Kidney Biopsy Case: AKI

A 54 year old man was referred to the Nephrology service due to AKI after presenting with lethargy and severe thirst. He had a long history of pulmonary and hepatic sarcoidosis which had been quiescent for some time. He likely had some baseline mild CKD with a serum creatinine of 1.3 mg/dl and 0.5 g/day proteinuria. His medications were unremarkable except for a calcium and vitamin D preparation which he had been taking for several months. His creatinine was 4.0 mg/dL and calcium was 13.5 mg/dl on presentation. He was volume resuscitated, treated for his hypercalcemia and proceeded to renal biopsy. Low power light microscopy is below which reveals an interstitial infiltrate with moderate fibrosis and some sclerosed glomeruli.

Higher power demonstrates multiple non-caseating granulomas. The granulomas consist of amorphous reddish material as well as multi-nucleated giant cells (below; top left and right of center).

Another example below of a granuloma (on the left of the panel) in a sick looking tubulo-interstitium.

The diagnosis was sarcoidosis-related granulomatous interstitial nephritis. He was commenced on high dose oral steroids and his renal function settled back down to normal over several weeks. Sarcoidosis does uncommonly affect the kidneys and is a major differential for granulomatous interstitial nephritis (see previous post). A teaching point for this case is not to presume the hypercalcemia is all iatrogenic. The high calcium points to sarcoid activity which was demonstrated nicely on the biopsy.

Page Kidney

Patient with a history of kidney transplant s/p biopsy 2 weeks prior now undergoing chemotherapy treatment for leukemia develops acute abdominal pain, worsening renal function and hypertension. Renal US followed by CT are shown below:

Renal US with dopplers

Renal US longitudinal view

Abdominal CT with renal tx on right lower quadrant

 

Abdominal CT with red-marked kidney parenchyma

Diagnosis: Page kidney is a condition where extrinsic renal compression from a haematoma or mass results in hypertension and loss of renal function. This condition was initially described by Irwin Page in an animal model with cellophane papers wrapped around the kidney in 1939 and, subsequently, clinically in 1955.Most cases are caused by a subcapsular haematoma following blunt trauma or invasive procedures (eg. renal biopsy). Few cases of spontaneous hematoma have also been reported. Acute renal failure is due to a decreased perfusion of the compressed kidney as a result of pressure exerted by the subcapsular haematoma. In our case, the drop in platelets (4,000) after chemotherapy might have precipitated the bleeding from the previously biopsied site.

Treatment involves relief of the pressure and restoration of blood flow by percutaneous drainage. Nephrectomy is recommended in cases not resolved by interventional nephrology. Conservative course (observation and medical management) has been performed in some case reports.

Πάντα ρεί - once more on the (right) fluids

Yet another manuscript evaluating fluids for IV replacement was published in JAMAthis week underscoring the importance and controversial nature of the topic. A large meta-analysis involving 10,868 patients from 38 trials showed that hydroxyethyl starch (HES) was associated with an increased risk of mortality and renal failure (RR 1.27; 95% CI 1.09 - 1.47). Of note, a recent large trial published in the NEJM in 2012 did not show an increased mortality but more patients who received resuscitation with HES were treated with renal-replacement therapy.

HES is mainly used by anesthesiologists and surgeons and has the potential advantage of decreasing the amount of total administered volume and sustaining intravascular volume for longer periods of time. The discussion about mortality and renal failure associated with HES has been going on for a long time, as has the discussion about the relative benefits of colloids vs. crystalloids. Despite the lack of strong evidence of superiority of HES over crystalloids, the clinical use has been increasing - even with the associated higher cost and safety concerns.

A major drawback for the supporters of HES was the realization that one of the leading authorities in the field and major proponent of HES, Joachim Boldt, has conducted one of the biggest cases of fraud in anesthesia with “false data published in at least 10 of the 91 articles examined, including, for instance, data on patient numbers/ study groups as well as data on the timing of measurements“. 80 articles have been retracted because the research was deemed unethical. A Cochrane review from 2012 did not find a significant difference in mortality even when the fraudulent studies were excluded. However, the current meta-analysis not only excluded the studies by Boldt, but also included 3 trials published in 2012 contributing more than half of the patients to the collective examined, thereby adding more weight to their analysis over prior ones. There was no difference in mortality when the Boldt papers were included in the analysis.

Side effects of HES mainly occur in the kidney but the exact pathophysiology of AKI associated with HES is unclear. Vacuolization as an injury pattern can be observed as discussed in an earlier post in this blog. In vitro HES showed a dose-dependent decreased viability of HK-2 cells (human immortalized proximal tubular cells) after incubation with HES130/0.4. A necropsy study suggested HES accumulation in the kidney might cause toxicity. 

What can we learn from this? Rigorous analysis and ongoing discussion and evaluation of data are of crucial importance in Medicine and scientific fraud, driven by motives such as recognition and money can cause data to shift to the wrong direction. There does not seem to be a major advantage of using HES over crystalloids and data on mortality and renal failure are tied between no difference and increased mortality/AKI in the HES group. From my perspective there seems to be no indication to use HES and this might be better for the kidney.

Posted by Florian Toegel

CNS mass and crystals after kidney transplantation

A gentleman with ESRD secondary to polycystic kidney disease comes in with vomiting and headache eight months after kidney transplantation. Brain MRI shows a small single enhancing lesion in the temporal lobe. Lumbar puncture reveals an elevated opening pressure (41), WBC 121 (77% lymphs), elevated total protein (210) and low glucose (41). Cultures are negative. 

The top 3 differentials of CNS masses in post-transplant kidney recipients are: neurotoxoplasmosis, lymphoma and tuberculoma. EBV negative status prior to transplantation increases your risk of post-transplant lymphoproliferative disorder (PTLD) and checking EBV VL could help with initial evaluation. Coming from endemic areas of tuberculosis (TB) raises the suspicion for tuberculosis. TB in kidney transplant recipients is a particular challenge both diagnostically and therapeutically. Atypical clinical presentations (extra-pulmonary) and negative tuberculin skin tests/sputum smears are frequent. The treatment of TB also has its own challenges, which include pharmacokinetic interactions between immunosuppressive and antituberculous medications (reduction of FK by more than 60% is required), allograft-related drug toxicities, and inadequate immune responses to Mycobacterium tuberculosis due to exogenous immunosuppression. 

In general, empirical therapy of neurotoxoplasmosis is instituted in immunosuppressed patients with an enhancing brain lesion, consisting of sulfadiazine, pyrimethamine and leucovorin. Reduction of immunosuppression is also indicated and follow up imaging is performed. Last resource if no improvement and negative work up is to perform a brain biopsy to obtain tissue specimen. 

Treatment of neurotoxo with high doses of sulfadiazine may precipitate acute kidney injury by crystal formation (~30% of patients), in particular if volume depletion is present and urine pH is 5.5 or less. Intra-renal crystalluria may be prevented by maintaining fluid intake above three liters per day (PO or IV). Monitoring of serial urinalyses for the development of crystalluria is recommended. For those developing crystalluria, intravenous bicarbonate solution to alkalinize the urine (goal pH above 7.15) is administered. The patient above developed significant AKI (creatinine increased from 1 to 4) after sulfadiazine treatment and crystals were identified in the urine (representative figure). 

Be aware of potential drugs/toxins** that might form intratubular crystals and precipiate AKI. Act pre-emptively with fluid hydration +/- alkalinization of urine depending on the toxin. 

 ** Acyclovir (IV), sulfonamides, ethylene glycol, high dose vitamin C, methotrexate, protease inhibitors, phophate enemas, orlistat 

 *** Remember that for MTX renal toxicity, there is glucarpidase as a last resource to quickly reduce MTX levels in patients with AKI and persistently high MTX levels 48 hrs after dosing.

Spare the Chloride

Fluid therapy is essential in ICUs and not surprisingly there is still much controversy about which fluid to use, how much and when. Nephrologists often roll their eyes at other subspecialty's preferences, e.g. surgeon's preferences for Ringers, citing the risk of hyperkalemia in renal failure patients given Ringers. I learned that normal saline is the preferred agent unless there is a special consideration such as acidemia necessitating alternatives. Now chloride, the partner of sodium that gets considerably less attention most of the time, enters the stage.

Yunos et al in JAMA suggest that too much of chloride increases acute kidney injury (AKI) episodes in tertiary ICUs and increases the need for renal replacement therapy (RRT) but does not affect mortality.

The physiological rationale for the detrimental effect of chloride on the kidney is described as vasoconstriction mediated by chloride in dog experiments and a possible role of tubuloglomerular feedback mediated vasoconstriction as well as decrease in GFR caused by increased distal chloride delivery. Furthermore they cite thromboxane mediated vasoconstriction caused by chloride and enhanced responsiveness to vasoconstrictor agents as possible physiological sequelae of chloride administration.

The authors of the JAMA article conducted a prospective, open-label sequential pilot study of patients admitted consecutively to the ICU. Initially patients were treated with chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin solution) and after that initial control period a chloride-restricted strategy was implemented with lactate (Hartmann solution), a balanced solution (Plasma-lyte 148) or chloride-poor 20% albumin as preferred agents.

The results were a lower increase in serum creatinine levels and fewer episodes of RRT in the chloride-restricted group but no differences in mortality, hospital or ICU length of stay or need for RRT after discharge.

How does this study affect our choice of ICU fluids? Certainly, these results are hypothesis generating and important but need to be viewed as preliminary given the design of the study. An accompanying editorialby Waikar mentions the Hawthorne effect as potential major concern. Clearly these important preliminary data need follow up in a controlled prospective trial. 

Posted by Florian Toegel

Less is More

Despite the fact that the kidney ultrasound is generally obtained as one of multiple recommendations when evaluating AKI, the benefit of kidney ultrasound is not clear. The post-renal causes of AKI are not very common. It adds to the cost and can subject patients to unnecessary work-ups by revealing incidentalomas. How often, then, is the ultrasound useful? 

In order to assess the prevalence of the post-renal AKI and determine a cost-effective use of the ultrasound, a single-center case-control study was conducted.

Their conclusion is that the prevalence of hydronephrosis requiring stenting or nephrostomy placement was only 0.4% in the low-risk group. The number to screen to find a case of urinary obstruction was 223. At what cost? In our institution the kidney ultrasound without Doppler costs $600. It costs $133,800 to find one case.

Who is the low-risk group patient? Based on the multivariate analysis, a patient was considered low-risk if he or she did not have a history of hydronephrosis and had no more than one of the following:

1. Recurrent UTI

2. Diagnosis to suspected obstruction (BPH, abdominal or pelvic cancer, one functional kidney, neurogenic bladder, pelvic surgery)

3. Non-African American

4. Absence of:  exposure to the following medications (ASA, diuretics, ACEI or IV vancomycin), congestive heart failure, or pre-renal AKI.

The study has limitations. Not all AKI patients were studied. The cases requiring non-surgical interventions were not counted. If we would have to implement this strategy, we don’t know what the cost of missing some cases of obstruction would be.

However, the implication is that we should not routinely order kidney ultrasound on every patient with AKI, particularly those in the low-risk group. In this era of cost constraint on medicine, less is usually more…

Or, here is what you can do. If your place has an ultrasound on the floor, with a little training you can have a quick look at the kidneys just to rule out obstruction in low risk patients. You acquire one more diagnostic skill, your students have one more fun on round, and your hospital saves significant amount of money!

Posted by Tomoki Tsukahara

Cisplatin again

In a previous post, we discussed the way the cilastatin prevents imipenem nephrotoxicity by inhibiting dihydropeptidase, a proximal tubular brush border enzyme which facilitates the uptake of imipenem metabolites into proximal tubular cells. This allows imipenem to be excreted unchanged in the urine. In the absence of cilastatin, imipenem would be unusable due to its significant adverse effects on the kidney.

Approximately 40-60% of patients who receive cisplatin develop nephrotoxicity and this is its most common severe adverse effect. The mechanism of this nephrotoxicity is not entirely clear and has been discussed in the past by Emily and Nate. Primarily, however, it is due to proximal tubular cell damage with apoptosis of the affected cells leading to polyuria, a fanconi-type syndrome and ATN.

A paper was just published in KI which looked at the effect of co-administration of cisplatin and cilastatin in rats. The rats were given a single dose of cisplatin and those that received cilastatin had significantly less uptake of cisplatin into the renal cortex and lesser manifestations of renal toxicity. Interestingly, the uptake into the medulla was not affected and the half-life of cisplatin was longer than in the controls. Because dihydropeptidase is specific to the proximal tubule, it did not affect uptake into cancer cells and so anti-tumor activity was preserved. Cisplatin toxicity is the bane of the life of nephrologists working in major cancer centers because, once it has set in, there isn’t much that you can do and it limits the amount of treatment that these patients can get for their tumors. This is a preliminary study and we can’t say that this is the panacea for cisplatin nephrotoxicity but it certainly is promising as well as being a fascinating insight into the mechanisms of renal damage caused by cisplatin.