Alan Segal

Defining acute kidney injury: what is the most appropriate metric?

Glomerular filtration rate (GFR) is the most widely accepted measure of kidney function. Acute kidney injury (AKI) is defined as a reduction in GFR. GFR is, however, rarely measured in clinical practice; instead, serum markers (primarily creatinine) are used to define AKI. Because serum creatinine level is not linearly related to GFR, the performance of this marker is associated with ascertainment bias and poor sensitivity. In this article we discuss the limitations and pitfalls of using serum markers to define AKI, and offer some suggestions for the future.

Four cases of nafcillin-associated acute interstitial nephritis in one institution

Background Over the course of 1 year, four patients in a single institution developed acute kidney injury most likely secondary to nafcillin-associated acute interstitial nephritis, indicating that this complication might not be as rare as is commonly believed. The main case presented here is that of a 73-year-old man with a history of chronic low back pain who presented with worsening back pain, as well as nausea, vomiting and volume depletion. Imaging studies revealed a soft tissue abscess in the left psoas major muscle.Investigations Physical examination, complete urine analysis, blood and urine cultures, measurement of peripheral eosinophil and plasma creatinine levels, and renal ultrasound.Diagnosis Nafcillin-associated acute interstitial nephritis.Management Discontinuation of nafcillin and provision of supportive care.

Application of pressure steps to mechanosensitive channels in membrane patches: a simple, economical, and fast system

Mechanosensitive channels (MSCs) have been described in a wide variety of cells, but the molecular mechanisms that couple membrane tension or deformation to channel activity (i.e., mechanotransduction) are not understood. The ability to measure the dynamics of the temporal relationship between the pressure stimulus and the channel response is a key tool for gaining insight into mechanotransduction. Several laboratories have designed pressure clamps, but these instruments are complex, costly, and not commercially available. This paper describes a simple and inexpensive system for applying fast pressure steps to a membrane patch. This system is easy to build and achieves submillisecond 20% to 80% step response times on par with the fastest pressure clamp described. Application to a stretch-activated nonselective cation channel in the kidney is used to demonstrate the system.

Potassium and the Dyskalemias

Potassium (K+) is the most abundant monovalent mineral in the body and the major intracellular cation. Only about 2 % of total body K+ is extracellular and maintenance of a proper ratio of K+ concentration across the cell membrane is required for many cellular processes. Ion channels selective for K+ dominate the resting permeability of most cells, so this ratio is also the main determinant of the resting membrane potential, which is especially critical for normal function of nerve, muscle, and the cardiac conduction system. Overall K+ balance is accomplished through mechanisms that involve transfer of ingested K+ into cells (internal K + homeostasis) and transport of K+ out of the body (external K + homeostasis), the latter primarily via the kidney. This chapter reviews the cellular and molecular physiology of potassium homeostasis, the pathophysiology of hypokalemia and hyperkalemia, and the diagnosis and clinical management of the dyskalemias.

Incomplete reprogramming after fusion of human multipotent stromal cells and bronchial epithelial cells.

Bone marrow-derived progenitor cells can fuse with cells of several different tissues, including lung, especially following injury. Despite many reports of cell fusion, few studies have examined the function of the resulting hybrid cells. We cocultured human multipotent stromal cells (hMSCs) and normal human bronchial epithelial cells (NHBEs) and observed the formation of hMSC/NHBE heterokaryons. The heterokaryons expressed several proteins characteristic of epithelial cells, such as keratin and occludin. Hybrid cells also expressed the mRNAs and proteins for 2 important ion channels that maintain bronchial and alveolar fluid balance: the cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial Na(+) channel (ENaC). By immunocytochemistry, CFTR was expressed in many hybrid cells but was absent or low in others. Whole-cell patch-clamp recordings demonstrated a glibenclamide-sensitive current in the presence of barium chloride, consistent with functional CFTR channels, in control NHBEs and hMSC/NHBE heterokaryons. Total cell capacitance measurements showed that the membrane surface area of heterokaryons was similar to that of NHBEs. Heterokaryons expressed the α- and γ-ENaC subunits but did not express the β-ENaC subunit, indicating the inability to form a complete ENaC channel. In addition, hybrid cells formed by the fusion of hMSCs with immortalized bronchial cells that expressed CFTR ΔF508 did not lead to reprogramming of the hMSC nucleus and expression of wild-type CFTR mRNA. Our data show that reprogramming can be incomplete following fusion of adult progenitor cells and somatic cells and may lead to altered cell function.

Nephrology Crossword: Dyskalemias

Varun Agrawal, Alan Segal and Kenar D. Jhaveri Division of Nephrology and Hypertension, Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, Vermont, USA and Division of Kidney Diseases and Hypertension, Hofstra Medical School, North Shore LIJ Health System, Great Neck, New York, USA Correspondence: Kenar D. Jhaveri, Division of Kidney Diseases and Hypertension, Hofstra Medical School, North Shore LIJ Health System, Great Neck, New York 11021, USA. E-mail: kdj200@gmail.com

Acute bacterial pyelonephritis resulting in acute kidney failure: a complication of chronic non-steroidal anti-inflammatory drug use?

Acute bacterial infection and inflammation of the renal parenchyma (pyelonephritis) is frequently diagnosed in clinical practice. A classical presentation for this process includes fever, flank pain and dysuria. Without obstruction, kidney hypoperfusion or exposure to nephrotoxic agents, a significant decline in glomerular filtration rate (GFR) generally does not occur. Here, we present a case of acute bacterial pyelonephritis in a woman whose key presenting feature was severe acute kidney injury (AKI) with a profound reduction in GFR. We propose that chronic use of non-steroidal anti-inflammatory drugs (NSAID) played a key role in this presentation by suppressing the symptoms of infection and inflammation, allowing for progressive parenchymal destruction as demonstrated on kidney biopsy. A 52-year-old woman presented with malaise, anorexia, confusion and vague abdominal discomfort. Flank pain, fever, rigors and dysuria were absent. Her only medication was hydrocodone/ibuprofen (15 mg/400 mg) every 4 h, taken for chronic back pain over the past year. She was oriented to person and place but had difficulty recalling recent events. Vital signs were temperature 37°C, blood pressure 140/90 mmHg, pulse 90 beats/min and respiratory rate 18 breaths/min. Diffuse abdominal tenderness without rebound or guarding was present. Urine sediment showed red blood cells and white blood cells but no casts. Blood tests revealed [Na] 131 mmol/L, [K] 3.3 mmol/L, [tCO2] 15 mmol/L, WBC 22.1 ¥ 10/L, haemoglobin 10.9 g/dL and serum creatinine 575 mmol/L (6.5 mg/dL) (baseline of 79.6 mmol/L (0.9 mg/dL) measured 1 year before admission). Non-contrast CT scan showed enlarged, unobstructed kidneys. On hospital day one, serum creatinine rose to 681 mmol/L (7.7 mg/dL) and haemodialysis was initiated. A kidney biopsy was performed, which showed acute pyelonephritis with an intense acute inflammatory reaction within the tubules with marked tubulointerstitial inflammation and neutrophilic infiltration (Fig. 1). Blood and urine cultures grew Escherichia coli. Renal function improved with

A case of acute kidney injury due to complex, partial, multifocal ureteral strictures

Background An 89-year-old man with a history of prostate cancer who had undergone radical prostatectomy 15 years ago presented with hyperkalemia (serum potassium level 6.9 mmol/l) and kidney failure (serum creatinine level 937 µmol/l [10.6 mg/dl]). Ultrasound scan of his kidneys showed mild bilateral hydronephrosis. Although placement of a bladder catheter led to an initial increase in glomerular filtration rate, the improvement was delayed and incomplete. Subsequently, the patients glomerular filtration rate decreased acutely. This unusual biphasic course of kidney injury begged explanation.Investigations Physical examination, measurements of serum creatinine level and electrolytes, imaging of the urinary tract (ultrasound and CT scans), and nephrostograms.Diagnosis Acute kidney injury due to upper (multiple ureteral strictures bilaterally) and lower (urethral) urinary tract obstruction.Management Placement of bladder catheter and percutaneous nephrostomy tubes followed by bilateral internal ureteral stents.