http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(7): 1169–1176 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.926758

STATE OF THE ART REVIEWS

Osmotic nephrosis with mannitol: review article Ali Zohair Nomani1, Zahid Nabi1, Humayun Rashid1, Jamal Janjua1, Hanna Nomani2, Azer Majeed1, Sohail Raza Chaudry1, and Ayesha Saad Mazhar1 Section of Nephrology, KRL Hospital, Islamabad, Pakistan and 2RMC, Rawalpindi, Pakistan

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1

Abstract

Keywords

Mannitol is commonly used to lower intracranial and intraocular pressures. Large doses/massive infusions of mannitol have been found to be associated with acute renal failure (MI-ARF), that is, osmotic nephrosis. While many researchers have reported individual experiences with this pathology, we felt that there is need of an updated comprehensive review of all reported cases with elaboration of etiology, pathogenesis, diagnosis and management plan for MI-ARF. The purpose of the present communication is to share our own experience with MI-ARF, to review the effect of mannitol on kidney function and to highlight the dynamics of MI-ARF with considerations for the cautious use of mannitol in patients with risk factors for kidney diseases.

Acute renal failure/injury, mannitol, osmotic nephrosis, mannitol-induced acute renal failure, mannitol-induced osmotic nephrosis

Introduction Osmotic nephrosis (ON) is defined as the structural changes that occur at cellular level in kidney, primarily proximal tubule, including intracytoplasmic vacuolization and swelling of tubular cells in the presence of certain solutes and without a change in the dynamics of osmotic forces. The term refers to a non-specific histopathological finding rather than defining a specific entity.1 It has a broad clinical spectrum that includes acute kidney injury and chronic kidney failure in rare cases. Responsible exogenous solutes include sucrose-containing IV (intravenous) immunoglobulin, mannitol, dextran, contrast dye and hydroxyethyl starch.1 Mannitol is an osmotic diuretic widely used to reduce intracranial and intraocular pressures because of its osmotic diuretic action and presumed antioxidant properties. Intravenous hypertonic mannitol was introduced by Homer Smith in 1940 to estimate glomerular filtration rate in humans and dogs. Smith noted the osmotic diuretic effect of mannitol followed by Selkurt in 1945 that showed effects of mannitol on ARF (acute renal failure).2–4 Several cases implicating MI-ARF (mannitol-induced ARF)/ MION (mannitol-induced ON) have been recognized. Excessive administration of mannitol is potentially dangerous in producing mannitol intoxication syndrome and ARF, especially in the elderly or patients with pre-existing renal failure.5–7

Address correspondence to Dr. Zahid Nabi, MBBS, FCPS, MRCPI, FRCPI, FCPS(Nep), FACP, Consultant Physician, Nephrologist and Head, Section of Nephrology, KRL Hospital, G9/1 PO Box 4400, Islamabad, Pakistan. E-mail: [email protected]

History Received 9 January 2014 Revised 11 March 2014 Accepted 11 May 2014 Published online 18 June 2014

The form of ARF in MI-ARF/MION is characteristically oliguric/anuric and follows a distinctive clinical course. There may either be no symptomatic presentation in ON or it may be confused with other nephrotic conditions such as tubular calcineurin-inhibitor toxicity.1 Most importantly, MI-ARF/ MION commonly occurs after high doses of mannitol (40.20 kg/day or cumulative dose of 40.40 kg in 48 hours). Considering this, it has been proposed that a low dose of mannitol acts as renal vasodilator while high-dose as renal vasoconstrictor.7,8 The authenticity of this hypothesis in context of MI-ARF/MION however remains uncertain because of scarce data and the renal dynamics need yet to be clarified.4,6–10 We herein report the first case of MI-ARF/ MION in a patient with stroke and otherwise healthy kidneys from Pakistan followed by a comprehensive review of literature concerning the pathogenesis, clinical presentation, risk factors, diagnostic approach, management and prognosis of ON in general and MI-ARF/MION in particular.

Materials and methods Pub medÕ , MedlineÕ , Medline PlusÕ , Pub Med CentralÕ and PakmedinetÕ search was undertaken using the keywords ‘‘osmotic nephrosis, mannitol-induced acute kidney/renal injury/failure’’. All studies pertaining to MI-ARF/MION conducted throughout the world up to February 2014 were included in this review. Full articles were reviewed; all available relevant statistics were searched for and included if mentioned by the authors. All data were chronologically sorted and categorized. Total number of cases and there specifications were studied and reported including the one and only case from Pakistan at our hospital. Results were

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and post-traumatic reflex sympathetic dystrophy were the immediate indications (Table 2). Chronic renal failure on the background was mentioned by four cases; three due to diabetic nephropathy (Van et al., Rello et al. and Sakemi et al.) and one with nephroangiosclerosis (Docci et al.; Table 2).5,11–13 In most cases, high-dose mannitol infusion was given.11–29 During mannitol infusion, hyperosmolarity was documented by most, that is, 13 reports/series while combined hyponatremia and hyperosmolarity in 8 reports/series (Table 2). Findings of urinary cytology were quoted by two reports/ series (Pe´rez-Pe´rez et al.: two of three cases and Dorman et al: six of eight cases) and both suggested recognition of swelling and vacuolization of renal tubular epithelial cells (8 of 11 cases; 73%; Table 2).16,26 Renal biopsy was done in one (Visweswaran et al.) revealing isometric tubular vacuolization of proximal tubules (Table 2).14 The average dose of mannitol implicated in causing MIARF/MION is quite variable. In most previously reported cases (0.85 kg in 48 hours, 2.05 kg in 96 hours, 1.00 kg in 60 hours, 0.55 kg in 28 hours, 0.87–1.00 kg over 3–6 days in three patients and 1.17 ± 0.43 kg in 58 ± 28 hours in four patients), the cumulative doses of mannitol were larger, that is, greater than 0.40 kg/24 hours (Table 2). On the other hand, as little as 0.20 kg in 36 hours, 0.20–0.60 kg over 1–4 days in five patients, 0.12–0.24 kg/24 hours or cumulative dose 40.40 kg/48 hours and 0.18 ± 0.06 kg/24 hours have also been reported to induce ARF (Table 2). In our patient, it was up to 0.24 kg given over 4 days (56 hours) at a rate not faster than 0.5 g/kg/h. The time of onset of MI-ARF is proposed to be as low as 12 hours with reported cases documenting time periods like 24–48 hours, 48 ± 22 hours, 3.5 ± 1.1 days up to a maximum of 7 days (Table 2).1,2,5,9,10 Discontinuance of mannitol has been mentioned as the primary mode of therapy in majority of reports.11,17,26,29–37 Eleven reports/series mentioned the use of dialysis with or without ultrafiltration in addition (Tsai et al., Pe´rez-Pe´rez et al., Van et al., Sakemi et al., Gadallah et al., Hung et al., Suzuki et al., Rabetoy et al., Dorman et al., Rello et al., Borges et al.; Table 2). Total recovery without dialysis specifically was narrated by two reports/series (Docci et al. and Visweswaran et al.).12,14 Final outcome as recovery or death was mentioned by 13 reports/series (Table 2). Twentyseven cases were reported as complete or near complete recovery (27 of 31 cases, i.e., 87.09%) while three reports/ series four cases reported death (4 of 31, i.e., 12.90%);

expressed in tabulated forms and described using descriptive statistics.

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Results We first describe a case presentation followed by a comprehensive review on MI-ARF/MION. A 56-year-old gentleman with well-controlled uncomplicated type 2 diabetes mellitus and well-controlled hypertension presented in stupor for 5 hours with acute onset ischemic stroke in the territory of left anterior and middle cerebral artery covering more than two-third of the cerebral hemisphere. He was started on antiplatelets, statins and supportive care. Mannitol was given considering the detrimental effects of peri-infarct cerebral edema on level of consciousness on day 2 (i.e., 42 hours from admission). It was given as an initial IV dose of 0.03 kg infused over 30 minutes and continued at 0.06–0.09 kg/ 24 hours afterwards. On day 3 (i.e., 60 hours from admission), despite adequate fluid intake and no episode of hypotension, the patient developed ARF with oliguria. Mannitol was continued because of persistent cerebral edema with monitoring of RFTs (renal function tests). The renal profile further worsened on day 4 (i.e., 84 hours from admission) when eventually nephrology consultation was sought. All other possible causes of ARF including nephrotoxic drugs were excluded one by one and no culprit other than a possible MIARF/MION was identified. A renal biopsy was planned. Mannitol was immediately stopped (cumulative dose of 0.24 kg given over 56 hours). Subsequent renal profile showed progressive improvement with complete resolution of ARF and normalization of RFTs over the course of next 4 days and biopsy, therefore, was deferred (Table 1). The close time relationship between mannitol infusion and acute deterioration of renal function in the absence of recognizable causes with normalization of RFTs on withdrawal implied mannitol as proximate cause of ARF in this patient. On the basis of above, diagnosis of MI-ARF/MION was made. The patient eventually gained full consciousness and was discharged home in a stable state with normal RFTs and urinary output. Upon literature review, we found 23 case reports/series from the earliest in 1970 until February 2014. Cumulative case count for the case reports/series was 55. Among the reports/series, raised intraocular pressure was identified as primary indication for giving mannitol in four cases (Table 2). In nine, intracranial hypertension was the primary cause (Table 2). In one case each, refractory heart failure Table 1. Daily progress labs of our patient.

Hours from admission (Day #)

Lab parameter

Serum urea (mmol/L) Serum Cr. (mmol/L) Cr. Clearance (ccs/min) Serum Na (mmol/L) C.serum osm. (mOsm/kg) Osmolar gap (mOsm/kg) Urine output/24 h (ml)

0h (A)

12 h (1)

36 h (2)

60 h (3)

84 h (4)

108 h (5)

132 h (6)

156 h (7)

180 h (8)

204 h (9)

228 h (10)

252 h (11)

276 h (12)

300 h (13)

324 h (14)

11.7 106 73.1 138 293 12 2170

12.8 114 67.9 141 296 12 2020

29.9 123 63 137 292 27 1760

55.3 282 27.5 136 305 49 1120

74.2 397 19.5 127 286 64 560

78.2 353 21.9 140 306 66 290

46 150 51.6 138 294 46 1430

42.5 123 63 141 301 38 1860

33.5 106 73.1 141 303 28 1980

26.4 114 67.9 136 289 28 1690

18.2 97 79.8 135 287 18 1780

16.7 94 82.4 136 291 13 1860

17.1 97 79.8 137 291 14 2130

16.4 88 88 136 288 13 2060

14.6 88 88 138 292 12 1970

Note: A, admission; Na, sodium; Cr., creatinine; Osm., osmoles; kg, kilogram; ccs, creatinine clearances; C., calculated; h, hours.

Osmotic nephrosis with mannitol

DOI: 10.3109/0886022X.2014.926758

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Table 2. Literature review statistics for MI-ARF/MION (reports/series).

Author

Cases 9

Quoted/suggested dose of mannitol

Time of onset

Tsai et al.

1

Raised intraocular pressure

7 days



Doi et al.27 Pe´rez-Pe´rez et al.16

1 4

– –

– 48 ± 22 h

Van Hengel et al.5

1

Visweswaran et al.14 Du et al.28

1 14

Post-traumatic reflex sympathetic dystrophy Refractory heart failure –

– 1.17 ± 0.43 kg in 58 ± 28 h –

24–48 h –

High dose –

Sakemi et al.13

1

Raised intraocular pressure

24–48 h

0.12–0.24 kg/24 h

Nakhoul et al.29 Gadallah et al.6

1 1

Intracranial hypertension Raised intraocular pressure

– –

Hung et al.10

1

Intracranial hypertension

24–48 h

– 40.20 kg/24 h or 40.40 kg/48 h 0.30 L 20% every 4 h

2

Intracranial hypertension





Lin et al.31 Docci et al.12

1 1

– Intracranial hypertension

– 24–48 h

– 0.40 kg/48 h

Rabetoy et al.32 Dorman et al.26

1 8

Intracranial hypertension Intracranial hypertension

28 h 3.5 ± 1.1 days

Rello et al.11 Horgan et al.33

1 1

Intracranial hypertension –

12–48 h –

Weaver et al.34 Gutschenritter et al.35 Goldwasser et al.15

1 1 2

Raised intraocular pressure Intracranial hypertension Intracranial hypertension

– – –

Whelan et al.36 Borges et al.37

1 8

– –

– –

0.55 kg over 28 h 0.18 ± 0.06 kg/24 h; 0.87–1.00 kg in 3–6 days 0.20 kg 1.00 kg in 60 h; 0.20–0.60 kg in 1–4 days 0.20 kg in 36 h – 0.40 to 0.90 kg/24 h; 0.85 kg in 48 h, 2.05 kg in 96 h Massive infusion –

Goodwin et al.24

1







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Indication of mannitol

30

Concomitant findings

Outcome

Hyponatremia, Hyperosmolality – Hyponatremia, Hyperosmolarity Hyperosmolarity

Recovered

– Hyponatremia, Hyperosmolarity Hyponatremia, Hyperosmolarity Hyperosmolarity –

Recovered –

Hyponatremia, Hyperosmolarity Hyponatremia, Hyperosmolarity – Hyponatremia, Hyperosmolarity – Hyperosmolarity

Recovered

Hyperosmolarity –

Recovered –

– – Hyperosmolarity

– – –

– Hyponatremia, Hyperosmolarity –

– 7 recovered, 1 died

– 2 recovered, 2 died Recovered

Recovered – Recovered

Recovered – Recovered Died Recovered



Note: MI-ARF, mannitol-induced acute renal failure; MION, mannitol-induced osmotic nephrosis; h, hours.

indicating an overall good recovery rate with timely discontinuance of mannitol and concomitant use of dialysis when indicated (Table 2). Usual time of recovery for renal functions after MI-ARF has been proposed to be on the 5th or 6th day (Pe´rez-Pe´rez et al.).16 Among the observational studies conducted so far, that is, five (2005–2014), a total of 311 cases of MI-ARF were identified (Table 3). All specified some form of cerebrovascular accident (CVA) with intracranial hypertension, that is, cerebral trauma, subarachnoid hemorrhage and intracerebral hemorrhages; as the primary reason of infusing mannitol. Chen et al. reported the incidence rate of MI-ARF in the setting of CVA and mean time to onset of ARF to be 20.30% and 5–11 days (based on patient’s age), respectively, while the study by Kim et al. reported an incidence rate of 10.5%.17,18 Chen et al. proposed a mortality rate of 0–3% for MI-ARF.17 In the setting of acute CNS (central nervous system) insult, two of the studies (Fang et al. and Dziedzic et al.) concluded that accumulative doses of mannitol is associated with MI-ARF while the other three (Chen et al., Gondim et al. and Kim et al.) suggested that mannitol is safe in patients with

otherwise healthy kidneys and that MI-ARF appears to be associated with chronic insults to the kidneys such as diabetes or hypertension.8,17–20 Furthermore, Kim et al. concluded that higher mannitol infusion rate is associated with more frequent and more severe AKI (acute kidney injury; Table 3).18

Discussion Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol.2 Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure and reduction in cerebrospinal fluid volume and pressure may result.4,8,9 As a diuretic, mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes.4,5,9,10 It is rapidly excreted in the urine with a half-life of 70–100 minutes.4,8 Pathogenesis of MI-ARF/MION has

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Table 3. Literature review statistics MI-ARF/MION (observational studies). Total no. of patients with ARF

Author

Primary diagnosis

Conclusion

19

53

Cerebral trauma/CNS insult

17

Chen et al.

94

Subarachnoid hemorrhage/CNS insult

Dziedzic et al.8 Gondim Fde et al.20

0 11

Intracerebral hemorrhages/CNS insult CNS insult

153

Intracerebral hemorrhages/CNS insult

Fang et al.

Kim et al.18

Accumulative doses of mannitol is an independent risk factor for MI-ARF Elderly patients have higher rate of mannitol-induced impairment of renal function after SAH than middle-aged patients Mannitol is safe under control of osmolality With maintenance of normovolemia and monitoring of the osmotic gap, MI-ARF appears to be associated with chronic insults to the kidneys such as a history of diabetes or hypertension, not mannitol dose, or osmolality A higher mannitol infusion rate is associated with more frequent and severe ARF. Additionally, age  70 years, DBP  110 mm Hg, and established renal dysfunction are associated with development of ARF

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Note: ARF, acute renal failure; CNS, central nervous system; SAH, subarachnoid hemorrhage; MI-ARF, mannitol-induced acute renal failure; MION, mannitol-induced osmotic nephrosis; DBP, diastolic blood pressure.

not been clarified yet but renal vasoconstriction produced by high concentrations of mannitol and changes induced in extracellular fluid volume, tubular pressures, osmolarity and osmolar gap may be the contributing factors.4,8–10 The true understanding of MI-ARF/MION however warrants detailed review of the pharmacodynamics of mannitol. The effects of mannitol on renal profile are characterized by following:4–6,8,10 (1) Profound diuresis/natriuresis, (2) Isometric tubular vacuolization, (3) Impairment of urinary concentration and dilution capacity, (4) Divertissement of medullary hypertonicity, (5) Raised renal interstitial and intratubular pressures, (6) Increased extracellular fluid volume, (7) Changes in cortical and medullary blood flow, Diuretic effects of mannitol Intravenous administration of mannitol results in a brisk diuretic/natriuretic response. Depending on dose, urine flow in humans may reach 20–30% of the filtered load of water and up to 10–15% of the filtered sodium (Na) may be excreted during the height of diuresis.4,8,10,11 Excretion of other ions such as calcium, magnesium, phosphate and bicarbonate is also increased. Mannitol induces the production of endogenous natriuretic agents and suppresses antinatriuretic hormone systems, thereby contributing to the diuretic/natriuretic effects.4,8,10 Tubular effects of mannitol Many studies in the past have focused on the tubular effects of mannitol as the dominant mechanism by which the diuretic effect is achieved. However, in addition to its actions on salt and water reabsorption along the nephron, mannitol has important glomerular, systemic and renal hemodynamic effects which may influence and modulate the tubular actions of mannitol. It is freely filtered in the glomerulus with minimal tubular resorption (7%) and 90% of injected mannitol is excreted in the urine within 24 hours4,11 (Figure 1).

Proximal tubule Mannitol has no direct inhibitory effect on Na transport in the proximal nephron. It rather indirectly influences Na transport by virtue of its effect on water reabsorption. The obligatory presence of mannitol in the tubular fluid reduces water reabsorption. As a result, the concentration of Na in tubular fluid decreases. Consequently, cellular water content falls and concentration gradient against which Na must move increases. This in turn diminishes outward transport of Na. At the same time, it increases passive backflux of Na into the tubule leading to a progressive reduction in net Na reabsorption (Figure 1). When tubular Na concentration reaches to a level 30–40 mmol/L below that in peritubular fluid, a limiting gradient for Na transport is reached and net Na reabsorption stops.1,4,11,12 The consequent effects of swollen and vacuolized tubular cells (ON) leads to a substantial and reversible reduction in proximal luminal diameter.11–13 This has been reported in animals given large doses of mannitol and one human report revealed multiple large homogeneous vacuoles (isometric tubular vacuolization) packing the cytoplasm of multiple tubular epithelial cells with enlargement of cells to the extent that tubular lumen was not easily discernible.11,12,14 Loop of Henle Mannitol induces a marked reduction in water and salt reabsorption in the descending and thin ascending limbs, respectively, followed by incomplete recapture of the increased Na tubular load in the thick ascending limb (Figure 1).4,8,14 Distal tubule and collecting duct The delivery of salt and water to the distal tubule and collecting duct is markedly increased during osmotic diuresis. However, the final segments of the nephron fail to recapture the increased delivered loads of salt and water and the high distal flow rate overwhelms the capacity for Na reabsorption in the later part of collecting duct (Figure 1).4,14

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DOI: 10.3109/0886022X.2014.926758

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Figure 1. Tubular effects of mannitol showing the movement of water and sodium across tubular membranes.

Urinary solute excretion and medullary tonicity Osmotic diuresis tends to abolish the ability to concentrate or dilute urine. Goldwasser and Fotino postulated that increased urinary solute excretion may trigger an intense tubuloglomerular feedback resulting in afferent arteriolar vasoconstriction and thus a reduced GFR (glomerular filtration rate) and subsequent oliguria/anuria. Urinary concentration and dilution ability is severely impaired and urine osmolality tends to approach isotonicity during peak diuresis. This osmotic intrusion is partly attributed to medullary washout and loss of medullary hypertonicity.4,14,15 Extracellular fluid volume and renal vascular dynamics Mannitol typically increases the extracellular fluid volume causing dilutional hyponatremia. Being hypertonic itself, it increases the plasma osmolarity and osmolar gap. It has been postulated that at lower doses, mannitol can increase the cortical and medullary renal blood flow but at higher concentrations, it tends to cause renal vasoconstriction.4,6–8,11 Safe and potentially harmful dose of mannitol It has been accredited by some researchers that the harmful effects of mannitol are directly related to its dose. Others tend to differ with this school of thought. To treat oliguria,

0.05–0.20 kg mannitol is commonly used intravenously as a 15–20% solution over 24 hours. To reduce intracranial or intraocular pressure, the usual dose is 0.15–0.20 g/kg intravenously over 30 to 60 minutes as a 20% solution.4,8,14,16 The paradox of ‘‘osmotic nephrosis’’ has shown that a large dose of mannitol given to rabbits causes swelling and vacuolization of proximal tubular cells.6,8,14 Similar tubular changes have occasionally been seen in renal biopsies from patients undergoing mannitol diuresis.14 The close time to event relationship of a large dose of mannitol infusion and the subsequent development of an oliguric ARF as reported by researchers supports the hypothesis of a dose to effect relationship, at least to some extent. Mannitol-induced tubular vacuolization The earliest publication describing tubular vacuolization dates back to 1954 by Hamburger et al. who described the histology of mannitol-induced ARF in rabbits.17 The first English language article describing this effect was published by Maunsbach et al. in 1962 who injected cats with mannitol and observed the vacuolization of proximal tubular epithelial cells followed by DiScala et al. who did a similar experiment on dogs in 1965.18,21 The first human case was described by Goodwin et al. in 1970.22

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Histolopathology characteristics

Differentiating mannitol-induced osmotic nephrosis

Histologically, ON is characterized by a focal or less often diffuse ‘‘clear cell’’ transformation of proximal tubular epithelial cells showing isometric fine vacuolization of the cytoplasm. The straight part of the proximal tubule is primarily involved and in severe cases also the convoluted part. Severely affected tubules are often seen side by side to normal appearing tubules. The distal tubules and the collecting ducts are more or less unchanged. Occasionally, parietal epithelial cells lining Bowman‘s capsule, podocytes, or interstitial cells may be affected and show vacuoles (Figure 2).1,23,24 Early changes of ON are tiny vesicles under the apical cell membrane. During further development, the number of vesicles increases gradually filling the cytoplasm. Probably due to fusion, the vacuoles increase in size from the apex to the basal parts of the cell finally measuring 1–4 mm in diameter. Most vacuoles appear empty by light and electron microscopy. In late stages, the vacuoles may contain an amorphous electron dense material. The nucleus is gradually displaced to the basal part of the cells and becomes distorted by the adjacent vacuoles. Mitochondria and other cell organelles remain unchanged (Figure 2).1,10,11,23,25,26 Tubular vacuolization causes gradual cell swelling and may lead to narrowing but not to complete occlusion of the tubular lumens. The brush border and the basal labyrinth usually are well preserved. By electron microscopy and enzyme histochemistry, the vacuoles were identified as lysosomes.10,11,22,23,26,27 The sequelae of ON are unpredictable since repeat biopsies are usually not performed. In most cases, the vacuolization will completely vanish without sequelae. In other cases with protracted renal failure, the vacuolization may persist without significant other morphological changes of the kidney. In few cases with irreversible renal failure, tubular atrophy, interstitial fibrosis and accompanying inflammation can occur (Figure 2).23

The differential diagnosis of ON includes several histologic ‘‘look-alikes’’, which can usually be distinguished by careful examination. In paraffin sections, the isometric vacuolization seen in calcineurin-inhibitor toxicity is indistinguishable from ON. Electron microscopy, however, reveals dilated endoplasmatic reticulum as the cause of vacuolization in the former. ON cannot be differentiated from lipid storage in tubular cells (foam cells) as seen in nephrotic syndrome, in case of liver failure or intoxication. In case of lipid storage, foam cells are often found in the interstitial space to an extent never seen in ON. In ischemic renal damage, the proximal tubules contain vacuoles of variable size accompanied by a loss of the brush border, bleb formation, often a desquamation of the epithelium from the basement membrane and signs of regeneration. Large or even giant vacuoles in proximal tubules are seen in glycol (ethylene glycol) intoxication (accompanied by calcium oxalate crystals) and sometimes after rapamycin therapy and in potassium depletion (accompanied by Periodic Acid Schiff-positive granules in the collecting ducts). In glycogen storage diseases, in diabetic hyperglycemia and renal tumors the cytoplasm of the affected tubular cells appears completely empty since the glycogen is suspended within the cytosol and not membrane-bound.1,10,11,16,17,23

Figure 2. Focal lesions of tubular cells showing diffuse ‘‘clear-cell’’ transformation due to isometric fine vacuolization of cellular cytoplasm. An amorphous material can be seen occupying tubular lumens in a few tubuli. The nucleus has been displaced to the basal part of the cells and distorted by the adjacent vacuoles. Intervening interstitium shows leukocytic infiltration.

Pathogenesis [pinocytosis theory] The most widely accepted explanation for lesions in ON is the ‘‘pinocytosis theory’’. Mannitol and similar solutes can enter tubular cells via pinocytosis, form vacuoles that subsequently

Figure 3. Schematic representation of pinocytosis showing uptake of mannitol molecules by tubular epithelial cells leading to subsequent vacoulization.

Osmotic nephrosis with mannitol

DOI: 10.3109/0886022X.2014.926758

Figure 4. Algorithm for plan of action when suspecting MI-ARF.

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Plan to administer Infusion Mannitol I/V

Look out for high risk

Pre-exisng renal disease

Diabetes Mellitus

Elderly paent

Look out for onset of AKI

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Usual me of onset at 2448 hours

Usual dose for AKI > 400g 24hours

Oliguric/ anuric AKI

+ Stop Mannitol / Look for Possible lab indicators

Hyponatremia

Increased osmolar gap

Hyperosmolarity

Suspicion of osmoc nephrosis

Urine cytology for tubular vacuolizaon

Invesgate further via

Renal biopsy for osmoc nephrosis

Posive for osmoc nephrosis

Other known causave agents ruled out

Negave but strong close me relaonship

Mannitol induced Osmoc Nephrosis Urgent Nephrologist review→Reversed by Mannitol cessaon→Consider Hemo/Peritoneal dialysis

fuse with each other and with lysosomes containing hydrolytic enzymes (Figure 3). It is at this level where lysosomal degradation and digestion can get impaired in diseases like diabetes mellitus and chronic kidney diseases that predisposes to MI-ARF. While earlier and mild vacuolar changes are reversible, more overt damage can result in permanent injury to the renal tubules.1,11,21–23

Conclusions A comprehensive review of all the mentioned studies so far suggested that MI-ARF/MION can manifest in a time frame between 12 hours and 7 days depending upon individual case

scenarios but usually between 24 and 48 hours. The dose of mannitol as implicated by case reports/series is usually higher than 0.40 kg/day but doses as low as 0.15–0.20 kg/day can cause MI-ARF/MION and higher rates of infusion are associated with more severe injury. Discontinuation of mannitol is the primary mode of therapy but dialysis (hemo/ peritoneal) with or without ultra filtration when indicated in addition can be life-saving. With the above, good clinical recovery is generally the rule with an overall good prognosis. Furthermore, urinary cytology and at times renal biopsy (in doubtful cases) can provide a useful clue to the diagnosis of MI-ARF/MION. A proposed algorithm for early diagnosis and management follows (Figure 4).

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Acknowledgments We thank all the medical and paramedical staff at MITC KRL Hospital for rendering their precious time and contribution towards completion of this article. A.Z.N., Z.N., H.R., J.J., H.N., A.M., S.R.C., A.S.M. contributed equally to this work; they designed the article, did data collection, did thorough search, analyzed the data, wrote, reviewed and approved the final form of this article.

Declaration of interest All authors are currently working in the department of medicine at KRL hospital. Reprints and permissions information is available at www.nature.com/reprints. Authors declare no competing interest.

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Osmotic nephrosis with mannitol: review article.

Mannitol is commonly used to lower intracranial and intraocular pressures. Large doses/massive infusions of mannitol have been found to be associated ...
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