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ORIGINAL ARTICLE
Year : 2019  |  Volume : 16  |  Issue : 3  |  Page : 121-127

Severe hypothyroidism-associated acute renal failure – A case series from North India and review of literature


1 Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission15-May-2019
Date of Acceptance04-Oct-2019
Date of Web Publication18-Nov-2019

Correspondence Address:
Dr. Abhilash Chandra
Department of Nephrology, 4th Floor, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Lucknow - 226 010, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_16_19

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  Abstract 


Background: Several cases of complete or partially reversible renal failure have been reported in association with severe hypothyroidism, which have responded to thyroxine replacement. However, its risk factors, pathology, pathophysiology, and time of recovery remain unclear.
Aim: We report our experience with 31 cases of renal failure in association with severe hypothyroidism, from a goiter-endemic belt in North India, along with a review of existing literature.
Materials and Methods: We retrieved cases presenting to our centre, from August 2013 to April 2018 and collected information regarding clinical presentation, laboratory parameters including renal and thyroid function tests, creating kinase, urinary findings and follow-up data pertaining to time and extent of renal function recovery. In three cases, renal biopsies were also done, and these were reviewed by a pathologist.
Results: In our study, females slightly outnumber males. More than one-third of patients were known hypothyroid and had defaulted on medications. The severity of serum thyroid-stimulating hormone and CK elevation were not associated with the severity of renal failure or its extent or time of recovery. Older age, coexistence of diabetes mellitus and/or hypertension, higher serum creatinine at presentation, and urinary abnormalities (proteinuria and/or active sediments) correlated significantly with lack of complete renal recovery. All the three biopsies revealed significant tubulointerstitial fibrosis.
Conclusions: Thyroid function tests should be performed in the evaluation of unexplained renal failure, even in cases with underlying chronic kidney disease. It is also an important preventable cause of renal failure in known hypothyroid patients.

Keywords: Acute kidney injury, chronic kidney disease, hypothyroidism, renal insufficiency


How to cite this article:
Rao NS, Chandra A, Malhotra KP. Severe hypothyroidism-associated acute renal failure – A case series from North India and review of literature. Thyroid Res Pract 2019;16:121-7

How to cite this URL:
Rao NS, Chandra A, Malhotra KP. Severe hypothyroidism-associated acute renal failure – A case series from North India and review of literature. Thyroid Res Pract [serial online] 2019 [cited 2019 Dec 12];16:121-7. Available from: http://www.thetrp.net/text.asp?2019/16/3/121/271148




  Introduction Top


Overt hypothyroidism is associated with reduced not glomerular function rate(GFRs).[1] Large observational studies have shown a higher prevalence of low estimated GFR (eGFR) with subclinical and overt hypothyroid states.[2],[3] A causal relationship is difficult to establish, but over the years, a number of cases have been reported all over the world, where severe hypothyroidism has been associated with renal dysfunction and thyroid hormone replacement has led to improvement in renal function, lending plausibility to the existence of hypothyroidism-associated renal failure.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] We present a case series of 31 patients, who had severe hypothyroidism with renal failure at the time of presentation, and varying reversibility of renal failure after thyroid hormone replacement. To our knowledge, this is the largest case series of hypothyroidism-associated renal failure, till date in literature.


  Materials and Methods Top


Our center is a tertiary care referral hospital in North India, a region endemic to goiter and iodine deficiency. Cases were collected from August 2013 to April 2018. Follow-up of individual cases ranged from a minimum of 3 months to a maximum of 3.5 years. Records were retrieved from individual case files and from the hospital information system. In cases where data were insufficient, telephonic calls were made if feasible. Clinical details of a total of 31 patients were noted, with regard to age, sex, symptoms and signs of overt hypothyroidism at presentation (symptoms of weight gain, hoarseness of voice, constipation, cold intolerance, menorrhagia; and physical signs of facial puffiness, bradycardia and delayed relaxation of deep tendon reflexes), presence of comorbidities, laboratory parameters such as renal function tests, thyroid-stimulating hormone (TSH), T4 and/or free T4 levels, routine urinalysis, and microscopy (dipstick examination for urinary albumin and microscopy to look for red blood cells and white blood cells) and creatine kinase (CK) levels where available. Renal biopsies were performed in three cases. Serum TSH, T4, and free T4 were measured by direct chemiluminescence using the Acridinium Ester Technology on the ADVIA Centaur XP analyzer (Siemens Healthcare, New York, USA). Serum creatinine was measured by Jaffe's kinetic method on Beckman Coulter AU480 (Beckman Coulter Inc., California, USA). eGFR at baseline was calculated using the Chronic Kidney Disease (CKD) Epidemiology Collaboration equation. Serum CK levels were measured by modification of IFCC method on Beckman Coulter AU480 (Beckman Coulter Inc., California, USA).

Severe hypothyroidism was defined as a TSH value >45 mIU/L, along with either T4 value <2 μg/dL or free T4 <0.89 ng/dL. Serum CK was designated as abnormal if >171 U/L in males and >145 U/L in females. Complete recovery of renal function was taken as eGFR of >60 ml/min/1.73 m2. A fall of serum creatinine by more than 25% was designated as “any recovery.”

Patients were labeled with having CKD if documented records of raised serum creatinine existed before the presentation with hypothyroid state and/or accompanied by small kidneys on ultrasound examination. Furthermore, long-standing diabetes with albuminuria and bland sediments, along with fundus findings of proliferative diabetic retinopathy and no obvious secondary cause, was labeled as diabetic kidney disease. Three patients underwent renal biopsies: two had partial recovery of renal function and one had nephrotic syndrome along with renal dysfunction which recovered completely on follow-up.

Statistical analysis

Data were analyzed using SPSS version 16 (IBM Corporation, New York, USA). As the sample size was small, medians were calculated instead of means, categorical variables were compared using the Fisher's exact test, and continuous variables were compared using the Mann–Whitney U-test. P < 0.05 was considered as statistically significant.


  Results Top


The clinical and demographic parameters of the 31 cases are presented in [Table 1]. Among the 31 cases analyzed, no sex preponderance was seen, about a third were diabetic, and a third were hypertensive. Twelve patients (38%) were known cases of primary hypothyroidism and had defaulted on thyroxine for 2 or 3 months. At the time of presentation to our outpatient department (OPD), 11 patients (36%) showed no overt signs and symptoms of hypothyroidism. Even in the absence of overt signs and symptoms, the presence of one or more of subtle indicators such as edematous state in the absence of proteinuria and hypoalbuminemia, myalgias, elevated mean corpuscular volume on complete blood count, and euvolemic hyponatremia prompted testing for thyroid status in the other patients. There was no correlation between the severity of TSH elevation and the degree of renal dysfunction at presentation. Similarly, there was no correlation between serum TSH at the end of follow-up and renal recovery.
Table 1: Clinical history, physical and laboratory findings, and follow-up at our center

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Of the 21 cases where CK levels were available, 7 (33%) had elevated CK at the time of presentation. However, since in-house test for CK-MM fraction and urinary myoglobin is not available at our center, further testing to look for rhabdomyolysis-associated renal failure could not be performed. Serum CK levels did not correlate with the severity of TSH elevation at presentation or renal dysfunction and its recovery.

Mild-to-moderate renal impairment was encountered in the majority of patients, with a median of 229.8 μmol/L and mean serum creatinine of 264.31 μmol/L and mean eGFR of 28.7 ml/min/1.73 m2. Urinary albumin ranged from nil to 3+ proteinuria detected on dipstick examination. A completely normal urine examination was, however, the most frequent finding. Serum albumin levels were normal in 66%, and hypoalbuminemia correlated with worse renal function at detection (Spearman's rho −0.615, P = 0.000) and poorer renal recovery on follow-up (P = 0.000).

Complete recovery of renal dysfunction was seen in 18 of 31 patients. Patients who did not recover renal function completely were older, were more likely to have diabetes and/or hypertension as comorbidities, had worse eGFR at presentation, and were also more likely to have urinary abnormalities (P< 0.05), as shown in [Table 2]. Patients with diabetes and/or hypertension were 22 times likelier to not recover renal function completely. A logistic regression was performed to ascertain the effects of age, presence of diabetes and/or hypertension, and serum creatinine at the time of presentation, on the likelihood of complete recovery of renal function, as presented in [Table 3]. The model explained 67.4% of variance in the recovery of renal function and correctly classified 90.3% of patients.
Table 2: Comparison of patients with and without complete renal recovery after thyroxine supplementation

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Table 3: Predictors of complete renal recovery

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Among the 13 patients who did not have complete renal recovery, two underwent renal biopsies (cases 6 and 25 in [Table 1]) and one case in the complete recovery group underwent a renal biopsy (case 28 in [Table 1]) [Figure 1]. In case 6, a renal biopsy was done in week 2 after thyroxine supplementation, when renal function, though improved, did not normalize, and active urinary sediments persisted. Biopsy showed IgA nephropathy (M0 E2 S0 T1); however, the patient did not have complete recovery even at 6-month follow-up despite steroids and conservative therapy [Figure 1]a. In case 25, the patient was biopsied at day 8 of presentation (6 days after starting thyroxine) because the patient presented with dialysis-dependent renal failure and proteinuria, which were difficult to attribute to hypothyroidism. Renal biopsy was suggestive of membranous nephropathy with segmental sclerosis. The patient improved subsequently, became dialysis independent by 6 weeks, and remained in follow-up on conservative treatment [Figure 1]b. Finally, case 28 presented with edematous illness, thought to be secondary to steroid-resistant nephrotic syndrome. He was biopsied in view of massive proteinuria (21 g/day), hypoalbuminemia, and hypercholesterolemia, after adequate decongestion. Thyroxine was started a day following the biopsy when the report was received [Figure 1]c. Tacrolimus was started after 6 weeks of thyroxine supplementation, after recovery of renal function.
Figure 1: Renal biopsies in patients with severe hypothyroidism and renal dysfunction: (a) Section of renal biopsy showing a glomerulus with mesangial and endocapillary hypercellularity and thickened basement membranes (H and E, ×200). (b) Section of renal biopsy showing a glomerulus with marked thickening of basement membranes and segmental mesangial sclerosis (H and E, ×200). (c) Section showing renal biopsy with all three glomeruli showing segmental mesangial sclerosis (H and E, ×100)

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  Discussion Top


Hypothyroidism results in impaired renal function predominantly by its effect on lowering cardiac output and renal blood flow.[1] Two more mechanisms that are thought to contribute to renal dysfunction include tubular secretion of creatinine and creatinine release from muscle.[15] However, reversible renal dysfunction secondary to overt primary hypothyroidism has been reported infrequently in literature, mainly as case reports. [Table 4] is a compilation of various published reports of hypothyroidism-associated reversible renal failure, with clinical details and laboratory findings. Data from studies by Chertow and Kuhlback have not been included in the table, as the pretreatment serum creatinine in these studies did not exceed the upper limit of normal range and would not qualify as renal failure.[13],[14] Briefly, 46 cases were collected compiled from case reports and two prospective studies (Montenegro et al. studied 39 consecutive symptomatic hypothyroid patients, of whom 22 patients had a serum creatinine of higher than 1.1 mg/dl, and Kreisman and Hennessey evaluated renal functions in patients of thyroid carcinoma with induced hypothyroidism prior to radionuclide scanning, in whom 5 turned out to have renal failure).[5],[6] Hypothyroidism-associated renal failure occurred with overt symptoms of hypothyroidism in 35 of 40 cases and CK enzyme elevation in 10 of 11 cases. Two patients were diabetic and four were reported to have CKD of a total of 21 cases. In the 12 cases where information regarding urinalysis was available, 8 showed normal findings. Complete recovery of renal function was reported in 39 of 46 cases.
Table 4: Review of available literature

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Male predominance was seen in all the reports, other than the study by Montenegro et al. (20 of 22 cases in the study by Montenegro were female, whereas in the rest, 18 of 21 cases were male).[5] Our patients (all belonging to a goiter-endemic belt) had no specific sex preponderance, and CK enzyme elevation was observed only in 33% of cases. Eighteen of our 23 cases (where information was available) had high thyroid peroxidase antibodies, and it is well known that autoimmune thyroiditis has a 90% predilection for women. While it has been argued that serum creatinine elevation could be occurring more commonly in males, due to higher muscle mass, it is unlikely that creatinine generation is the predominant mechanism for deranged renal function tests in hypothyroidism. Serum CK elevation is not a universal finding in overt hypothyroidism (up to 60% of cases), and commonly, only modest elevations are seen.[18] Therefore, it is not surprising that only a proportion of our patients had an abnormal CK level, also lending plausibility to an observation that renal failure in hypothyroid patients needs not to be associated with CK elevation and rhabdomyolysis. Again, urinary abnormalities attributable to hypothyroidism were infrequent and mild, arguing against hypothyroidism-associated intrinsic renal disease. Furthermore, the three biopsies done in our series did not show any predilection of a single renal pathology. These observations lend support to the observation that hemodynamic effects of hypothyroidism are primarily causative to renal dysfunction. Our findings are supported by similar observations by Kreisman and Hennessey, in their study of induced severe hypothyroidism prior to radionuclide scanning, who noted a consistent and predictable rise in serum creatinine – a finding which again argues for primary hemodynamic effects of the hypothyroid state.[6]

Reversibility of renal failure after thyroxine supplementation remains the most consistent way of demonstrating a possible cause-and-effect relationship between hypothyroidism and renal failure. However, as renal failure worsens, recoverability of renal function diminishes. This effect can be noted in our series (lower eGFR at baseline was significantly associated with lack of complete recovery, P = 0.000), as well as older reports. In fact, most cases described so far have documented an only mild-to-moderate rise in serum creatinine, excluding the initial report by Woodrow et al., where serum creatinine ranged from 565.76 to 1255.28 μmol/L, and postthyroxine improved, but not completely in all three cases (229.84–539.24 μmol/L).[17] In Woodrow's series, all three patients had underlying stable CKD. Studies, including ours, have shown increasing prevalence of subclinical and overt hypothyroidism with decreasing GFR, for which many contributing factors have been enumerated such as altered iodine metabolism and peripheral resistance to thyroid hormone actions.[2],[3],[19],[20] It is unclear whether patients in the Woodrow's series and the patients labeled as CKD from our series represent true hypothyroidism-associated renal failure or not. However, even in our series, the improvement in renal function occurred with no other intervention other than thyroxine supplementation, which strengthens the case for hypothyroidism-associated acute kidney injury.

Time of recovery could not be systematically studied in our study, as well as from older reports. Fixing a time of recovery was difficult, as the majority of patients were on OPD follow-up and had 2–4-week intervals between serum creatinine reports. In our study, complete recovery occurred between 6 and 12 weeks. Other authors have described the recovery of renal function between 8 weeks and 10 months.[3],[4],[10] This wide range of recovery time makes it difficult for a clinician to investigate the underlying intrinsic renal pathologies. As most cases of mild-to-moderate renal impairment start showing improvement in around 4 weeks, all cases with advanced renal failure, no improvement at 4 weeks, presence of heavy proteinuria, and active sediments on urine examination warrant workup for other etiologies.

The three cases which underwent renal biopsy showed the presence of varied lesions on histology including one case each of IgA nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy with segmental sclerosis. While all of these lesions are commonly encountered in renal biopsies and neither could be directly attributed to hypothyroidism, it was observed that mild-to-moderate degree of interstitial fibrosis and tubular atrophy was present in all three cases and segmental mesangial sclerosis in two of the cases. Marked basement membrane thickening and segmental mesangial sclerosis as noted in case 25 are uncommon findings in routine biopsies. Similar findings were reported by Salomon et al. in a series of seven renal biopsies from hypothyroid patients.[21] They reported the thickening of glomerular and tubular basement membranes in all the cases. One of their cases, who underwent a repeat biopsy after thyroxine supplementation, showed a significant reduction in the basement membrane thickness. The interplay of factors linking hypothyroidism to basement membrane thickening and increased interstitial ground substance in renal parenchyma is currently not known. It has been suggested that narrowing of capillary lumens may be causative in reducing filtration and functional alterations in tubular epithelium due to hypothyroidism.

Based on our own biopsy findings and those of Salomon et al., we are inclined to consider increased collagen formation or fibrogenesis as the final common pathways in hypothyroid-related renal lesions. A corollary can be obtained from studies in the lung and liver in hypothyroid patients. An association has been reported between subclinical hypothyroidism and nonalcoholic steatohepatitis and fibrosis.[22] Similarly, idiopathic pulmonary fibrosis has been seen to be more common in patients with hypothyroidism than in the general population.[23]

Recognition of hypothyroidism, based on typical symptoms and signs, remains the mainstay in diagnosing this treatable cause of renal injury. It is pertinent to note that overt severe hypothyroidism may manifest with only subtle signs and symptoms. In a patient who visits a nephrologist with unexplained renal failure, it is possible that these signs may be missed. Hyponatremia may be attributed to diuretics prescribed for generalized edema, anemia could be attributed to concomitant menorrhagia and nutritional causes, myalgias may be dismissed as nonspecific, and pleural and pericardial effusions could prompt extensive cardiac and immunologic assessment. In our setting, where a sizeable proportion of hypothyroidism-associated renal failure occurred in patients who were known cases of primary hypothyroidism and had defaulted on thyroxine supplementation, this also becomes an important preventable cause of renal injury. Educating the hypothyroid patient to maintain compliance to medications and regular follow-up with a physician is imperative in preventing drug default in the future. Preventing drug default becomes more important in patients with underlying CKD, as renal function is less likely to recover completely.


  Conclusions Top


To our knowledge, this is the largest case series of patients with severe hypothyroidism-associated renal failure published in literature. Hypothyroidism is associated with mild-to-moderate decrements in renal function in the majority of cases and is reversible partially to completely over weeks to months. Factors such as older age, presence of diabetes and hypertension, and worse renal function at presentation are associated with poorer renal recovery on follow-up. Finally, it is important to counsel hypothyroid patients to maintain compliance to thyroxine supplementation as drug default is a preventable cause of renal failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Montenegro J, González O, Saracho R, Aguirre R, González O, Martínez I, et al. Changes in renal function in primary hypothyroidism. Am J Kidney Dis 1996;27:195-8.  Back to cited text no. 5
    
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Chertow BS, Motto GS, Shah JH. A biochemical profile of abnormalities in hypothyroidism. Am J Clin Pathol 1974;61:785-8.  Back to cited text no. 13
    
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Kuhlback B. Creatine and creatinine metabolism in thyrotoxicosis and hypothyroidism; A clinical study. Acta Med Scand Suppl 1957;331:1-70.  Back to cited text no. 14
    
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den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol (Oxf) 2005;62:423-7.  Back to cited text no. 15
    
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Woodrow G, Brownjohn AM, Turney JH. Acute-on-chronic renal failure and hyponatraemia associated with severe hypothyroidism. Nephrol Dial Transplant 1993;8:557-9.  Back to cited text no. 17
    
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Hekimsoy Z, Oktem IK. Serum creatine kinase levels in overt and subclinical hypothyroidism. Endocr Res 2005;31:171-5.  Back to cited text no. 18
    
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Chandra A. Prevalence of hypothyroidism in patients with chronic kidney disease: A cross-sectional study from North India. Kidney Res Clin Pract 2016;35:165-8.  Back to cited text no. 19
    
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Salomon MI, Di Scala V, Grishman E, Brener J, Churg J. Renal lesions in hypothyroidism: A study based on kidney biopsies. Metabolism 1967;16:846-52.  Back to cited text no. 21
    
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Kim D, Kim W, Joo SK, Bae JM, Kim JH, Ahmed A, et al. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin Gastroenterol Hepatol 2018;16:123-310.  Back to cited text no. 22
    
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Oldham JM, Kumar D, Lee C, Patel SB, Takahashi-Manns S, Demchuk C, et al. Thyroid disease is prevalent and predicts survival in patients with idiopathic pulmonary fibrosis. Chest 2015;148:692-700.  Back to cited text no. 23
    


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