case study on diabetes insipidus

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ICEECE2012 Poster Presentations Clinical case reports - Pituitary/Adrenal (58 abstracts)

Central diabetes insipidus: about two clinical cases

C. nogueira 1, , m. matos 1, , c. esteves 1, , g. jorge 1 , j. couto 2 , c. neves 1, , j. queirós 1 , e. vinha 1 , i. bernardes 1 & d. carvalho 1,.

1 Centro Hospitalar São João, Porto, Portugal; 2 Instituto Português de Oncologia, Porto, Portugal; 3 University of Porto, Porto, Portugal.

Introduction: Central diabetes insipidus (CDI) is produced by the destruction of the magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei which results in decreased arginine vasopressin (AVP) synthesis and secretion.

Case report 1: Forty-five year old female, previously healthy, was observed in April 2011 complaining of polydipsia, polyuria, nocturia and weight loss since January. Diabetes mellitus (DM) was excluded and she was admitted for study of possible diabetes insipidus. Water deprivation test was suggestive of CDI. Magnetic resonance imaging (MRI) showed infundibular hypophysitis and no hyperintense signal in the neurohypophysis. Autoimmune diseases, infections and infiltrative diseases were excluded. Imaging (chest x-ray, abdominal ultrasound, mammography, breast ultrasound and thoracoabdominal CT) was normal. No other pituitary deficits were shown. She started therapy with oral desmopressin with clinical improvement.

Case report 2: Fourty-three year old man, previously healthy, was seen in August 2011 complaining of polydipsia, polyuria and nocturia during the previous 3 months. DM was excluded. Water deprivation test was positive for CDI. Pituitary MRI was normal, with normal signal of high intensity in the neutohypophysis. He had no other hormonal deficits. Autoimmune and infectous diseases were excluded. After initiation of oral desmopressin the symptoms disappeared.

Discussion: In both cases it was not determined the etiology of CDI, as it may occur in 20–50% of CDI cases. In our institution is not possible to determine antibodies towards vasopressin secretory cells, which does not allow the diagnosis of this autoimmune form of CDI. The infundibular hypophysitis, observed in the first case, can occur in about 50% of idiopathic cases and more frequently in women. The lymphocytic hypophysitis can be diagnosed by pituitary biopsy, but it’s a very aggressive procedure and almost never performed. These cases highlight the difficulty of the etiologic diagnosis of CDI. However, proper treatment allows the symptoms control.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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A Case of Diabetes Insipidus

By David F. Dean (rr)

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“Amanda Richards,” a 20-year-old junior in college, is majoring in biology and hopes to be a pediatrician one day. For about a month, she has been waking up frequently at night to go to the bathroom. Most recently, she has noticed that she needs to go to the bathroom during the day more often, almost hourly. Students read about these symptoms and then answer a set of directed questions designed to teach facts and principles of physiology using reference books, textbooks, the Internet, and each other as sources of information. The case has been used in a sophomore-level course in human anatomy and physiology as well as in senior-level course in general physiology.

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• Learn about the similarities and dissimilarities between diabetes insipidus and diabetes mellitus.
• Understand the basic differences between the four types of diabetes insipidus.
• Be able to define and describe excessive thirst and urination in adults.
• Understand the methods by which diabetes insipidus is diagnosed and treated.
• Learn about other conditions which produce symptoms similar to those produced by diabetes insipidus.
• Be able to describe the physiological effects of antidiuretic hormone other than the maintenance of body water balance.

Pituitary diabetes insipidus; diabetic; antidiuretic hormone; ADH; vasopressin; osmoreceptors; osmolarity; polyuria; polydipsia; supraoptic nuclei; kidney function

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Undergraduate lower division, Undergraduate upper division

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Diabetes Insipidus Case Study (60 min)

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You just started your shift, what nursing assessments will be your priority at this point?

• Assess ventilator and respiratory status, lung sounds, SpO2
• Assess EVD system for integrity and that it is draining appropriately
• Complete neuro exam including pupils, GCS, reflexes, and LOC.
• Full set of vitals plus assessing IV sites for signs of infiltration or infection
• Assessing foley site and urine output
• Turning and assessing skin top to tail

Mrs. Ford’s vital signs are as follows: BP 124/68 MAP 86

HR 84 Temp 98.9 RR 16 (ventilated) ICP 12

She is not on any sedation. You determine her GCS is 6, she withdraws to pain, but does not open her eyes. Her pupils are equal and reactive bilaterally, 4mm. For this hour she has put out 120 ml of urine that is clear and yellow. She is receiving normal saline at 75 mL/hour as well as tube feeds at 40 mL/hour. Her EVD is open at 15 cmH 2 O and draining a clear pink fluid, 6 ml this hour.

faq lesson=”true” blooms=”Application” question=”Calculate her cerebral perfusion pressure.”]

• CPP = MAP – ICP
• 86 – 12 = 74 mmHg [/faq]

Given the assessment information that you have, what are you most concerned for with this patient?

• Immobility – skin and muscle breakdown
• Increased ICP → herniation → death
• Damage to Pituitary and/or Hypothalamus glands → can cause SIADH, DI, temperature regulation issues, as well as issues with CNS functions like breathing
• This patient clearly has a significant brain injury. I would be concerned for and monitoring for the following complications:

Hourly urine output for Mrs. Ford For the last 3 hours were 180 mL, 240 mL, and 440 mL. The urine is clear and barely pale yellow. Her blood pressure is 108/56, HR is 104. Her ICP is 15.

What could be going on physiologically with Mrs. Ford?

• This is likely Diabetes Insipidus due to the known neurological issue and the excessive output of clear, barely pale yellow urine.
• Neurological damage can cause damage to the pituitary gland – causing a LACK of secretion of ADH (Antidiuretic Hormone). This means the patient can no longer retain water and therefore begins to dump water excessively – this is why the urine looks almost like water.
• This will cause the blood to be super concentrated and could cause a lot of other issues because of it.

What further diagnostic testing do you expect the provider to order?

• Note: Polyuria WITHOUT hyperosmolality may indicate Primary Polydipsia – a condition in which patients literally drink water excessively and send themselves into a water intoxication/hypernatremic state.
• Check a CMP with serum osmolality to see if she is hyperosmolar or hypernatremic
• Check urine specific gravity and urine osmolarity – again this can tell us if she’s dumping lots of urine or if she’s just dumping a ton of water. Low specific gravity indiacates DI.

Lab Values: Na + 155 mg/dL Serum osmo 310 mOsm/kg Urine SG 1.005

Explain the significance of these lab values considering the patient's diagnosis.

• The patient is dumping excessive amounts of water in the urine, that is why her urine specific gravity is so low
• Because of the loss of water, the blood is now super concentrated, creating hypernatremia and a high serum osmolality.

What medications and or treatment changes do you expect the provider to order?

• The IV fluids need to be changed to D5W or D10W
• Free water via the OG tube will also help with the sodium levels
• DDAVP (Desmopressin) or Vasopressin should be ordered to replace the ADH that isn’t working

The provider orders the following:

Free water flush via OG Tube – 200 mL q4h

Change IVF to D5W at 125 mL/hr

Desmopressin (DDAVP) 2 mcg IV push q 12h

Daily weight

q4h Sodium and Serum Osmolality levels

You set the tube feeding pump to administer the free water and change the IV fluids while waiting for the DDAVP from the pharmacy

What regular monitoring will need to be done for Mrs. Ford during this treatment?

• Hourly urine output + urine specific gravity
• Continue frequent monitoring of vital signs and ICP/CPP
• Re-draw labs as ordered to ensure sodium is not being corrected too quickly

After 2 days of treatment, misses Fords urine output and urine specific gravity return to Baseline. However, she continues to have a GCS between 4 + 6, and now her left pupil is 8mm and fixed. The nurse notes her respiratory rate is erratic, her ICP is 18, and her heart rate is dropping.

What do you believe could be happening to Mrs. Ford at this time?

• Mrs. Ford may be experiencing brain herniation due to the bleeding and swelling in and around her brain
• Unfortunately, many times these patients cannot be returned to their normal baseline due to the extent of the damage.

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Sheehan's syndrome with diabetes insipidus. A case study

• PMID: 447511

A case of a woman in whom Sheehan's syndrome and diabetes insipidus were found is presented. This association is very uncommon, but well-documented cases have been reported. Controversial opinions about the primary lesion still exist. To find out whether the pituitary gland responds to hypothalamic releasing factors, three kinds of test were performed. The failure of the pituitary to respond suggested pituitary damage. Because diabetes insipidus was present, presumably the hypothalamus was also damaged. A review of the literature and different opinions about the primary anatomic lesions in this syndrome are discussed.

Publication types

• Case Reports
• Diabetes Insipidus / complications*
• Diabetes Insipidus / physiopathology
• Hypopituitarism / complications*
• Hypopituitarism / physiopathology
• Hypothalamo-Hypophyseal System / physiopathology

• Open access
• Published: 08 May 2024

Preoperative peripheral inflammatory markers are predictors of postoperative central diabetes insipidus in craniopharyngioma patients: a retrospective study

• Jing Wang 1 , 2 ,
• Guanghui Wang 1 ,
• Lidong Cheng 1 ,
• Hongtao Zhu 1 ,
• Junwen Wang 1 ,
• Xinmin Ding 2 ,
• Hongquan Niu 1 ,
• Kai Zhao 1 &
• Kai Shu 1  

BMC Cancer volume  24 , Article number:  572 ( 2024 ) Cite this article

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Postoperative central diabetes insipidus (CDI) is commonly observed in craniopharyngioma (CP) patients, and the inflammatory response plays an important role in CPs. We aimed to evaluate the predictive value of preoperative peripheral inflammatory markers and their combinations regarding CDI occurrence in CPs.

The clinical data including preoperative peripheral inflammatory markers of 208 CP patients who underwent surgical treatment were retrospectively collected and analyzed. The preoperative peripheral white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelet (PLT), neutrophil-to-lymphocyte ratio (NLR), derived-NLR (dNLR), monocyte-to-lymphocyte ratio (MLR) and PLT-to-lymphocyte ratio (PLR) were assessed in total 208 CP patients and different age and surgical approach CP patient subgroups. Their predictive values were evaluated by the receiver operator characteristic curve analysis.

Preoperative peripheral WBC, neutrophils, NLR, dNLR, MLR, and PLR were positively correlated and lymphocyte was negatively associated with postoperative CDI occurrence in CP patients, especially when WBC ≥ 6.66 × 10 9 /L or lymphocyte ≤ 1.86 × 10 9 /L. Meanwhile, multiple logistic regression analysis showed that WBC > 6.39 × 10 9 /L in the > 18 yrs age patients, WBC > 6.88 × 10 9 /L or lymphocytes ≤ 1.85 × 10 9 /L in the transcranial approach patients were closely associated with the elevated incidence of postoperative CDI. Furthermore, the area under the curve obtained from the receiver operator characteristic curve analysis showed that the best predictors of inflammatory markers were the NLR in total CP patients, the MLR in the ≤ 18 yrs age group and the transsphenoidal group, the NLR in the > 18 yrs age group and the dNLR in the transcranial group. Notably, the combination index NLR + dNLR demonstrated the most valuable predictor in all groups.

Conclusions

Preoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, are promising predictors of postoperative CDI in CPs.

Peer Review reports

Introduction

Craniopharyngioma (CP) is a common benign tumor arising from squamous cell nests in the primitive Rathke’s pouch in the central nervous system. The point prevalence of CPs is approximately 0.5–2.5/1,000,000 in the population [ 1 ]. Accompanied by increased knowledge of CPs and improved endoscopic surgery and radiation therapy, the surgical outcomes for CPs have significantly improved [ 2 , 3 ]. However, the postoperative process in each patient is different due to various postoperative complications, including central diabetes insipidus (CDI) and multiple pituitary hormone deficiencies [ 2 ].

CDI is the most common complication in CPs after surgery mainly resulting from the impairment of hypothalamic posterior pituitary function [ 1 ]. Briefly, postoperative CDI is characterized as a triphasic response of urine volume. The prevalence of postoperative CDI in CPs has been reported elsewhere to be up to 90% [ 4 ]. Although CDI has been well studied for decades, the management of this entity remains controversial. Numerous factors for the prediction of postoperative CDI occurrence have been identified in previous publications, such as patient age, tumor histopathological type, tumor volume, and cerebrospinal fluid leakage [ 5 , 6 ].

A cerebral inflammatory response is often observed and displays a close relationship with tumor prognosis in multiple tumors, including CPs [ 7 , 8 ]. Increasing studies have demonstrated that inflammatory cytokines, including IL-6, IL-8, CXCL1, etc., are closely related to CPs development [ 9 , 10 ]. Although these inflammatory factors have shown predictive value, medical expenses have limited their clinical application. Thus, finding a simpler, readily available, inexpensive method is urgent. Numerous studies have demonstrated that peripheral inflammatory markers and their combinations can be used for monitoring nonspecific inflammatory responses in various pathological situations [ 11 , 12 , 13 ], as well as inflammation monitoring, differential diagnosis, and prognosis prediction of CPs [ 7 , 13 , 14 , 15 ]. However, there remains a lack of comprehensive investigations into whether there are correlations between preoperative peripheral inflammatory markers and postoperative CDI in CPs, which is the purpose of this study.

The clinical data of 267 patients diagnosed with CPs who underwent surgical treatment in the neurosurgery department of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2016 to October 2021 were retrospectively collected and analyzed. The exclusion criteria were as follows: (1) patients with preoperative CDI; (2) patients who underwent radiotherapy or surgical treatment before; (3) patients with an infectious disease or severe organ dysfunction, such as failure of the lung, heart, liver and kidney; (4) patients with incomplete clinical data; and (5) patients taking diuretics or anti-inflammatory reagents postoperatively.

Data collection and study design

Clinical variables, including sex, age, laboratory examinations and surgical approach, were recorded directly from the medical records. The location of tumors was analysed from magnetic resonance images (MRI) performed by two independent experienced senior neurosurgeons and classified into Q-type, S-type and T-type according to the criteria described in a previous report [ 16 ]. The volumes of tumors were measured with preoperative MRI and the extent of tumor resection was evaluated by postoperative MRI and described as gross total resection (GTR, more than 95% of tumor resected) or subtotal resection (STR, the residual tumor volume was less than 20%) [ 17 , 18 ]. The blood specimens for laboratory examination in our current study were collected from each patient at admission, daily during the first week after the operation and every 2–3 days during the subsequent weeks postoperatively. The preoperative pituitary functions were evaluated with blood tests and patients with hypopituitarism were given preoperative steroid replacement (PSR) treatment until the cortisone supplementation was adequate, and then the surgery was performed. The counts of white blood cells (WBC), neutrophils, lymphocytes, monocytes and platelet (PLT) were directly collected from the peripheral blood tests and the combined inflammatory markers, including NLR (neutrophil-to-lymphocyte ratio; NLR = neutrophils/lymphocytes), dNLR [derived-NLR; dNLR = (WBC-neutrophils)/lymphocytes], MLR (monocyte-to-lymphocyte ratio; MLR = monocytes/lymphocytes) and PLR (platelet -to-lymphocyte ratio; PLR = platelet /lymphocytes), were calculated. CDI was identified by two independently experienced neurosurgeons during treatments for CPs in the first week postoperatively, in terms of the diagnosis described previously [ 19 ]. In general, the laboratory tests used for monitoring CDI include: (1) increased urine output (more than 300 ml for 3 consecutive hours); (2) elevated serum sodium concentration (higher than 145 mmol/l); and (3) reduced urine specific gravity (less than 1.005).

Statistical analysis

All statistical analyses were performed using IBM SPSS statistics software, version 23.0. For the normally and abnormally distributed data, continuous variables were described as the mean ± standard deviation and median (interquartile range, IQR) [M (P25, P75)], respectively. Differences between the two independent groups were compared by Student’s independent t-test and the Mann-Whitney U test. Qualitative data were summarized as counts and percentages and were analyzed using the Chi-square tests or Fisher’s exact tests (expected count ≤ 5). We used multiple logistic regression to identify independent predictors of preoperative peripheral inflammatory markers for postoperative CDI of CPs patients. Meanwhile, to evaluate the predictive value of inflammatory markers on early postoperative CDI, we drew a receiver operator characteristic (ROC) curve. The area under the curve (AUC) was automatically calculated. p  < 0.05 was considered statistically significant.

Patients’ characteristics, peripheral inflammatory markers and CDI data

Of the 208 patients, postoperative CDI was identified in 93 patients (44.7%). Numerous clinical data regarding age, age groups, sex, surgical approach, tumor volume, preoperative pituitary functions, extent of tumor resection and tumor location displayed no significant differences between the CDI and non-CDI groups. The preoperative WBC and neutrophil counts in patients with postoperative CDI were significantly higher than those in patients without CDI ( p  < 0.001 and p  = 0.011, respectively), while the lymphocyte count in patients with CDI was lower ( p  = 0.008). The monocytes and PLT did not show a significant difference between the CDI and non-CDI groups. In addition, the combined inflammatory markers NLR, MLR, dNLR and PLR displayed higher levels in CPs with CDI than in CPs without CDI (all p  < 0.05) (Table  1 ).

Multiple logistic regression analysis showed that the incidence of CDI was increased when preoperative WBC was higher than 6.66 × 10 9 /L ( p  = 0.002) or lymphocyte was lower than 1.86 × 10 9 /L ( p  = 0.022) (Table  2 ).

In addition, although there was no significant difference, compared with patients with hypopituitarism and received PSR, patients with normal pituitary function had a tendency of higher levels of preoperative inflammatory markers including WBC, neutrophil, monocyte, PLT, NLR, MLR and PLR (Additional Table  1 ).

Clinical analysis in different subgroups

To evaluate the impact of preoperative inflammatory markers on postoperative CDI in young and adult patients, we divided participants into two age subgroups. As shown in Table  3 , the WBC, neutrophils and NLR displayed significant differences between the CDI and non-CDI in the > 18 yrs age group (WBC: p  = 0.001, neutrophils: p  = 0.024 and NLR: p  = 0.003), but not in ≤ 18 yrs age group (all p  > 0.05). The MLR was elevated in the ≤ 18 yrs age group with CDI compared with those without CDI ( p  = 0.007). However, the MLR was not evaluated differently in the > 18 yrs age group with and without postoperative CDI. Moreover, the dNLR was closely related to CDI occurrence in both ≤ 18 and > 18 yrs age groups ( p  = 0.014 and p  = 0.011, respectively).

Next, we further explored the preoperative inflammatory markers in patients who underwent surgery using different surgical approaches (Table  4 ). Of 189 patients undergoing the transcranial approach, the WBC, neutrophils, NLR and dNLR were predominantly higher in the CDI group than in the non-CDI group (WBC: p  = 0.001, neutrophils: p  = 0.030, NLR: p  = 0.004 and dNLR: p  = 0.003), while the lymphocytes was lower ( p  = 0.023). In addition, the monocyte, MLR and dNLR were associated with CDI prevalence in the transsphenoidal approach patients (monocytes: p  = 0.017, MLR: p  = 0.011 and dNLR: p  = 0.022).

Furthermore, multiple logistic regression analysis showed that the incidence of CDI was increased when preoperative WBC was higher than 6.39 × 10 9 /L ( p  = 0.035) in > 18 yrs age group, WBC was higher than 6.88 × 10 9 /L ( p  = 0.022) or lymphocyte was lower than 1.85 × 10 9 /L ( p  = 0.029) in transcranial group, respectively (Table  5 ).

ROC curve analysis and predictive values

The corresponding ROC curves and AUC are shown in Table  6 ; Fig.  1 . Among the 208 CP patients, the AUCs were 0.641 (0.565–0.717) for NLR, which demonstrated the highest accuracy in predicting CDI occurrence. The evaluation of paired combinations of these inflammatory makers indicated that NLR + dNLR was the best predictor with an AUC of 0.681 (0.607–0.755) (Fig.  1 a). Further investigation revealed that the best accuracy for predicting CDI was obtained with MLR [AUC: 0.729 (0.580–0.878)] and NLR + dNLR [AUC: 0.731 (0.579–0.883)] in the ≤ 18 yrs age group (Fig.  1 b); NLR [AUC: 0.635 (0.547–0.722)] and NLR + dNLR [AUC: 0.667 (0.582–0.753)] in the > 18 yrs age group (Fig.  1 c); dNLR [AUC: 0.628 (0.545–0.711)] and NLR + dNLR [AUC: 0.661 (0.581–0.742)] in the transcranial approach group (Fig.  1 d); and MLR [AUC: 0.828 (0.643-1.000)] and NLR + dNLR [AUC: 0.889 (0.716-1.000)] in the transsphenoidal approach group (Fig.  1 e). Notably, among all inflammatory markers and their paired combinations, NLR + dNLR might be a discriminative parameter for predicting the prevalence of postoperative CDI.

The predictive value of the preoperative peripheral inflammatory markers. The predictive value of NLR, MLR, dNLR, PLR and their combinations in 208 CP patients ( a ), ≤ 18 yrs age group ( b ), > 18 yrs age group ( c ), transcranial approach group ( d ), and transsphenoidal approach group ( e )

Despite the fact that a long-term survival rate has been achieved in CP patients, the postoperative process is different in each individual, mainly resulting from multiple complications, particularly from CDI and the subsequent disturbance of water and electrolytes [ 19 ]. The incidence rate of CDI after surgery in CPs has been reported in an extensive range of 1.6–93% [ 5 , 6 ]. In our study, postoperative CDI was identified in 93 CP patients (44.7%), revealing a similar incidence to that in most previous reports. Inflammatory markers have been reported to play essential roles in tumor development, tumoral calcification, patient prognosis and the prevalence of postoperative complications including hypopituitarism [ 7 , 20 , 21 ]. However, little is known about the impact of the inflammatory markers on postoperative CDI in CPs.

Chronic inflammation plays pivotal roles in various brain diseases, such as hydrocephalus, cerebral hemorrhage, cerebral infarction, traumatic brain injury and gliomas [ 8 , 22 , 23 ]. Most recently, the inflammatory response in CPs has been well studied [ 9 , 24 , 25 ]. To quantitatively evaluate the inflammatory response, various inflammatory markers, either in cerebrospinal fluid (CSF) or in peripheral blood, have been evaluated in previous publications. The detection of inflammatory markers in CSF could directly reflect the inflammatory response in the brain. However, the clinical application has been limited for the following reasons: (1) CSF acquisition was invasive and inconvenient; (2) the value of inflammatory markers in CSF lacked certain reference intervals; and (3) these markers in CSF could not be detected continuously. Therefore, in our current retrospective study, we explored whether preoperative peripheral inflammatory markers and their combinations were associated with postoperative CDI occurrence in CPs.

The peripheral levels of WBC, neutrophils, lymphocytes and monocytes are identified as general markers of nonspecific inflammatory responses in the central nervous system (CNS). Increasing clinical data have indicated that peripheral WBC, neutrophils and monocytes play proinflammatory roles, while lymphocytes dominantly participate in the anti-inflammatory procedures [ 26 , 27 ]. For example, WBC and neutrophil counts were positively correlated with the malignancy of gliomas [ 28 ]. A higher peripheral blood WBC count and lower lymphocyte count indicated a poor prognosis in glioblastoma patients [ 29 , 30 ]. Moreover, higher levels of preoperative WBC and neutrophils might be potential markers to differentially diagnose papillary CPs [ 7 ]. In our study, we observed that higher WBC (≥ 6.66 × 10 9 /L) or lower lymphocyte (≤ 1.86 × 10 9 /L) in the total CP patients (Tables  1 and 2 ), higher WBC (> 6.39 × 10 9 /L) in the > 18 yrs age patients, higher WBC (> 6.88 × 10 9 /L) or lower lymphocytes (≤ 1.85 × 10 9 /L) in the transcranial approach patients (Tables  3 , 4 and 5 ) were closely associated with the elevated incidence of postoperative CDI. All of the above suggested that the inflammatory response might be closely associated with the prevalence of postoperative CDI in CPs and the WBC and lymphocytes may be the high-risk factors. Moreover, the WBC did not show differences between young patients with CDI and without CDI (Table  3 ). This result might have occurred because of: (1) the different clinical features of pediatric CPs; and (2) the statistical bias from the small young CP population in the current study. In addition, the dual function of monocytes has been demonstrated in various tumors [ 38 ]. However, monocyte function in CPs remains uncertain. Here, we report a relatively lower monocyte count in patients without CDI than in those with CDI after transsphenoidal surgery (Table  4 ). Unfortunately, multiple logistic regression analysis revealed that monocyte was insufficient for increasing the risk of postoperative CDI in patients with CPs (Table  5 ).

Considering the coexistence of pro-inflammation and anti-inflammation in the pathological circumstances of patients, the combined inflammatory markers NLR, dNLR, PLR and MLR have been used to evaluate the balance between pro- and anti-inflammation [ 20 , 31 ]. Moreover, these combined markers were more reproducible and accurate than routine blood cell counts. Higher NLR and MLR were associated with elevated mortality, neurological deterioration and poor outcome in cerebral hemorrhage patients [ 22 , 32 ]. In glioma patients, elevated NLR, PLR and MLR are reliable predictors of a poor outcome [ 8 , 33 ]. A higher NLR was correlated with a poor outcome in CPs [ 15 ]. In addition, PLR played roles in predicting neurological outcomes in comparison to PLT count alone [ 34 ]. Our study found that CP patients with postoperative CDI had higher levels of combined inflammatory markers, including NLR, MLR, dNLR and PLR (Table  1 ), indicating that the balance shifting towards a proinflammatory effect in CPs might result in a higher incidence of CDI. For single inflammatory markers, ROC curve analysis showed that NLR in the total CPs and the > 18 yrs age group, MLR in the ≤ 18 yrs age group and the transsphenoidal group, and dNLR in the transcranial group were the most valuable predictive markers for postoperative CDI occurrence (Table  6 ; Fig.  1 ), indicating that preoperative peripheral neutrophils and monocyte can also mediate the effect of the proinflammatory response on postoperative CDI. Meanwhile, for the paired combination of these four markers, the best predictive performance for CDI was proven in the application of preoperative NLR + dNLR in CPs regardless of age and surgical approach (Table  6 ; Fig.  1 ), suggesting that the combination of preoperative peripheral NLR + dNLR might be used as a promising potential biomarker for postoperative CDI prediction in CP patients.

In addition, a growing number of researchers have reported that the location, removal rate and tumor volume of CPs can affect the occurrence of postoperative CDI [ 35 , 36 ]. However, we did not draw these conclusions in this study. One possible reason of this inconsistency may depend on definition of the extent of tumor resection. Although we defined GTR as more than 95% of tumor resected and defined STR as 80–95% of tumor resected in this study [ 17 , 18 ], majority of the reported investigations were stood on another standard as GTR as 100% and STR as more than 90% [ 37 , 38 , 39 , 40 ]. This may reflect the inconsistency between our study and previously reported statistical results. In addition, for tumor locations, QST classification was used. Previous studies have shown that patients with T-type CPs are more likely to have postoperative sodium metabolism disorder and hypothalamic-pituitary dysfunction [ 16 ]. In this study, only 23 of the 208 patients with CPs had T-type CPs, 17 of the 208 patients with CPs accept STR of the tumor. The small sample size may be the reason why this study did not reach the above conclusions, and further studies with larger sample sizes are needed in the future. Meanwhile, previous studies have suggested that the incidence of postoperative CDI in CP patients is not determined by a single factor, but by a combination of various factors such as GTR/STR removal rate, tumor location, tumor volume, surgical approach, etc., among which whether the pituitary stalk is preserved is particularly important [ 41 , 42 , 43 ]. The lack of further distinction between whether the tumor invaded the pituitary stalk and whether the pituitary stalk was preserved by surgery may be another reason why we were unable to reach the above conclusions. Of note, although there was no statistical significance, the location, removal rate and tumor volume of CPs had a tendency to affect postoperative CDI in this study (Table  1 ). Furthermore, although there was no significant difference, this study found that preoperative PSR might have an effect on preoperative inflammatory markers in patients with CPs, but this effect did not interfere with postoperative CDI (Table  1 and Supplementary Table 1 ). Due to the fact that the dose of corticosteroids could not be extracted from the patient’s medical records, the effect of cortisone dose on preoperative inflammatory markers and postoperative CDI could not be determined. Follow-up studies are needed to further prove whether the use of PSR will affect the stability of the prediction model constructed in this study.

There are still some limitations of this retrospective study. (1) Our study only collected data from a relatively small proportion of CP patients in a single clinical center. Therefore, multicenter studies and larger numbers of patients are needed to verify our preliminary results; (2) the time interval between CPs onset and blood collection are different in each patient, which might have caused bias in data collection due to the differences in the inflammatory response at different stages of disease.

In this study, we observed that preoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, were promising predictors of postoperative CDI occurrence in CPs. This method of calculating preoperative circulation inflammatory markers can more accurately predict postoperative CDI and provide guidance for perioperative fluid management in CP patients.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Area under the curve

Magnetic resonance images

Central diabetes insipidus

• Neutrophil-to-lymphocyte ratio

Central nervous system

Platelet-to-lymphocyte ratio

• Craniopharyngioma

Cerebrospinal fluid

Preoperative steroid replacement

Derived-NLR

Receiver operator characteristic

Gross total resection

Subtotal resection

Interquartile range

White blood cells

Monocyte-to-lymphocyte ratio

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This study was funded by the National Natural Science Youth Foundation of China (No.81602204); the funding from the Hubei Province Association of Pathophysiology, China (No.2021HBAP007); and the Scientific Research Initiation Fund for Talent Introduction of Shanxi Bethune Hospital, Shanxi Province, China (2021RC006).

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Department of Neurosurgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China

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All authors contributed to the study conception and design. Data collection was performed by J.W., G.W., L.C. and H.Z. Data analysis was performed by K.Z., K.S., X.D. and JW.W. Material preparation was performed by H.N., K.Z. and K.S. The first draft of the manuscript was written by J.W. and all authors commented on previous versions of the manuscript. All authors reviwed the manuscript.

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All experimental protocols were performed with relevant guidelines and regulations and approved by the Institutional Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (No.TJ-IRB20220568). Meanwhile, the informed consent was waived by the Institutional Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (No.TJ-IRB20220568) since it was a retrospective study only.

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Wang, J., Wang, G., Cheng, L. et al. Preoperative peripheral inflammatory markers are predictors of postoperative central diabetes insipidus in craniopharyngioma patients: a retrospective study. BMC Cancer 24 , 572 (2024). https://doi.org/10.1186/s12885-024-12324-4

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Bendamustine-induced nephrogenic diabetes insipidus – A case report

Audrey desjardins.

1 Faculty of Pharmacy, Université de Montréal, Montreal, Canada

Viviane Le-Nguyen

Léa turgeon-mallette, chloé vo, jean-samuel boudreault.

2 Division of Hematology and Oncology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada

Jean-Philippe Rioux

3 Division of Nephrology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada

4 Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada

Amélie Veilleux

Introduction.

In patients with relapsed or refractory lymphoma, high-dose chemoimmunotherapy with subsequent autologous hematopoietic cell transplantation (HCT) is a standard of care. Bendamustine, an alkylating agent, is used in the BeEAM (bendamustine, etoposide, cytarabine, melphalan) protocol for conditioning therapy before autologous HCT in patients with relapsed or refractory lymphoma who are eligible for transplant. There is no consensus regarding an optimal salvage regimen and the approach varies according to toxicity.

Case report

We present a case of partial nephrogenic diabetes insipidus after receiving bendamustine, as part of the BeEAM protocol.

Management and outcome: The patient was managed with parenteral fluid administration and intranasal desmopressin before the condition resolved on its own.

We summarize published reports of bendamustine-induced diabetes insipidus.

Bendamustine is an alkylating agent often used as curative and palliative treatment of B cell Non-Hodgkin and Hodgkin lymphomas, for which it has shown to be very effective. 1 – 3 It is also part of the BeEAM protocol (bendamustine, etoposide, cytarabine and melphalan), used in autologous hematopoietic cell transplantation (HCT) for patients with relapsed/refractory lymphoma. 4 Autologous HCT is associated with a variety of possible complications, including infections secondary to chemotherapy-induced aplasia, and adverse effects of the medication used. 5 Regarding bendamustine, examples of common adverse effects (≥15%) are nausea, vomiting, fatigue, headache, rash, stomatitis and pancytopenia, and less common ones that can be seen are chest pain, tachycardia and nasal congestion. 6 A very rare adverse effect that is seldom reported in the literature is nephrogenic diabetes insipidus (NDI).

NDI is defined as the kidneys’ inability to concentrate urine due to antidiuretic hormone resistance (ADH). 7 It results in severe polyuria causing thirst and polydipsia. Few cases of drug-induced NDI have been published with bendamustine. 8 , 9 To date, no study in the literature states a clear association between NDI and bendamustine. This adverse event needs prompt recognition for optimal management. In this article, we present a case of a 48-year-old patient who received bendamustine in the BeEAM protocol and subsequently developed partial nephrogenic diabetes insipidus. Written consent was obtained from the patient.

Our case concerns a 48-year-old male with a history of syphilis and heterozygous AS sickle cell trait. Mantle cell lymphoma with multiple lymphomatous polyposis had been diagnosed based on a bone marrow biopsy. The patient received three cycles of R-Maxi CHOP and three cycles of R-High Dose-Ara-C (Nordic protocol 10 ) with complete response on the CT scan. His peripheral blood stem cells (PBSC) were mobilized and harvested on his last cycle of R-High Dose Ara-C with granulocyte-colony stimulating factor (G-CSF) and plerixafor. Seven months after his diagnosis and two months after his last chemoimmunotherapy, he underwent the BeEAM protocol for an autologous HCT, which consists of bendamustine 200 mg/m 2 intravenously given on days –8 and –7, cytarabine 200 mg/m 2 intravenously twice a day on days –6 to –3, etoposide 100 mg/m 2 intravenously twice a day on days –6 to –3, and melphalan 140 mg/m 2 intravenously on day –2. 4 He was only taking vitamin D supplements at the time.

Baseline laboratory workup was unremarkable, as shown in Table 1 . On day –8, he began the BeEAM protocol and received his first dose of intravenous bendamustine 440 mg (200 mg/m 2 ). He also received intravenous fluids as part of the BeEAM protocol. From day –6, his urine output, serum sodium and serum creatinine started to increase ( Figure 1 ). His urine output markedly increased from 3725 mL on day –8 to 7425 mL on day –3 and the serum creatinine increased from 75 µmol/L on day –7 to 155 µmol/L on day –3. His serum sodium also increased to a peak of 155 mmol/L on day –2. During this time, the patient only complained of mild nausea. Vital signs were stable. Forced diuresis with furosemide was suspended and oral hydration was optimized.

Laboratory results on day –8, day –6 and day 0.

Serum sodium and urine output during hospitalization.H*: D5% + 1/2 NS + KCl 20 mEq alternating with NS + KCl 20 mEq.

On day –1, the patient started complaining of polyuria, nocturia and thirst. However, he could not drink, since he had severe mucositis and odynophagia due to his chemotherapy, which led him to be put on total parenteral nutrition a few days after. A nephrology consultation request was made. Laboratory studies revealed the following values: random urine sodium 56 mmol/L; random urine osmolality 307 mOsm/kg and specific urine gravity from urinalysis 1.006. Despite the normal range of urine osmolality, the nephrologist team suspected a nephrogenic diabetes insipidus (NDI) along with concomitant dehydration in absence of other identified causes of polyuria. However, no water deprivation test or desmopressin challenge was done since the patient had developed an acute kidney injury (AKI), and required fluids for his hypernatremia and his upcoming HCT. After the HCT, the patient’s infusion was first switched to 0.45% sodium chloride and subsequently to dextrose 5%. Serum sodium levels showed little improvement while fluid balance improved but remained negative. On day 5, desmopressin 1 mcg was administered subcutaneously with no effect on diuresis. The following day, a desmopressin (4 mcg) challenge was administered intravenously and showed a 33% increase from baseline urine osmolality of 204 mOsm/kg to an average of 277 mOsm/kg with a decrease in diuresis. These values were compatible with a diagnosis of diabetes insipidus. The patient remained polyuric and highly dependent on fluids due to his hypernatremia. Since he was partially responsive to the desmopressin challenge, intranasal desmopressin was started on day 8. The dose was increased until it reached desmopressin 40 mcg twice daily intranasally on day 11 ( Figure 1 ). A brain magnetic resonance imaging (MRI) was then performed on day 12 to rule out central lymphomatous infiltrates, which came back negative and therefore reinforced a diagnosis of partial NDI. On day 13, his natremia returned to normal range along with diuresis decreased to 600-800 cc/8 h, intravenous dextrose 5% was stopped. Desmopressin was weaned off and then stopped on day 15. By then, the patient’s nocturia had markedly improved and NDI was considered resolved. On day 18, the patient was discharged from the hospital. To this day, he remains in remission of his lymphoma.

Diabetes insipidus

Diabetes insipidus (DI) is a condition where water homeostasis by vasopressin is impaired. It can be caused by a decreased vasopressin secretion (central diabetes insipidus) or the kidney’s resistance to the vasopressin action (nephrogenic diabetes insipidus). 11 In either case, the kidneys are unable to fully concentrate the urine and urine osmolality is low. Thus, patients with DI show symptoms of polyuria, nocturia and polydipsia. 11 Serum osmolality and natremia can be within normal limits if the patient can drink enough to compensate for the water loss. 12 , 13 A urine osmolality below 300 mOsm/kg along with serum hyperosmolality and polyuria suggests the presence of DI. 11 , 12 To diagnose DI or to differentiate between types of DI, a water deprivation test with the administration of desmopressin can be done. The patient is placed under water restriction to stimulate the secretion of endogenous vasopressin, and its impact on urine concentration is measured through urine osmolality. In DI, urine osmolality remains low since endogenous vasopressin action is deficient. 12 Desmopressin is then administered, with urine osmolality measured before and after. Since central DI is caused by a lack of vasopressin, the administration of desmopressin will have a significant impact on urine osmolality, with elevations from 100 to 800% in complete central diabetes insipidus (CDI) and 15 to 50% in partial CDI. 14 As for nephrogenic diabetes insipidus (NDI), kidneys are resistant to vasopressin and desmopressin will have little to no effect on urine osmolality. However, many patients are only partially resistant to ADH and may respond with an up to 45% elevation in urine osmolality. 14

Both CDI and NDI can be acquired or inherited. Common acquired causes of CDI include neoplasms, trauma and neurosurgery. Most of these causes can be identified from the patient’s history or the brain MRI. 12 Common acquired causes of NDI include drugs, metabolic disturbances, such as hypercalcemia and hypokalemia, and renal disease. 12 In these cases, the condition is often reversible with cessation of the causative drug or correction of the metabolic disturbance. 15 Both CDI and NDI may also be idiopathic. The most common drug to cause NDI is lithium. Other involved pharmacological classes are antibiotics, antiviral agents, antifungal agents, antineoplastic agents (cyclophosphamide, ifosfamide) and antipsychotics. 15 – 17 Treatments include sodium restriction and desmopressin for CDI. Thiazides and NSAIDs can also be considered for chronic types of NDI. In any case, appropriate fluid intake is essential and correction of the underlying cause should be sought whenever possible. 11 – 13

Case management

DI was suspected with the presentation of polyuria, thirst and low urine osmolality. A partial NDI diagnosis was made based on the desmopressin challenge resulting in an increase of 33% in urinary osmolality from baseline. A water deprivation test was not performed to confirm the diagnosis since the patient had just received chemotherapy and had developed an AKI. DI can be a manifestation of primary or secondary brain tumors involving the hypothalamic-pituitary region. However, pituitary involvement is rare in lymphomas and is usually seen on the brain MRI. 18 Moreover, HCT would not have been performed in patients with central nervous system infiltrates in mantle cell lymphoma. In our case, the brain MRI was negative for any lymphoma infiltrate and CDI was ruled out.

Kidney injuries, including acute tubular necrosis and ureteral obstruction, are potential causes of acquired NDI. 12 In our case, the patient developed an AKI in the days following bendamustine administration. Dose-intensified bendamustine in HCT conditioning regimens has been associated with all-grade AKI. 19 – 21 Besides bendamustine, the patient was not exposed to any other drugs known for causing AKI or nephrogenic DI at the time of presentation. Although he had received three doses of cyclophosphamide as part of the Nordic protocol, his last dose of cyclophosphamide was administered two months earlier. Furthermore, the timing between the administration of bendamustine and the onset of dilute polyuria consisted of a few days, similar to other cases in the literature. 8 , 9 This suggests bendamustine was the cause of NDI and not cyclophosphamide. The drug was already discontinued at the time of DI diagnosis and there was no rechallenge. NDI also resolved without needing long-term treatment, which points towards the cause being an adverse drug reaction. The Naranjo adverse drug reaction score reveals a score of 7 which indicates a probable adverse drug reaction (Supplemental Material 1. Naranjo Algorithm Assessment). 22 Of note, individuals with sickle cell trait are at risk for various renal complications such as hyposthenuria, a defect in the capacity to concentrate urine. 23 , 24 If present, this condition could have contributed to our patient’s presentation.

As mentioned, a crucial part of treating nephrogenic DI is to correct the underlying cause. In our case, bendamustine was suspected early in the process. However, the only two bendamustine doses in the BeEAM protocol had been administered by the time the diagnosis was made, so the underlying cause was already corrected. As for the management of hypernatremia and AKI, oral hydration was difficult since the patient had severe odynophagia due to his chemotherapy. Intravenous 0.45% saline was therefore administered and later switched to dextrose 5%, which are both appropriate in the context of hypernatremia. The rate of fluid administration was revised daily. Furthermore, desmopressin was used to reduce polyuria associated with DI and to limit high fluid intake. Desmopressin is usually not the first line of treatment for nephrogenic DI as patients tend to be resistant to its effects, thus requiring higher doses. 12 However, our patient demonstrated a partial response when the desmopressin challenge was administered (the urine osmolality increased by 33%). Therefore, we considered it was beneficial to continue with intranasal desmopressin in this case, especially as thiazides and NSAIDS were not appropriate due to AKI.

Bendamustine is an alkylating agent that has three structural elements: a 2-chloroethylamine alkylating group, a benzimidazole ring, and a butyric acid side chain. 25 It acts by alkylating and crosslinking DNA strands, causing cell death via several pathways. 6 There are case reports of Fanconi syndrome combined with NDI that are caused by ifosfamide, another alkylating agent which also acts via a chloroethylamine group. 26 – 30 The mechanism by which ifosfamide causes NDI is unclear, but the hypokalemia associated with impaired proximal tubular function might be a contributing factor. It is thought that acquired forms of NDI are due to defects or reduced expression of aquaporin 2, a vasopressin-regulated water channel of the collecting duct, but they appear to be reversible after discontinuation of the causing agent. 31 Bendamustine could have caused NDI in our patient by a similar mechanism. However, bendamustine does not seem to cause Fanconi syndrome.

Literature review

We have only found two published case reports on NDI involving bendamustine ( Table 2 ). The first case is a 59-year-old male who developed partial NDI following the first cycle of bendamustine and dexamethasone for light chain amyloidosis. 8 The second case is a 59-year-old male who developed NDI within days of completing his sixth cycle of rituximab and bendamustine for chronic lymphocytic leukemia. 9 Our patient’s presentation is similar to these case reports found in the literature. All three cases had an onset of DI symptoms within a few days of taking bendamustine, although the case by Derman et al (2017) only developed DI after the sixth cycle. Our case is most similar to the case report by Uwumugambi et al (2016), in which the patient was diagnosed with partial NDI and where toxicity was reversible. The patient was initially treated with a low sodium diet and hydrochlorothiazide 12.5 mg daily orally, with only a modest improvement in polyuria. Intranasal desmopressin was then initiated which resulted in a drastic improvement in symptoms. The patient was kept on bendamustine and after four more cycles without any recurrence, desmopressin and HCTZ were discontinued. From these case reports, it suggests that longer exposure to the offending drug lengthens the time required for recovery. This trend was also noted in a systematic review on causes of reversible NDI. 15

Summary of the case reports on bendamustine-induced NDI.

D5W: dextrose 5%; NS: normal saline; die: once daily; bid: twice daily; HCTZ: hydrochlorothiazide; uOsm: urine osmolality.

Although rare cases of bendamustine-related diabetes insidipus have been described, this report is the first involving BeEAM conditioning preceding autologous HSCT. 8 , 9 Despite the rarity of this entity, prompt treatment is essential. In our patient’s case, it occurred a few days after he received bendamustine, and presented itself as partial nephrogenic diabetes insipidus with polyuria and urinary osmolality below 300 mOsm/kg. Our patient was then treated with intranasal desmopressin along with intravenous fluids. His NDI was resolved after eight days of treatment. The patient had a successful HCT, and he remains in remission of his disease. Further studies are needed to clarify the mechanism by which bendamustine causes NDI and to identify potential risk factors. NDI should be suspected in patients exposed to bendamustine who subsequently develop hypernatremia and polyuria. We recommend treating NDI according to the best available evidence.

Patient consent: Written consent was obtained from the patient.

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JSB has served on advisory boards for Janssen, Celgene, Amgen, and BMS.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs: Audrey Desjardins https://orcid.org/0000-0002-8268-1238

Jean-Samuel Boudreault https://orcid.org/0000-0003-4737-9153