Sodium-Lithium Countertransport Activity in Red Blood Cells of Patients With IgA Nephropathy

Boero, R; Fabbri, A.; Esposti, Ezio Degli; Guarena, Cesare; Forneris, Giacomo; Lucatello, A.; Sturani, A; Quarello, F; Fusaroli, M; Piccoli, Giuseppe

doi:10.1016/0272-6386(93)70096-h

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…We showed that inhibitor characteristics of NHA2 expressed in yeast matched those of SLC activity, including insensitivity to amiloride (a hallmark of plasma membrane NHE), and sensitivity to phloretin and quinidine. In addition to genetic predisposition to hypertension and cardiovascular disease, elevated SLC has also been reported in subjects with diabetic and IgA nephropathy (33,34). There is evidence that renal Li ϩ clearance, which is inversely related with proximal tubule Na ϩ reabsorbtion, is reduced in patients with high SLC (35).…”

Section: Discussionmentioning

confidence: 99%

A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

Xiang

Feng

Muend

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

132

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Phylogenetic analysis of the cation/proton antiporter superfamily has uncovered a previously unknown clade of genes in metazoan genomes, including two previously uncharacterized human isoforms, NHA1 and NHA2, found in tandem on human chromosome 4. The NHA (sodium hydrogen antiporter) family members share significant sequence similarity with Escherichia coli NhaA, including a conserved double aspartate motif in predicted transmembrane 5. We show that HsNHA2 (Homo sapiens NHA2) resides on the plasma membrane and, in polarized MDCK cells, localizes to the apical domain. Analysis of mouse tissues indicates that NHA2 is ubiquitous. When expressed in the yeast Saccharomyces cerevisiae lacking endogenous cation/proton antiporters and pumps, HsNHA2 can confer tolerance to Li ؉ and Na ؉ ions but not to K ؉ . HsNHA2 transformants accumulated less Li ؉ than the salt-sensitive host; however, mutagenic replacement of the conserved aspartates abolished all observed phenotypes. Functional complementation by HsNHA2 was insensitive to amiloride, a characteristic inhibitor of plasma membrane sodium hydrogen exchanger isoforms, but was inhibited by phloretin. These are hallmarks of sodium-lithium countertransport activity, a highly heritable trait correlating with hypertension. Our findings raise the possibility that NHA genes may contribute to sodium-lithium countertransport activity and salt homeostasis in humans.sodium-lithium countertransport ͉ yeast expression ͉ red blood cell ͉ pancreas

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Section: Discussionmentioning

confidence: 99%

A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

Xiang

Feng

Muend

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

132

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“…They found >50% of IgA-N patients develop HTN [16]. Genetic factors and variability in SLC-T kinetics might already be present among IgA-N patients before presenting with IgA-N or HTN development [16, 17]. Our patient had a family history of HTN and had an incidental finding of IgA-N on renal biopsy.…”

Section: Discussionmentioning

confidence: 82%

“…Our case brings many essential questions to the surface regarding SLC-T expression as a marker and a transporter involved in lithium metabolism and clearance. As mentioned before, abnormal SLC-T expression, as a marker, is seen in primary HTN, IgA-N with HTN, and IgA-N with a significant family history of HTN [11, 15, 16]. Possibly, as an active transporter, SLC-T not only affects lithium efflux from the red cells but also chronic lithium use affects the kinetics of SLC-T [17, 18].…”

Section: Discussionmentioning

confidence: 99%

An Overlooked Link between IgA Nephropathy and Lithium Toxicity: A Case Report

Mehandru

Kaur

Ghias

et al. 2021

Case Rep Nephrol Dial

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Lithium is one of the first-line agents for treating bipolar disorder. Although this agent is highly effective in treating mood disorders, renal toxicity is a frequent side effect. Lithium metabolism is affected by sodium-lithium counter-transporter (SLC-T) in erythrocytes. The high activity of SLC-T can result in decreased urinary lithium clearance and may lead to accumulation of lithium in the distal renal tubular cells, causing lithium toxicity. SLC-T is a genetic marker in primary hypertension (HTN), HTN in pregnancy, diabetic nephropathy, and IgA nephropathy (IgA-N) with HTN. Patients with IgA-N have been reported to have enhanced SLC-T activity and are likely to have considerably lower renal fractional clearance of lithium. Therefore, patients taking lithium for bipolar disorder with coexisting IgA-N can have severe lithium-induced nephropathy and nephrotoxicity even at therapeutic serum levels. Serum lithium levels reflect only extracellular lithium concentration. However, lithium exerts its effects once it has moved to the intracellular compartment. This phenomenon illustrates the reason why patients with significantly elevated serum levels might be asymptomatic. Creatinine clearance is inversely related to the duration of lithium therapy. The degree of interstitial fibrosis on renal biopsy has been known to be associated with the duration of lithium therapy and cumulative dose. We present a case with a past medical history of bipolar disorder treated with lithium for almost 20 years. His family history was significant for HTN. The patient was diagnosed with renal insufficiency of unknown causes, for which he underwent renal biopsy. The renal biopsy showed a typical lithium-induced tubulointerstitial nephritis and a coincidental finding of IgA-N. We suspect a high activity of SLC-T seen in IgA-N, and the adverse effects of lithium on SLC-T activity might cause reduction of urinary lithium clearance and accumulation of lithium in distal renal tubular cells, contributing to nephrotoxicity. There is a lack of the literature on the coexistence of IgA-N and lithium nephrotoxicity. We recommend in patients with concomitant IgA-N, taking lithium, more frequent monitoring of renal functions, and dose adjustments may reduce the risk of lithium-induced nephrotoxicity.

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“…The negative correlation between k Na and serum creatinine in the Caucasian subjects is of particular interest since elevated countertransport activity, which may incorporate reduced k Na , has been associated with impaired renal function in both diabetic 41,42 and non-diabetic subjects. 43,44 Perhaps it is more than a coincidence that reduced k Na values have been reported not only in hypertension and vascular disease 15,16 but also in the diabetic with overt nephropathy, 45 a condition which itself is associated with hypertension.…”

Section: Discussionmentioning

confidence: 99%

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups

et al. 1998

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Sodium-lithium countertransport activity has been proposed as a marker for hypertension and is lower in black compared to Caucasian subjects both with and without vascular disease. The question arises of what is the primary kinetic locus of the altered behaviour of the countertransporter in black subjects and whether this is also seen in normotensive subjects from other non-Caucasian ethnic groups.We The clinical and laboratory characteristics of the subjects were similar in all four ethnic groups. Minor differences noted were: significantly higher mean height, weight and serum creatinine concentration (P Ͻ 0.001) and significantly lower plasma triglyceride concentration (P = 0.02) in the black compared to the other

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Sodium-Lithium Countertransport Activity in Red Blood Cells of Patients With IgA Nephropathy

Cited by 6 publications

References 29 publications

A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

An Overlooked Link between IgA Nephropathy and Lithium Toxicity: A Case Report

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups

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Sodium-Lithium Countertransport Activity in Red Blood Cells of Patients With IgA Nephropathy

Cited by 6 publications

References 29 publications

A human Na + /H + antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

A human Na + /H + antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

An Overlooked Link between IgA Nephropathy and Lithium Toxicity: A Case Report

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups

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A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

A human Na ⁺ /H ⁺ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension