Download Glucose production by the human kidney—its importance has been

2996
pressure natriuresis response may exist in hypertension.
Both mechanisms would blunt pressure natriuresis and
may be important in the pathogenesis of hypertension.
It is now important to extend these exciting preliminary
observations to studies of tubules in the human
condition.
References
1. Noel J, Pouyssegur J. Hormonal regulation, pharmacology, and
membrane sorting of vertebrate N a + / H + exchanger isoforms.
Am J Physiol 1995; 268:C283-296
2. Orlowski J, Kandasamy RA, Shull GE. Molecular cloning of
putative members of the Na/H exchanger gene family. J Biol
Chem 1992; 267:9331-9339
3. Aronson PS. Ion exchangers mediating NaCl transport in the
proximal tubule. Wien Klin Wochenschr 1997; 109: 435-440
4. Rosskopf D, Dusing R, Siffert W. Membrane sodium-proton
exchange and primary hypertension. Hypertension 1993; 21:
607-617
5. Ng LL, Fennell DA, Dudley C. Kinetics of the human leucocyte
Na + -H + antiport in essential hypertension. / Hypertens 1990;
8: 533-537
6. Davies JE, Ng LL, Ameen M, Syme PD, Aronson JK. Evidence
for altered N a + / H + antiport activity in skeletal muscle cells and
vascular smooth muscle cells of the spontaneously hypertensive
rat. ClinSci 1991; 80: 509-516
7. Rosskopf D, Fromter E, Siffert W. Hypertensive sodium-proton
exchanger phenotype persists in immortalized lymphoblasts from
essential hypertensive patients. A cell culture model for human
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8. Ng LL, Sweeney FP, Siczkowski M, Davies JE, Quinn PA,
Krolewski B, Krolewski AS. N a + / H + antiporter phenotype,
abundance and phosphorylation of immortalized lymphoblasts
from humans with hypertension. Hypertension 1995; 25: 971-977
9. Sweeney FP, Quinn PA, Ng LL. Enhanced Mitogen-activated
protein kinase activity and phosphorylation of the N a + / H +
exchanger isoform 1 of human lymphoblasts in hypertension.
Metabolism 1997; 46: 297-302
Nephrol Dial Transplant (1998) 13: Editorial Comments
10. Siffert W, Rosskopf D, Moritz A et al. Enhanced G protein
activation in immortalized lymphoblasts from patients with
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11. Siffert W, Rosskopf D, Siffert G et al. Association of a human
G-protein beta3 subunit variant with hypertension. Nat Genet
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12. de la Sierra A, Coca A, Pare JC, Sanchez M, Vails V, UrbanoMarquez A. Erythrocyte ion fluxes in essential hypertensive
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13. Ng LL, Simmons D, Frighi V, Garrido MC, Bomford J,
Hockaday TDR. Leucocyte N a + / H + antiport activity in Type 1
insulin dependent diabetic patients with nephropathy.
Diabetologia 1990; 33: 371-377
14. Takahashi E, Abe J, Berk BC. Angiotensin II stimulates p90" k
in vascular smooth muscle cells. A potential N a + - H + exchanger
kinase. Circ Res 1997; 81: 268-273
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in transgenic mice overexpressing Na + -proton exchanger. Circ
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Nephrol Dial Transplant (1998) 13: 2996-2999
Glucose production by the human kidney—its importance has been
underestimated
Michael Stumvoll
Medizinische Universitatsklinik, Abteilung fur Endokrinologie u n d Stoffwechsel, Tubingen, G e r m a n y
Introduction
In the post-absorptive state, glucose must be continuously delivered into the circulation in order to meet
energy requirements of tissues, such as brain and red
blood cells, which use only glucose as their fuel. Only
liver and kidney are able to release glucose into
the circulation because other tissues lack glucose6-phosphatase. Release of glucose into the circulation
Correspondence and offprint requests to: Dr Michael Stumvoll,
Medizinische Universitatsklinik, Otfried-Mtiller-Str. 10, D-72076
Tubingen, Germany.
occurs by two processes: gluconeogenesis, the de novo
synthesis of glucose from non-glucose precursors; and
glycogenolysis, the breakdown of glycogen, a carbohydrate polymer formed directly from glucose or indirectly via gluconeogenesis. Both processes contribute
about equally to the glucose delivered into the systemic
circulation [1].
It has long been recognized that on a gram-for-gram
tissue basis, the gluconeogenic capacity of the kidney
exceeds that of the liver [2]. Nevertheless, based on
net balance experiments finding no significant difference in arterial and renal-vein glucose concentrations
in the basal state [3], the human kidney has until
2997
Nephrol Dial Transplant (1998) 13: Editorial Comments
recently been regarded as contributing insignificantly
to post-absorptive glucose production.
Methodological considerations
This traditional textbook view of the human kidney
releasing insignificant amounts of glucose was based on
net balance data of glucose, i.e. the mathematical product of arteriorenal venous difference of glucose concentrations (obtained through a sampling catheter in a
renal vein) and renal blood flow. The net balance
approach, however, does not take into consideration
simultaneous release and uptake of glucose by the
kidney. Thus, by merely representing the difference
between uptake and release of a substrate, net balance
measurements cannot evaluate the contribution of an
organ to the entry and removal of a substrate from the
systemic circulation. For example, with classically
employed isotope dilution determination of systemic
glucose flux, entry of glucose into the circulation is
quantified by the dilution of the plasma glucose tracer
concentration by unlabelled glucose released into the
circulation. If the kidney were to take up and release
glucose at equal rates, there would be no arteriorenal
venous glucose difference, and net glucose balance
would be zero. Nevertheless, release of unlabelled glucose into the circulation by the kidney would dilute the
plasma glucose tracer concentration and contribute to
the isotopic estimation of glucose entry into the circulation. Therefore a combination of net balance and isotopic techniques with measurement of substrate as well
as tracer concentrations is necessary to assess individually the uptake and release of glucose by the kidney [4].
that the human kidney should account for approximately half of all gluconeogenesis and thus be as
important a gluconeogenic organ as the liver. If the
human kidney were a gluconeogenic organ comparable
to the liver, it should play an important role in glucose
homeostasis under a variety of conditions, e.g. hypoglycaemia, fasting, renal failure, diabetes mellitus and
acidosis.
Hormonal regulation of renal glucose release
Administration of insulin to normal volunteers [6] and
type I diabetics withdrawn from insulin [7] suppressed
renal glucose release, which is in agreement with animal
and in vitro data. Glucagon does not stimulate renal
gluconeogenesis in vitro and infusion of glucagon
designed to increase plasma glucagon concentrations
threefold in normal volunteers had no effect on renal
glucose production measured isotopically while doubling hepatic glucose production [8].
In isolated renal cortical tissue catecholamines have
been shown to stimulate gluconeogenesis. In a recent
study in healthy humans, designed to measure renal
glucose production isotopically, adrenaline acutely
increased systemic glucose production by 60%, hepatic
glucose release by 50%o and renal glucose production
by 100%o [5]. It is of note that in this study, infusion
of adrenaline, which resulted in circulating concentrations of adrenaline similar to those observed during
hypoglycaemia, caused a sustained increase in renal
glucose release that by 3 h accounted for essentially all
of the increased appearance of glucose in the circulation. Other factors shown to influence renal glucose
release are summarized in Table 1.
Uptake and release by the human kidney
Renal gluconeogenic substrates
An appropriate combination of renal net balance and
isotopic tracer techniques was recently used in healthy,
post-absorptive humans [5]. These studies showed that
the human kidney simultaneously takes up and releases
appreciable amounts of glucose. Renal glucose release
accounted for about 25% of all glucose released into
the circulation and its uptake of glucose accounted for
approximately 20% of all glucose removed from the
circulation. These results thus refuted textbook wisdom
that the human kidney plays only a minor role in
glucose homeostasis.
In humans, lactate, glutamine, alanine, and glycerol
are the main gluconeogenic precursors. In vitro studies
have suggested lactate, pyruvate, glycerol, fructose,
propionate, and certain amino acids including glutamine, glutamate, and proline as potential renal precursor
candidates [9]. Studies of uptake and incorporation
into glucose of potential gluconeogenic precursors by
the human kidney using appropriate tracer methods
have shown that lactate, glutamine and glycerol, but
not alanine, a major hepatic gluconeogenic precursor
accounted for over 90% of the glucose produced [10].
Renal gluconeogenesis
Hypoglycaemia
The normal human kidney contains negligible amounts
of glycogen and kidney cells other than proximal
tubules, that could theoretically store glucose, lack
glucose-6-phosphatase. Thus, essentially all renal glucose release is probably due to gluconeogenesis.
Gluconeogenesis accounts for about 40-50%> of systemic
glucose release in postabsorptive humans. Since renal
glucose release is responsible for 20-25%> of systemic glucose release under this condition, it follows logically
Gluconeogenesis plays a major role in prevention and
reversal of hypoglycaemia. Observations in animals
that removal of liver and kidney results in more rapid
and more profound hypoglycaemia than mere removal
of the liver first suggested that renal glucose release is
important for the prevention of hypolgycaemia and
may play a role in glucose counterregulation. More
recently it has been demonstrated in dogs that insulin-
Nephrol Dial Transplant (1998) 13: Editorial Comments
2998
Table 1. Factors affecting renal gluconeogenesis
Stimulation
Inhibition
Catecholamines'
Glucocorticoides
Aldosterone
Insulin deficiency (Diabetes mellitus)*
Parathyroid hormone
Vitamin D
Thyroxine
Growth hormone
Angiotensin
Adrenalectomy
Acid-base-balance
Acidosis
Alkalosis
Others
Prolonged fasting
Exercise
High-protein diet
Liver failure
Free fatty acids
Hormones
Insulin"
Calcitonin
Branched-chain amino acids
In vitro and animal data summarized from [9] and [18]. aAvailable data in humans.
induced hypoglycaemia stimulates renal glucose release
while suppressing hepatic glucose release [11]. The fact
that in humans adrenaline, at plasma concentrations
seen during hypoglycaemia, stimulates renal glucose
release [5], suggests that these findings regarding a role
for the kidney in glucose counterregulation are applicable to humans.
URINE
TUBULE
PLASMA
GLUTAMINE
2NH 4 *
Fasting
During fasting hepatic glycogen stores become depleted
and gluconeogenesis accounts for a progressively
greater proportion of renal glucose release. In humans
fasted for 60 h, the kidney accounts for over onethird of all glucose released into the circulation [3].
With more prolonged fasting, hepatic glucose release
decreases and renal glucose release becomes even more
important.
1/2 GLUCOSE
2 HC03-
Fig. 1. Renal ammoniagenesis and gluconeogenesis.
Diabetes mellitus
Renal failure
Requirements of exogenous insulin in insulindependent diabetics who develop end-stage renal failure tend to decrease. The most widely accepted
explanation for this is loss of renal insulin excretion
resulting in a prolonged biological half-life of the
hormone [12]. Moreover, it has been observed that
renal-failure patients without diabetes are prone to
develop hypoglycaemia [13]. Conceivably, reduced
renal gluconeogenesis may be a contributing factor to
both decreased insulin requirements and increased
hypoglycaemic risk in patients with and without diabetes. In addition, since the human kidney also takes
up considerable amounts of glucose, loss of renal tissue
could contribute to reduced glucose disposal and thus
insulin resistance seen in uraemia [14].
Gluconeogenesis is considered the primary cause for
increased glucose release in diabetic patients. Kidneys
from experimentally diabetic animals have increased
activity of gluconeogenic enzymes and increased release
of glucose. Preliminary data indicate that in type I
diabetic patients withdrawn overnight from insulin
have increased renal glucose release [7]. These observations suggest that renal overproduction of glucose may
contribute to fasting hyperglycaemia in type I diabetes.
Acidosis
Substantial net renal glucose release has originally been
observed in patients with severe respiratory acidosis,
providing the first evidence ever for glucose production
by the human kidney [15]. It has been reported that
Nephrol Dial Transplant (1998) 13: Editorial Comments
during chronic acidosis, as much as 40% of glutamine,
a major renal gluconeogenic precursor extracted by
the kidney, could have been converted to glucose [16].
In vitro studies have demonstrated that acidosis
increases renal production of glucose from glutamine
or glutamate. During acidosis, animal kidneys extract
increased amounts of glutamine (five times more than
the gut) for generation of ammonia and bicarbonate.
Thus increased renal glucose formation during acidosis
is currently viewed as an outlet for the increased
formation of a-ketoglutarate derived from glutamate
and glutamine, thus conserving carbon [17] (Figure 1).
Conclusions
Recent studies in vivo using a combination of isotope
and net balance techniques have corroborated earlier in
vitro studies and animal experiments in providing evidence that the kidney plays an important role in normal
carbohydrate homeostasis and under common pathologic situations such as in patients with diabetes mellitus
and renal insufficiency. Further studies are needed to
examine (i) regulation of renal glucose metabolism by
substrate availability, insulin, and other hormones, and
(ii) the contribution of the kidney to hypoglycaemia
counterregulation and adaptive changes during fasting,
acidosis, exercise, trauma, and other stresses associated
with increased gluconeogenesis.
References
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5. Stumvoll M, Welle S, Chintalapudi U, Perriello G, Gutierrez O,
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8. Stumvoll M, Meyer C, Kreider M, Perriello G, Gerich J. Effects
of glucagon on renal and hepatic glutamine gluconeogenesis in
normal postabsorptive humans. Metabolism (in press)
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J. Human kidney substrate utilization and gluconeogenesis.
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human kidney. Nature 1966; 212: 1589-1590
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Nephrol Dial Transplant (1998) 13: 2999-3001
Methicillin-resistant Staphylococcus aureus (MRSA) infection in
glomerulonephritis—a novel hazard emerging on the horizon
Masaki Kobayashi 1 and Akio Koyama 2
d e p a r t m e n t of Nephrology, Tokyo Medical University Kasumigaura Hospital, Inashiki, and i n s t i t u t e of Clinical Medicine,
University of Tsukuba, T s u k u b a , Ibaraki, J a p a n
Introduction
Infections with antibiotic-resistant bacteria have
recently increased and infection by methicillin-resistant
staphylococci (MRSA) is one typical example. Shortly
Correspondence and offprint requests to: Masaki Kobayashi MD,
Department of Nephrology, Tokyo Medical University Kasumigaura
Hospital, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan.
after methicillin came into clinical use, MRSA strains
were first detected in the UK in 1961 [1]. These strains
were subsequently isolated in many countries including
Japan. MRSA as a nosocomial pathogen has become
a serious problem both from a clinical and epidemiological standpoint [2]. Staphylococci have been
identified as causal agents in the genesis of glomerulonephritis. Most reports linking staphylococcal infection
in glomerulonephritis emphasize two clinical settings: