the diagnosis and management of AKI in patients with cirrhosis. They first proposed diagnostic criteria for Hepatorenal syndrome (HRS) in 1996 and last updated them in 2007 (covered by RFN). Since their first publication, there has been much work done in defining AKI with RIFLE, AKIN and KDIGO and this is reflected in the ICA’s latest guidance. This time, they have gone beyond defining HRS to include staging of AKI in patients with cirrhosis and proposed how this could be used to inform management.
Here are the definitions they propose (the ICA-AKI classification):

The first thing to note is that they’ve removed the fixed threshold of sCr of ≥ 1.5 mg/dl (133 mmol/l) from the old criteria and brought in an absolute increase in sCr.  Indeed, the eagle eyed amongst you will have noticed that their definitions and staging of AKI are based on the KDIGO criteria but with the use of urine output removed. The rationale for this being that patients with cirrhosis can often be oliguric with avid sodium retention but still have preserved renal function. Conversely, they can have an increased urine output as a result of diuretic therapy.
Whilst a sCr less than 7 days before admission would be the ideal result to use as baseline, they have pragmatically suggested that the most recent value available in the last 3 months can be used. When this is not available, the admission sCr should be used as baseline. They do not recommend using the reverse application of the MDRD formula to calculate an estimate of baseline sCr as MDRD is known to be inaccurate in patients in cirrhosis (covered in a previous RFN post ). If no previous sCr is available and the admission value is ≥ 1.5 mg/dl (133 mmol/l), decisions should be based on clinical judgement.
Moving onto management, the ICA has suggested the following algorithm:

Treatment for those with AKI stage 1 is outlined in the table. Note that the plasma volume expansion can be with crystalloid or albumin (or blood in the case of GI bleeding) at this stage. Those who present with AKI stage 1 who progress are then treated in the same way as patients who present with AKI stage 2 and 3 i.e. stopping the diuretics and 48 hours of albumin 1g/kg (max dose 100g per day). Further management then varies on the aetiology and whether or not this is HRS, which the algorithm helpfully informs. The new criteria for HRS:

Again, they have removed the cut off value in sCr from the diagnosis in favour of a dynamic change in sCr as per the ICA-AKI criteria. Importantly, they have suggested revising the diagnostic criteria for type 1 HRS and with it the indications for treatment with vasoconstrictors. Type 1 HRS is currently defined as a doubling of the initial sCr to level ≥ 2.5mg/dl (226 mmol/l) in < 2 weeks. Evidence however suggests that a higher sCr at the beginning of treatment leads to a lower chance of response to vasoconstrictors and albumin. With the new algorithm, patients at AKI stage 2 or 3 or who have progression from stage 1 that meet all the other criteria for HRS, should receive treatment with vasopressors irrespective of the final value of sCr. This will allow treatment earlier and hopefully lead to better outcomes though at present there is no data to confirm this.

No consensus was reached on the optimal management of those patients who present with AKI stage 1 but then have stable renal function (i.e. do not regress or progress). Whilst all agreed that if the patient has a final sCr ≥ 1.5 mg/dl (133 mmol/l), they should be treated according to the right side of the algorithm, most of them had concerns about the use of vasoconstrictors for those with HRS if the sCr was < 1.5 mg/dl (133 mmol/l). Hence, they advise to treat these patients on a case-by-case basis.




Authored by David Baird,
Royal Infirmary of Edinburgh

Renal Function after Off- or On-Pump CABG: CORONARY Trial is next #NephJC

The next Nephrology online journal club (#NephJC) will discuss the results of the CORONARY Trial, presented at the late breaking session at the ASN and published this year in JAMA. The trial compared patients undergoing their first coronary artery bypass graft (CABG) surgery using an off- or on-pump technique. The main study published previously revealed no difference with respect to the composite outcome of 30-day mortality, myocardial infarction, stroke or acute kidney injury (AKI) requiring dialysis. The renal function trial was a prespecified substudy involving 2975 (of a total 4752) consecutive patients enrolled in CORONARY with baseline and post-operative serum creatinine data. The renal substudy patients had similar characteristics to the overall CORONARY population.

Outcomes of Interest:

• Post-operative AKI was defined as a 50% increase in the serum creatinine concentration within 30 days of surgery (highest creatinine within 30 days was used).
• Loss of renal function at 1 year = 20% loss in eGFR (using CKD-EPI).

Patients:

• Worldwide enrolment with 42% from Asia and the remainder mostly from Europe (21%) and the Americas (<1% were African American).
• Baseline characteristics of note were a mean age of 68 years, BMI 27, >80% male, almost half were diabetic and a similar number of ‘urgent’ cases between the groups.
• Almost a quarter had CKD (eGFR <60mls/min) and the mean eGFR was 74-75mls/min in the 2 groups.

Results:

• There were 561 AKI events (median time of 2 days post-op to peak creatinine) with a reduced rate with off-pump (17.5%) V. on-pump (20.8%) surgery (adjusted RR 0.83 [CI 0.72-0.97]; p = 0.01).
• Mean eGFR at 1 year was 72 mL/min with off-pump and 73 mL/min with on-pump.
• No significant difference in loss of eGFR at 1 year between off-pump (17.1%) V. on-pump (15.3%) surgery (P = 0.23).
• Those with CKD derived a greater benefit in reduced AKI with off-pump surgery but eGFR loss at 1 year remained insignificant.
• Over 200 patients crossed over between the groups (evenly split) and results of the intention to treat were similar to as-treated analysis.
• Multiple alternative definitions of AKI & loss of kidney function did not alter the main results.

Discussion:

Dialysis requiring AKI has detrimental effects on long-term kidney function. Less severe AKI is more common with major cardiac surgery (only just >1% had AKI requiring dialysis in the original CORONARY trial). It is less clear what effect these more subtle derangements have on long-term function. This study suggests that these ‘mild’ AKI events may not have much longer-term significance, contrary to observational studies [ref, ref]. As pointed out by the authors, this finding has implications for other interventions in mild AKI such as for contrast nephropathy. Does preventing a subtle GFR dip in this scenario have a long-term benefit? The study is limited somewhat by the unique situation studied in the trial (although cardiac surgery provides a very ‘convenient’ insult in which to study AKI). Also, we are relying on serum creatinine and all its limitation to assess kidney function. Moreover, not all eligible patients had creatinine values measured and single measurements and imputed values were often used for the analysis.

Verdict:

This study provides good evidence that off-pump CABG decreases the rate of non-severe AKI but that this does not appear to translate into better renal function at 1 year. When I first heard the results of this study at the ASN (a somewhat deflating session along with lots of other negative/inconclusive Nephrology studies), I was disappointed with the small magnitude of the AKI decrease with off-pump surgery. I had expected the toxic milieu associated with on-pump surgery (aortic cross clamping, exposure to bypass circuit, changes in blood pulsatility) to be associated with much higher rates of AKI, compared to off-pump. The study also questions my preheld assumption that acute drops in GFR, from mild to severe, had a continuous magnitude of impact on long term renal function.

Feel free to get involved by joining the live Twitter chat on Tuesday 26^th August at 9pm Eastern using #NephJC. Also, check out www.nephjc.com for more background and past journal clubs.

NephMadness 2014 Part 4 - AKI Bracket

In the AKI bracket one team caught my eye, RIPC, Remote Ischemic Preconditioning. This is a procedure of inducing transient ischemia in the arm by inflating a BP cuff for 5 minutes x2 with an interim deflation for 5 minutes. This procedure was done before coronary angiography, aneurysm repair and was shown to reduce myocardial ischemia, renal injury and contrast-induced nephropathy. These procedures have a high prevalence and there are no other therapies to reduce CNI other than fluids (see ACT trial on N-acetyl cysteine), this team is a good contender this year. Hopefully we will see more evidence for this simple procedure. However, my favorite from this group is normal saline, simple, cheap effective, global! How many times has an acute renal failure case, presented to you as a complicated mess by a resident, been solved by some salty water!! I love it! This team goes all the way to the final four for me.

Remember to fill out your NephMadness 2014 brackets! Find them at eAJKD

DREAM-CARD. Diuresis Related Endpoints After Major CARDiac surgery

This is my contribution to the Dream RCT in Nephrology poll being coordinated by UKidney. As a nephrologist it seems one spends a lot of time trying to rationalize the use of diuretics in the Cardio-Thoracic ICU. Volume overload and reduction in preload are common and very valid concerns for patients post cardiac surgery. Diuresis to remedy this problem is a physiologically appropriate management strategy. However, as a nephrologist it is not uncommon to see patients that have been diuresed to the point where renal perfusion is compromised. Admittedly this is anecdotal and we see a biased group of cardiac surgery patients. There is evidence that an episode of dialysis requiring AKI in any hospitalized patient increases risk of progression to CKD even if renal function recovers enough for the patient to come off dialysis.

Cardiovascular, renal and survival outcome data for dialysis-requiring AKI in post cardiac surgery patients with relatively preserved pre-op GFR is lacking. It is possible that increased renal outcomes or mortality associated with dialysis-requiring AKI in this group of patients may offset any benefits achieved by cardiac surgeries such as CABG and valve repair. This is the motivation for this ‘dream’ trial. Conducting such a trial would be a very large and difficult undertaking due to the many sources of bias in such a trial and also the fact that blinding a trial involving a dialysis machine is impossible. This would be a very difficult trial to roll out in the real world but here is my best effort!

Inclusion criteria;
Preoperative eGFR over 60ml/min (MDRD)
Elective non-transplant cardiac surgery

Exclusion criteria;
Previous cardiothoracic surgery Macroalbuminuria or greater
Previous AKI events Hospitalizations in the preceding 6 months
Aortic cross clamp time longer than usual as judged by blinded independent panel
Unexpected intraoperative complications as judged by blinded independent panel
Patients requiring RE-intubation after the initial perioperative period (removed from final analysis)

Interventions: The interventions will be randomized into two arms determined by Central Venous Pressure (CVP).
Target CVP: 1) Below 6mmHg versus 2) Below 12mmHg

The approach used to reach this target maybe be determined by the individual clinician. Use of IV Lasix infusion, IV Lasix bolus, concomitant thiazide use or dialysis for the purposes of ultrafiltration (UF) will be documented. Total doses of Lasix and number of days Lasix was used will be documented. Total daily UF achieved by dialysis and number of days on dialysis will be documented. Whether continuous RRT therapy or intermittent therapy was used will also be documented. All the usual demographics and variables will be documented such as serial body weights, urine outputs, blood pressures, serum creatinines and number of days in hospital.

Post discharge patients will be followed. All post surgical hospital admissions and diagnoses will be documented. If patients had elevated creatinines at discharge, serial monthly creatinines will be measured until stable. If patients are discharge home but still on dialysis, the number of days on dialysis before recovery will be documented. The dialysis status of those remaining on dialysis will be followed. All patients will be followed with a yearly creatinine (MDRD). Follow up will be for five years.

The primary endpoint will be mortality
The secondary endpoint will be a composite of renal endpoints including the development of CKD and ESRD.

The goal will be to determine if those who underwent aggressive postoperative volume reduction as assessed by CVP have increased mortality. Furthermore, will those who required mechanical UF to reach their CVP goal have worse renal outcomes?
Remember readers this is a ‘DREAM’ trial, one that is likely never to happen especially as the funding source will be from the large coffers of the RFN! Another major benefit of doing such a trial would be the accumulation of a large amount of useful data.
Vote for DREAM-CARD, badly needed evidence for rounding in the CT-ICU!

The end of the road for urinary eosinophils?

Nate wrote a couple of posts in the past about the use (and misuse) of urinary eosinophils for the diagnosis of acute interstitial nephritis (AIN). Since the original report describing the use of this test in the NEJM in 1986, a number of papers and commentaries have been published that cast doubt on its true effectiveness. A paper was recently published in CJASN that looked at the accuracy of this test in a series of patients who had kidney biopsies for AKI between 1994 and 2011.

The authors examined the biopsy and urine results of 566 patients who had biopsies and a urinary eosinophil test over the course of the study. Overall 91 patients had biopsy-confirmed AIN, 73 of whom were considered to be drug-induced. 31.6% of patients had UE>1%, the traditional cut-off for the diagnosis of AIN. The majority of these did not have AIN and the distribution of positive UE was uniform across diagnoses. As a result, the sensitivity and specificity of this test for the diagnosis of AIN were poor. Using 1% UE as a cut-off, the sensitivity was 30.8% and the specificity was 68.2%. The PPV was 15.6% and the NPV was 83.7%. Using a more stringent cut-off of 5%, the sensitivity decreased to 19.8%, the specificity, PPV and NPV were 91.2%, 30% and 85.6% respectively.

One significant limitation of this study was that it was restricted to patients who had kidney biopsies and the majority of patients with suspected AIN do not have kidney biopsies. However, I would imagine that this should bias the results towards favoring UE as a test as presumably patients with more severe disease would be more likely to have a biopsy. Another issue is the potential that there was a bias towards biopsying patients who did not have UE (and so were not thought to have AIN in the initial impression). This could have the effect of reducing sensitivity.

Notwithstanding this, the fact that the distribution of positive UE was so well distributed among the various diagnoses combined with the very low sensitivity of this test would suggest that the use of this test should no longer be routine in the diagnosis of AKI. At best, a negative test helps rule out AIN in patients with a low pre-test probability while a positive test is not particularly useful. As the authors of the accompanying editorial point out, even in drug-induced AIN, the infiltrate may not have a high proportion of eosinophils, suggesting that in many cases there may not even be a plausible biologic rationale for this test.

CKD after AKI in the ICU

I give a regular talk to the residents in the ICU on CRRT and one of the things that I focus on is prognosis. We all know that the outcomes of patients requiring CRRT in the ICU are poor. Multiple studies have shown that the mortality is 40-60% and that this mortality rate has not changed in the last 20 years. However, something that residents are less aware of is that, in the event that a patient survives their stay in the ICU, the majority will not require long term dialysis - approximately 80%. This is sometimes difficult to appreciate when you see patients on HD at discharge from the ICU but most of these will recover at least some renal function. One question, however, is how much function they recover and if this has any bearing on their overall mortality.

A paper recently published in CJASN goes a long way towards answering these questions. This was a retrospective cohort study of all 1220 patients admitted to the ICU requiring CRRT in a single center in the Netherlands between 1994 and 2010. As expected, the in-hospital mortality was high (55%). Of those who survived, 12% did not recover enough renal function to come off dialysis after discharge.

The commonest reasons for admission were thoracic surgery and sepsis. 20% of patients had pre-existing CKD, 48% had normal baseline renal function. There was no baseline in the remainder. At the time of discharge from hospital, 60% of patients had some degree of renal dysfunction (30% eGFR 30-60, 15% eGFR 15-30, 15% eGFR 0-15 including the 12% on HD). Of note, more than half of the patients with an eGFR <15 at discharge had pre-existing CKD. Unadjusted patient and renal survival is shown in the table:

The independent predictors of long term mortality were age, a surgical diagnosis, malignancy and an eGFR < 30. Similarly, the predictors of future need for dialysis were pre-existing CKD, and an eGFR < 30 at discharge. Interestingly, an eGFR between 30 and 60 was not associated with an increased risk of mortality or need for RRT in the future, relative to those with normal renal function at discharge.

This study adds to our knowledge of the predictors of outcomes after an episode of AKI requiring CRRT. No-one should be surprised that patients with significantly reduced GFR at discharge at are increased risk of mortality and need for eventual dialysis. However, it is reassuring that, in those patients who have an eGFR >60 at discharge, the likelihood of them requiring dialysis in the future is very low. It would be interesting to know if the presence of proteinuria modified the relationship between eGFR and mortality/need for dialysis, particularly in those with an eGFR between 30 and 60 at discharge but unfortunately, these data were not available.

What are you smoking?

I recently saw an interesting case series published in CJASN where they reported four cases of oliguric AKI  associated with synthetic cannabinoids use. Renal biopsy revealed acute tubular injury in three of them and calcium oxalate crystals  in two.

Interestingly, around the same period of time I was rotating in nephrology consult service and had an elderly patient with history of paraplegia and neurogenic bladder (on intermittent self-catheterization), who was brought to the ER with altered mental status for which he was intubated for airway protection. On presentation, he was found to have acute kidney injury (Cr 6.0). His renal function continued to deteriorate with no specific etiology for his renal failure, so he had a renal biopsy which showed evidence of an active tubulointerstitial nephritis with marked tubular injury and calcium oxalate crystals present within the tubular lumina. Remarkable findings in his history included the recent use of cannabinoids. He never had history of renal stones. His home medication includes: methadone, oxycodone, nortriptyline and pregabalin. Admission labs showed normal osmolar gap and negative toxicology analysis. Urine microscopy showed muddy brown casts with no identifiable crystals.  Abdominal ultrasound did not reveal any renal calculi. Renal replacement therapy was started for uremic symptoms and he continued to require replacement therapy after his discharge.

The use of these synthetic cannabinoid preparations has increased significantly in the United States over the past few years, and the incidence of acute kidney injury (AKI) from use of these agents  is underestimated. CDC investigators have identified 16 patients (15 males; median age, 18.5 years) from 6 states who presented to emergency departments in 2012 with acute kidney injury after smoking a synthetic cannabinoid product.  Six patients had acute tubular injury and three had acute interstitial nephritis. Even though we can relate tubular injury and interstitial nephritis to the use of cannabinoids  , presence of calcium oxalate crystals was perplexing. In the case series reported in CJASN, they mentioned the presence of calcium oxalate crystals in two patients, but the mechanism of development of these crystals was not fully elucidated . We are hypothesizing that synthetic cannabinoids could be the potential cause for calcium oxalate deposition in this patient (after all causes of secondary hyperoxaluria were excluded). One possible explanation is that synthetic cannabinoids contain additional compounds which are plant in origin and these may be oxalogenic

Synthetic cannabinoids use should be in our differential diagnosis for unexplained AKI in young adult population as it can cause either ATN or AIN or both. A high index of suspicion is required as they may not be detected on routine urine drug screens.

Posted by Mahmoud Kamel