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Diabetes Insipidus

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• Case Report
• Open access
• Published: 23 July 2024

Sheehan’s syndrome presenting with panhypopituitarism and central diabetes insipidus: a case report

• Chin-Fang Chen 1 ,
• Yu-Cheng Liang 1 ,
• Meng-Jie Tsai 1 &
• Horng-Yih Ou 1  

BMC Endocrine Disorders volume  24 , Article number:  120 ( 2024 ) Cite this article

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Metrics details

Sheehan’s syndrome is a rare condition, which is classically characterized by anterior pituitary hypofunction following postpartum shock or hemorrhage. While diabetes insipidus (DI) is not commonly associated with Sheehan’s syndrome, we present a rare case of a multiparous female developing rapid-onset panhypopituitarism and DI following severe postpartum hemorrhage.

Case presentation

A previously healthy 39-year-old woman, gravida 5, para 4, presented with hypovolemic shock after vaginal delivery, attributed to severe postpartum hemorrhage, necessitating emergent hysterectomy. Although her shock episodes resolved during hospitalization, she developed intermittent fever, later diagnosed as adrenal insufficiency. Administration of hydrocortisone effectively resolved the fever. However, she subsequently developed diabetes insipidus. Diagnosis of Sheehan’s syndrome with central diabetes insipidus was confirmed through functional hormonal tests and MRI findings. Treatment consisted of hormone replacement therapy, with persistent panhypopituitarism noted during a ten-year follow-up period.

Conclusions

Sheehan’s syndrome is a rare complication of postpartum hemorrhage. Central diabetes insipidus should be suspected, although not commonly, while the patient presented polyuria and polydipsia. Besides, the potential necessity for long-term hormonal replacement therapy should be considered.

Peer Review reports

Sheehan’s syndrome is a rare condition, which is classically characterized by anterior pituitary hypofunction following postpartum shock or hemorrhage. While diabetes insipidus (DI), which instead involves the posterior pituitary peptide hormone, is not commonly associated with Sheehan’s syndrome [ 1 , 2 ], we present a case of a multiparous female who experienced a unique combination of rapid onset of panhypopituitarism and DI following a episode of severe postpartum hemorrhage.

A previously healthy 39-year-old woman, gravida 5, para 4, at 41 weeks pregnant, was transferred to our emergency department in hypovolemic shock. Three hours earlier, she had delivered a healthy full-term male infant weighing 3500 g through vaginal delivery, without the use of any instruments or excessive uterine pressure. However, one hour after delivery, significant postpartum vaginal bleeding occurred, despite receiving intravenous Oxytocin (40IU, IV) and Methylergonovine (0.8 mg, IV). Consequently, she received a transfusion of 10 units of packed red blood cells (RBC) and 1 unit of fresh frozen plasma (FFP). The estimated blood loss was 3,000 ml before transferring to our emergency department.

Upon arrival, the patient was presented with profound shock, including a body temperature of 34.8 °C, respiratory rate of 30 breaths per minute, and undetectable blood pressure. Physical examination revealed stupor consciousness, pale conjunctiva, and severe respiratory distress. Initial laboratory findings showed hemoglobin 10.0 g/dL, platelet 113,000 cells/mm3. Arterial blood gas analysis indicated pH 6.601, PCO 2 104.9 mmHg, bicarbonate 10.4 mmol/L, and PO 2 30 mmHg. Coagulation studies indicated prothrombin time 18.75/11.10 s and an activated partial thromboplastin time 185.55/28.9 s. Due to her critical condition, an emergent hysterectomy was performed, revealing a laceration of the right uterine artery, with a substantial transfusion of 9 units of whole blood, 37 units of packed RBC, 36 units of platelets, and 36 units of FFP, due to intraoperative blood loss of 11,300 ml. Following the surgery, the patient was admitted to the intensive care unit.

The patient’s hospitalization became complicated when she developed catheter-related sepsis and the bloodstream infection caused by Enterococcus faecalis and oxacillin-resistant Staphylococcus sciuri . Additionally, she experienced disseminated intravascular coagulopathy, acute renal insufficiency, and ischemic hepatitis. Proper administration of fluids and antibiotics, including vancomycin, ampicillin and sulbactam, led to improvements in renal and liver function and the recovery from the shock episode. Despite completing a course of antibiotics, the patient experienced intermittent fever for 2–3 weeks. Subsequently, she was diagnosed with adrenal insufficiency based on low cortisol levels (8 AM/4 PM: 5.6/4.0 µg/dL). The fever resolved after administering intravenous hydrocortisone 100 mg daily. However, she soon developed polyuria on the 30th day, with a significant increase in urine output, up to 11,070 ml/day. Given the clinical suspicion of Sheehan’s syndrome with DI, further investigations were conducted.

To assess anterior pituitary function, the patient underwent Insulin hypoglycemia/ thyrotropin-releasing hormone (TRH) test/ luteinizing hormone-releasing hormone (LHRH) test ( Table 1 ), which revealed adrenal insufficiency, growth hormone deficiency, secondary hypogonadism, and secondary hypothyroidism. Panhypopituitarism was diagnosed. Water deprivation/desmopressin tests ( Table 1 ) showed increased urine osmolarity and decreased urine amount post desmopressin (DDAVP) infusion. Central DI was confirmed.

Magnetic resonance imaging (MRI) of the sellar region (Fig.  1 ) was performed one month postpartum, revealing a heterogeneous signal within the normal-sized pituitary gland, consistent with acute hemorrhage and necrosis. A follow-up sellar region MRI (Fig.  1 ), at 10 years later, revealed a very small size of the remaining pituitary gland.

MRI for head with the focus in the sella with and without Gadolinium contrast medium. MRI for head with the focus in the sella, sagittal view without Gadolinium contrast medium ( A ), and with Gadolinium contrast medium ( B ), corneal view without Gadolinium contrast medium ( C ) and with Gadolinium contrast medium ( D ), revealed there was slight heterogeneous signal within the pituitary gland. The size of the pituitary gland was within normal range. There was no normal enhancement of the gland itself except the pituitary stalk. The picture of hemorrhage and necrosis of the pituitary gland was compatible with Sheehan’s syndrome. Follow-up MRI of sellar region after 10 years, sagittal view without Gadolinium contrast medium ( E ), and with Gadolinium contrast medium ( F ), corneal view without Gadolinium contrast medium ( G ) and with Gadolinium contrast medium ( H ) revealed very small pituitary gland. The previous intra-glandular hemorrhage was not visualized this time. The pituitary stalk was in the midline

Following the diagnosis of Sheehan’s syndrome with DI, the patient received intranasal desmopressin acetate 10 mcg BID, oral cortisone acetate 25 mg BID, levothyroxine sodium 100 mcg QD, and conjugated estrogens 0.625 mg QD to address the hormonal deficiencies. Over ten years of follow-up, her panhypopituitarism persisted, necessitating long-term hormone replacement therapy.

Sheehan’s syndrome is classically characterized by reduced anterior pituitary hormone secretion following postpartum shock or hemorrhage. In 1963, Sheehan and Whitehead described varying degrees of pathological alterations including atrophy and scarring change in 90% of the posterior pituitary lobes from postpartum hypopituitary patients examined post mortem. Whitehead also reported constant hypothalamic damage characterized by marked atrophy of the supraoptic nuclei and, to a lesser extent, of the paraventricular nuclei, though, none of these patients had a history of transient DI [ 1 ].

Over the years, several studies had investigated antidiuretic function in patients with Sheehan’s syndrome [ 3 , 4 , 5 , 6 , 7 , 8 ]. Despite being asymptomatic for polyuria, most patients showed impaired osmoregulation of vasopressin secretion, including impaired maximal urine osmolality, insufficient urinary arginine vasopressin (AVP) excretion, elevated plasma osmolality, reduced urine-plasma osmolality ratios, and impaired plasma vasopressin response to plasma osmolality compared with normal control groups, both at baseline or after provocative test such as water deprivation / vasopressin or hypertonic saline infusion test. Patients also took a longer time to reach maximal urinary osmolality compared with normal subjects during functional tests.

From a clinical perspective, DI associated with Sheehan’s syndrome exhibits characteristic features. First, it tends to be partial rather than complete DI. Bakiri et al. and Jialal et al. reported that patients diagnosed with Sheehan’s syndrome and DI had a less than 50% increase in their maximal urine osmolality after water deprivation/vasopressin test [ 4 , 5 , 6 ]. Therefore, they concluded that failure of arginine-vasopressin secretion is more often partial. Atmaca, Tanriverdi et al. also disclosed that the patients diagnosed with DI all revealed partial DI. Hence, long term treatment of DI may be necessary in only a few cases.

Second, the onset of DI in Sheehan syndrome tends to be late, and the course tends to be transient. In Iwasaki’s series, only 4 of 12 had a history of transient symptomatic polyuria in their immediate postpartum period and one had DI for about 7 months after delivery. None of them developed permanent DI (all remission 10 months later). Robert L. at el. reported a case report with DI and Sheehan syndrome, and the interval between the postpartum hemorrhage and symptoms of polyuria was 11 years [ 9 ].

The reasons for DI to be partial and transient might be explained. The function of some vasopressin neurons that had been damaged as a result of the pituitary ischemic may recover. In addition, a decrease in the metabolism of vasopressin caused by disappearance of plasma vasopressinase that normally circulates during pregnancy also contributes. This enzyme is known to persist for 4–6 weeks after delivery. Finally, chronic deficiency of the hormone may lead to increased renal sensitivity to vasopressin.

Our case was diagnosed with adrenal insufficiency, which presented persistent fever on the 25th day after postpartum hemorrhage. Polyuria occurred soon after glucocorticoid replacement on the 30th day. Due to glucocorticoid deficiency, it is reasonable to presume that her DI might onset earlier than we noticed. After a water deprivation/desmopressin test, central DI, characterized by decreased release of AVP, was diagnosed. She was followed for years till now, and DDAVP therapy was still necessary for her to relieve polyuria. In comparison with the previously reported cases, the DI in this patient was unique as it occurred after steroid replacement for adrenal insufficiency, resulted in complete loss of antidiuretic function, had an early-onset, and was permanent in course.

Interestingly, although early research mostly suggested that DI was late onset, the fact is that early onset is not rare. Olmes, Solomayer et al. had performed a systematic review of Sheehan’s syndrome and DI, and identified eight relevant case reports published between 1990 and 2021 [ 10 ]. Most of the patients encountered severe blood loss, following hypotension or shock, similar to our case. The interval between birth and the initial manifestation of symptoms ranged from 24 h to 19 days after delivery in all cases [ 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]., with a median of 8.8 days. In our case, the patient developed symptoms on the 30th day. Five reports described accompanying hormone disorders with adrenal insufficiency, hypothyroidism and hypogonadism. Moreover, six reports mentioned the diagnosis of central DI, and the use of desmopressin to treat DI in the context of Sheehan’s syndrome.

The possible mechanism by which glucocorticoid replacement exacerbates DI is that glucocorticoids inhibit the synthesis of AVP in the hypothalamus through negative feedback. In return, hypocortisolism can result in elevated AVP levels and increased sensitivity to AVP [ 2 , 18 , 19 ]. Therefore, in our case, hypocortisolism might have initially masked the clinical manifestations of AVP deficiency; however, once steroid replacement therapy was initiated, the deficiency in AVP became symptomatic.

As for the pathogenesis of neurohypophyseal damage, it is difficult to determine. During pregnancy, the pituitary gland is enlarged physiologically [ 20 ]. Pituitary enlargement causes compression of the anterior hypophyseal artery, resulting in mild pituitary ischemia. Severe postpartum hemorrhage may lead to necrosis of the enlarged pituitary glands [ 12 ]. Typically, Sheehan’s syndrome presents initially as anterior pituitary hormonal dysfunction. Although most patients with Sheehan’s syndrome had atrophy of the posterior pituitary lobe and hypothalamic nuclei, AVP deficiency manifested as DI is very rare and occurs when a large portion of the neurohypophysis is destroyed [ 1 ]. However, it is still unclear whether DI is due to the posterior pituitary lobe damage or the insufficient hormone secretion by the hypothalamus.

Imaging study may offer an insight into such an issue. MRI imaging in our patient at the time of diagnosis revealed hemorrhage and necrosis of the pituitary gland, a distinct feature from previously reported ones. Originally, Sheehan’s syndrome was described as ischemic necrosis pathologically in the anterior pituitary following postpartum shock or hemorrhage without any image characteristics mentioned. However, depending on the time interval of event and image taking, non-hemorrhagic pituitary apoplexy [ 21 ] or empty sella have been the most common image finding in Sheehan’s syndrome. There were only few reports like ours on early image findings after postpartum hemorrhage in Sheehan’s syndrome. In a study measuring sella size and content in Sheehan’s syndrome by high resolution computerized tomography with time interval from postpartum hemorrhage to scan varied from 0.5 to 22 years (mean 11 years), an empty sella of a relatively small size was reported to be a common radiological finding, and the content varies from pituitary stalk only (26/57), stalk and other pituitary tissues (20/57), and a sella of pure CSF density (11/57) [ 22 ]. The hemorrhage of pituitary gland initially in our case might be due to hemorrhagic infarction or bleeding tendency because of complicated DIC course.

The extent of neurohypophyseal and adenohypophyseal defects was reported to be correlated. Iwasaki found 4 patients with very poor vasopressin response to hypertonic saline infusion had almost complete anterior pituitary hormone deficiency, where 4 other patients with normal or nearly normal vasopressin response had only partial or isolated anterior pituitary hormone deficiency [ 3 ]. Therefore, the risk for development of posterior pituitary dysfunction is increased if more complete loss of anterior pituitary hormone function loss exists [ 23 ]. It was applied to our case. Our patient suffered from anterior hypopituitarism with concurrent DI.

Sheehan syndrome is a rare complication of postpartum hemorrhage. Central diabetes insipidus should be suspected, although not commonly, while the patient presented polyuria and polydipsia. Besides, the potential necessity for long-term hormonal replacement therapy should be considered.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

diabetes insipidus

red blood cells

fresh frozen plasma

partial pressure of carbon dioxide

oxygen partial pressure

desmopressin

thyrotropin-releasing hormone

luteinizing hormone releasing hormone

magnetic resonance imaging

twice daily

arginine vasopressin

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Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, No. 1 University Road, Tainan, 70101, Taiwan

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Chin-Fang Chen - designed the study, interpreted the data and drafted the manuscript. Yu-Cheng Liang - reviewed the manuscript. Meng-Jie Tsai - reviewed the manuscript. Horng-Yih Ou - coordinated the study and reviewed the manuscript. All authors read and approved the final manuscript.

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Chen, CF., Liang, YC., Tsai, MJ. et al. Sheehan’s syndrome presenting with panhypopituitarism and central diabetes insipidus: a case report. BMC Endocr Disord 24 , 120 (2024). https://doi.org/10.1186/s12902-024-01654-w

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DOI : https://doi.org/10.1186/s12902-024-01654-w

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Lithium-Associated Nephrogenic Diabetes Insipidus or Catatonic Stereotypical Drinking?

A case report and literature review.

Mahgoub, Yassir MD; Yapar, Irem MD; Harbold, Delaney BS

Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, Hershey, PA [email protected]

Penn State College of Medicine, Hershey, PA

Received October 2, 2023; accepted after revision November 5, 2023.

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Exploring the Impact of Diabetic Nephropathy on Kidney Health

Late-stage treatment options, tips for healthy kidneys.

Diabetic nephropathy is a form of long-term, chronic kidney disease resulting from having had diabetes for several years. Diabetes causes higher-than-normal blood glucose levels, which damage some of the kidney’s blood vessels over time. Damaged blood vessels in the kidneys and other factors, like inflammation, lead to kidney damage.

Around 40% of people with diabetes eventually develop long-term kidney damage, and it is the leading cause of end-stage renal (kidney) disease worldwide.

This article discusses how diabetes affects the kidneys, including symptoms, causes, diagnosis, treatment, and general tips for preventing kidney damage. 

Kayoko Hayashi / Getty Images

What Are the Symptoms of Diabetic Nephropathy?

Initially, diabetic nephropathy doesn’t cause any symptoms. However, symptoms arise as the kidneys worsen over time.

Some potential symptoms could include the following:

• Dry, itchy skin
• Extremely high blood pressure
• Fruity smelling breath
• Swelling in your ankles and feet
• Muscle cramps
• Nausea 
• Poor concentration
• Shortness of breath
• Urinating too much or too little
• Weight loss

What Causes Diabetic Nephropathy?

Diabetic nephropathy is a complication of diabetes mellitus, a medical condition that leads to high blood glucose. It can occur in almost all diabetes types, including type 2, type 1, and pancreatogenic. These types differ somewhat, but all involve the body’s ability to produce or respond to the hormone insulin .

Scientists aren’t completely clear why some people with diabetes develop kidney disease. Elevated glucose may lead to long-term damage to the blood vessels in the kidneys. Other factors common in people with diabetes, like inflammation and high blood pressure, may also play a role.

However, diabetic nephropathy doesn’t occur right when you first get diabetes. It may take around 10 years to develop, though this can vary greatly.

Other Risk Factors

Some factors increase the chance that you’ll develop diabetic nephropathy. For example, you have a higher risk of diabetic nephropathy if you are male or advanced in age. People who’ve had diabetes for a long time also have higher risks, as do people who already have other diabetes complications, like retinopathy .

Examples of additional risk factors include:

• Carrying a lot of excess adipose tissue (fat)
• Having elevated levels of fats in the blood (e.g., high LDL cholesterol ) 
• Having high blood pressure
• Having poorly controlled diabetes with high blood glucose levels

You may improve these risk factors via lifestyle changes and medications.

Stages of Kidney Disease

Stage refers to how well the kidneys remove waste from the body and perform other vital functions. It’s defined by the rate at which the small components of your kidneys can filter blood to help make urine, called the estimated glomerular filtration rate or eGFR. 

In stage 1, the kidneys are only slightly damaged, and in stage 2, they are a bit more so. However, symptoms are usually absent.  

If the kidney damage continues, you might develop stage 3, 4, or 5 (end-stage) disease. Symptoms like swelling and fatigue might begin mildly in stage 3, then expand and worsen as the kidneys become more damaged in advanced kidney disease, stages 4 and 5.

If not treated, stage 5 kidney disease leads to symptoms that are ultimately fatal, like coma . 

How Is Diabetic Nephropathy Diagnosed?

Clinicians take a medical history, perform a medical exam, and check the results of additional tests to diagnose diabetic nephropathy. Usually, someone with diabetic nephropathy already knows that they have diabetes. But if they don’t, a healthcare provider will order blood tests for diabetes, like blood glucose and hemoglobin A1c .

Screening people with diabetes for nephropathy is critical, as people with early disease might not know that they have it. 

Microalbuminuria Urine Tests

Microalbuminuria urine tests can be used earliest in the disease. Normally, only very small amounts of protein, called albumin , in your blood should end up in your urine. The microalbuminuria test shows if more albumin than usual is in your urine. The term "microalbuminuria" has lately been replaced with "moderately increased albuminuria."

In a variation of this test, the albumin-to-creatinine ratio (ACR), the amount of albumin present in the urine, is divided by the amount of creatinine in your urine. People with kidney disease have higher ACRs. 

Serum Creatinine Blood Test

The serum creatinine test measures the amount of creatinine in the blood. Creatinine is a waste protein that the body disposes of through the kidneys, but its levels increase in kidney disease.

Healthcare providers use serum creatinine to calculate the estimated glomerular filtration rate (eGFR). The eGFR is high in people with normal kidneys but has lower results in people with more advanced kidney disease.  

Screening for Kidney Disease

The American Diabetes Association recommends using urine microalbuminuria and serum creatinine with eGFR to screen for diabetic nephropathy in people with type 1 diabetes who’ve had it for at least five years and in people with type 2 diabetes as soon as they are diagnosed, with additionally yearly screenings.

Kidney Biopsy

A kidney biopsy is an invasive procedure to remove a sample of your kidney and examine it under a microscope. It is usually not needed to diagnose diabetic nephropathy. However, it might be helpful if it’s not clear if diabetes or some other type of problem led to your kidney disease.

How Is Diabetic Nephropathy Treated?

With the exception of a kidney transplant, treatments don’t cure diabetic nephropathy, but they can help prevent your kidneys from getting worse.

Medications for Blood Glucose Management

It’s critical to keep your blood sugar under control, and many different medications can help with that. Your choices will depend on the type of your diabetes, its severity, and your personal preferences. 

Some key examples include the following:

• Insulin, especially for type 1 diabetes
• Glucophage (metformin) , which is usually the first drug used in type 2 diabetes
• SGLT-2 medications like Invokana (canagliflozin)
• GLP-1 medications, like Byetta (exenatide,) may slow the progression of diabetic nephropathy

However, many other medications for diabetes are potential options.

Other Medication Types

High blood pressure is common in people who have diabetes and can further damage the kidneys, so some people also need medications to lower their blood pressure. Often, healthcare providers prescribe an ACE inhibitor-type medication like Capoten (captopril).

Because heart disease is also a big problem in diabetes, many people will also need medication for that, such as a statin drug like Lipitor (atorvastatin). These medications may not directly improve your kidneys but may help prevent heart attack and stroke.

Diet and Other Lifestyle Changes

People with diabetic nephropathy need to follow a diet that is healthy for their diabetes but also their kidneys. The following eating patterns may be beneficial:

• Avoiding foods high in sugar and processed carbohydrates (e.g., cookies and soft drinks)
• Eating a diet with whole-grain carbohydrates and fiber, like from oatmeal and fresh fruits and vegetables
• Eating foods high in omega-3 fatty acids , such as fish like salmon
• Limiting protein (especially from proteins high in saturated fats , like beef or other animal source)
• Limiting sodium to 2,300 mg per day or less

Some people with kidney disease may also need to limit the amount of high-potassium foods they eat, but check with a healthcare provider before making this adjustment.

Regular exercise also helps reduce glucose levels, lower blood pressure, and decrease stress in people with diabetic nephropathy, which may all help slow the disease. Ideally, over 150 minutes of aerobic activity a week is recommended. Quitting smoking is also essential.  

Other Treatments for Complications

People with stage 3 diabetic nephropathy or higher may also need additional treatment to help reduce issues from chronic kidney disease. Depending on context, this might include:

• Iron supplementation to treat anemia
• Phosphate binders to treat bone problems related to kidney disease
• Sodium bicarbonate, if the blood is becoming too acidic 

People with end-stage (stage 5) kidney failure from diabetes will die of the condition unless they are treated with dialysis or a kidney transplant. However, you might need to consider your options during stage 4 disease. 

The majority of people with end-stage kidney disease go on dialysis . In this approach, you are connected to a machine that cleans your blood—similar to how your kidneys would have done. However, dialysis doesn’t work as well as a normal kidney, which can be time-consuming.  

Some people can now receive training to safely perform dialysis at home, potentially overnight. Discuss all your dialysis options with your nephrologist (kidney specialist) or other healthcare provider. 

Kidney Transplant

Some people with diabetic nephropathy can get a kidney transplant . In some cases, healthcare providers combine a kidney transplant with a pancreas transplant to treat diabetes directly.

Kidney transplants usually help people live longer and have a higher quality of life compared to dialysis. Since the body has two kidneys—and humans can live with only one—some people have a family member or friend donate a kidney for them, and others might get their kidney from a waiting list. 

However, some people with diabetic nephropathy are not able to get transplants, especially if their overall medical condition is fragile. 

What’s the Outlook for Someone With Diabetic Nephropathy?

People with diabetes who develop nephropathy have a higher risk of mortality than people with diabetes who don’t. These risks increase with later stages of kidney disease.  

Cardiovascular disease is a significant concern for all people with diabetes, including those who have diabetic nephropathy. For example, it’s more likely that someone with type 2 diabetes and early-stage nephropathy will have a heart attack or stroke than that they will develop end-stage kidney disease.

A significant number of people with diabetic nephropathy do eventually develop end-stage disease. But not all do, especially those diagnosed early and optimally treated. 

Proportionally, people with type 1 diabetes are more likely to develop end-stage kidney disease compared to people with type 2 diabetes. However, over half of people with diabetes on dialysis for nephropathy have type 2 disease because type 2 is comparatively more common.

If you’ve been diagnosed with diabetes but don’t have kidney damage, take steps to help prevent diabetic nephropathy or at least delay it. And if you already have some degree of kidney damage, you can act to slow or stop your kidney decline.

• Work closely with your healthcare provider to monitor and control your blood glucose. Take all your medications as prescribed, and don’t miss appointments.
• Discuss your dietary choices with a professional, such as a registered dietitian . Reduce highly processed carbohydrates, increase your intake of high-fiber foods like vegetables, limit your salt, and potentially change some of your protein choices.
• Find an exercise that you enjoy and can do regularly. 
• Talk with your healthcare provider about avoiding other sources of kidney injury (e.g., from non-steroidal anti-inflammatory drugs [ NSAIDs ] like Advil [ibuprofen] or from excess dehydration). 
• Quit smoking.

Roughly 40% of people with diabetes eventually develop diabetic nephropathy. It usually doesn’t happen until you’ve had diabetes for several years. People with early-stage diabetic nephropathy often don’t have any symptoms, so all people with diabetes need kidney monitoring.  

Some people with diabetic nephropathy eventually develop stage 5 kidney disease, which is fatal if not treated by dialysis or a kidney transplant. 

By being proactive about your health, you can help prevent diabetic nephropathy or slow its progression. By working closely with a medical professional on therapies and lifestyle changes, you can decrease your risk of end-stage kidney disease and reduce your risk of heart attack and stroke. 

Nordheim E, Geir Jenssen T. Chronic kidney disease in patients with diabetes mellitus . Endocr Connect . 2021;10(5):R151-R159. doi:10.1530/EC-21-0097

Thipsawat S. Early detection of diabetic nephropathy in patients with type 2 diabetes mellitus: a review of the literature .  Diab Vasc Dis Res . 2021;18(6):14791641211058856. doi:10.1177/14791641211058856

Cheo SW, Low QJ, Lim TH, et al. A practical approach to chronic kidney disease in primary care . Malays Fam Physician . 2022;17(1):10-19. doi:10.51866/rv1186

Tziomalos K, Athyros VG. Diabetic nephropathy: New risk factors and improvements in diagnosis .  Rev Diabet Stud . 2015;12(1-2):110-118. doi:10.1900/RDS.2015.12.110

McGrath K, Edi R. Diabetic kidney disease: diagnosis, treatment, and prevention .  Am Fam Physician . 2019;99(12):751-759.

Arnold M, Buelt A. Chronic kidney disease: evaluation and treatment guidelines from the VA/DoD . Am Fam Physician.  2020;102(6):378-379.

Selby NM, Taal MW. An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines .  Diabetes Obes Metab . 2020;22(Suppl 1):3-15. doi:10.1111/dom.14007

Wouk N. End-stage renal disease: Medical management .  Am Fam Physician . 2021;104(5):493-499.

Pérez-Sáez MJ, Pascual J. Kidney transplantation in the diabetic patient . J Clin Med . 2015;4(6):1269-80. doi:10.3390/jcm4061269

Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors . J Nephropharmacol . 2015;5(1):49-56.

By Ruth Jessen Hickman, MD Dr. Hickman is a freelance medical and health writer specializing in physician news and patient education.

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Severe hyponatremia and diabetes insipidus caused by low-dose cyclophosphamide in breast cancer patients: A case report and literature review

Affiliations.

• 1 Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
• 2 Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
• 3 Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
• PMID: 38552085
• PMCID: PMC10977568
• DOI: 10.1097/MD.0000000000037572

Rationale: Cyclophosphamide (CTX) is widely used in the treatment of malignancies and autoimmune diseases. Although severe hyponatremia caused by low-dose CTX chemotherapy is uncommon, it can lead to serious complications and even death.

Patient concerns: A 44-year-old woman with left-sided breast cancer suddenly experienced headaches, disorientation and weakness after receiving low-dose neoadjuvant chemotherapy combined with CTX and doxorubicin.

Diagnoses: The patient pathology showed invasive breast carcinoma. She developed severe hyponatremia and a generalized seizure after completing the first cycle of neoadjuvant chemotherapy with CTX and doxorubicin. Laboratory tests showed a serum sodium of 118 mmol/L (normal range 135-145 mmol/L) and potassium sodium 3.16 mmol/L (normal range 3.5-5.5 mmol/L). Subsequently, the patient developed secondary diabetes insipidus 4 hours after sodium supplementation, her 24-hour urine volume was 4730 mL (normal range 1000-2000 mL/24 hours), and the urine specific gravity decreased to 1.005.

Interventions: The patient was given intravenous sodium chloride (500 mL of 3%NaCl, 100 mL/hour) and potassium chloride (500 mL of 0.3%KCl, 250 mL/hour). Meanwhile, she was advised to reduce her water intake, and pituitrin was administered to prevent dehydration caused by diabetes insipidus.

Outcomes: The patient completely recovered after correcting of the serum sodium concentration (137 mmol/L) without any neurological deficits. After discontinuing pituitrin, her 24-hour urine volume was 2060 mL and the urine specific gravity was 1.015.

Lessons: This is a typical case of severe hyponatremia induced by low-dose CTX. Clinicians and healthcare providers should be aware of this potential toxicity, and appropriate monitoring should be implemented.

Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Time trend of serum sodium…

Time trend of serum sodium and potassium following the administration of low-dose CTX.…

Time trend of patient urine…

Time trend of patient urine volume following the administration of severe hyponatremia.

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• Life-threatening acute hyponatremia with generalized seizure induced by low-dose cyclophosphamide in a patient with breast cancer. Hwang SB, Lee HY, Kim HY, Lee ES, Bae JW. Hwang SB, et al. J Breast Cancer. 2011 Dec;14(4):345-8. doi: 10.4048/jbc.2011.14.4.345. Epub 2011 Dec 27. J Breast Cancer. 2011. PMID: 22323925 Free PMC article.
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Severe hyponatremia and diabetes insipidus caused by low-dose cyclophosphamide in breast cancer patients: A case report and literature review

Yanfang chen.

a Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

b Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

c Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Baoying Pan

Linying luo.

Cyclophosphamide (CTX) is widely used in the treatment of malignancies and autoimmune diseases. Although severe hyponatremia caused by low-dose CTX chemotherapy is uncommon, it can lead to serious complications and even death.

Patient concerns:

A 44-year-old woman with left-sided breast cancer suddenly experienced headaches, disorientation and weakness after receiving low-dose neoadjuvant chemotherapy combined with CTX and doxorubicin.

The patient pathology showed invasive breast carcinoma. She developed severe hyponatremia and a generalized seizure after completing the first cycle of neoadjuvant chemotherapy with CTX and doxorubicin. Laboratory tests showed a serum sodium of 118 mmol/L (normal range 135–145 mmol/L) and potassium sodium 3.16 mmol/L (normal range 3.5–5.5 mmol/L). Subsequently, the patient developed secondary diabetes insipidus 4 hours after sodium supplementation, her 24-hour urine volume was 4730 mL (normal range 1000–2000 mL/24 hours), and the urine specific gravity decreased to 1.005.

Interventions:

The patient was given intravenous sodium chloride (500 mL of 3%NaCl, 100 mL/hour) and potassium chloride (500 mL of 0.3%KCl, 250 mL/hour). Meanwhile, she was advised to reduce her water intake, and pituitrin was administered to prevent dehydration caused by diabetes insipidus.

The patient completely recovered after correcting of the serum sodium concentration (137 mmol/L) without any neurological deficits. After discontinuing pituitrin, her 24-hour urine volume was 2060 mL and the urine specific gravity was 1.015.

This is a typical case of severe hyponatremia induced by low-dose CTX. Clinicians and healthcare providers should be aware of this potential toxicity, and appropriate monitoring should be implemented.

1. Introduction

Cyclophosphamide (CTX) is a widely used antineoplastic drug that can be combined with other antineoplastic agents to treat various types of cancer, including breast, lymphoid, and pediatric malignancies. [ 1 – 3 ] Although CTX is widely used to manage various diseases, there have been only a few reports of hyponatremia caused by it. Hyponatremia is defined as a serum sodium concentration lower than 135 mmol/L. It is the most common electrolyte abnormality in both inpatient and outpatient settings. Severe hyponatremia (serum sodium <120 mmol/L) is a medical emergency that can led to irreversible brain injury or death if not promptly treated. [ 4 ] We report a case of severe symptomatic hyponatremia and diabetes insipidus that developed in a female breast cancer patient following the first cycle of chemotherapy containing low-dose CTX.

2. Case presentation

A 44-year-old woman presented to our hospital on January 17, 2023, with a left breast mass that had been present for more than 2 weeks. Her left breast had solid nodules measuring approximately 3.0 cm × 2.0 cm × 1.5 cm, which were classified as BI-RADS Class 4C after a breast ultrasound was performed. Histopathologic examination revealed infiltrating breast cancer, which was not a special type, with no estrogen receptor-positive cells, no progesterone receptor-positive cells, and no amplification of human epidermal growth factor receptor 2. However, 80% of the cells were positive for Ki-67. The patient was diagnosed with triple-negative breast cancer, which was staged as T2NxMx. The liver and kidney function, electrolyte levels, and other ancillary tests showed no abnormalities. There were no other medical issues in the patient history. Following extensive discussions with the patient, it was determined that initiating neoadjuvant chemotherapy would be the primary treatment approach.

On January 24, she received the first cycle of doxorubicin (100 mg/m 2 ) and CTX (500 mg/m 2 ) chemotherapy at 12:45. With supportive medications: 8 mg of dexamethasone, 5 mg of ondansetron, and 150 mg of aprepitant. During chemotherapy, the patient was administered 0.5 liters of isotonic saline for hydration and was advised to increase fluid intake to prevent hemorrhagic cystitis. The patient ingested approximately 2 liters of water after chemotherapy. At 17:00, the patient experienced palpitations, dizziness, and fatigue. Three hours later, the patient face appeared pale. Blood pressure was measured at 113/65 mm Hg, with a pulse rate of 68 beats per minute. ECG monitoring and low-flow oxygen (2 L/min) were used to improve the patient symptoms. At 20:00, the patient started experiencing delirium and speaking incoherently. An indwelling catheter was inserted to remove 800 mL of pale red urine. An emergency biochemistry examination showed a significant decrease in serum sodium levels from 138 to 118 mmol/L, and serum potassium levels from 4.28 to 3.16 mmol/L (Fig. ​ (Fig.1). 1 ). The patient was diagnosed with severe hyponatremia and immediately received intravenous sodium chloride (500 mL of 3% NaCl at a rate of 100 mL per hour). Subsequently, the patient was administered a potassium chloride injection (500 mL of 5% glucose with 10 mL of 15% potassium chloride) through intravenous drip.

Time trend of serum sodium and potassium following the administration of low-dose CTX. CTX = cyclophosphamide.

At 1:00 on January 25, the patient developed secondary diabetes insipidus after receiving sodium supplementation. Her 24-hour urine volume was 4730 mL (normal range: 1000–2000 mL/24 hours), with a urine output as fast as 1700 mL/h (01:00–02:00). Additionally, her urine specific gravity decreased to 1.005. An intravenous infusion of pituitrin was used to prevent dehydration caused by diabetes insipidus. Her serum sodium slowly rose to 121.2 mmol/L after 24 hours and 125 mmol/L after 48 hours (Fig. ​ (Fig.1), 1 ), and her mental status recovered. At the same time, the patient urine volume also returned to normal (Fig. ​ (Fig.2). 2 ). Diabetes insipidus has been effectively controlled. But on January 27, her serum sodium decreased to 119 mmol/L again without any neurological manifestations. After communicating with the patient, it was noted that she had consumed large quantities of water in a short time, which could have affected her electrolyte levels. She was advised to reduce her water intake. On January 28, 2023, the patient made a complete recovery and was discharged with a serum sodium level of 137 mmol/L and a serum potassium level of 3.98 mmol/L (Fig. ​ (Fig.1). 1 ). Three months later the patient underwent mastectomy for breast tumor in our hospital, the operation went smoothly, and after discharge the patient was followed up through WeChat, the patient did not have any discomfort, and the relevant indexes were all within the normal range.

Time trend of patient urine volume following the administration of severe hyponatremia.

3. Discussion

Hyponatremia caused by CTX can initially present with mild symptoms such as nausea, vomiting, weakness, headache, and dizziness. These symptoms may progress to more severe manifestations like irritability, lethargy, edema, confusion, and even loss of consciousness. In some cases, epileptiform seizures can also occur as severe symptoms. During CTX treatment, it is important to carefully monitor blood sodium levels and take prompt action to prevent further deterioration if patients experience any of these symptoms. To prevent further deterioration when patients develop the aforementioned symptoms, the clinical application of CTX should focus on monitoring blood sodium levels and taking timely action. When administered intravenously, hyponatremia typically occurs within 3 to 72 hours after administration. [ 5 – 13 ] CTX-induced hyponatremia can be caused by either the initial dose or multiple doses.

Severe hyponatremia is a serious and potentially life-threatening condition. [ 11 ] Early reported cases of severe hyponatremia were limited to patients treated with a single high-dose of CTX (30–40 mg/kg), [ 14 ] and the incidence of severe hyponatremia with high-dose CTX has been reported as 5.8% in a retrospective study. [ 15 ] However, with an increasing number of patients receiving CTX, moderate doses (20–30 mg/kg) [ 16 ] and even low doses of CTX (<20 mg/kg) [ 5 – 12 ] have been associated with severe hyponatremia. Symptomatic hyponatremia due to severe cyclophosphamide is very rare. The mechanism by which cyclophosphamide induces hyponatremia is unclear. However, it is believed that cyclophosphamide indirectly stimulates the release of antidiuretic hormone (ADH) and impairs the kidney ability to excrete water. [ 7 ]

In our study, the patient was administered CTX through intravenous infusion at a dose of 15 mg/kg. This resulted in severe hyponatremia, which was caused by the low-dose of CTX. The patient received hydration before and after administration of CTX to prevent hemorrhagic cystitis caused by the medication. Low serum sodium and potassium levels may be caused by an excess of water intake, leading to an overload of free water in the body. Physiologically, ADH is produced in the posterior pituitary gland in response to an increased plasma sodium concentration in order to conserve water. The syndrome of inappropriate antidiuretic hormone secretion is characterized by either a significant release of ADH in the absence of stimuli or by the increased action of ADH on the kidneys. [ 3 ] Drug-induced syndrome of inappropriate antidiuretic hormone can occur due to either one or both mechanisms. The patient had normal electrolyte levels and renal function, and there was no evidence of neurological or endocrine abnormalities prior to treatment with CTX. It is reasonable to think that both CTX and the patient excessive water intake contributed to the severe hyponatremia. Interestingly, while correcting the patient hyponatremia, the patient developed acute diabetes insipidus. We believe this is a secondary effect of sodium supplementation. Specifically, the addition of high concentrations of sodium chloride inhibits the release of antidiuretic hormone, resulting in the rapid excretion of a significant amount of fluid that had been previously retained in the patient body. Fortunately, our medical team detected and intervened in time to prevent the patient from experiencing further electrolyte disturbances or dehydration. To the best of my knowledge, this is the first reported case of diabetes insipidus in the treatment of severe hyponatremia caused by low doses of cyclophosphamide. This should capture the attention of clinical workers.

Cyclophosphamide infusion can result in severe hyponatremia, which can cause serious neurologic toxicities and be life-threatening, although it is rare. It is crucial for physicians to be mindful of this side effect and treat it accordingly. Firstly, the prevention of hyponatremia associated with CTX relies on careful monitoring of blood electrolytes. This includes obtaining baseline data before administering the CTX and conducting regular post-administration checks to detect any changes. Secondly, it is essential to avoid excessive fluid intake and closely monitor the patient mental status when caring for patients undergoing low-dose CTX chemotherapy. Early detection of any abnormalities can be achieved through vigilant observation of the patient psychoneurological status, which allows for the timely implementation of refined nursing interventions. The Clinical Practice Guideline on Diagnosis and Treatment of Hyponatremia [ 17 ] recommends the immediate intravenous administration of 3% sodium chloride solution in cases of severe hyponatremia. It also advises discontinuing the suspected medication.

4. Conclusion

In conclusion, our case highlights the rare occurrence of severe hyponatremia after administering low-dose CTX. Hypokalemia and secondary diabetes insipidus should also be considered in clinical practice when intravenous CTX is administered, particularly in patients with other underlying risk factors. In addition, healthcare providers should be aware of this potential toxicity, implement appropriate monitoring, and advise patients to notify their doctors if they experience any new or unusual symptoms.

Acknowledgments

We would like to credit the patient for her participation in this case study.

Author contributions

Data curation: Liye Li, Ruilian Ou, Linying Luo.

Supervision: Baoying Pan.

Writing – original draft: Yanfang Chen.

Writing – review & editing: Yulan Wu.

Abbreviations:

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

The authors have no conflicts of interest to disclose.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Guangzhou Health Science and Technology Program(20221A010056)

How to cite this article: Chen Y, Li L, Ou R, Wu Y, Pan B, Luo L. Severe hyponatremia and diabetes insipidus caused by low-dose cyclophosphamide in breast cancer patients: A case report and literature review. Medicine 2024;103:13(e37572).