Case Study: Progression of Renal Failure
- From: Jason@xxxxxxxxxx (Jason)
- Date: Sat, 27 Oct 2007 15:12:03 -0700
Nephrology Dialysis Transplantation 2004 19(12):3197-3199;
Vol. 19 No. 12
Progression of renal failure without proteinuria in a patient with type 1
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 1.72 mg/dl
up from 1.1 mg/dl; creatinine clearance 5569 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 68 month
period, his hypoglycaemic crises changed in pattern: he reported being
disoriented in space and time, and becoming aggressive, before losing
consciousness (blood glucose 2030 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).
What is the differential diagnosis and your diagnosis?
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 ?simple¹ explanation,
attributing them to severe hypoglycaemia, was not fully satisfactory, in
particular in the absence of severe neuropathy . 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 050);
antithyroid microsome 4970 IU/ml (normal 0100).
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 .
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 . The importance
of subtle changes in mood was stressed recently in a discussion of the
?subclinical¹ 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
dermalhypodermal 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
; the association with autoimmune hypothyroidism is also known as APS
type 3a, and may be more common than previously recognized .
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 .
1. Hierholzer K, Finke R. Myxedema. Kidney Int Suppl 1997; 59:
2. Kreisman SH, Hennessy JV. Consistent reversible elevations of serum
creatinine levels in severe hypothyroidism. Arch Intern Med 1999; 159:
7982[Abstract/Free Full Text]
3. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;
348: 26462655[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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