Progression of renal failure without proteinuria in a patient with type 1 diabetes

Giorgina Barbara Piccoli1, Elisabetta Mezza1, Manuel Burdese1, Massimo Terzolo2, Giorgio Grassi3, Francesca Bermond1, Giorgio Soragna1, Massimo Gai1, Franco Dani3, Alberto Jeantet1, Giuseppe Paolo Segoloni1 and Giuseppe Piccoli1

1 Chair of Nephrology, Department of Internal Medicine,2 Chair of Internal Medicine, San Luigi,3 Diabetic Care Unit, Department of Internal Medicine, University of Turin, Italy Email: gbpiccoli{at}hotmail.com; gbpiccoli{at}yahoo.it



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A.Z. is a 42-year-old Caucasian male who has had type 1 diabetes since the age of 19. He was referred to a nephrologist from an internal medicine ward because of a moderate renal dysfunction (serum creatinine 1.7–2 mg/dl up from 1.1 mg/dl; creatinine clearance 55–69 ml/min), which developed over a few months. Further tests revealed microalbuminuria (0.159 g/24 h), with a few red cells in the urinary sediment, and moderate anaemia (haemoglobin 11.1 g/dl), with glycated haemoglobin at 8.8%. Ultrasonography demonstrated kidneys of normal shape and echogeneicity; renal scintigraphy produced normal curves, with fine non-homogeneities, minor signs of urostasis and modest pelvic distension.

At his clinic visit, A.Z. was a sporty, well nourished person, in good clinical condition (weight 75.3 kg, height 180 cm, body mass index 23), and normotensive (blood pressure 110/75 mmHg; heart rate 64 beats/min). The only pathological finding was modest ankle oedema.

His clinical history, beside poorly controlled diabetes and his report of occasional hand and foot swelling, was unremarkable. He denied alcohol or drug abuse, as well as any self-prescribed medications. His therapy consisted only of injections of insulin, four times daily. He recently had developed severe depression after the death of one of his two daughters, which he reported to have been due to a congenital neuromuscular problem, though he was not able to recall the diagnosis precisely.

According to his wife, he recently had lost interest in living, changed his habits, stopped playing sport and gained weight. In the same 6–8 month period, his hypoglycaemic crises changed in pattern: he reported being disoriented in space and time, and becoming aggressive, before losing consciousness (blood glucose 20–30 mg/dl).

Tests for diabetic end-organ damage revealed: background retinopathy; neuropathy with reduction of vibratory sensibility; no sign of vasculopathy; and normotension.

Under the working diagnosis of a non-diabetic renal disease, the patient was hospitalized for a renal biopsy.

During hospitalization, he suffered a severe hypoglycaemic episode preceded by aggressive behaviour (blood glucose <30 mg/dl). The neurologist suggested a functional component to account for his mild ideomotor slowing and his aggressive behaviour. Electroencephalography revealed non-specific metabolic alterations.

After the hypoglycaemic episode, he reported muscular aches, which he admitted had been present for a few months, but were acutely exacerbated. Suspecting a link with the unspecified problem of his daughter, muscle enzymes were tested. His creatinine phosphokinase and lactic dehydrogenase levels were high (CPK 1960 U/l and LDH 1018 IU/l).



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What is the differential diagnosis and your diagnosis?



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The patient suffered from severe hypothyroidism.

The muscle aches were the symptoms leading to the correct diagnosis. They had been overlooked initially by the patient, who reported them only after his last severe hypoglycaemic crisis. The ‘simple’ explanation, attributing them to severe hypoglycaemia, was not fully satisfactory, in particular in the absence of severe neuropathy [1]. A metabolic cause was suspected, and thyroid hormones were tested.

His free-T3 and free-T4 levels were below the detection limits of the assay (free-T3 <1.19 pg/ml, free-T4 <1.8 pg/ml), with a high thyroid-stimulating hormone (TSH) level (57.5 IU/ml). Positivity to thyroid autoantibodies confirmed the immunological pathogenesis of his condition—antithyroxin peroxidase >1000 U/ml (normal range 0–50); antithyroid microsome 4970 IU/ml (normal 0–100).

Thyroxin therapy was started, with rapid reversal of the thyroid hormone deficit (free-T3 3.28 pg/ml, free-T4 10.74 pg/ml, TSH 27.0 IU/ml 1 month later). Subsequent to the initiation of treatment, his renal function returned to normal (serum creatinine 1 mg/dl, creatinine clearance 96 ml/min), haemoglobin increased (12.8 g/dl), no more hypoglycaemic crises were reported and he lost weight (6.3 kg).

The link between thyroid hormones and renal function has been known for decades, and the presence of reduced renal clearance in severe hypothyroid states has been confirmed repeatedly. While the rhabdomyolysis induced by extreme hypothyroidism may precipitate acute renal failure, complex effects on glomerulo-tubular balances are described in milder cases [2].

A search on Medline and Embase (September 5, 2003, combining Mesh, Emtree and free terms relating to hypothyroidism and those indicating renal function and kidney failure) retrieved 232 titles, 16 of which dealt with cases or series of cases of reversible renal dysfunction due to hypothyroidism. Most reported cases were of unexplained worsening of pre-existing renal failures of different aetiologies; none, however, was in the context of long-standing diabetes.

Upon re-evaluation of our case, we identify some elements that might have pointed towards hypothyroidism:

  1. The asthenia, depression and mild psychomotor slowing, together with weight gain, would, in a non-diabetic patient, probably suggest a hypothyroid state. However, both the family history and the long-lasting chronic disease suggested an alternative explanation [3]. The importance of subtle changes in mood was stressed recently in a discussion of the ‘subclinical’ hypothyroid states.
  2. The amimic facies, thick subcutaneous tissues and swelling of hands and feet, all typical of myxoedema, were interpreted as being due to the dermal–hypodermal affections frequent in long-lasting diabetes [1,3].
  3. The low pulse was overlooked (previous sportsman), even though a more rapid rate might be expected with moderate anaemia.
  4. As for the anaemia, a further sign of severe hypothyroidism [1,3], the renal dysfunction was too mild to be associated with erythropoietin deficiency (the iron status was normal).

In addition to recalling the association between renal and thyroid function, this case is of interest in that it underlines the link between autoimmune diseases and type 1 diabetes.

In the WHO classification (WHO, 1999), type 1 diabetes is characterized by autoimmune destruction of Langhans insulae. It has been associated with various autoimmune diseases, including complex pluriglandular syndromes [4]; the association with autoimmune hypothyroidism is also known as APS type 3a, and may be more common than previously recognized [4].

In the cases so far reported in the literature of renal dysfunction and severe hypothyroidism, thyroid disease was often overlooked because of the overlap between uraemic symptoms and hypothyroid ones. In A.Z., there also was a subtle overlap with the signs and symptoms of long-standing diabetes, which further hindered a timely diagnosis.

While some endocrine authorities propose thyroid function screening in all hospitalized patients, screening in the general population remains controversial [3,4]. However, several authors suggest that the rapid or unexplained worsening of renal failures reported are the tip of the iceberg of an under-diagnosed association, and they recommend performing TSH testing in all patients with the unexplained appearance or progression of kidney failure. This may be particularly important in high-risk populations, such as type 1 diabetics, in whom thyroid function tests should probably be included in the usual nephrological work-up [4].

Conflict of interest statement. None declared.



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  1. Hierholzer K, Finke R. Myxedema. Kidney Int Suppl 1997; 59: S82–S89[Medline]
  2. Kreisman SH, Hennessy JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med 1999; 159: 79–82[Abstract/Free Full Text]
  3. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003; 348: 2646–2655[Free Full Text]
  4. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002; 23: 327[Abstract/Free Full Text]




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